HAEMATOLOGY CLINICAL GUIDELINES (LANCASHIRE & SOUTH CUMBRIA)

May 2015

Review date: March 2016 (or earlier if new guidance published)

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Index:

Page No

Chronic Lymphocytic Leukaemia 3

Precursor Acute Lymphoblastic Leukaemia 10

Acute Myeloid Leukaemia (AML) 12

Myelodysplastic Syndrome 16

Chronic Myeloid Leukaemia 18

Chronic Myeloproliferative Disorders  Myelofibrosis 21  Polycythaemia Vera 26  Essential Thrombocythaemia 29

Investigation and management of patients with hairy cell leukaemia 33 (HCL)

Investigation and management of patients with T-cell Prolymphocytic 38 Leukaemia

Investigation and management of patients with large granular 42 lymphocyte leukaemia (LGL)

Guidelines on the diagnosis and management of Multiple Myeloma 46

Lymphoma 79

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GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF CHRONIC LYMPHOCYTIC LEUKAEMIA

These guidelines are to be used in conjunction with the BCSH guidelines (Oscier, et al 2012)

Diagnosis:

The diagnosis of chronic lymphocytic leukaemia (CLL) is based on lymphocyte morphology, the presence of more than 5 x 109/l circulating clonal B cells for > 3 months and characteristic immunopenotype. CLL is a chronic leukaemia of CD 5+ B-cells.

“Monoclonal B-lymphocytosis” (MBL-CLL) is diagnosed in individuals with less than 5x 10 9/l monoclonal CD5+ lymphocytes present without other symptoms (lymphadenopathy, organomegaly, cytopenias and general symptoms).

A typical case of CLL is characterised by the presence in the blood film of mainly small lymphocytes with clumped heterochromatin but variation in morphology can occur. Smear cells may be present.

Lymph node examination reveals a diffuse infiltration with lymphocytes with pseudofollicle formation.

For the diagnosis follow HMDS guidelines.

Investigations:

Essential: Full blood count

Immunophenotyping of peripheral blood

Direct antiglobulin test (DAT) and reticulocyte count

Serum immunoglobulines

Renal and liver biochemistry (including urate)

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Calculation of Binet stage (See Tab 1)

Viral screen for hepatitis B and C and HIV

Other recommended tests:

Bone marrow test is not necessary in patient with stage A CLL.

CT scans are not recommended at diagnosis

TP 53 deletion test is mandatory pre-treatment and before subsequent treatment

Bone marrow test should be performed

In case of phenotypically atypical CLL

For investigation of cytopenia in CLL

Before initiating chemotherapy

Lymph node biopsy is indicated in cases when diagnosis is no certain and/or the suspicion of transformation

CT scan/US are recommended

If the presence of splenomegaly is uncertain on physical examination

To assess lymphadenopathy before therapy

For the disease assessment when bulky lymphadenopathy is present in abdomen to diagnose progression

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Prognosis

The number of serum factors is known to have prognostic significance In CLL cases: LDH, beta 2 –microglobulin, soluble CD23, thymidine kinase, cytogenetic analysis (FISH 17p and possibly 11q), IgVH mutation, CD38 and ZAP-70.

Measurement of biomarkers is not recommended for patient with CLL outside clinical trials

The most important in clinical practice is detection of a TP 53 abnormality (deletion or mutation) as this will determine which type of treatment is appropriate – see below.

The presence of a TP 53 abnormality is not an indication for starting chemotherapy in otherwise asymptomatic patient.

Management of CLL

MBL-CLL: These patients have a low risk of developing progressive disease.

The clinical assessment of CLL symptoms is indicated (B symptoms, lymphadenopathy, splenomegaly). The monitoring of FBC is recommended every 3-6 months in the first year and if stable once a year later (preferably in the local surgery with clinical protocol provided).

Early stage (Binet’s stage A)

Clinical assessment and FBC monitoring preferably in GP surgery with provided clinical protocol containing indication for re referring to haematologist. No treatment indicated regardless of prognostic markers.

Indications for treatment:

1. Anaemia (Hb < 10 g/dl) and thrombocytopenia (<100 x 109/l) due to bone marrow infiltration by CLL 2. Progressive splenomegaly (>6 cm below costal margin) 3. Progressive, symptomatic lymphadenopathy (cluster >10cm diameter) 4. Progressive lymphocytosis with the increase of lymphocyte number more than 50% over 2-months or lymphocyte doubling time less than 6 months, 5. Autoimmune anaemia and thrombocytopenia not responsive to steroid therapy

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6. B symptoms: weight loss more than 10% in previous 6 months, extreme fatigue, fever >38 o for more than 2 weeks without evidence of infection

 Initial therapy for advanced, symptomatic CLL. TP 53 negative

The choice of treatment depends on age, performance status and comorbidities of the patient.

F-CR regimen is recommended as a front line therapy for fit patients outside clinical trials (recommended by NICE and IWCLL)

Patients can be considered for the FLAIR trail open in Blackpool (Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab - A randomised trial of FCR v R + long term ibrutinib in fitter patients with CLL.

Unfit patients may be offered chlorambucil or bendamustine chemotherapy but entry of patients into trials of these two agents in combination with anti CD 20 antibodies is strongly recommended. Combination of Chlorambucil and Ofatumumab can be prescribed through The Cancer Drugs Fund. Some patients in the unfit group may tolerate the FCR-lite regimen with reduced dose of fludarabine and cyclophosphamide.

 Initial therapy for advanced, symptomatic CLL TP 53 positive

Approximately 7% of CLL patients will have deletion of chromosome 17p or TP 53 mutation/dysfunction. They do not respond well to fludarabine-based therapy and should be considered for TP 53 independent therapy. The most appropriate for that group of cases would be treatment offered in clinical trials.

Outside clinical trials, alemtuzumab as a single agent or in combination with high dose of steroids (when large lymph nodes present) is an option. Subcutaneous alemtuzumab is better tolerated. At present this medication is only available in UK now through a Patient Access Scheme.

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The allotransplant option should be considered in patients aged below 65 with good performance status.

 Treatment of relapsed CLL.

The treatment choice of therapy depends on:

-The duration of the first remission,

-Age and performance status,

-First line treatment regimen and

-TP 53 status (the test should be repeated before the subsequent line therapy)

1 Fit patient, relapse < 12 months no TP 53 deletion – FCR when not given as first line, when fludarabine resistant consider clinical trials . If they are not available the patient should be offered bendamustine with rituximab treatment and assessed for allotransplant. Other options may be CHOP- R and ofatumumab therapy.

Ibrutinib treatment should be considered in patients over 70 without comorbidities and over 60 with comorbidities as available through The Cancer Found.

2, Fit patient relapsed 12-24 months with no TP53 abnormality should be consider clinical trials. If they are not available Bendamustine with Rituximab or Alemtuzumab may be given. Allotransplant should be considered. Another option is immunotherapy with Ofatumumab in patient resistant to both: Rituximab and Alemtuzumab.

3 Fit patient with relapsed CLL after 24 months since the last treatment should be considered for clinical trials. If not available: Rituximab with Bendamustine may be given or FCR repeated..

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When TP 53 deletion is present high dose of methylprednisolone with alemtuzumab treatment is indicated, again the trial option should be investigated and allotransplant considered for fit patient. Ibrutinb therapy can be given through The Cancer Drugs Fund. Ofatumumab may be the effective (but response last only for the short time) only treatment option in patients resistant to Alemtuzumab.

Less fit patient: In a case of fludarabine resistance and/or TP53 abnormality, the patient should be considered for clinical trials in the first instance. When trials are not available the patient could be offered Bendamustine in combination with rituximab. The combination of Idelalisib with Rituximab is available for prescription through the Cancer Drugs Fund.

When a TP 53 abnormality is present, alemtuzumab with high dose methylprednisolone can be considered The other option of treatment in this context is ofatumumab. FCR lite with an attenuated dose of cyclophosphamide and fludrabine may be effective and well tolerated option in selected cases of relapsed CLL.

When a patient is sensitive to alkylating agents, chlorambucil (combination with rituximab may be advisable but the fouding is not provided and evidence in literature is scarce)

Unfit patient can be offered best supportive car and referred to palliative care.

 Supportive care: 1. Transfusion of blood products (irradiated lifelong for fludarabine or alemtuzumab treated patients) 2. Infections: All patients should be screened for Hepatitis B, C and HIV prior starting chemotherapy 3. Antimicrobial prophylaxis against Pneumocystis jivoreci and herpes simplex and zoster is advocated for patients receiving immunochemotherapy 4. Patients treated with alemtuzumab should be monitored regarding CMV reactivation and receive antifungal prophylaxis 5. Intravenous immunoglobulin infusion can be indicated in patients with recurrent infections and low IgG level. (antibiotic prophylaxis may be considered when needed as well)

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 Treatment of autoimmunity:

Autoimmune haemolytic anaemia and/or thrombocytopenia are common in patients with CLL. These can be be treated with Prednisolone 1 mg/kg for 2-4 weeks. The second option could be Rituximab 375 mg/m2 weekly for 4 weeks. Cyclosporin or mycophenolate mofetil can be given as a third line therapy.

Failure of treatment for autoimmunity may be an indication to chemotherapy treatment in CLL.

Table 1 Binet staging system

Binet Stage Features A <3 Lymphoid area B >3 Lymphoid area C Haemoglobin < 100g/l or platelet count<100 x 109/l

List of trials for CLL patient available in Network

1. RIAltO: A randomised Investigation of Alternative Ofatumumab-containing regiments in less fit patients with CLL. (opened at RBH) 2. FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab - A randomised trial of FCR v R + long term ibrutinib in fitter patients with CLL.

Author Dr M Rockika

Ratified by LSCCN Haematology NSSG 15th March 2015

Review date: March 2016

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GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL)

General Points:

 The comments regarding transfer to Blackpool without performing a bone marrow examination when the diagnosis of acute leukaemia is strongly suspected applies for ALL. Often ALL can only be distinguished from AML by flow cytometry.  MRD assessment is a critical part of the management of adult ALL. Bone marrow samples should be sent to Adele Fielding’s lab in London at diagnosis and post phase II induction as an absolute minimum. Samples are sent post phase I induction if part of the UKALL14 trial but these results are not disclosed.  MRD assessment should occur regardless of whether the patient enters a clinical trial.  Tissue typing of all patients <65 years old should be performed at presentation, with samples sent to Sheffield & the HSCT lab in Manchester.  All patients with confirmed ALL should be discussed at the network MDT once cytogenetic analysis is available.  Patients should have holistic support with clinical nurse specialist input and written information about their disease  Patients with white cell counts >50 can deteriorate rapidly. All patients with suspected acute leukaemia with white cell counts >50 and potentially suitable for intensive chemotherapy should be discussed with the attending consultant at Blackpool. This conversation should take place as soon as acute leukaemia is suspected, 24 hours per day. This should not wait until the following day. The advantage of this approach is that early complications can be addressed and early transfer to Blackpool arranged.  Note that Blackpool has a ring-fenced bed at all times that can be used to facilitate the urgent transfer of patients from around the Network with suspected acute leukaemia.

Management of patients aged 16 – end of 18th year:

 All patients in this age group should be treated at the Young Oncology & Adolescents Unit (YOU) at the Christie Hospital.

Management of patients aged 19 but less than 25:

 Patients aged up to their 25th birthday with ALL should essentially be treated on a paediatric protocol.  Essentially though from a practical point of view these patients should be referred to Blackpool in the first instance to establish a diagnosis.  Philadelphia negative ALL - patients should be referred to the Christie Hospital in Manchester to consider entry into the UKALL 2011 trial.  Philadelphia positive ALL – these patient are not eligible for the UKALL 2011 trial. Patients aged 19 – 25 can enter into the UKALL14 trial. If they decline this trial, then

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they should receive two courses of induction chemotherapy with Imatinib, followed by an allogeneic procedure at the first opportunity.  Patients in this age group should be given the choice of having this treatment at the Young Oncology & Adolescents Unit (YOU) at the Christie Hospital, or more locally within Lancashire at Blackpool Victoria.

Management of patients aged >25 but less than 60:

 These patients should be offered entry into UKALL14.  If they decline the trial, they should be treated as per protocol but without the addition of the monoclonal antibodies.  Patients aged 55 or over can enter the ALL60+ if they are considered unsuitable for the UKALL 14 trial.

Management of patients aged >60 but less than 65:

 These patients are eligible for entry into both UKALL14 and the ALL60+ trials.

Management of patients aged greater than 65:

 These patients should be evaluated in Blackpool & offered entry in the ALL60+ trial.  Patients with Philadelphia positive disease can be treated successfully with high dose Imatinib combined with steroids outside a trial.  Philadelphia negative disease in elderly patients is a difficult situation. Three agent induction without the use of asparaginase may reduce early mortality. Attenuation of induction chemotherapy e.g. omission of day 29 chemotherapy may be required. Omission of consolidation may also be required, moving directly to standard maintenance. CNS directed therapy should be considered as for patients under the age of 65.

Treatment of relapsed ALL:

 These patients should be discussed once again at the Network MDT.  There is no current trial within the network. There may be a role for entry into trials involving monoclonal antibodies, but this would need exploration with other centres around the country.  Relapsed ALL has a very poor prognosis. Flag-Ida may have a role in this situation.  Allogeneic transplantation should occur in CR2 if this has not already been performed.

Author Dr P Cahalin

Ratified by LSCCN Haematology NSSG 15th March 2015

Review date: March 2016

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GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF ACUTE MYELOID LEUKAEMIA (AML)

General points:

 In general, patients up to the age of 70 are usually candidates for intensive chemotherapy. If acute leukaemia is strongly suspected (e.g. pancytopenia with circulating blasts, or large numbers of circulating blasts on the blood film) these patients should be referred directly to Blackpool. They will usually need a bone marrow examination for trial purposes and if the diagnosis is obviously an acute leukaemia, the bone marrow should be left until the patient arrives in Blackpool.  It may take up to a week for the cytogenetics to become available & the formal report to come back from HMDS. Once the bone marrow has been done in Blackpool, the patient could return home if not unwell or febrile and have local blood count monitoring until the results become available.  Blackpool is happy to see all other patients with acute myeloid leukaemia to discuss treatment options and this can even be done on the telephone.  Cases of acute promyelocytic leukaemia are a haematological emergency. They should be referred at the slightest suspicion to Blackpool, 24 hours a day. Notably, these patients usually present with a pancytopenia. Clotting tests including D-Dimers are of crucial importance in raising suspicion of this very treatable condition. Suspected APML patients should be referred at the slightest indication of such via telephone communication to Blackpool to arrange urgent transfer to Blackpool.  All patients therefore presenting with a pancytopenia, or those with circulating blasts, should have a full coagulation profile performed as soon as possible, and this must include fibrinogen & D-Dimers.  All patients with confirmed AML should be discussed at the network MDT once cytogenetic analysis is available.  Patients should have holistic support with clinical nurse specialist input and written information about their disease  Patients with white cell counts >50 can deteriorate rapidly. All patients with suspected acute leukaemia with white cell counts >50 and under the age of 75 should be discussed with the attending consultant at Blackpool. This conversation should take place as soon as acute leukaemia is suspected, 24 hours per day. This should not wait until the following day. The advantage of this approach is that early complications can be addressed and early transfer to Blackpool arranged.  Note that Blackpool has a ring-fenced bed at all times that can be used to facilitate the urgent transfer of patients from around the Network with suspected acute leukaemia.

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Definitive treatment for non-APML patients:

1. Patients under the age of 60:

 These patients are usually always eligible for intensive chemotherapy and entry into the AML19 trial, when it opens. If a patient declines entry into the AML19 trial or is not eligible, then standard DA3 + 10 chemotherapy should be given.  Risk stratification is critical in AML. All cases of suspected / proven acute myeloid leukaemia should be have samples sent to HMDS. Cytogenetics should be performed on every case. If there is a dry tap, a trephine core should be sent in cytogenetic medium for cytogenetic analysis. If there is a dry tap but circulating blasts, then 20mls of blood should be sent for cytogenetic analysis & HMDS review.  Patients in the AML19 trial will have a risk score allocated after their response to induction chemotherapy is known. This will determine whether or not they are poor risk and proceed to a stem cell transplant. The situation for non-trial patients is more complicated. Poor risk patients in terms of cytogenetics should proceed to stem cell transplantation in first remission; equally well good risk patients should not proceed to transplantation in first remission. The situation is more complicated in AML defined as standard risk using cytogenetics. The evaluation of the AML 17 risk score in these non- trial patients may help the decision making process.  Evidence from the AML 15 trial showed that standard risk patients with a sibling donor do benefit from a sibling allograft in first remission and therefore these patients should proceed to transplant in 1st CR.  The evaluation of patients for potential allografts should start in all patients under the age of 70 on admission to Blackpool. These patients should have samples sent to Sheffield & the HSCT lab in Manchester for tissue typing at presentation.

2. Patients in the age group 60 – 70 years:

 The majority of these patients again will be candidates for intensive chemotherapy and should be considered for the AML18 trial. Comments for patients under the age of 60 generally apply to this age group i.e. same day referral where the diagnosis is strongly suspected.  Non-trial patients who are eligible for intensive chemotherapy should have DA3+10.  Patients under the age of 70 should be considered for a reduced intensity allograft in first remission if suitable.  The evaluation of patients for potential allografts should start in all patients under the age of 70 on admission to Blackpool. These patients should have samples sent to Sheffield & the HSCT lab in Manchester for tissue typing at presentation.

3. Patients in the age range 70 – 80 years:

 These patients can often be treated with an intensive or non intensive approach.

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 The decision to go down either route depends upon their past medical history, other co- morbidities and the patient’s wishes. It also depends on leukaemia related factors such as cytogenetics and the rate of their disease progression.  In general these patients should be seen in Blackpool for assessment. If they are not very proliferative then they can usually be seen as an outpatient; however if they clearly have very proliferative disease with rapidly rising white cell counts, then they should be referred via a telephone call for inpatient assessment, as outlined in “General Points”  It is particularly preferable to wait for cytogenetic results in this age group to risk stratify the patient appropriately, unless the white cell count is >20 at presentation or rising rapidly.

4. Patients in the age range 80+ years:

 These patients are usually never suitable for intensive chemotherapy, given the very high mortality rate.  These patients should either be treated with a palliative approach, low dose Cytarabine off trial or consideration of the LI1 trial.  Azacitidine for those patients with 20 – 30% blasts may also be another option, with the advantage of being able to give this at a local level.  The only reason to refer these patients to Blackpool is therefore for consideration of entry of these patients into the LI-1 trial.  This should be done as an outpatient referral.  Full HMDS review and cytogenetic analysis should usually be made available before referral.  If the patient is not fit for outpatient assessment here in Blackpool, then a supportive approach should be adopted in the local hospital until they are able to be discharged.  Before referring to Blackpool, it should be made very clear to the patient and their family that the only point of referral to Blackpool is to consider the entry into a national trial. They must be willing to commute backwards and forwards to Blackpool on a 4 – 6 weekly basis. If the patient is not willing to do this then clearly there is no rationale for referral to Blackpool in the first place.  The use of Hydroxycarbamide is permitted to control elevated white cell count at the local hospital before patients go into the LI-1 trial.  Responsibilities of Blackpool are:- o To assess the patient for suitability for non-intensive chemotherapy o To offer them the possibility of the LI-1 trial according to organ dysfunction o To enrol them into the LI-1 trial if that is their wish o To arrange low dose cytarabine if randomised to this by the district nurses or the family at a local level, including the return of cytotoxic waste o To arrange an end of treatment assessment to evaluate response  Responsibility of the local hospital are:- o All blood count monitoring o All blood product support o All admissions for neutropenic sepsis & other supportive care o Palliative treatment and end of life care, if appropriate

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 Clearly the aim of treatment in these very elderly patients with acute leukaemia is maximising quality of life and that local care and support is the best way of providing this.  In the AML14 trial, no patients treated with low dose Cytarabine who had complex cytogenetics achieved CR. In the non-intensive part of the AML16 trial thus far, there does appear to be a very small CR rate of approximately 5 – 10% with low dose cytarabine for such patients. If such a patient does not wish to enter the LI-1 trial, then it may be preferable to offer best supportive care with white cell count control with Hydroxycarbamide.

Definitive treatment for APML patients:

 Please note the comments above regarding prompt assessment of the coagulation & same day referral to Blackpool.  Molecular monitoring in APML patients is critical and should start at diagnosis with blood and bone marrow sent to David Grimwade’s lab in London. This should occur regardless of whether the patient enters a clinical trial.  Patients deemed fit for intensive chemotherapy should be offered AML19, when it opens.  If a patient declines entry into the AML19 trial or is not eligible, then standard AIDA chemotherapy should be given.  The APL Coagulopathy study should be offered to the patient.  Patients with APML over the age of 60 represent a difficult problem. They cannot be entered into the AML18 trial but if fit, could be considered for the AML19 trial. APML patients not entered into this trial can be considered for the ATRA + arsenic combination or a modified AIDA approach.

Relapsed or refractory patients:

 These patients should be discussed once again at the Network MDT.  Refractory patients in the AML 19 trial will usually be deemed to be high risk and should be offered the high risk randomisation.  Relapsed patients who were in AML17 can be offered the high risk arm of AML 19 and enter the trial at this point.  FLAG-Ida chemotherapy remains the preferred option for treating relapsed or refractory AML outside a clinical trial.  All patients should be discussed with the transplant centre to consider stem cell transplantation in CR2.  Relapsed APML or molecular positivity following end of consolidation chemotherapy – arsenic trioxide followed by stem cell transplantation.

Author Dr P Cahalin

Ratified by LSCCN Haematology NSSG 15th March 2015

Review date: March 2016

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GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF MYELODYSPLASTIC SYNDROME

These guidelines are a summary of the 2013 BCSH Guidelines on Myelodysplastic syndrome.

Diagnosis:

 The diagnosis of MDS should be considered in all unexplained cytopenia(s)  Cytogenetics should be performed in all such cases  Management recommendations for myelodysplasia have largely evolved through the IPSS and, as such, are driven by the IPSS system. “Low risk” MDS are those patients with IPSS low/intermediate I disease; “high risk” MDS includes those patients with IPSS intermediate II/high risk disease  No recommendations can be made to predict response to recommended therapy in relation to the revised IPSS scoring system, which should be used to evaluate prognosis in all patients, but not yet to guide therapy.  All patients with confirmed myelodysplasia should be discussed at the network MDT once cytogenetic analysis is available.  Patients should have holistic support with clinical nurse specialist input and written information about their disease  The IPSS score should be calculated for all patients before the MDT discussion

Management of low risk disease:

 As above, all such patients should be discussed at the network MDT  One can consider a trial of erythropoietin if required  Consider horse ATG if age less than 60 years with either normal cytogenetics or trisomy 8  Deletion 5q disease – consider trial of erythropoietin as first line therapy. If this fails, or the patient is not deemed suitable for this trial, consider lenalidomide if there is an isolated deletion 5q with transfusion dependence. This is NICE approved.  Deletion 5q disease with transfusion dependence & one additional cytogenetic abnormality can be treated with lenalidomide through the Cancer Drugs Fund.  Consider all low risk patients who might be a potential allograft candidate for this potentially curative therapy early. In particular, low risk patients but with life-threatening cytopenias such as significant neutropenia, should have be offered a transplant consultation.  Low risk patients may progress, with changes in their blood counts, such falling haemoglobin, transfusion dependence, worsening neutropenia or thrombocytopenia. If this occurs, patients should have a re-assessment marrow examination to decide further treatment options, as well as having further MDT review.  Elderly low risk patients who have deteriorating counts should not therefore be simply placed on azacitidine without a repeat marrow assessment.

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Management of high risk disease:

 This is essentially decided according to whether or not a patient will be eligible for allogeneic stem cell transplant. As always, these patients must be discussed at the network MDT, when the cytogenetic analysis is known and the IPSS score has been calculated.  If patients are deemed to be transplant eligible, the next decision is based around the blast percentage. If blasts are less than 10%, one could consider an up-front allogeneic transplant without preceding chemotherapy. This may necessitate a direct referral to Manchester Royal Infirmary for this purpose. In this situation, consideration should be given to entry into the FIGARO trial at Manchester Royal, which compares the novel conditioning regimen FLAMSA-BU with standard conditioning regimens.  However if blasts are greater than 10%, these patients will need induction chemotherapy before stem cell transplantation, and as such they should be referred to Blackpool to be seen in the outpatient clinic for such a discussion.  If a patient is deemed not eligible for allogeneic stem cell transplantation, the options are as follows: 1. Supportive care alone with blood product support and treatment of infection with antibiotics. 2. Azacitidine 3. One could consider intensive chemotherapy without stem cell transplantation if (a) no significant co-morbidities, (b) there is a good performance status and (c) the karyotype is not high risk.

Author Dr P Cahalin

Ratified by LSCCN Haematology 15th March 2015 NSSG

Review date: March 2016

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GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF CHRONIC MYELOID LEUKAEMIA

Diagnosis:

 The question of whether or not initial assessment on the peripheral blood is acceptable is controversial. There are those that argue that the management of CML is now driven by response assessments and that therefore previously identified prognostic factors are now less important. This is the view that has been taken for the current national CML trial, SPIRIT 3.  However, others argue that an initial bone marrow examination should be performed at diagnosis. This is to completely exclude the possibility of blast phase (although rare at diagnosis and usually obvious from the peripheral blood findings). Advocates of bone marrow examination at diagnosis argue that it is useful to identify additional chromosomal abnormalities (ACA) at diagnosis, so that a comparison can be made to the diagnostic sample if they are identified at a later date.  Therefore, blood or marrow should be sent to HMDS Leeds  Consideration could be given to sending blood or marrow for cytogenetics to the Christie Hospital, especially if a rapid confirmation is required, as usually FISH results can be obtained within 48 hours.  No samples should now be sent to Manchester Royal Infirmary for the exclusion or confirmation of CML.  There is no need to perform a bone marrow trephine at diagnosis.  To have confirmed chronic phase disease, all of the following criteria should be met: o less than 15% blasts in the blood, o less than 30% blasts plus promyelocytes in the blood, o less than 20% basophils in blood, o greater than 100 x 109/L platelets o no evidence of an extramedullary leukaemic involvement, with the exception of hepatosplenomegaly.  Once the diagnosis has been confirmed, there should be discussion at the network MDT.  Patients should have holistic support with clinical nurse specialist input and written information about their disease

Treatment:

 Hydroxycarbamide can be used for a short time before initiating a tyrosine kinase inhibitor.  Clinical trial participation should be offered to all newly diagnosed patients with CML. The current trial for this is SPIRIT 3, and Dr Cahalin would be pleased to accept referrals to discuss this trial with newly diagnosed CML patients.  At present, there is no evidence to state that imatinib should be superseded by other tyrosine kinase inhibitors as first line treatment for chronic myeloid leukaemia. The initial starting dose should be 400 mg daily.

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 However, NICE have permitted the use of nilotinib as 1st line use in CML. Whether this upfront use is better than initial treatment with imatinib and then swapping to nilotinib if imatinib fails remains to be seen.  The crucial importance of compliance should be emphasised right from the initial diagnosis.  Patients should have access to clinical nurse specialist support, as well as receiving written and verbal information on the disease & imatinib / nilotinib.

Monitoring:

These are based on the European LeukaemiaNet recommendations for the management of chronic myeloid leukaemia 2013, published in Blood (volume 122: 872 – 884).

 Blood should be taken at 3, 6 and 12 months following the initiation of imatinib and sent to HMDS Leeds for molecular monitoring.  There is no indication to perform ongoing bone marrow examination for monitoring purposes, as peripheral blood BCR ABL monitoring is sufficient.  All patients in the Network should have on-going monitoring samples sent to HMDS, regardless of when they were diagnosed. This means that no samples should now be sent for molecular monitoring at Manchester Royal Infirmary. All on-going monitoring for these patients historically monitored in Manchester Royal should now occur in Leeds.  Information about the original breakpoint should be provided with the first sample being sent to Leeds, or even just stating on the first request form “Previously monitored in Manchester – please discuss with Manchester lab to get breakpoint information.”  At 3 months, failure of imatinib is defined by the non-achievement of a complete haematological response. An optimal level would be having a BCR ABL level less than 10%. A warning that a patient may not be progressing as desired would be complete haematological response with a BCR ABL level greater than 10%.  At 6 months, an ideal BCR ABL level would be less than 1%. Failure would be defined as having a BCR ABL level of great than 10% at this time point. A warning would be having a BCR ABL level between 1 and 10% at this time point.  After 12 months on imatinib, the optimal achievement would be that of a major molecular response, i.e. a BCR ABL level less than 0.1%. Failure would be defined as having a BCR ABL level greater than 1%, equivalent to not having achieved a complete cytogenetic response. BCR ABL level between 0.1 to 1% would be a warning that the patient would not be progressing as optimally desired. Many patients however remain entirely stable in the long-term with levels between 0.1 and 1%.

At subsequent time points, confirmed loss of a major molecular response in two consecutive tests, one of which will have a BCR ABL level greater than 1%, would confirm failure.

Throughout the treatment, again compliance to imatinib or nilotinib therapy should always be emphasised.

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Failure of imatinib requiring a second generation tyrosine kinase inhibitor:

 The patient’s case should be re-discussed at the Network MDT  Firstly, compliance to imatinib should be explored in detail.  Blood should be sent for BCR ABL1 kinase domain mutation testing at HMDS Leeds.  The patient and any siblings should have tissue typing performed.  The second generation tyrosine kinase inhibitor to be used will usually be nilotinib, as this has NICE approval for this indication.  As per monitoring on imatinib, there are ELN defined time points with regard to optimal response, a warning response or failure of a response to a second generation tyrosine kinase inhibitor.  At three months, no complete haematological response is a failure of a second line TKI. An optimal response would be an achievement of a BCR ABL level less than 10%, with a warning response corresponding to a BCR ABL level of 1 – 10%.  At six months on a second generation TKI, an optimal response would be a BCR ABL level less than 10%. Failure would be an inability to achieve a BCR ABL level greater than 10% at this time point.  At 12 months on a second generation TKI, the optimal response would be a BCR ABL less than 1%. Failure at this time point would correspond to a BCR ABL of greater than 10%.

Note that the current ELN guidelines state that allogeneic stem cell transplantation remains the recommendation of all eligible patients that require a third line tyrosine kinase inhibitor. This may be because of failure of and/or intolerance to two previous tyrosine kinase inhibitors.

Author Dr P Cahalin

Ratified by LSCCN Haematology 15th March 2015 NSSG

Review date: March 2016

20

GUIDELINES FOR INVESTIGATION AND MANAGEMENT OF PRIMARY MYELOFIBROSIS (PMF)

Diagnostic criteria for primary myelofibrosis (PMF) - BCSH 2012

Diagnosis requires A1+A2 and any two B criteria

A1 Bone marrow fibrosis ≥3 (on 0-4 scale)

A2 Pathogenetic mutation (eg Jak2, CALR or MPL), or absence of both BCR-abl and reactive causes of bone marrow fibrosis

B1 Palpable splenomegaly

B2 Unexplained Anaemia

B3 Leuco -erythroblastosis

B4 Tear – drop poikilocytes

B5 Constitutional symptoms*

B6 Extramedullary haematopoiesis (histology)

*Drenching night sweats, weight loss >10% over 6 months, unexplained fever > 37.5C or diifuse bone pain.

Diagnostic criteria for post PV and post ET myelofibrosis - BCSH 2012

Diagnosis requires A1+A2 and any two B criteria

A1 Bone marrow fibrosis ≥3 (on 0-4 scale)

A2 Previous diagnosis of PV or ET

B1 New palpable splenomegaly or increase of spleen size ≥ 5cm

B2 Unexplained Anaemia with 20g/l drop from baseline

B3 Leuco erythroblastic blood film

B4 Tear – drop poikilocytes

B5 Constitutional symptoms*

B6 Extramedullary haematopoiesis (histology)

*Drenching night sweats, weight loss >10% over 6 months, unexplained fever > 37.5C or diifuse bone pain.

21

Prognostic Criteria*

Variable IPSS DIPSS DIPSS+

Age >65 ● ● ● Constitutional Sy ● ● ● HB < 100 g/l ● ●● ● WCC >25 X 109/l ● ● ● Circulating blasts ≥ 1% ● ● ●

Transfusion Dep ● Plts < 100 X 109/l ● Karyotype (unfavourable) ●

 Unfavourable Karyotype: +8; -7/7q-; i(17q);inv (3);-5/5g-; 12p-;11q23 rearrangement

 IPSS: low risk, 0 points; intermediate-1 risk, 1 point; intermediate-2 risk, 2 points; high risk, 3 to 5 points;  DIPPS: low risk, 0 points; intermediate-1 risk, 1 to 2 points; intermediate-2 risk, 3 to 4 points; high risk, 5 to 6 points;  DIPPS-plus: low risk, 0 points; intermediate-1 risk, 1 point; intermediate-2 risk, 2 to 3 points; high risk, 4 to 6 points.

 IPSS is only validated at diagnosis, whilst the DIPSS/DIPSS+ is dynamic

Risk Group IPSS DIPSS DIPPS+ MS(years) MS(years) MS(years) Low 11.3 NR 15.7

INT1 7.9 14.2 6.5

INT 2 4 4 2.9

HIGH 2.3 1.5 1.3

MS – Median Survival, NR – Not reached

22

Management of myelofibrosis:

General points

1. All patients should be risk stratified using the IPSS at diagnosis or DIPSS+ at any other time to assess prognosis and guide treatment strategies.

2. Patients with an IPSS risk of intermediate 2 or high should be assessed for their suitability to undergo an allogeneic stem cell transplant. If deemed unsuitable for a transplant option then they should be considered for a trial or treatment targeted to their symptoms.

3. Patients with IPSS low risk/Intermediate 1 without symptoms can be observed.

4. Patients with IPSS low risk/intermediate 1 with symptoms should be considered for a trial or treatment targeted to their symptoms.

5. All patients should be discussed at MDT with appropriate histology/molecular studies reviewed at HMDS Leeds.

6. All patients should have holistic support with clinical nurse specialist input and written information about their disease.

Treatment:

Symptomatic splenomegaly

Medical Management:

 1st line – Hydroxycarbamide, Ruxolitinib (available via the Cancer Drug Fund for intermediate /high risk Primary myelofibrosis, Post ET/PV Myelofibrosis who are deemed unsuitable for a stem cell transplant)  2nd line – Immunomodulatory agents – Thalidomide and prednisolone. (consider lenalidomide if anaemia and platelets > 100)

Surgical management:

Routine splenectomy is inappropriate due to its high risk of morbidity and mortality. It should be restricted to carefully selected patients with extensive pre-operative assessment. The laparascopic route is not suitable due to high risk of bleeding. Typical indications would include:

 Drug refractory symptomatic splenomegaly  Drug-refractory anaemia  Symptomatic portal hypertension  Severe catabolic symptoms.

23

Radiotherapy:

Radiotherapy can be considered for patients who are deemed unsuitable for surgery and have an adequate platelet count (>50 X 109 /l)

Anaemia

Options include:

 Red cell transfusion programme (iron chelation not routinely recommended).  Erythropoietin trial in patients with inappropriately low erythropoietin levels (< 125 u/l)  Androgens – Danazol first line for a minimum of 6 months before assessing response  Immunomodulators – Thalidomide and prednisolone, Lenalidomide

Constitutional Symptoms

 Consider Myelosuppression or Ruxolitinib for symptoms that are impinging on quality of life. (available via the Cancer Drug Fund for intermediate /high risk Primary myelofibrosis, Post ET/PV Myelofibrosis who are deemed unsuitable for a stem cell transplant)

Myelosuppression

 Indications for myelosuppressive treatment include : 1. Control of hyperproliferative symptoms 2. Splenomegaly and hepatomegaly 3. Leucocytosis and or thrombocytosis

 Hydoxycarbamide is the first line choice. Inteferon alfa and anagrelide are alternative options in selected cases.

Author Dr S Kolade

Ratified by LSCCN Haematology 15th March 2015 NSSG

Review date: March 2016

24

Investigation algorithm for myelofibrosis:

Suspected myelofibrosis Clinical features: Splenomegaly; anaemia;leucoerythroblastic blood film; constitutional symptoms; ^LDH; TDP’s ; extramedullary haematopoeiss

If not progression of known Bone marrow biopsy with ET/PV then molecular studies trephine for assessment of required – Jak 2, CALR, MPL, reticulin. (BCR-abl if negative) Cytogenetic assessment Note: MPL not routinely done at HMDS – needs to be specifically requested if Jak2 and CALR negative

Diagnosis confirmed ( see text)

Prognosis - History of constitutional symptoms/transfusion FBC/Blood film/peripheral blood CD34 count Karotype

25

GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF POLYCYTHAEMIA VERA

Investigation algorithm:

Hct > 0.52 in men Hct > 0.48 in women

1. History and Examination 2. FBC/Film 3. Renal and liver function 4. Ferritin/iron profile 5 .JAK 2 V617F assay

Jak2 V617 Jak2 V617 +ve -ve

Serum EPO

EPO - Low EPO - Normal or Raised

1. Jak2 – exon 12 Consider other causes of assay erythrocytosis . Including apparent 2.Additional investigations and investigate as appropriate (see (see appendix )* appendix)** Polycythaemia Vera

JAK 2 mutational assay should only be undertaken at HMDS LEEDS

Note: A Hct > 0.56 in women and > 0.60 in men is evidence of true erythrocytosis

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Diagnosis (Modified BCSH diagnostic criteria for polycythaemia vera )

JAK2-positive polycythaemia vera

A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)

A2 Mutation in JAK2

Diagnosis requires both criteria to be present

JAK2-negative polycythaemia vera

A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women.

A2 Absence of mutation in JAK2

A3 No cause of secondary erythrocytosis

A4 Palpable splenomegaly

A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells

B1 Thrombocytosis (platelet count >450 X 109/l)

B2 Neutrophil leucocytosis (neutrophil count > 10 X 109/l in non-smokers; >12.5 X 109/l in smokers)

B3 Radiological evidence of splenomegaly

B4 Endogenous erythroid colonies or low serum erythropoietin

Diagnosis requires A1 + A2 + A3 + either another A or two B criteria

Treatment of Polycythaemia Vera

1. Risk Stratification :

High risk

A.Age > 60

B.Previous Thrombosis

Low risk

None of the above risk factors

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2. Management:

 All patients should have cardiovascular risk factors reviewed and managed appropriately  All patients should start on low dose Aspirin (75mg daily) unless contraindication (caution with platelet count above 1000 X 109/l due to the risk of bleeding)  Low risk patients – Venesect to a target HCT < 0.45 (consider cytoreductive treatment if poor tolerance of venesection, symptomatic or progressive splenomegaly, significant thrombocytosis, progressive leucocytosis)  High risk patients – Cytoreductive treatment, +/- Venesection

Cytoreductive treatment

 Age < 40 - 1st line : Inteferon alpha ; 2nd line Hydroxycarbamide  Age > 40 – 1st line : Hydroxycarbamide; 2nd line Inteferon alfa, anagralide  Consider radioactive phosphorus or Busulfan as second line treatment in those over 75 (increased risk of transformation to acute leukaemia)

 All patients starting on cytoreductive treatment or changing treatment must be discussed at an appropriate MDT .

 All molecular studies/ histology should be sent to HMDS Leeds for review.

 Previously diagnosed patients being represented to the MDT for change of treatment without results at HMDS Leeds, requires formal presentation of molecular studies for oversight by the MDT.

 Patients should have holistic support with clinical nurse specialist input and written information about their disease.

Appendix 1

Secondary investigations of erythrocytosis:  Red cell mass studies *  Abdominal ultrasound*  Bone marrow aspirate and trephine with cytogenetic analysis*  Erythroid burst forming unit cultures*  Arterial oxygen dissociation studies **  High affinity Hb variant studies**  Sleep studies**  Lung function tests**  EPOR, VHL, PHD2 mutational analysis** Author Dr S Kolade

Ratified by LSCCN Haematology 15th March 2015 NSSG

Review date: March 2016

28

GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF ESSENTIAL THROMBOCYTHAEMIA

Proposed diagnostic criteria for essential thrombocythaemia. (BCSH)

Diagnosis requires A1–A3 or A1 + A3–A5

A1 Sustained platelet count >450 × 109/l

A2 Presence of an acquired pathogenetic mutation (e.g. in the JAK2 , CALR or MPL genes)

A3 No other myeloid malignancy, especially PV*, PMF†, CML‡ or MDS§

A4 No reactive cause for thrombocytosis and normal iron stores

Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers displaying a spectrum of morphology with predominant large megakaryocytes with A5 hyperlobated nuclei and abundant cytoplasm. Reticulin is generally not increased (grades 0–2/4 or grade 0/3)

1. * PV,polycythaemia vera ;excluded by a normal haematocrit in an iron-replete patient. 2. † PMF, primary myelofibrosis ; indicated by presence of significant marrow bone marrow fibrosis (greater or equal to 2/3 or 3/4 reticulin) AND palpable splenomegaly, blood film abnormalities (circulating progenitors and tear-drop cells) or unexplained anaemia. 3. ‡ CML, chronic myeloid leukaemia; excluded by absence of BCR-ABL1 fusion from bone marrow or peripheral blood. 4. § MDS, myelodysplastic syndrome ; excluded by absence of dysplasia on examination of blood film and bone marrow aspirate.

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* BCR-abl testing recommended if other molecular tests are negative and/or if positive and there are atypical features eg. basophilia

**Bone marrow examination is recommended by the World Health organisation classification to confirm the diagnosis but may always be clinically indicated

*** The requirement for cytogenetic analysis on the bone marrow be guided by blood and bone marrow morphology.

Molecular testing should only be undertaken at HMDS Leeds

Treatment of Essential Thrombocythaemia (ET)

1. Risk Stratification :

High risk

A.Age > 60

B.Previous ET related haemorrhagic or thrombotic event

C. Platelet count > 1500 X 109/l

Intermediate risk

A. Age 40-60 with no high risk features

Low risk

A. Ag e<40 with no high risk features

Microvascular complications not responding to aspirin should be stratified as high risk.

2. Management:

 All patients should have cardiovascular risk factors reviewed and managed appropriately  All patients should start on low dose Aspirin (75mg daily) unless contraindication (caution with platelet count above 1000 X 109/l due to the risk of bleeding)  High risk patients should be started on cytoreductive treatment with a platelet target <400 X 109/L  Low and intermediate risk patients should generally not be started on cytoreductive treatment outside the context of a clinical trial or if they are symptomatic : progressive splenomegaly; erythromelalgia not responsive to aspirin; uncontrolled bleeding with high platelet counts.

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Cytoreductive treatment

 1st line – Hydroxycarbamide  2nd line – Anagrelide  Consider interferon alfa in young patients and in high risk pregnancy  Consider radioactive phosphorus or busulfan in those with short life expectancies (risk of leukaemic transformation)

 All patients starting on cytoreductive treatment or changing treatment must be discussed at an appropriate MDT .

 All molecular studies/ histology should be sent to HMDS Leeds for review.

 Previously diagnosed patients being represented to the MDT for change of treatment without results at HMDS Leeds, requires formal presentation of molecular studies for oversight by the MDT.

 Patients should have holistic support with clinical nurse specialist input and written information about their disease.

Author Dr S Kolade

Ratified by LSCCN Haematology 15th March 2015 NSSG

Review date: March 2016

31

Diagnostic pathway for investigation of thrombocytosis

Platelet count > 450 X109/l

Blood Film CRP/ESR Ferritin/iron profile

Acute phase Iron Deficiency response

Reactive Repeat FBC

Repeat FBC

Persistent unexplained thrombocytosis

Molecular genetics: JAK2 V167F, MPL exon 10, CALR, BCR –ABL* Bone Marrow ** Cytogenetic analysis *** Note:MPL needs to be specifically requested from HMDS

Diagnosis

32

GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF HAIRY CELL LEUKAEMIA (HCL)

Introduction: Hairy cell leukemia (HCL) is an uncommon chronic B cell lymphoproliferative disorder characterized by the accumulation of small mature B cell lymphoid cells with abundant cytoplasm and “hairy” projections within the peripheral blood, bone marrow and splenic red pulp. Presents with splenomegaly and variable pancytopenia.

Presentation: Presents with symptoms relating to splenomegaly or cytopenias (example; anaemia, thrombocytopenia, neutropenia, monocytopenia). Physical examination reveals palpable splenomegaly in 80 – 90% of cases. Hepatomegaly and lymphadenopathy are only present in 20 and 10% of patients respectively.

Laboratory Findings: 60 – 80% of patients present with pancytopenia, approximate frequency as follows:

 Anemia 85%  Thrombocytopenia 80%  Neutropenia 80%  Monocytopenia 80%  Abnormal liver function tests 20%  Hypergammaglobulinemia 20%  Leukocytosis (total white cell count >10,000/microL) 10 – 20%

Characteristic hairy cells in blood identified in 90% of patients. Bone marrow often dry tap due to fibrosis. Diagnosis usually from trephine with diffuse or interstitial infiltrate. Mast cells may be numerous. Extravasated red cells are frequently seen.

Immunophenotype – CD19, CD20, CD22 and CD25. Usually lack CD5, CD10, CD21 and CD23.

Hairy cells characteristically express CD11c, CD103, CD123 (bright) and cyclin D1 (usually weak).

Genetic features – Majority of cases demonstrate BRAF mutation. HMDS will screen for this.

Cytochemical Findings: Demonstration of tartrate-resistant acid phosphatase (TRAP) marrow slides (not as specific as flow cytometry) . Now largely obsolete.

33

Investigation: Bone marrow aspirate, cell markers, trephine and peripheral blood sample / blood film ( EDTA ) to be sent to HMDS Leeds.

HMDS Level 3 Bexley Wing St James’ Institute of Oncology Beckett Street Leeds LS9 7TF

CT scan of neck, thorax, abdomen and pelvis as indicated.

Hairy cell leukemia variant now considered to be a distinct entity from hairy cell leukaemia and will not be discussed in these guidelines.

Management: Many patients are asymptomatic and can be observed for months or years after the diagnosis is established before requiring treatment. No clear advantage to early treatment.

Indications For Treatment: Significant cytopenias. Absolute neutrophil count less than 1 with repeated infections. Symptomatic anaemia with a haemoglobin less than 10 or bleeding due to a platelet count less than 100.

Symptomatic splenomegaly or symptomatic adenopathy.

Constitutional symptoms (example fever, night sweats, fatigue, weight loss).

Initial treatment:

 Cladribine – see network protocols  Pentostatin - see network protocols

iv or sc preparations can be used.

With purine analogues prophylaxis with Septrin and Acyclovir is recommended. This should be continued until the CD4 count is over 200 or for up to three months post completion of therapy. GCSF can be given but currently not recommended in the BCSH guidelines. Blood products should be irradiated indefinitely.

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 Single agent Rituximab at a dose of 375 mg/m2 for four weeks can be considered in patients whose comorbidities preclude the use of nucleoside analogues.

This treatment can also be considered in neutropenic patients due to hairy cell leukemia in whom the inevitable worsening of cytopenias for two to four weeks post treatment is considered high risk. Example :- those presenting with intercurrent infection, those requiring intensive care or frailty.

Definitive treatment with nucleoside analogues can be considered later.

Response assessment: Bone marrow aspirate, trephine, cell markers and peripheral blood ( EDTA ) should be assessed four to six months after completion of therapy once peripheral blood counts have maximally recovered. Samples should be sent to HMDS Leeds.

Complete remission requires morphological absence of hairy cells in the blood and bone marrow and normalisation of any organomegaly and cytopenia.

A partial response (PR) requires normalisation of peripheral counts, together with at least 50% reduction in organomegaly and bone marrow hairy cells and less than 5% circulating hairy cells.

All other responses are known as non- responses (NR).

Those patients not attaining complete remission following nucleoside analogue can be considered for a second course of treatment at the same dose at an interval of four to six months. Consideration should be given to the addition of rituximab.

Eradication of minimal residual disease (MRD), in contrast to overtly persistent disease, should not be the aim of therapy except as part of a clinical trial.

35

Second-line treatment:

 Relapses after several years can be effectively treated with the same or alternate purine analogue. Consideration should be given to the addition of Rituximab 375 mg2. The number of doses and schedule will differ according to clinician preference (concurrent or sequential) - see network protocols .

 Interferon Alpha can be considered although complete remissions are uncommon. Treatment with interferon alpha is now rarely used but can be considered in patients failing treatment with purine analogue. This has previously been used to improve pancytopenia in patients who are unable to tolerate subsequent purine analogue therapy with fewer infectious complications but this role has now been largely superceded by Rituximab.

Common toxicities of interferon alpha include flu like symptoms, anorexia, fatigue, nausea, vomiting, diarrhoea, dry skin, peripheral neuropathy and central nervous system dysfunction including depression or memory loss. Elevated serum liver enzymes are the most common laboratory abnormality other than myelosuppression.

Splenectomy: Possible indications for splenectomy in hairy cell leukemia include:

 Symptomatic splenomegaly (massive enlargement, pain, infarction, rupture)  Pancytopenia which is still present after other treatments.  As a temporising measure in symptomatic pregnant females.  Splenectomy largely obsolete and purine analogues generally obviate the need for splenectomy in most other settings.

 Other experimental therapy to be discussed with tertiary centre. Anti-CD22 antibody (BL22) anti-CD25 antibody

Resistant disease

Only 4 percent of patients obtain no initial benefit. Consideration should be given to using a different purine analog from the one initially chosen in combination with rituximab. . Other options include IFNa, splenectomy, or one of the available monoclonal antibodies directed against B cell determinants on the malignant cell.

36

Management of pregnancy

Prevalence of the disease in pregnant women is extremely low. There are limited data to guide treatment definitively. It seems reasonable, as for other patients, to avoid therapy in the absence of symptoms. If treatment is required, interferon alpha would be reasonable first line treatment.

Author Dr DE Howarth

Ratified by LSCCN Haematology NSSG May 2015

Review date: June 2016

37

GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF T-CELL PROLYMPHOCYTIC LEUKAEMIA (T-PLL)

Introduction

T-cell prolymphocytic leukaemia (T-PLL) is a rare T-cell neoplasm composed of lymphoid cells, typically with involvement of the peripheral blood, bone marrow, lymph nodes and spleen. T- PLL comprises approximately 2% of mature lymphocytic leukaemias in adults. Mean age of presentation 65 years.

Presentation

Most patients with T-PLL present with elevated white blood count, hepatosplenomegaly (75%) and generalised lymphadenopathy (50%). Anaemia (36%) and thrombocytopenia (51%) can be seen. Skin infiltration and serous effusions (ie pleural) can occur.

Laboratory Findings

Peripheral blood lymphocytosis. Interstitial pattern of bone marrow infiltration. Skin infiltration most commonly involves the face. The spleen demonstrates dense lymphoid infiltrates in the red pulp, but often invade the splenic capsule. Lymph node involvement is diffuse with involvement of the paracortical areas.

Immunophenotype CD52 (strong). Pan T-cell markers (CD2, CD3 and CD7). TDT not expressed. Expression of CD4 and CD 8 is variable. Co-expression of CD4 and CD8 is practically unique to T-PLL.

Genetic Features

T-cell genes receptor genes are clonally rearranged. Chromosome abnormalities are common. Rearrangements involving TCL1 are common and relatively specific to T-PLL.

38

Investigations

Blood film slides, peripheral blood, bone marrow aspirate, trephine and bone marrow cell markers to be sent to HMDS Leeds, Level 3, Bexley Wing, St James’ Institute of Oncology, Beckett Street, Leeds LS9 7TF.

CT scan of neck, thorax, abdomen and pelvis as indicated.

Management

Many patients are asymptomatic and can be observed. 30% of patients with T-CLL present with initially stable or slow progressive disease. It is however advisable to monitor these patients more closely than patients with other chronic leukaemias as progression can occur rapidly.

Indications for Treatment

Symptomatic anaemia, thrombocytopenia or neutropenia.

Systemic symptoms such as weakness, night sweats, weight loss or fever.

Skin infiltration, pleural effusion or central nervous system involvement.

Progressive disease demonstrated by increasing lymphocytosis and/or rapidly enlarging lymph nodes, spleen and liver.

Initial Treatment

Alemtuzumab is initial treatment of choice. Intravenous route recommended (see network protocol). Premedication with paracetamol and Piriton recommended .Slowly escalating doses advised in week one. Antibiotic prophylaxis against pneumocystis, viral infection and fungal infections are recommended (as per local practise). Cytomegalovirus quantitative PCR monitoring recommended on a weekly basis. Antibiotic prophylaxis recommended post-two months completion of therapy. Maximal duration of therapy - 18 weeks.

Pentostatin, Fludarabine and Cladribine have utility. Pentostatin is the most commonly used purine analogue in this condition. Response of Pentostatin considered to be inferior to Alemtuzumab, although no direct comparisons in clinical trials.

39

Historical agents such as Chlorambucil and CHOP are now usually considered to be of low efficacy.

Response Evaluation

Six to eight weeks following initiation of therapy, peripheral blood, bone marrow aspirate, trephine and cells markers should be sent to HMDS Leeds and CT scan whole body as indicated.

Repeat staging investigations on a six to eight weekly basis.

Post-Remission Therapy

All eligible patients should be referred to tertiary centre for consideration of either a bone marrow allograft ( Christie Hospital or Manchester Royal Infirmary ) or autograft ( Blackpool Victoria Hospital ). Initial referral should be made before initiation of therapy. Usual requirement to have obtained complete remission post-therapy.

Maintenance therapy should not be given outside a clinical trial.

Management of suboptimal response or refractory disease

Alemtuzumab intravenously can be given in combination with Pentostatin. Alemtuzumab intravenously three times weekly for up to three months and Pentostatin 4mg m2 given intravenously weekly for four weeks followed by alternate weekly administration for up to six months. Prophylactic antibiotics including antiviral, antifungal and antibacterial agents recommended for two months post-completion. High infection risk with this regime despite antibiotic prophylaxis.

Single agent purine analogues can be considered.

There is a dearth of literature and evidence concerning the management of suboptimal or refractory disease. Advise discuss with tertiary centre for possible clinical trial.

40

Management of Relapse T-cell PLL

Repeat treatment with Alemtuzumab or purine analogue.

Enrolment in clinical trial, as little information exists on the treatment of recurrent T-cell PLL

Author Dr DE Howarth

Ratified by LSCCN Haematology NSSG May 2015

Review date: June 2016

41

GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF LARGE GRANULAR LYMPHOCYTE LEUKAEMIA (LGL)

Introduction: Large granular lymphocyte leukaemia (LGL) is characterised by peripheral blood and marrow lymphocytic infiltration with LGL’s, splenomegaly and cytopenias, most commonly neutropenia. The LGL is a morphological distinct lymphoid subset that is larger than most circulating lymphocytes and has characteristic azurophilic granules containing acid hydrolases. LGL’s comprise 10-15% of normal peripheral blood mononuclear cells.

LGL’s arise from two major linages 85% are CD3 positive, CD57 positive, CD56 negative T- cells. The remaining 15% are CD3 negative, CD56 positive natural killer (NK) cells.

Epidemiology: 2% to 5% of chronic lymphoproliferative disorder. Median age 60 years, associated with other disorders in 40% of cases particularly rheumatoid arthritis. Also association between MGUS, multiple myeloma, myelodysplastic syndrome and post bone marrow transplant.

Clinical Features:

Neutropenia (84%). Infections typically involve skin, oropharyngeal and perirectal areas but pneumonia can also occur. Opportunistic infections are uncommon.

Anaemia (50%). Transfusion dependent (20%) ;association with autoimmune haemolytic anaemia and pure red cell aplasia.

Thrombocytopenia (20%).

B symptoms (30%).

Diagnosis: Peripheral blood and slides, bone marrow aspirate, trephine and cell markers to be sent to HMDS Leeds:

HMDS Leeds Level 3 Bexley Wing St James’ Institute of Oncology Beckett Street Leeds LS9 7TF

42

Peripheral blood - absolute lymphocyte count usually raised but may be normal. Absolute numbers of LGL’s usually increased. Characteristic morphology.

Bone marrow may be hypercellular, normocellular or slightly hypocellular with mild to moderate reticulin fibrosis. Monoclonal LGL’s usually less than 50% of nucleated cells. Interstitial and or intrasinusoidal infiltration of clonal, CD8 expressing T-Cells accompanied by lymphoid aggregates or nodules comprised of reactive (polyclonal) T and B cells.

Immunophenotype great majority of T – LGL leukaemia’s express CD3, CD8, CD16, CD57 and the alpha/beta T-cell receptor (TCR) but do not usually express CD4, CD56 or CD28.

Clonal nature of T-cell LGL leukaemia most easily demonstrated by molecular studies of T-cell receptor. Identification of clonally rearranged T-cell receptor genes is the key factor in the diagnosis of T - LGL leukaemia (to be performed at HMDS Leeds).

Serological findings: Rheumatoid factor, the most common abnormality (60%). Antinuclear antibodies 40 – 50%. Serum protein electrophoresis may show hypergammaglobulinemia and a polyclonal pattern in about one half of patients. Also association with MGUS.

Imaging – CT scan, US scan as indicated.

Treatment: Not all patients with LGL leukaemia require treatment at the time of diagnosis. Active treatment for symptomatic disease only. Most cases have an indolent clinical behaviour with medium survival over ten years.

Indications for treatment:

 Severe neutropenia (less than 0.5)  Moderate neutropenia (absolute neutrophil counts <1 with recurrent infections)  Symptomatic or transfusion dependent anaemia.  Severe thrombocytopenia (very rare event <20) or bleeding and higher platelet threshold – clinical decision.  Associated autoimmune conditions (example rheumatoid arthritis) requiring therapy

Initial Treatment: Immunosuppressive therapy. Methotrexate, Cyclophosphamide, Cyclosporine. These drugs can be combined with prednisolone as indicated.

Single agent therapy with prednisolone however not recommended.

43

Methotrexate (up to 10 mg/m2 weekly) with or without prednisolone is the most commonly used initial therapy especially for patients with neutropenia as a primary symptom. Response is seen in 50% of patients with time to response ranging from two to twelve weeks. Monitor FBC, renal and liver function tests.

Low dose Methotrexate 5 – 7.5 mg per week gradually increasing to 15 – 20 mg per week over one to three months has similar efficacy.

Cyclophosphamide (50 to 100 mg daily). Overall response rate 55 to 65% in previously untreated patients. One study showed efficacy along with prednisolone in the presence of pure red cell aplasia. Not a good option for neutropenic patients. Monitor FBC and renal function. Alkylating agent so advise regarding fertility, long term small risk of MDS, AML.

Cyclosporine response rate 56% 5-10 mg/kg per day orally in two divided doses for at least three months. Adjusted therapeutic blood level of 200 to 400 ng/mL. Close monitoring of renal function.

Low dose cyclosporine (1 to 1.5 mg/kg orally every 12 hours) with or without low dose GCSF led to a return of normal neutrophil count in one small study where the neutrophil count was less than 0.5

Toxicities include gastrointestinal disturbance, nephrotoxicity, hypertension, neurotoxicity and secondary malignancy. Blood pressure, creatinine, blood glucose, liver function tests, potassium and magnesium should be monitored.

Methotrexate and Cyclosporine can be continued indefinitely as tolerated. Cyclophosphamide should not be administered for longer than six to twelve months for responders.

Discontinuation of methotrexate and cyclosporine can be considered in patients who achieve complete remission for one to two years but studies show that the disease is likely to return slowly following cessation.

Other treatments: GCSF can be considered for neutropenia only. Erythropoietin can be given for anaemia only. Both have poor success rates.

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Blood transfusion – consider chelation once ferritin > 1000.

Treatment of relapsed or resistant disease

Consider the use of one of the immunosuppressive drugs not previously used.

Advise discussion with tertiary centre for possible clinical trials. Other drugs with anecdotal benefit: purine analogues, alemtuzumab, tacrolimus, azathioprine, anti lymphocyte globulin (ALG).

Author Dr D E Howarth

Ratified by LSCCN Haematology NSSG May 2015

Review date: June 2016

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GUIDELINES ON THE DIAGNOSIS AND MANAGEMENT OF MULTIPLE MYELOMA

Contents

1) Methodology, epidemiology and clinical presentation

2) Diagnosis, prognostic factors and disease monitoring

3) Imaging techniques in myeloma

4) Management of common medical emergencies in myeloma patients

5) Myeloma bone disease

6) Renal impairment

7) Induction therapy including management of major toxicities and stem cell harvesting

8) Management of refractory disease

9) Allogeneic stem cell transplantation

10) Maintenance therapy

11) Management of relapsed myeloma

References

Appendices

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1. Methodology, epidemiology and clinical presentation

1.1 Methodology:

The production of these guidelines involved the following steps:  Review of current BCSH guidelines  Review of European Society of Medical Oncology(ESMO) Guidelines  Review of International Myeloma Federation Guidelines  Review of Recently published Network guidelines in the UK  Review of NHS England proposed pathway for Myeloma  Review by Network Haematologists involved in Myeloma care  Review of HMRN Leeds epidemiology data

1.2 Incidence, prevalence and epidemiology in UK and LSCCN  Incidence: 6-7/100,000 per annum (http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma/incidence/index.htm) 90-100 cases per annum in the LSCCN

 Prevalence appears to be increasing as evidenced by improving survival rates (Brenner et al, 2009; Kumar et al, 2008).  1% of all cancers and ∼10% of all haematological malignancies  mortality is 4.1/100 000/year  The median age at presentation is approximately 70 years. Only 15% of patients are aged less than 60 years.  Myeloma is preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in virtually all patients (Landgren et al, 2009).  MGUS progresses to MM at a rate of 1% per year.  Asymptomatic or Smouldering Myeloma (SMM) progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter (Kumar et al, 2009)

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1.3 Clinical Presentation:

Routine presenting clinical features include symptoms of:  Calcium- Hypercalcemia  Renal impairment  Anaemia  Bone disease  Recurrent or persistent bacterial infection  Hyperviscosity  Incidental finding of paraproteinemia, raised ESR, Total protein, Globulin,

Emergency presentation with Spinal cord compression, Hypercalcemia and renal failure require immediate investigations and treatment. Patients with suspected Myeloma require urgent Haematology referral in accordance with the LSCCN pathway.

2. Diagnosis, prognostic factors and disease monitoring

2.1 Investigation and diagnosis

 FBC, Blood Film, ESR, Coagulation screen, Group and save  U+Es, LFTs, Calcium and albumin, CRP  LDH  β2-microglobulin  Immunoglobulins with Electrophoresis and immunofixation of serum and urine with quantification of monoclonal protein  Skeletal survey  Bone marrow aspirate and trephine with plasma cell phenotyping by either immunohistochemistry or flow cytometry –To be reviewed by the Network diagnostic centre which is Leeds HMDS  Virology Hep B , Hepatitis C, HIV 1 and 2

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Additional test that may be required are:  Plasma viscosity (if suspected hyperviscosity)  Serum free light chains (in light chain myeloma)  24 hour urine for Bence-Jones protein quantification  Creatinine clearance  MRI or CT scan.  HLA Typing (If potential candidate for Allograft)

2.2 Diagnostic criteria and differential diagnosis

 The diagnosis (and differentiation from MGUS) should be made using the IMWG criteria as outlined in the BCSH guidelines for the Diagnosis and Management of Multiple Myeloma (Feb 2014).  All diagnoses should be made or reviewed by the Multidisciplinary Team (MDT) (National Institute for Health and Clinical Excellence [NICE], 2003).  Consider using the NUTS criterion to exclude Amyloidosis Neuropathy- Peripheral or Autonomic at the time of diagnosis Urine Dipstick for protein to exclude proteinuria Troponin T or BNP – If high, proceed with an ECG and a ECHO to look for Amyloid Soft tissue involvement- Large tongue, Bruising related to Factor X deficiency

2.3 Monitoring and indications for starting therapy:

 Chemotherapy is indicated for the management of symptomatic myeloma defined by the presence of ROTI (IMWG 2003)  Asymptomatic myeloma patients should be monitored under the supervision of a Consultant Haematologist.(BCSH Feb 2014)  Monitoring of patients with asymptomatic myeloma should include regular (typically 3- monthly) clinical assessment for the emergence of ROTI and measurement of serum and urinary M-protein (and SFLC when indicated). (BCSH Feb 2014)  Repeat BM examination and skeletal imaging should be considered prior to the start of treatment (BCSH Feb 2014)

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2.4 Prognostic factors and staging in symptomatic myeloma

 The International Staging System based on serum albumin and 2-microglobulin should be used Stage I: Serum β2-microglobulin < 3.5mg/l and serum albumin ≥ 35g/l Median survival- 62 months Stage II: Neither I or II Median survival- 45 months Stage III: Serum β2-microglobulin ≥5.5mg/l Median survival: 29 months

 FISH studies are recommended for all patients at diagnosis as they provide important prognostic information but their role in directing therapy remains uncertain.  Newer techniques for prognostic assessment should continue to be utilised in the context of clinical trials to evaluate future incorporation in to routine clinical practice.

2.5 Measuring Response to Therapy

 Response to therapy should be defined using the IMWG uniform response criteria  The SFLC assay should be used to assess response in all patients with light chain only, non secretory and oligosecretory disease

2.6 Rare myelomas

Plasma Cell Leukaemia

 Plasma cell leukaemia (PCL) may be primary or secondary to multiple myeloma and is characterized by the presence of >20% circulating plasma cells and/or an absolute level of > 2.0x109/l (Kyle et al, 1974).

IgD, E and M Myelomas

 The clinical features are similar to that of other myelomas but Bence-Jones proteinuria, extramedullary involvement, lytic lesions and amyloidosis seem to be more frequent (Jancelewicz et al, 1975)

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Non-secretory myeloma

 The SFLC assay is informative in approximately two thirds of patients (Drayson et al, 2001).  The clinical presentation is similar to standard myeloma, but anaemia and lytic lesions may be seen more frequently while renal failure is uncommon (Morris et al,2010 ; BCSH Feb 2014).

3. Imaging techniques

 The skeletal survey remains the screening technique of choice at diagnosis.

 The skeletal survey should include a postero-anterior (PA) view of the chest, antero-

posterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri

and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic

areas should be specifically visualized with appropriate views

 Computerized tomography (CT)scanning or magnetic resonance imaging (MRI) should be

used to clarify the significance of ambiguous plain radiographic findings, such as equivocal

lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain

radiographs, such as ribs, sternum and scapulae

 Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in

myeloma patients with or without vertebral collapse. Urgent CT scanning is an alternative,

when MRI is unavailable, intolerable or contraindicated.

 CT or MRI is indicated to delineate the nature and extent of soft tissue masses and where

appropriate, tissue biopsy may be guided by CT scanning

 There is insufficient evidence to recommend the routine use of positron-emission

tomography (PET) or 99mTechnetium sestamibi (MIBI) imaging. Either technique may be

useful in selected cases for clarification of previous imaging findings preferably within the

context of a clinical trial

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 Bone scintigraphy has no place in the routine staging of myeloma

 Routine assessment of bone mineral density cannot be recommended, owing to the

methodological difficulties of the technique and the universal use of bisphosphonates in all

symptomatic myeloma patients.

4. Management of common medical emergencies in myeloma patients

4.1 Hyperviscosity

 All patients with high protein levels should undergo fundoscopy, which may demonstrate retinal vein distension, haemorrhages and papilloedema.  Patients usually have raised plasma viscosity and symptoms commonly appear when it exceeds 4 or 5 mPa. This usually corresponds to a serum IgM level of at least 30 g/l, an IgA level of 40 g/l and an IgG level of 60 g/l (Mehta and Singhal 2003).

Management:

 Symptomatic hyperviscosity should be treated with therapeutic plasma exchange with saline fluid replacement  If plasmapheresis is not immediately available but hyperviscosity symptoms are present, consider isovolaemic venesection with saline replacement as a holding measure  Effective treatment of the underlying disease should be started as soon as possible

4.2 Hypercalcaemia

 Up to 30% of myeloma patients present with hypercalcaemia in the context of active disease.  Exclude other causes like Hyperparathyroidism Management:  CoCa- 2.6-2.9- Oral/IV Hydration  CoCa- >2.9- IV Hydration +/- Diuretics, Bisphosphonate- Zoledronate is the bisphosphonate of choice. ( Reduced dose Pamidronate(30mg) to be considered in Renal impairment)

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 Refractory Hypercalcemia: If persistent beyond 72 hours, consider repeat Bisphosphonate therapy+/- Corticosteroids and Calcitonin.

4.3 Cord compression

Compression of the spinal cord from extramedullary foci of disease occurs in 5% of patients with myeloma during the course of their disease (Kyle et al, 2003). The management should be in accordance with the MSCC pathway for the LSCCN with the involvement of the spinal cord co-ordinator

 If cord compression is suspected on clinical grounds, Start Dexamethasone 40 mg daily for 4 days with appropriate PPI cover.  Urgent MRI should be performed and neurosurgical or spinal surgical / clinical oncology consultation obtained  Local radiotherapy is the treatment of choice for non-bony lesions and should be commenced as soon as is possible, preferably within 24 h of diagnosis. A dose of 30Gy in 10 fractions is recommended  Surgery is recommended for emergency decompression in the setting of bony compression and/or to stabilize the spine  If cord compression is a presenting symptom, it is important to concurrently pursue a rapid diagnosis and to institute systemic therapy as soon as possible

4.4 Early Infection

 It has been reported that up to 10% of patients die of infective causes within 60 days of diagnosis (Augustson et al, 2005). Neutropenia is not usually a factor in early infection (Augustson et al, 2005)  24-h access to specialist advice for the patient and/or primary care team is crucial.  Any febrile myeloma patient should be treated promptly with broad-spectrum antibiotics. Intravenous antibiotics are required for severe systemic infection or neutropenic sepsis as per the Neutropenic sepsis policy. Aminoglycosides should be avoided, if possible.

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5. Myeloma bone disease

5.1 Clinical features of bone disease

 Bone disease occurs in 80-90% of myeloma patients.  This can present as bone pain, pathological fractures/spinal cord compression and hypercalcaemia (Coleman 1997; Croucher and Apperley 1998; Terpos and Dimopoulos 2005).  Skeletal events compromise mobility and day-to-day independence, decrease quality of life (Cocks et al, 2007; Terpos and Rahemtulla 2004; Vogel et al, 2004) and increase overall treatment costs.

5.2 Bone fractures

Appropriate specialist input should to be sought

 Local radiotherapy is helpful for pain control  Long bone fractures require stabilization and subsequent radiotherapy  Large lytic lesions may cause skeletal instability an orthopaedic opinion should be sought and pre-emptive surgery considered in selected patients.  Vertebral fractures may require specialized clinical interventions including vertebroplasty and kyphoplasty. Myeloma UK facilitated a Spinal Myeloma working group Pathway is attached below.

5.3 Bisphosphonates

 Bisphosphonate therapy is recommended for all patients with symptomatic multiple myeloma, whether or not bone lesions are evident(BCSH Feb 2014)  Zoledronic acid should be the bisphosphonate of choice  Sodium clodronate is less effective than zoledronic acid but has a significantly lower incidence of BONJ(Myeloma IXtrial- Morgan et,al, 2010 )  Duration of treatment is left at the discretion of the treating Haematologist based upon the clinical needs of each individual patient. However, this needs to be reviewed after 2 years.

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 Bisphosphonate break as advised by BNF after 4 years of therapy is recommended  Renal impairment: Dose modifications as listed in the Appendix  Dental evaluation should be carried out before starting IV bisphosphonate therapy

6. Renal Impairment

6.1 Incidence and pathophysiology

 Incidence is about 20-25% (Knudsen et al, 1994) at the time of presentation and about 50% at some time during their disease (Eleutherakis-Papaiakovou et al, 2007; Kyle 1975).  It is possible to reverse renal insufficiency in approximately half of patients but the remainder will have some degree of persistent renal impairment and of these, 2-12 % will require renal replacement therapy (Clark et al, 1999).  Patients presenting with renal failure have a high early death rate; of 367 newly diagnosed myeloma patients with serum creatinine >199 mmol/l, 29.4% died within 60 days of diagnosis (Augustson et al, 2005).  It is therefore critically important to prevent renal failure, or if established, to reverse it as this will significantly improve survival (Knudsen et al, 2000).

6.2 Prevention of Renal Failure

 Early diagnosis of both new and relapsed myeloma enables early intervention and thus prevention of renal damage (Augustson et al, 2005; Drayson et al, 2006).  Investigations for Amyloidosis need to be considered pro-actively – NUTS Criterion  Renal function is optimized by maintenance of a high fluid intake, at least 3 litres/day (MRC Working Party on Leukaemia in Adults, 1984) and all patients should be instructed as to the importance of this throughout the course of the disease.

6.3 Early Management of Renal Failure

 Vigorously rehydrate with at least 3 litres of normal saline daily  Treat precipitating events eg hypercalcaemia, sepsis and hyperuricaemia and discontinue nephrotoxic drugs, particularly NSAIDs  Administer high dose dexamethasone unless otherwise contraindicated pending initiation of definitive treatment which should be started without delay

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 Monitor SFLC levels  Identify and treat infection vigorously  Renal dose modification of drugs and particularly the bisphosphonates is critical

7. Induction Therapy

7.1 The broad aims of treatment in myeloma are:  to control disease  maximise quality of life  to prolong survival These goals are achieved by a combination of specific disease-directed therapy and supportive care. It is important to tailor treatment to the individual patient. Although high-dose therapy (HDT) is recommended where possible, many patients will not be able to receive such therapy because of advanced age, specific problems or general poor performance status.

7.2 Treatment decisions should be made in the context of an  MDT and should take into account individual patient factors and patient choice.  Patients should be treated as part of national trials if available.  NHS England is working on national guidance for Myeloma which advises that treatment decision needs to be made based upon whether a patient is transplant eligible or has renal impairment.  LSCCN Myeloma Chemotherapy Regimens should be followed

7.3 Induction: Intensive patients (suitable for HDT and PBSCT) Induction therapy – Myeloma

 Consider entering into intensive arm of Myeloma XI trial  If not eligible, or patient does not want to enter trial, use Thalidomide containing regimes like CTD, MPT chemotherapy or the Bortezomib based therapy in the context of NICE TA 311(Apr 14) like Vel-Dex, VCD, VTD, VMP in accordance with the LSCCN chemotherapy protocols particularly in the context of renal impairment not responding to adequate hydration.

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 Treat until maximum response + 1 further cycle (min 4 cycles).  VTE risk stratification should be used to select antithrombotic prophylaxis Eg: Aspirin 75mg or prophylactic doses of LMWH.  Assess response after 2 cycles  After maximal response mobilise with Cyclophosphamide and/or G-CSF (doses as per local protocols)  Proceed to Melphalan PBSCT 200 mg/m2 (Renal dose modification: Melphalan 140mg/m2 if Creatinine >200umol/L

7.4 Induction therapy – Plasma cell leukaemia

 Use either a Bortezomib based regime (eg PAD or VCD) for plasma cell leukaemia, or DT- PACE if any contraindication to Velcade containing regimen or failure to achieve a PR after 2 cycles of PAD.

7.5 Induction: Non-Intensive Patients (those not suitable for HDT)

 Consider entering into non-intensive arm of Myeloma XI trial  If not eligible, or patient does not want to enter trial, use CTDa chemotherapy, if tolerated. Maximum of 9 courses.  MPT may be preferred if patient intolerant of high dose steroids or requires simpler scheduled regimen.  For both CTDa, VTD and MPT, VTE risk assessment followed by Aspirin 75mg or prophylactic doses of LMWH should be used as thromboprophylaxis.  Bortezomib based regimes VTD, Vel/Dex, VCDa, VMP (velcade, melpahalan and prednisolone) should be used in patients either unable to tolerate or has contra-indications to thalidomide.  All patients receiving Bortezomib should be monitored closely for peripheral neuropathy. See LSCCN Myeloma Chemotherapy Regimens for details.  Our network has used the once weekly Bortezomib with equal efficacy and less toxicity as evidenced in several clinical trials. This should be used as an alternative schedule, particularly in older patients.

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8. Intensification for non-responders (primary refractory disease)

 This represents about 5% of patients. They are defined as those with <25% reduction in paraprotein after 2 cycles of CTD or < 50% reduction after 4 cycles. These patients should change to a Bortezomib containing regimen.  Treatment for these patients once identified, should be VCD chemotherapy, 2-6 courses until maximum response.  If a Partial Response or greater seen, proceed to consolidation therapy with High dose Melphalan Auto PBSCT.  If less than PR (ie less than 50% fall in paraprotein) with VCD or PAD – consider treatment with VDT-PACE/ DT-PACE to further cytoreduce prior to Autograft Disease monitoring should be using modified EBMT/IMWG criteria

9. Allografts

 Seek Allograft opinion for patients who are <40 years old, 17p del, Plasma cell Leukaemia patients and for selected patients if early relapse post autograft or refractory to multiple lines of therapy, with good performance status.

10. Maintenance therapy

 The role of maintenance therapy remains unclear in the context of the new drugs. Therefore, its role is being assessed as a part of the Myeloma XI trial in the UK No benefit has been demonstrated for the role of maintenance with chemotherapy (Belch et al, 1988; Drayson et al, 1998).

11. First Relapse

 Aim to enter in clinical trial where possible.  If no clinical trial is available, first relapse therapy will depend on whether the patient is suitable for a second autograft:  Bortezomib cannot be used if it has been used previously as per the New Cancer Drugs Fund policy

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11.1 Intensive

 Following results from Myeloma X trial , a second autograft should be performed at first relapse in patients: • who were previously treated with standard chemotherapy and autologous transplantation • with progressive disease ≥12 months from time of first transplant. • with a Performance Status (PS) of 0-2 (ECOG). • with adequate hepatic, renal, pulmonary and cardiac function.

 Patients should be offered a Bortezomib –containing induction regimen such as PAD or VTD/VCD (up to 4 cycles) ahead of the transplant to reduce the disease burden.  If frozen stem cells are stored these can be used. Otherwise re-mobilisation may be possible.  High dose Melphalan conditioning is used as per first autograft (dependent on renal function)

11.2 Non Intensive

 If the patient is NOT suitable for a second autograft they should be offered Bortezomib (Velcade) as per NICE guidance (www.nice.org.uk/TA129)  This can be given with a steroid (usually Dexamethasone) and can also be combined with an alkylating agent such as cyclophosphamide (eg VCD) or as VTD  Details of dosing and dose modifications may be found in the LSCCN Myeloma Chemotherapy Regimens.  The response to Bortezomib will be measured after a maximum of four cycles of treatment, and treatment is continued only in people who have a complete or partial response  If CR is achieved, treatment can be stopped after a further 2 cycles. Patients will receive up to a maximum of 8 x 21-day cycles.  If bortezomib was given as first line treatment under the criteria above then a thalidomide or lenalidomide containing regimen may be offered as a second line option.

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11.3 Second relapse

 Lenalidomide (Revlimid) and Dexamethasone as per NICE guidance if patient has had previous thalidomide.  Patients should receive aspirin 75mg or low dose LMWH as thromboprophylaxis. If additional risk factors are present full dose LMWH or warfarin should be considered  The manufacturer will provide free drug for any Lenalidomide used after 26 cycles of Therapy

11.4 Third or subsequent relapse

 Entry into a clinical trial should be considered whenever possible.  Patients may be retried on a thalidomide containing regimen (eg CTD or MPT).  Alternatively consider Pomalidomide, Dexamethasone or bendamustine, combined with thalidomide and dexamethasone.

11.5 Local radiotherapy

Some patients may relapse with local disease, eg. spinal plasmacytoma, with little evidence of active disease elsewhere. Such patients, especially if they are beyond first relapse, may be treated with local radiotherapy, avoiding the additional toxicity of systemic therapy, which would be an option for subsequent disease re-activation.(BCSH Feb 2014)

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References

Augustson, B.M., Begum, G., Dunn, J.A., Barth, N.J., Davies, F., Morgan, G., Behrens, J., Smith, A., Child, J.A. & Drayson, M.T. (2005) Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United kingdom Medical Research Council trials between 1980 and 2002--Medical Research Council Adult Leukaemia Working Party. Journal of Clinical Oncology, 23, 9219-9226.

Belch, A., Shelley, W., Bergsagel, D., Wilson, K., Klimo, P., White, D. & Willan, A. (1988) A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. British Journal of Cancer, 57, 94-99.

Brenner, H., Gondos, A., & Pulte, D. (2009). Expected long-term survival of patients diagnosed with multiple myeloma in 2006–2010. haematologica, 94(2), 270-275.

Cocks, K., Cohen, D., Wisloff, F., Sezer, O., Lee, S., Hippe, E., Gimsing, P., Turesson, I., Hajek, R., Smith, A., Graham, L., Phillips, A., Stead, M., Velikova, G. & Brown, J. (2007) An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. European Journal of Cancer, 43, 1670-1678.

Clark, A.D., Shetty, A. & Soutar, R. (1999) Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Reviews, 13, 79- 90.

Coleman, R.E. (1997) Skeletal complications of malignancy. Cancer, 80, 1588-1594.

Croucher, P.I. & Apperley, J.F. (1998) Bone disease in multiple myeloma. British Journal of Haematology, 103, 902-910

Drayson, M.T., Chapman, C.E., Dunn, J.A., Olujohungbe, A.B. & Maclennan, I.C. (1998) MRC trial of alpha2b-interferon maintenance therapy in first plateau phase of multiple myeloma. MRC Working Party on Leukaemia in Adults. British Journal of Haematology, 101, 195-202.

Drayson, M., Tang, L.X., Drew, R., Mead, G.P., Carr-Smith, H. & Bradwell, A.R. (2001) Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood, 97, 2900-2902.

Drayson, M., Begum, G., Basu, S., Makkuni, S., Dunn, J., Barth, N. & Child, J.A. (2006) Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials. Blood, 108, 2013-2019.

61

Durie, B.G., Harousseau, J.L., Miguel, J.S., Blade, J., Barlogie, B., Anderson, K., Gertz, M., Dimopoulos, M., Westin, J., Sonneveld, P., Ludwig, H., Gahrton, G., Beksac, M., Crowley, J., Belch, A., Boccadaro, M., Cavo, M., Turesson, I., Joshua, D., Vesole, D., 55 Kyle, R., Alexanian, R., Tricot, G., Attal, M., Merlini, G., Powles, R., Richardson, P., Shimizu, K., Tosi, P., Morgan, G. & Rajkumar, S.V. (2006) International uniform response criteria for multiple myeloma. Leukemia, 20, 1467-1473.

Eleutherakis-Papaiakovou, V., Bamias, A., Gika, D., Simeonidis, A., Pouli, A., Anagnostopoulos, A., Michali, E., Economopoulos, T., Zervas, K. & Dimopoulos, M.A. (2007) Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leukemia and Lymphoma, 48, 337-341.

Jancelewicz, Z., Takatsuki, K., Sugai, S. & Pruzanski, W. (1975) IgD multiple myeloma. Review of 133 cases. Archives of Internal Medicine, 135, 87-93

Knudsen, L.M., Hippe, E., Hjorth, M., Holmberg, E. & Westin, J. (1994) Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group. European Journal of Haematology, 53, 207-212.

Knudsen, L.M., Hjorth, M. & Hippe, E. (2000) Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. European Journal of Haematology, 65, 175-181.

Kumar, S., Hayman, S., Buadi, F., Lacy, M., Stewart, K., Allred, J., ... & Dispenzieri, A. (2008, December). Phase II trial of lenalidomide (RevlimidTM) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. In Blood (ASH Annual Meeting Abstracts) (Vol. 112).

Kumar, S., Flinn, I.W., Parameswaran, Hari, N., Callander, N., Noga, S.J., Stewart, A.K., Glass, J., Raje, N., Rifkin, R.M., Shi, H., Webb, I.J., Richardson, P.G. & Rajkumar, S.V. (2009) Novel three- and four-drug combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for newly diagnosed multiple myeloma: encouraging results from the multi-center, randomized, phase 2 EVOLUTION Study. Blood (ASH Annual Meeting Abstracts), 114, Abstract 127.

Kyle, R.A. (1975) Multiple myeloma: review of 869 cases. Mayo Clinic Proceedings, 50, 29-40

Kyle, R.A., Maldonado, J.E. & Bayrd, E.D. (1974) Plasma cell leukemia. Report on 17 cases. Archives of Internal Medicine, 133, 813-818.

Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispenzieri, A., Fonseca, R., Rajkumar, S.V., Offord, J.R., Larson, D.R., Plevak, M.E., Therneau, T.M. & Greipp, P.R. (2003) Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proceedings, 78, 21-33.

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Landgren, O., Kyle, R. A., Pfeiffer, R. M., Katzmann, J. A., Caporaso, N. E., Hayes, R. B., ... & Rajkumar, S. V. (2009). Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood, 113(22), 5412-5417.

Mehta, J. & Singhal, S. (2003) Hyperviscosity syndrome in plasma cell dyscrasias. Seminars in Thrombosis and Hemostasis, 29, 467-471.

Morgan G., DaviesF., GregoryW., Bell S.E., SzubertA., Navarro CoyN., DraysonM., Owen R.G., Jackson G.H., Child J.A.(2010 ) Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study J Clin Oncol 28:7s, (suppl; abstr 8021)

Morris, C., Drake, M., Apperley, J., Iacobelli, S.,van Biezen, S.,Bjorkstrand, B.,Goldschmidt,H., Jouet, J.P., Harousseau, J-L, Morgan, G., de Witte, T., Niederwieser, D., Gahrton, G. for the myeloma subcommittee of the chronic leukaemia working party of the EBMT (2010) Efficacy and outcome of autologous transplantation in rare myelomas. Haematologica, in press

MRC working party on leukaemia in adults (1984) Analysis and management of renal failure in fourth MRC myelomatosis trial.. British Medical Journal, 288, 1411-1416. National Institute for Health and Clinical Excellence. (2003) Improving outcomes in haematological cancers-The Manual. Available at: http://www.nice.org.uk/docref.asp?d=90429

Terpos, E. & Dimopoulos, M.A. (2005) Myeloma bone disease: pathophysiology and management. Annals of Oncology, 16, 1223-1231. Terpos, E. & Rahemtulla, A. (2004) Bisphosphonate treatment for multiple myeloma. Drugs Today (Barc), 40, 29-40.

Vogel, C.L., Yanagihara, R.H., Wood, A.J., Schnell, F.M., Henderson, C., Kaplan, B.H., Purdy, M.H., Orlowski, R., Decker, J.L., Lacerna, L. & Hohneker, J.A. (2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist, 9, 687-695.

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APPENDICES

Appendix 1 - Monitoring

Response subcategory Response criteria CR as defined below plus  normal SFLC ratio Stringent complete response (sCR)  Absence of phenotypically aberrant plasma cells by multiparameter Flow cytometry  Negative immunofixation in serum and urine  Disappearance of any soft tissue plasmacytomas Complete response (CR)  <5% bone marrow plasma cells

 Serum and/or urine M protein detectable by immunofixation but not on electrophoresis or Very good partial response  >90% reduction in serum M protein and urine (VGPR) M protein level <100mg/24hr

 >50% reduction of serum M protein and Partial response (PR) reduction in 24hr urinary M protein by >90% or to <200mg/24hr

 Not meeting criteria for CR, VGPR, PR or Stable disease (SD) progressive disease

Requires at least one of the following –  >25% increase in serum M protein in 3 months (absolute increase must be >5g/l)  >25% increase in urine M protein in 3 months (absolute increase must be >200mg/24hr)  >25% increase in the difference between involved and uninvolved SFLC levels Progressive disease (PD) (applicable only to patients without measurable serum and urine M protein. Absolute increase must be >10mg/dl  >25% increase in bone marrow plasma cell percentage (absolute percentage must be >10%)  Development of new bone lesions or soft tissue plasmacytoma  Development of hypercalcaemia

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Appendix 2– Dose modifications of Bisphosphonates Bisphophonates Recommended dose reductions of bisphosphonates in renal impairment

Creatinine Sodium clodronate Pamidronate Zoledronate Clearance

>30mls /min No dose modification If Cr Cl: If Cr Cl: 30-60mls/min: 30-39mls/min: The 3mg infusion rate 40-49mls/min: should not 3.3mg exceed 90mg 50-59mls/min: over 4 3.5mg hours ≥ 60mls/min: >60mls/min: 4mg 90mg over 2 hrs

10 -30 Half dose 30 mg to be Not ml/min given over 2- recommended 4 hours

< 10 ml/min Contra indicated 30 mg to be Not recommended given over 2- 4 hours

Appendix 3- Staging

Staging is now done using the International Staging System (ISS) for Multiple Myeloma which defines 3 risk categories. However, the ISS should not determine the choice of therapy for individual patients.

ISS Criteria Median survival in Stage months

I Serum β2-microglobulin < 3.5mg/l and 62 months serum albumin ≥ 35g/l

II Neither I or II 45 months

III Serum β2-microglobulin ≥5.5mg/l 29 months

Certain cytogenetic and molecular genetic abnormalities have been shown to predict outcome in myeloma. It is generally accepted that the t(4:14), t(14;16) and deletion 17p,t(14:20) and 1q gain demonstrated by FISH, confer an adverse outcome. At present, the consensus is that no clinical

65 or treatment decisions can be guided by genetic factors, however, centres may wish to assess FISH at diagnosis to provide prognostic information, and possibly influence treatment decisions in the future as new data emerges.

When to treat

Following a diagnosis of multiple myeloma, patients can be divided into those with either asymptomatic or symptomatic disease. Those who are asymptomatic require close monitoring by a Consultant Haematologist, however, early intervention or treatment is not required. Treatment with chemotherapy is indicated for the management of symptomatic myeloma (1) This is as defined by the presence of Myeloma-related organ or tissue impairment (ROTI) defined in table below:

Myeloma-related organ or tissue impairment (ROTI) (International Myeloma Working Group, 2003)

Clinical effects due to Definition myeloma Increased calcium Corrected serum calcium >0.25mmol/l above the upper limit of normal levels or >2.75mmol/l

Renal insufficiency Attributable to myeloma (exclude other causes) Anaemia Haemoglobin 2 g/dl (1.2 mmol/l) below the lower limit of normal or haemoglobin <10 g/dl (<100 g/L or 6.2 mmol/l)

Bone lesions Lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify)

Other Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 2 episodes in 12 months)

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Appendix 4 – NHS England Draft Treatment Algorithms

67

68

69

70

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Appendix 5 - Spinal Pathway

Spinal Myeloma Working Group Pathway

Patient with known history of myeloma presenting with persistent back or radicular pain/weakness

NO ABNORMAL NEUROLOGY

Myeloma with spinal involvement: pain/instability/progressive deformity, or, risk of neurological dysfunction.

CT SCAN (Sagittal and coronal reconstructions) If concerned ∞ about stability MRI SCAN WHOLE SPINE Assess pars, facet joints, pedicles, posterior

/anterior wall involvement to determine if

instability is a concern. Conduct SINS assessment** MDT Management Review∞ ] If bony destruction is present on CT (Surgeon, Haematologist, Radiotherapist and (suggesting spinal instability) consider brace Δ Radiologist) or surgical intervention

Pain significantly Pain not significantly Epidural mass with risk affecting day to day affecting day to day of cauda equina or cord functioning (or VAS pain functioning (or VAS pain compression score ≥6) score ≤ 6)

+/- Brace*** (if Cement Augmentation* high risk of Steroids, Radiotherapy, Chemotherapy ¥ deformity) /Radiotherapy or combination

of both (according to MDT After 2-3 Cycles of review) Repeat MRI after 2/3 cycles of chemo if on-going chemotherapy (Canal Clear?) pain affecting QOL.

¥ Balloon Kyphoplasty – creation Yes No of cavity, injection of cement with Assess for cement potential restoration of VB height MDT Management Review∞ augmentation

based on risk of VB

¥ collapse Vertebroplasty – injection of cementContinue to Medicalstabilise Managementfracture +/- brace***

* Antibiotic prophylaxis recommended for all patients undergoing cement augmentation (to avoid potential risk of severely debilitating discitis)

** Spinal Instability Neoplastic Score

*** Thermoplastic/TLSO brace if available to prevent72 progressive deformity +/- further vertebral body collapse

Δ High risk patient – e.g., patient with bilateral facet joint destruction, therefore posing risk of spondylolisthesis

¥ See appendix for clinical data pertaining to Balloon Kyphoplasty, Vertebroplasty and Radiotherapy

Spinal Myeloma Working Group Pathway

Patient with known history of myeloma presenting with persistent back or radicular pain/weakness

ABNORMAL NEUROLOGY

Cord compression / cauda equina / signs & symptoms of neurological dysfunction

Contact Spinal cord co-ordinator immediately and follow the LSCCN MSCC pathway MRI SCAN WHOLE SPINE∞

CT scan (SINS assessment**)

Bloods – FBC, Total protein, Calcium, ESR, Renal Function, Soft Tissue involvement:Clotting Bone Involvement

Urgent liaison with MDT∞ Cord compression due to bone involvement

(Haematologist, Radiotherapist, Radiologist and Surgeon) Steroids, Radiotherapy, Chemotherapy

Spinal decompression Immediate neurological No Improvement improvement (unusual) +/- stabilisation (cement augmentation +/- metal work) 2-3 cycles Chemotherapy

No MDT Management Repeat MRI (Canal Clear?) ¥ Review∞ Yes Cement Augmentation* /Radiotherapy or combination of both (according to MDT review) Pain not significantly affecting Pain significantly affecting day

day to day functioning (or VAS to day functioning (or VAS pain ¥ pain score ≤6) score ≥6) Balloon Kyphoplasty – creation of cavity, injection of cement with potential restoration of VB height

Continue Medical Management +/- brace***

¥ Vertebroplasty – injection of cement to stabilise fracture * Antibiotic prophylaxis recommended for all patients undergoing cement augmentation (to avoid potential risk of severely debilitating discitis)

** Spinal Instability Neoplastic Score

*** Thermoplastic/TLSO brace if available to prevent progressive deformity +/- further vertebral body collapse 73 Δ High risk patient – e.g., patient with bilateral facet joint destruction, therefore posing risk of spondylolisthesis

¥ See appendix for clinical data pertaining to Balloon Kyphoplasty, Vertebroplasty and Radiotherapy

∞ As per National Cancer Guidelines

Spinal Myeloma Working Group Pathway

Patient with Plasmacytoma

SOLITARY NOT SOLITARY

NO ABNORMAL ABNORMAL NEUROLOGY Treat as a patient with Multiple NEUROLOGY Myeloma according to standard pathway

RADICAL DXT URGENT LIAISON WITH MDT

(Surgeon, Haematologist, Radiotherapist and Radiologist) Consider cement augmentation Treat according to MDT If risk of instability or if pain is review decision significantly affecting day to day functioning (VAS pain score ≥6)

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Appendix 6 - Spinal Team Referral form

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Appendix 7- MSCC pathway http://online.lthtr.nhs.uk/start.asp

Diagnostic Algorithm for Suspected Metastatic Spinal Cord Compression (MSCC)

Suspected MSCC

Liaise Immediately with MSCC coordinator (LTHTR Bleep 2664)

1. Start Dexamethasone + Omeprazole 2. If spinal instability suspected - Nurse flat Clinical diagnosis of MSCC - VTE prophylaxis (as per local guidelines) Very frail 3. Manage acute pain as per guidelines Refer to Palliative care team (see treatment algorithm)

Urgent MRI at local hospital • Whole spine • Within 24 hours of presentation • If appropriate spinal instability to be commented on in report

Confirmed MSCC

YES - NO - • Consider Radiotherapy for pain • Follow treatment algorithm for confirmed MSCC • Action tissue diagnosis and appropriate treatment • If no prior cancer diagnosis refer to CUP team (if not known to have cancer)

Lancashire Teaching Hospitals main switchboard:01772 716565 76

Treatment Algorithm for Metastatic Spinal Cord Compression {MSCC)

Confirmed MSCC

Liaise Immediately with MSCC coordinator {LTHTR Bleep 2664)

Transfer to specialist cancer centre 1. Complete paralysis > 24 hours MSCC coordinator to facilitate discussion between Consultant Spinal 2. Frail Surgeon and Consultant Oncologist within 4 working hours 3. Poor life expectancy

Single Level, multiple (limited) but Single or Multiple levels - surgery deemed unsuitable otherwise favourable Good Performance Status Good Performance Status Severe neurological deficit <24 hours Life expectancy >3/12 Or Neurological deficit < 24 hours Mild neurological deficit

YES NO YES NO Consider Liverpool Care Pathway / Preferred Priorities for care Refer to Spinal surgeon for treatment as per Urgent Flaccid paralysis NICE Guidance > 24 hours Radiotherapy

Pain not optimally Pain well controlled controlled

Consider post-op Refer to appropriate Radiotherapy tumour-specific team Refer to Palliative Care immediately team (administer Commence rehabilitation as Consider within 2 weeks) appropriate palliative Radiotherapy

Commence Commence rehabilitation as rehabilitation as appropriate appropriate

Lancashire Teaching Hospitals main switchboard:01772 716565

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Myeloma Imaging Guidelines:

Fig 1. Algorithm of suggested recommendations. CT, computed tomography; MR(I) magnetice resonance (imaging); PET positron emission tomography; R/T, radiotherapy. http://www.bcshguidelines.com/documents/myeloma_imaging_guidelines_2006.pdf

Author Dr M Punnekar

Ratified by LSCCN Haematology 14 May 2015 NSSG

Review date: March 2016

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GUIDELINES FOR THE MANAGEMENT OF LYMPHOMA

1. Diagnosis and clinical assessment Histological diagnosis must where possible be made on a good quality tissue biopsy and should not rely on the results of FNA alone. It is network policy that following initial local examination of the primary diagnostic biopsy all samples in newly diagnosed or relapsed cases must be referred to HMDS Leeds as soon as the possibility of lymphoma has been raised on histology. Performance of additional tests such as extended immunohistochemistry at the local laboratory is discouraged. This will delay the final diagnosis and may use up valuable histological material.

Where possible all new and relapsed/refractory cases must be brought to the Haematology MDT for discussion before treatment is initiated.

Assessment must include a full history and examination, ECG, chest X-ray and assessment of ECOG performance status. If anthracyclines-based chemotherapy is being considered and where there is a history of, or risk factors for cardiac disease e.g > 70 years, hypertension, diabetes, heavy smoking or alcohol excess, or symptoms or ECG changes to suggest cardiac disease, there must be a formal assessment of cardiac function by echocardiogram or MUGA scan.

At the initial MDT discussion plans for further MDT review of interim or end of treatment restaging investigations, and further discussion of additional treatment e.g. radiotherapy, stem cell transplantation, maintenance therapy, will be discussed.

2. Classical Hodgkin’s lymphoma The following tests are to be performed:  FBC, ESR, U&Es, creat, LFTs, calcium  Hepatitis B, C and HIV serology  PET-CT scan where treatment is with curative intent  MRI scan for assessment of disease in the oropharynx and Waldeyer’s ring, sinuses and nasal cavity, and paraspinal areas where there is a suspicion of spinal cord compromise  Bone marrow trephine biopsy unless stage I/IIA, presence of unequivocal evidence of marrow infiltration on PET-CT scan or when knowledge of marrow infiltration will not affect management e.g an elderly patient with stage III disease, palliative management

Stage and prognostic group must be determined according to the German Hodgkin’s Lymphoma Study Group (GHSG) criteria (appendix 1). The Hasenclever score must be determined for advanced stages (appendix 2). Patients with stage IIB disease with bulk and/or extra-nodal disease will be managed as for advanced stage disease.

2.1 Early stage, no risk factors Standard treatment is: ABVD x 2 cycles + 20-30Gy IFRT Where there is a concern regarding the acute or long term toxicity of radiotherapy the use of a longer course of chemotherapy alone may be considered. These patients must have a 79 | P a g e

baseline PET-CT scan followed by a repeat after three cycles ABVD. If metabolic CR is achieved it may be reasonable to omit IFRT – this reduces progression-free survival by approximately 5% with no as yet demonstrable effect on overall survival. Patients must be appraised of the risks, benefits and uncertainties of this approach.

2.2 Early stage, risk factors Standard treatment: ABVD x 4 + 30Gy IFRT There is no evidence to support the omission of RT in these patients.

2.3 Advance stage, ≤ 60 years and fit Standard treatment options will be either: ABVD x 6-8 cycles or escalated BEACOPP x 6 cycles Although interim PET appears to be predictive of outcome in patients treated with ABVD the optimal management of interim PET-positive patients is unclear and is the subject of ongoing clinical trials. It is not presently recommended.

On completion of chemotherapy patients must have a repeat of all abnormal baseline investigations including a PET-CT scan 6 weeks after the last dose of chemotherapy, followed by further MDT discussion.

Where patients have received escalated BEACOPP and metabolic CR is achieved consolidation radiotherapy may be omitted. If complete metabolic response has not been achieved further treatment with 30Gy DXT will be given to residual FDG avid lesions where possible. Where RT is not feasible there should be rebiopsy or at least close follow up of the lesions with repeat PET-CT scan.

Patients treated with ABVD must be considered for consolidation RT to sites of original bulk or residual lesions >1.5cm. At present it is unclear whether RT can be safely omitted where there are residual lesions >1.5cm on CT that are PET-negative.

Patients with progressive disease will be managed as for refractory disease.

2.4 Hodgkin’s lymphoma in older patients > 60 years Combination chemotherapy may be offered to those considered non-frail but escalated BEACOPP must not be used. There is no clear optimal regimen and the choice will depend on several factors: age, comorbidity, patient preference. ABVD is associated with a higher treatment-related mortality, a high rate bleomycin toxicity and there may be a contraindication to anthracyclines. All oral regimens such as DECC may be preferable in some patients.

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Standard options in the non-frail patient are: ABVD or VEPEM-B or ChlVPP or DECC Palliative chemotherapy options in the frail patient are single agent etoposide+/- steroids, vinblastine, DECC.

2.5 Management of relapsed, refractory and progressive disease All patients must be referred to the Haematology MDT for further discussion. Rebiopsy should be undertaken where the duration of first remission is > 5 years.

Where the duration of first remission has been > 5years, there are no B symptoms and the relapse is localised treatment with standard-dose chemotherapy and IFRT is an option.

2.5.1 Candidates for high dose therapy Patients must be restaged with PET-CT scan and bone marrow trephine biopsy.

For the occasional patient who has relapsed > 5 years after primary therapy with early stage disease and without B symptoms standard dose chemotherapy and IFRT alone may be considered.

Prognostic factors prior to salvage chemotherapy in patients undergoing autologous stem cell transplant are: remission duration < 1 year, extranodal disease, B symptoms (appendix 3). However, the metabolic remission status following salvage is the best predictive factor.

Where high dose therapy is indicated the first goal of treatment is a metabolic CR before proceeding to PBSC mobilisation. The choice of initial salvage regimen will depend on patient and local factors. Options are ICE, DHAP, GEM-P. If the response is < metabolic CR treatment must be changed to an alternative salvage regimen e.g gemcitabine-cisplatin- steroid, GDCVP, followed by PBSC mobilisation if in metabolic CR. Note that although brentuximab vedotin may be an attractive option it is not funded by NCDF or approved by NICE for this indication at the time of writing.

Where PBSC mobilisation is successful and the patient maintains sufficient performance status and cardiorespiratory function the response must be consolidated with BEAM autograft.

End of treatment restaging PET-CT scan must be discussed at the MDT. Consolidation RT must be considered where there is a dominant site of relapse at an initially involved site e.g bulky disease and residual abnormalities.

Where metabolic CR has not been achieved with salvage chemotherapy BEAM autograft may still be offered with curative intent. However, the outcomes are poor. Younger patients < 50 years should be offered referral to an allogeneic stem cell transplant centre to discuss the risks and benefits of allogeneic transplant.

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Referral for allogeneic transplantation should be offered for younger patients relapsing after autologous transplant. Repeat autologous transplant may be considered if there is a long duration of remission e.g > 5 years since first transplant.

2.5.2 Patients who are not candidates for high dose therapy Combined-modality therapy should be considered, especially when there is early stage relapse, patients have not previously received RT or have relapsed outside an initial RT field. Salvage radiotherapy alone is an alternative option, especially for older patients with early stage relapse, without B symptoms and good performance status.

The most appropriate chemotherapy regimen will depend on age, performance status, frailty status, comorbidity and organ function, availability of funding. Suitable options are: gemcitabine or gemcitabine combinations (Gem-P, GDCVP), ChlVPP, brentuximab vedotin, vinblastine, DECC, single agent etoposide/steroids. Palliative RT for local disease control should be considered.

Early referral to the palliative care team should be considered.

3. Lymphocyte predominant Hodgkin’s lymphoma Staging and clinical assessment should be as for Hodgkin’s lymphoma. 3.1 Early stage For Stage IA disease standard options are observation where there has been complete excision or IFRT

For stage IIA standard treatment is IFRT.

3.2 Advanced stage Due to the difficulty distinguishing LPHD from diffuse large B-cell lymphoma, especially T- cell rich variant, this should be managed as for diffuse large B-cell lymphoma.

3.3 Relapse Repeat biopsy is essential – reactive lymphadenopathy is common and LPHD may also transform to diffuse large B-cell lymphoma. Localised relapse outside a previously irradiated area should be treated with IFRT. Relapse within a previously irradiated area should be treated with CHOP-R x 6. If not fit for CHOP options are CVP-R or single agent rituximab.

4. Diffuse large B-cell lymphoma The following tests should be performed:  FBC, ESR, U&Es, creat, LFTs, calcium, LDH, urate  Hepatitis B, C and HIV serology

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 PET-CT scan where treatment is with curative intent  MRI scan for assessment of disease in the oropharynx and Waldeyer’s ring, sinuses and nasal cavity, and paraspinal areas where there is a suspicion of spinal cord compromise  Bone marrow aspiration and trephine biopsy where the findings are likely to influence management i.e this could be omitted in an elderly patient with CT evidence of advanced stage disease or where management will be palliative.  CT scan brain and CSF exam where at high risk of CNS lymphoma.

The IPI and age-adjusted IPI must be calculated (see appendix 4).

4.1 Stage IA, non-bulky

Standard treatment is R-CHOP21 x 3 + IFRT 30Gy

If there are concerns regarding the acute or late toxicity of RT R-CHOP x 6 is an alternative.

4.2 Stage IA, bulky – IVB

Standard treatment is R-CHOP21 x 6 cycles

Diffuse large B-cell lymphoma at special sites DLBCL testis should be treated with RCHOP21 x 6 + prophylactic RT to the contralateral testis following orchidectomy (see also intrathecal prophylaxis). 6 x R-CHOP21 should be considered for stage I disease at extranodal sites e.g gastric DLBCL. Primary cerebral diffuse large B-cell lymphoma must be referred to the network Brain Cancer MDT. Primary mediastinal B-cell lymphoma should be treated with RCHOP21 x 6 cycles followed by consolidation RT. Dose-adjusted EPOCH-R x 6-8 cycles without consolidation RT is an option where there are concerns about the toxicity of RT. 4.3 ‘Double hit’ lymphomas Results with R-CHOP21 are poor – median survival < 12 months. It is not clear that any regimen or high dose therapy is superior. However, treatment with alternatives such as more intensive therapy with R-CODOX-M/R-IVAC or dose-adjusted R-EPOCH must be considered. The choice will depend on the presence or risk of CNS disease, and patient factors and preference. Note that R-EPOCH does not include agents with significant CSF penetration so treatment will be given with intrathecal chemotherapy or systemic high-dose methotrexate. 4.5 Patients not fit for full-dose RCHOP Note that it is possible to give full-dose R-CHOP21 to patients up to 85 years with good performance status and adequate cardiac function, especially when given with primary GCSF prophylaxis.

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Options are 50% R-CHOP21 x 6 cycles (mini-RCHOP) or RCHOP21 with etoposide in place of doxorubicin (British Columbia Cancer Agency regimen).

For frail patients consider CVP, low dose oral etoposide +/- steroids or oral DECC.

4.6 End of treatment restaging and further treatment

Although interim PET appears to be predictive of outcome in patients treated with R-CHOP the optimal management of interim PET-positive patients is unclear. It is the subject of ongoing clinical trials and is not presently recommended.

Patients with stage IA bulky – IVB should have an end of treatment PET-CT scan 6 weeks after the last dose of chemotherapy. The case must be reviewed at MDT to consider additional therapy, particularly RT.

It must be noted that the role of consolidation RT to sites of previous bulk and residual anatomical abnormalities is unclear. The benefit of PET-directed consolidation RT to residual metabolic abnormalities has not yet been demonstrated. The use of consolidation RT should be decided at the MDT on a case by case basis in conjunction with a radiation oncologist. There should be rebiopsy or at least close follow up of residual FDG-avid lesions with repeat PET-CT scan before treatment.

Patients with testicular diffuse large B-cell lymphoma should receive prophylactic RT 30Gy to the contralateral testis.

4.7 CNS prophylaxis This should be offered to all patients with a raised LDH and more than one extranodal site (note tonsillar or splenic involvement is not extranodal, two lung lesions count as one site), and to patients with involvement of the breast, epidural region and testis. Patients should receive intrathecal methotrexate 12.5mg with each of cycles 1-3 (cycles 1-4 for testicular lymphoma). Following MDT discussion systemic high-dose methotrexate 3g/m2 should be considered for patients deemed to be of especially high risk of CNS relapse e.g multiple extranodal sites, high LDH, high-risk IPI, taking into consideration age, performance status, goal of treatment and renal function. 4.8 Management of relapse and refractory disease For patients relapsing from CR repeat biopsy should be considered, especially for late relapsed and where high dose therapy is an option. Patients should be restaged with bone marrow aspiration and trephine biopsy. Where high dose therapy or combination chemotherapy is being considered PET-CT scan should be performed.

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The second-line age-adjusted IPI (appendix 5) and time to relapse from CR must be calculated for patients considered fit for autologous transplant. They should receive 3 cycles of salvage chemotherapy followed by repeat PET-CT scan. Salvage regimen will generally be R-ICE, R-DHAP or R-GEM-P. Where metabolic CR has not been achieved the significant negative impact on prognosis must be discussed with the patient. Autologous transplant remains an appropriate option however, the patient should be appraised of alternatives e.g referral for consideration of experimental treatments, such as allogeneic transplant, novel therapies. Where the patient is unfit for autologous transplant treatment options will depend on age, performance status, comorbidity, previous treatments. Options are gemcitabine or gemcitabine combinations, pixantrone, low dose oral etoposide +/- steroids, DECC, palliative RT.

5. Burkitt’s and Burkitt’s-like lymphoma Clinical assessment as for diffuse large B-cell lymphoma but there is no role for PET-CT scan. CSF examination is mandatory. Patients are at high risk of tumour lysis syndrome and treatment is usually given with Rasburicase prophylaxis. Patients must be referred to Blackpool Teaching Hospitals for treatment.

5.1 First line treatment R-CODOXM/R-IVAC (as per the RCM Trial) for two cycles irrespective of stage. Prophylaxis for tumour lysis must be used.

If the patient is unfit for RCODOXM/R-IVAC options are dose-adjusted EPOCH-R x 6-8 cycles or R-CHOP x 6 -8 cycles. It should be noted that the results with R-CHOP are poor. There are encouraging results published with EPOCH-R in small studies and this is associated with considerably less treatment-related morbidity and minimal tumour lysis syndrome. EPOCH-R does not include CNS-directed therapy and intrathecal prophylaxis or systemic high-dose methotrexate must be given with each cycle.

5.1 Relapse/refractory disease The prognosis is poor and there is very little evidence on which to base management. Where the patient is fit for high dose therapy they should receive intensive salvage chemotherapy followed by allogeneic or autologous stem cell transplantation depending on age, performance status, comorbidity, duration of first remission and donor availability.

6. T-cell and NK-cell lymphoma

The following tests should be performed:  FBC, ESR, U&Es, creat, LFTs, calcium, LDH, urate, immunoglobulins, DCT  Hepatitis B, C and HIV serology  PET-CT scan neck, chest and abdomen

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 MRI scan for assessment of disease in the oropharynx and Waldeyer’s ring, sinuses and nasal cavity, and paraspinal areas where there is a suspicion of spinal cord compromise  Bone marrow aspiration and trephine biopsy where the findings are likely to influence management i.e this could be omitted in an elderly patient with CT evidence of advanced stage disease or where management will be palliative.  CT scan brain and CSF exam where at high risk of CNS lymphoma.

The IPI/age-adjusted IPI must be calculated (and the Peripheral T-cell lymphoma prognostic score for PTCL (appendix 6).

Indications for CNS prophylaxis are as for diffuse large B-cell lymphoma. End of treatment restaging is as for diffuse large B-cell lymphoma. Note the evidence base for PET in T-cell lymphoma is lacking and it’s use is extrapolated from experience in diffuse large B-cell lymphoma. Rebiopsy must be attempted before diagnosis of relapse or refractoriness based purely on metabolic abnormalities on PET.

6.1 Peripheral T-cell lymphoma (PTCL) Stage I-II disease should be treated with CHOP x 3 – 6 cycles and 30Gy IFRT. Advanced stage should be treated with CHOP x 6-8 cycles. In younger patients with chemosensitive disease consolidation with high dose therapy and autologous stem cell transplant should be offered. Relapsed/refractory disease where the patient is a candidate for high dose therapy should be treated with platinum-based salvage chemotherapy e.g ICE, DHAP, GEM-P, followed by autologous stem cell transplant if not given in first response. Allogeneic transplantation should be considered in first response for younger fit patients.

If high dose therapy is not feasible options are GEM-P, gemcitabine as a single agent, oral low dose etoposide +/- steroid, DECC. Activity has been demonstrated with novel agents such as pralatrexate and romidepsin, and bendamustine, brentuximab in CD30 +ve cases - these are not approved for funding at the time of writing.

6.2 Anaplastic T-cell lymphoma alk negative Management is as for PTCL. Note that brentuximab vedotin is an option for relapsed/refractory disease. 6.3 Primary cutaneous anaplastic T-cell lymphoma Primary cutaneous anaplastic T-cell lymphoma should be treated with excision +/- local RT. 6.4 Anaplastic T-cell lymphoma alk +ve Management as for PTCL but prognosis is better than alk –ve form. Hence high dose therapy in first response is generally not considered except where there are poor prognostic features such as high risk IPI, PIT score or peripheral blood involvement. Relapse management is as for PTCL. Note that brentuximab vedotin is also an option. 86 | P a g e

6.5 Angioimmunoblastic T-cell lymphoma Careful clinic-pathologic correlation at the MDT is particularly important for this form of lymphoma. It should be noted that occasional spontaneous and durable remissions may occur. Newly-diagnosed patients often respond very well to high dose steroids, these may be used to improve performance status but responses are rarely durable. First line treatment should be CHOP x 6 cycles. In suitable patients in first CR autologous stem cell transplant should be offered. Where the patient is not fit for CHOP options are attenuated CHOP, FC, gemcitabine, thalidomide, steroids alone. At relapse rebiopsy is important as B-cell lymphoproliferations and DLBCL may occur. Treatment options at relapse are platinum-based salvage chemotherapy e.g GEM-P, followed by high dose therapy with autologous or allogeneic transplant in younger, fitter patients. Palliative options are gemcitabine, etoposide +/- steroids or steroids alone. Thalidomide, cyclosporin A and alemtuzumab should also be considered – there are several anecdotal reports of efficacy. Although brentuximab has shown to be acitive in a significant number of CD30+ve cases it is not funded at the time of writing.

6.6 Enteropathy-associated T-cell lymphoma Treatment must involve gastroenterology and nutritional support. The high risk of gastrointestinal perforation must be noted and initial surgical resection considered.

Initial treatment should be CHOP x 1 initially followed by alternating IVE-intermediate dose methotrexate (as per SNLG protocol and ideally within the current NCRI trial available at RLUH). Consolidation with autologous stem cell transplant should be considered in first response.

Older patients or those where performance status is insufficient for IVE-methotrexate should continue CHOP for 6 cycles. Where CHOP is not feasible management should be steroids and palliation.

6.7 Extranodal NK/T-cell lymphoma, nasal type Localised disease should treated with RT 50-55Gy. More advanced stages should be treated with asparaginase or asparaginase-containing regimens e.g SMILE. Consolidation with autologous or allogeneic transplant may be considered in younger, fitter patients.

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7. Follicular lymphoma The following tests should be performed:  FBC, U&Es, creat, LFTs, calcium, LDH, Igs/serum electrophoresis  Beta-2-microglobulin  Hepatitis B, C serology  CT scan neck, thorax and abdomen  MRI scan for assessment of disease in the oropharynx and Waldeyer’s ring, sinuses and nasal cavity, and paraspinal areas where there is a suspicion of spinal cord compromise  Bone marrow aspiration and trephine biopsy where the findings are likely to influence management e.g a well patient with stage III low volume disease where initial management will be observation would not benefit.  PET-CT scan should be considered to clarify whether a patient has early stage disease if initial IFRT is being considered.

The FLIPI and FLIPI-2 scores must be calculated (see appendix 7).

Remission status should be determined with an end of treatment CT scan +/- repeat bone marrow biopsy.

7.1 Stage IA and IIA disease Standard treatment should be IFRT 24Gy.

Initial observation is an alternative option where there is concern regarding the potential toxicity of RT. There is no randomised comparison of IFRT and observation in such patients and long term treatment-free survival has been shown in those who did not receive RT. Hence observation is an alternative option, especially for older patients.

7.2 Advanced stage, low volume disease Definitions of low volume disease are given in appendix 8.

Standard treatment should be observation. It is recognised that some patients may prefer to have treatment and they should be managed as in 7.3

7.3 Symptomatic advanced stage disease This will also apply to asymptomatic patients who do not meet the criteria for low volume disease. Initial treatment should be rituximab and chemotherapy. The optimal chemotherapy is unclear but generally CVP-R x 6-8 cycles or bendamustine-R x 6 cycles will be used (now approved by NCDF). CHOP-R x 6 cycles may be considered where there is bulky lymphadenopathy or a clinical suspicion of high grade transformation. Chlorambucil-R or single-agent R are options for older patients and those with poor performance status and comorbidities.

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Patients achieving at least PR should be offered maintenance rituximab every two months for two years.

7.4 Follicular lymphoma grade 3b Management is as for diffuse large B-cell lymphoma.

7.5 Relapsed and refractory follicular lymphoma Since there is a high risk of transformation to high grade lymphoma rebiopsy should be performed where possible. Treatment will generally be rituximab-chemotherapy. If patients have relapsed while on rituximab maintenance therapy or within six months of rituximab-based treatment should be chemotherapy alone. The choice of treatment will depend on several factors including age, FLIPI score at presentation, performance status and cardiac function, comorbidity, initial treatment and duration of response, potential for high dose therapy at this point or in the future.  The initial chemotherapy may be repeated if there was previously a good and/or prolonged response  R-CHOP x 6 especially if consolidation with autologous or allogeneic stem cell transplant is being considered (R-IVE, R-ICE or R-DHAP depending on previous exposure to alkylating agents and/or anthracyclines)  Bendamustine-R  Fludarabine-based treatment, either F-R or FC-R (avoid if potential transplant candidate)  Bortezomib-R (not approved for funding at time of writing).  Autologous or allogeneic stem cell transplant where the duration of remission has been short and the patient is younger and lacks significant comorbidity  Zevalin, especially where patients have relapsed soon after R-chemo or have been refractory and do not have large volume disease  Single agent rituximab is an option if the patient may not tolerate cytotoxic therapy  Palliative chlorambucil or low dose etoposide +/- steroids where patients are heavily treated or frail and unlikely to tolerate other therapies IFRT should be considered for localised relapse or where relapse is dominated by disease at a localised site. Patients achieving a second or third at least partial remission should receive maintenance rituximab every three months for two years where maintenance was not given in first remission.

7.6 Transformed follicular lymphoma If they are anthracycline-naïve patients should receive R-CHOP x 6 cycles. The option of consolidation with autologous stem cell transplant should be discussed with younger fit patients. If they are unable to have anthracyclines salvage regimens as for relapsed DLBCL

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or gemcitabine should be used. Allogeneic stem cell transplantation should be considered in younger, fit patients.

Intensification with high dose therapy may be unnecessary in chemotherapy-naïve patients i.e discordant presentations with diffuse large B-cell and follicular lymphoma, and in patients with localised disease. Both these groups appear to have a better prognosis with chemotherapy alone +/- RT.

8 Mantle cell lymphoma The following tests should be performed:  FBC, U&Es, creat, LFTs, calcium, LDH, beta-2 microglobulin  Hepatitis B, C serology  CT scan neck, thorax and abdomen  Endoscopy should be performed if the patient has GI symptoms  There is no role for PET-CT scan.  Bone marrow aspiration and trephine biopsy where the findings are likely to influence management e.g for a well patient with stage III low volume disease where initial management will be observation marrow biopsy will not be helpful.  CT/MRI scan brain and CSF examination in selected cases – note higher incidence of CNS disease in mantle cell lymphoma.

The MIPI (or MIPI-B if Ki67% is available) should be calculated

8.1 Stage I/IIA, non-bulky disease Offer IFRT although it should be stressed to the patient that the evidence base is weak.

8.2 Advanced stage disease A significant minority of patients with advanced stage disease are asymptomatic and have indolent disease. They may remain well for several years. Hence observation should be offered. Younger, fit patients should be offered Nordic regimen followed by BEAM/LEAM and autologous stem cell transplantation if PR/CR achieved. Alternatives are CHOP-R x R, bendamustine-R, FC-R. Maintenance rituximab every three months for two years is an option following R-CHOP. For less fit patients less intensive treatment with CVP-R or chlorambucil should be considered. Palliative RT should be considered for local disease control.

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8.3 Relapsed/refractory disease Management will depend on age, performance status, comorbidity, previous treatments especially rituximab exposure, eligibility for stem cell transplant, and suitability and eligibility for funding for ibrutinib. DHAP-R x 3 cycles followed by autologous stem cell transplant should be offered if not performed in first response.

Treatment options are:  ibrutinib  rituximab-chemotherapy unless relapsing within six months of rituximab-based therapy or on maintenance rituximab.  chemotherapy options are CHOP, CVP, bendamustine, bortezomib.

Younger fit patients following previous transplant should be offered allogeneic transplant.

Options for more frail patients are CVP-R, chlorambucil, steroids, IFRT for local disease control.

It should be noted that temsirolimus and lenalidomide have proven efficacy in relapsed disease but are not approved for funding at time of writing.

9 Marginal zone lymphoma The following tests should be performed:  FBC, U&Es, creat, LFTs, calcium, LDH, Igs and serum electrophoresis  CT scan neck, thorax and abdomen  There is no role for PET-CT scan  Bone marrow aspiration and trephine biopsy where the findings are likely to influence management i.e symptomatic advanced stage disease  For gastric MALToma H. pylori serology or breath tests if not demonstrated histologically

9.1 Gastric MALToma Surgery should be avoided unless required to control bleeding or repair perforation.

Initial treatment for stage IE disease should be antibiotic H.pylori eradication therapy followed by repeat gastroscopy and rebiopsy every six months for two years. Note it may take up to 12 months for disease to regress completely. The efficacy of H.pylori eradication should be checked and repeat or second line antibiotics given if required. Note that the presence of the MALT-1 gene rearrangement confers relative resistance to antibiotic therapy alone but does not influence initial management at present.

Treatment of persistent or recurrent localised disease should be IFRT.

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Treatment of more advanced stages or recurrent or persistent disease where RT is not feasible should be treated as for follicular lymphoma. Note that fludarabine-based regimens have demonstrable efficacy in MALTomas. After two years gastroscopy should only be performed if symptomatic.

9.2 MALToma at other sites Stage IA/IIA may be treated with IFRT. Observation is another option depending on the site of disease.

Asymptomatic patients with more advanced stages without large volume disease should be observed.

Symptomatic or patients with advanced stage, and relapsed patients should be treated as for follicular lymphoma.

9.3 Systemic Marginal zone lymphoma This includes Waldnestrom’s macroglobulinaemia (lymphoplasmacytic lymphoma with paraprotein at any concentration accoriding to WHO definition), lymphoplasmacytic lymphoma, systemic marginal zone lymphoma, nodal marginal zone lymphoma, splenic marginal zone lymphoma. The following tests should be performed:  FBC, DCT, film to look for cold agglutination, U&Es, creat, LFTs, calcium, LDH, Igs/serum electrophoresis/band quantitation, Beta-2-microglobulin  Plasma viscosity if there are hyperviscosity symptoms or ad very high IgM level  Bone marrow aspiration with flow cytometry, and trephine biopsy  Hepatitis B, C serology  Consider CT scan neck, thorax and abdomen if there is large volume lymphadenopathy, clinical suggestion of abdominal or thoracic masses. However, presentation with marrow infiltration and low volume lymphadenopathy is more common and CT scan may not be helpful in assessing response.  MRI scan for assessment of disease in the oropharynx and Waldeyer’s ring, sinuses and nasal cavity, and paraspinal areas where there is a suspicion of spinal cord compromise  PET-CT scan is not indicated – this form of low grade lymphoma is often FDG inavid  Anti-MAG antibodies and neurology referral for nerve conduction studies if there is neuropathy

Remission status assessment will depend on the presenting features but paraprotein quantification will often be sufficient where there was a significant band.

9.3.1 Stage IA, non-bulky disease

Consider IFRT or observation alone if there is likely to e significant treatment-related toxicity.

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9.3.2 Advanced stage disease Consider splenectomy to relieve mechanical symptoms or hypersplenism where splenomegaly is the dominant clinical finding and there is no or only a low level of marrow infiltration. Plasma exchange for hyperviscosity symptoms Treatment should be with chemotherapy and rituximab. The choice of chemotherapy will depend on age, comorbidity, performance status, eligibility for future stem cell transplantation and the presence of neuropathy. Chemotherapy options are CVP, bendamustine, fludarabine, cyclophosphamide-dexamethasone (CD), FC, chlorambucil. If there is severe pancytopaenia due to heavy marrow infiltration or the patient is unfit for cytotoxic therapy consider single agent rituximab.

9.3.3 Relapsed and refractory disease Rebiopsy should be performed if there is clinical suspicion of high grade transformation. Treatment should be rituximab-chemotherapy. This applies to rituximab naïve patients and to those with previous rituximab exposure where a response has been maintained for at least six months. The choice of treatment will depend on several factors including age, performance status and cardiac function, comorbidity, initial treatment and duration of response, potential for high dose therapy at this point or in the future.  The initial chemotherapy may be repeated if there was previously a good and prolonged response  CVP-R or chlorambucil-R  Bendamustine-R  CD-R  Bortezomib-R  Fludarabine-based treatment, either F-R or FC-R (avoid if potential transplant candidate)  R-CHOP x 6 especially if consolidation with autologous or allogeneic stem cell transplant is being considered  Autologous or allogeneic stem cell transplant where the duration of remission has been short and the patient is younger and lacks significant comorbidity  Single agent rituximab is an option if the patient may not tolerate cytotoxic therapy  Palliative chlorambucil or low dose etoposide +/- steroids where patients are heavily treated or frail and unlikely to tolerate other therapies IFRT should be considered for localised relapse or where relapse is dominated by disease at a localised site.

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10. Follow up of Hodgkin’s and non-Hodgkin’s lymphoma There is little evidence to support the use of any follow up strategy. The available evidence (for Hodgkin’s lymphoma) shows that in the majority of relapses symptoms or signs are first reported by the patient. There is no evidence to support the use of routine surveillance imaging. Patients with high grade and Hodgkin’s lymphoma in first complete remission should be followed up for three years from completion of treatment. Since patients with low grade and mantle cell lymphoma will eventually relapse lifelong follow up should generally be offered. However, individual circumstances should be considered e.g older, frail patients, or patients in continuing remission 3-5 years after RT for localised disease can be discharged. Follow up should be every three months of the first year, every 4 months for the second, every six months thereafter. Patients who have undergone stem cell transplantation should be followed up indefinitely.

Follow up should primarily involve clinical assessment. Although there is no evidence to support the use of routine blood tests in monitoring the following tests may be appropriate at each visit: FBC, (and ESR for Hodgkin’s lymphoma), U&Es, creatinine. LFTs, calcium and LDH (+ immunoglobulins for marginal zone lymphoma with paraproteinaemia).

On discharge the potential late effects of treatment must be reviewed with the patient and their GP. Measures to potentially reduce late effects e.g smoking cessation, avoidance of sun exposure, lifestyle adjustment to limit cardiac effects, must be reiterated. GPs should be advised of the risk of late second malignancies, cardiac and pulmonary complications. They must also be aware of the need to monitor thyroid function following neck irradiation – hypothyroidism may occur up to 30 years after treatment.

Women treated with mediastinal radiotherapy before the age of 35 years must be offered entry into the breast cancer National Notification Risk Assessment and Screening programme.

On discharge patients must be given the details of the Clinical Nurse Specialist to contact if they have any concerns.

Patients with Hodgkin’s lymphoma must receive irradiated blood products for life.

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Appendices

Appendix 1: German Hodgkin’s Lymphoma Study Group and EORTC Staging of Hodgkin’s Lymphoma

EORTC GHSG Risk factors; A: Bulky mediastinal mass A: Bulky mediastinal mass B: Age >=50yrs B: Extranodal disease C: Raised ESR C: Raised ESR D: >= 4nodal involved regions D: >= 3 involved nodal regions

Raised ESR means >50mm/hr without B symptoms, > 30mm/hr with B symptoms

Treatment Groups Early favourable CS I-II, no risk factors CS I-II with no risk factors

Early unfavourable CS I-II, 1 risk factor CS I, CS IIA with 1 risk factor (intermediate) CS IIB with C/D but without A/B

Advanced CS III-IV CS IIB with A/B; CS III-IV

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Appendix 2: Hasenclever score for advanced Hodgkin’s lymphoma Prognostic factors are: male, >45yrs, stage IV disease, Hb <10.5, albumin<40, lymphs <0.6 or < 8% WBCs, WBC > 15

IPI % cases DFS 5yrs OS 5yrs 0 7 84 89 1 22 77 90 2 29 67 81 3 23 60 78 4 12 51 61 5+ 7 42 56 For grouped IPIs 0 or 1 29 79 90 >=2 72 60 74 0-2 58 74 86 >=3 42 55 70 0-3 81 70 83 >=4 19 47 59

Appendix 3: Predictive factors in Hodgkins’ lymphoma at relapse in patients undergoing autologous stem cell transplantation (Moskowitz C et al. Blood 2001)

Risk factors are remission duration < 1 year, extranodal disease, B symptoms

Risk factors EFS 5yrs

0 - 1 83% 2 27% 3 10%

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Appendix 4: IPI and age-adjusted IPI for diffuse large B-cell lymphoma (Shipp et al, NEJM 1993)

Risk factors: age > 60yrs, stage III/IV, raised LDH, ECOG >=2, > 1 site of extranodal disease.

For age-adjusted IPI (more predictive in patients <60ys): stage III/IV, raised LDH, ECOG>=2

IPI and age-adjusted IPI all ages age <60yrs low risk 0-1 0 low-intermediate risk 2 1 high-intermediate risk 3 2 high risk 4-5 3

Overall survival at 5 years according to IPI low 73% 83% low-intermediate 51% 69% high 43% 46% high-intermediate 26% 32%

Appendix 5: Second line age adjusted IPI in relapsed diffuse large B-cell lymphoma in the prediction of outcome for autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma (Hamlin et al, Blood 2003)

Relapsed DLBCL, all treated with ICE. Age adjusted IPI calculated at initiation of second line therapy

Risk factors: LDH, stage III/IV, performance status (ECOG≥ 2)

Factors PFS OS 0 Low 70% 74% 1 Intermediate 39% 49% 2-3 High 16% 18%

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Appendix 6: Peripheral T-cell lymphoma prognostic score (Gallamini A et al, Blood 2004) 385 patients treated, CHOP in 78%, auto/alloBMT in 12%.

Relapse risk Age >60yrs 1.73 LDH > normal 1.90 BM involvement 1.45 ECOG ≥2 1.71

No. factors 5yr OS 10yr OS O 62.3% 54.9% 1 52.9% 38.8% 2 32.9% 18% ≥ 3 18.3% 12.6%

Compare this with the IPI as for DLBCL in the same group of patients

5yr OS 10yr OS Low 58.9% 50% Low-int 45.6% 32.3% High-int 39.7% 29.8% High 18.3% 9.1%

Appendix 7: FLIPI scores in follicular lymphoma Risk factors are: >60yrs, Hb < 12, stage III/IV, >4 nodal sites, raised LDH

IPI %age of patients 10yr overall survival Low (0-1 factor) 36% 70.7%

Intermediate (2 factors) 37% 51%

High ( 3 factors) 27% 35.5% Nodal areas in the FLIPI Score (bilateral disease =2 points)

Cervical: Preauricular, upper cervical, median or lower cervical, posterior cervical, supraclavicular Mediastinal: Paratracheal, mediastinal, hilar, retrocrural Axillary: Mesenteric: Coeliac, splenic, hepatic, portal, mesenteric Para-aortic: Para-aortic, common iliac, external iliac Inguinal: Inguinal, femoral Other: Epitrochlear, popliteal

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FLIPI-2 score (Federico et al, 2009): 827 newly diagnosed patients treated for follicular lymphoma: 559 had rituximab, 49% had CHOP/CHOP-like chemo (73% of these with R), 8% had CVP (40% of these with R), 25% had fludarabine-based (71% with R), 4% had HD therapy. Median follow up 38 months. Excluded patients managed with ‘watchful waiting’

Risk factors: High beta-2 microglobulin, BM involvement, longest diameter of involved node >6cm, Hb < 12, age > 60yrs

FLIPI-2 (all) N % PFS 3yrs OS 3yrs

Low risk (0 factors) 20% 20% 91% 99%

Intermediate risk (1-2 factors) 53% 69% 96%

High risk (3-5 factors) 27% 51% 84%

FLIPI -2 (treated with R)

Low risk (O factors) 89%

Intermediate risk (1 factor) 73%

High risk (3-5 factors) 57%

Appendix 8: Definitions of low volume disease in advanced follicular lymphoma 1. By GELF criteria low volume excluded if any of these are present: Involvement of >= 3 nodal sites each with a diameter of >3c, Any nodal or extranodal mass with diameter >=7cm B symptoms Splenomegaly Pleural effusions or ascites Cytopenias i.e WBC <1.0, platelets < 100 Leukaemia i.e > 5.0 circulating malignant cells

2. NCRI criteria in the ‘watch and wait’ trial: Normal LDH Largest nodal mass < 7cm No more than 3 nodal sites with a diameter of 3cm or more No significant serous effusions clinically or on CT scan Splenomegaly <=16cm on CT scan

Author Dr MP Macheta

Ratified by LSCCN Haematology 15th March 2015 NSSG

Review date: March 2016

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