Myeloproliferative neoplasms Management of essential thrombocythemia, polycythemia vera, myelofibrosis: a practical approach and future directions
C.N. Harrison ABSTRACT The discovery of the JAK2 V617F mutation, and other molecular abnormalities underlying the Haematology and Oncology, Philadelphia negative myeloproliferative neoplasms (MPN) triggered an explosion of interest and data Guy's and St Thomas' NHS in the field. At the time of the initial description of JAK2 V617F in 2005, results from two major clinical Foundation Trust, studies (ECLAP and PT-1) were also published and contributed important clinical insights. In the sub - Guy's Hospital, sequent nine years, our understanding with regard to pathogenesis, and the development of therapeu - London, UK tic strategies for these seemingly straightforward conditions has further expanded, and there is now a completely new therapeutic paradigm, especially for patients with myelofibrosis, but also increas - ingly those with essential thrombocythemia and polycythemia vera. This article focuses upon treat - Correspondence: ment strategies for the MPNs, and reviews risk stratification and standard therapies for these diseases, Claire N. Harrison with a detailed focus upon contentious areas. E-mail: [email protected] Learning goals At the conclusion of this activity, participants should: Hematology Education: - appreciate the importance of achieving an accurate diagnosis in MPN; the education program for the - understand current management strategies in PV and ET, including when to use cytoreductive ther - annual congress of the European apy; Hematology Association - understand the benefits of JAK inhibition in MF but also the potential toxicities; - be able to appreciate the need for novel therapies in MPN but that their use, particularly for ET and 2014;8:265-274 PV, will require long-term studies with clinically meaningful benefits and solid health economic data.
Introduction for this entity. The entity of pre-fibrotic fibro - sis remains controversial, and further interna - tional collaboration and educational efforts are Exponential expansion in our knowledge of 4 the pathogenesis of myeloproliferative neo - underway to improve this aspect. plasms (MPN) has occured and a growing breadth of therapeutic options are available. Management of essential thrombo - Treatment strategies for MPN vary from cythemia and polycythemia vera watchful wait, aspirin, venesection to allo - geneic stem cell transplant (alloSCT) or the These patients benefit from aggressive risk choice of an expanding and perhaps bewilder - 1 management for vascular disease. Aspirin is ing number of clinical trials. This article on widely used, but whilst there is evidence from treatment strategies for these conditions con - the ECLAP study for this strategy in PV, 5 this siders first essential thrombocythemia (ET) remains controversial in ET, 6 and bleeding is a and polycythemia vera (PV), and then risk particularly for patients with significant ¥ 9 myelofibrosis (MF), incorporating both pri - thrombocytosis (>1000 10 /L) but may occur mary and secondary to ET or PV (i.e. PMF, at lower platelet counts too. The target for PET-MF, PPV-MF, respectively). The natural venesection in PV has been controversial and starting point for each of these discussions is was based upon a small series of patients in an the need to achieve an accurate diagnosis; a elegantly conducted but old study. 7 The potential diagnostic algorithm is shown in ECLAP study concluded that evidence for the Figure 1. For the MPN exclusion of reactive target of 0.45 was not found, 8 but the recently states (see footnote to Figure 1) has been sim - reported CYTO PV study strongly supports plified with the utilization of specific molecu - control of the hematocrit to below at least lar abnormalities, as exemplified by the recent 0.45, though, importantly, there were differ - description of Calreticulin (CALR) ences in the leukocyte counts of the two arms 2,3 mutations. Having excluded a reactive disor - of this study which may have accounted for der, it is ideal to use as much diagnostic infor - some of the 44% reduction in risk of thrombo - mation as possible to be able to assign the sis. 9,10 An unanswered dilemma which arises in patient to a particular category of MPN, since, clinical practice is whether to control the although an MPN unclassified (MPN U) cate - hematocrit of a patient with a diagnosis of ET gory exists, there is insufficient information to who has the JAK2 V617F mutation and whose make robust management recommendations hematocrit is above 0.45 but ostensibly nor - Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 265 | 19 th Congress of the European Hematology Association
mal, and whether greater use of the red cell mass may be for this purpose (Table 1 and summarized in 15,16 ). For required. The discovery of the CALR mutations may ulti - patients with ET, the recently described International mately result in the adoption of different treatment sched - Prognostic Scores for ET (IPS ET) 17,18 can separate ules for patients with CALR mutated compared with JAK2 patients for both overall survival and thrombosis risk. mutated disease, although there is no evidence for this at However, this score reclassifies a significant number of present. Nor is there any evidence to support managing previously high- and low-risk patients, and generates a patients with a JAK2 exon 12, MPL exon 10 mutation or large intermediate risk category for which no treatment patients with high or low JAK2 V617F allele burdens dif - algorithm has been tested. Indeed the intermediate-risk ferently either. patient group in ET is controversial and variably defined. Data from the ongoing PT-1 trials will describe the benefit of aspirin versus aspirin plus hydroxycarbamide (HU) for When to consider cytoreductive therapy in poly - an intermediate-risk group defined by age 40-60 years cythemia vera and essential thrombocythemia, and with no high-risk (age <60 years, no prior thrombosis, ¥ 9 which agent to use platelets <1500 10 /L) nor cardiovascular risk factors. High-risk PV has in the past been less well defined than Cytoreductive therapy in ET and PV is used to reduce ET, but a recent international collaboration has improved the risk of thrombosis, control disease-related symptoms this situation. Here, adverse points were assigned to and, where possible, reduce the risk of progression. Since age 67 years or over (5 points), age 57-66 years (2 points), ¥ 9 thrombosis is the most commonly encountered complica - leukocyte count 15 10 /L or over (1 point) and venous tion, it is the most rational factor upon which to base risk thrombosis (1 point), to inform a prognostic model that stratification; a number of schemes have been proposed included low-risk (0 points), intermediate-risk (one or 2
Figure 1 Schematic of diagnostic algorithm for MPN.
Causes of erythrocytosis other than PV: chronic hypoxia, lung disease, hypopnea, high altitude, congenital cyanotic heart disease, defective oxygen transport, high-affinity hemoglobins, red cell metabolic defects (low 2,3-DPG) methemoglobinemia, heavy smoking (carboxyhemoglobinemia), renal tumors, cystic/polycystic kidney disease, renal transplantation, renal hypoxia (e.g. renal artery stenosis), cerebellar hemangioma, hepato - cellular carcinoma, administration of androgenic steroids, Cushing syndrome, Conn syndrome, pheochromocytoma (rarely), Bartter syndrome. Causes of thrombocytosis other than ET: iron deficiency, blood loss (acute or chronic), hyposplenism/splenectomy, surgery, acute bacterial infection, sepsis (e.g. pneumonia), septicemia, meningitis, diverticular abscess, etc., chronic inflammation (e.g. vasculitides), inflammatory bowel disease, connective tissue disorders, rheumatoid arthritis, malignancies. Causes of fibrosis other than PMF: hematologic malignancies (e.g. chronic myeloid leukemia), acute myelofibrosis (AML M7), myelodysplasia, myeloma, hairy-cell leukemia, non-Hodgkin lymphoma, Hodgkin disease, systemic mastocytosis, metastatic carcinoma, infections (e.g. tuberculosis, leishmaniasis), drugs/toxins (e.g. benzene, thorotrast), irradiation, bone disease (e.g. Paget disease), osteoporosis, hyperparathyroidism, hypoparathyroidism, inflammatory diseases (e.g. systemic sclerosis), systemic lupus erythematosis, grey platelet syndrome.
| 266 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 points) and high-risk (≥3 points or more) categories with JAK2 V617F allele burden, 22 and for ET, the presence of median survival of 26, 15, and 8.3 years, respectively. 11 the CALR seem to correlate with better prognosis and This study also identified the contribution of abnormal lower risk of thrombosis. 3,23,24 karyotype to prognosis but it was not included in the final Choice of cytoreductive therapy for ET and PV is rela - score due to the lower numbers of patients tested. tively limited and a better evidence base is desirable. Any novel markers for thrombosis risk or survival Current published recommendations are summarized in should be robust and easily measurable. Current candi - Table 2. 13,25 Interferon-alpha (IFN) and HU are the main - dates include the leukocyte count, 11,19 reticulin grade, 20-22 stay of therapy and there is an ongoing interest in IFN,
Table 1. Risk stratification of polycythemia vera, essential thrombocytopenia and primary myelofibrosis patients.
POLYCYTHEMIA VERA Conventional risk stratification 1 High risk PV - ANY ONE of the following: Age >60 years Previous documented thrombosis, erythromelagia (if refractory to aspirin) Platelets > 1000x10 9/L* Diabetes or hypertension requiring pharmacological therapy* Significant (i.e. >5 cm below costal margin on palpation) or symptomatic (pain, early satiety) splenomegaly. Low-risk PV Patients not having any of the above risk factors. N.B. This may be an indication for treatment rather than a risk factor per se.* International polycythemia vera study stratification. 11 Risk factors (weight) Age ≥67 years (5 points) Age 57-66 years (2 points) Leukocyte count ≥15x10 9/L (1 point) Venous thrombosis (1 points), Abnormal karyotype (identified but no weight) Risk categories Low-risk (sum of scores 0 points) Intermediate-risk (sum of scores 1 or 2 points) High-risk (sum of scores ≥3 points)
ESSENTIAL THROMBOCYTHEMIA Conventional risk stratification 2 High risk ET - ANY ONE of the following factors Age >60 years Platelet count >1500x10 9/L Previous thrombosis, erythromelagia (if refractory to aspirin) Previous hemorrhage related to ET Diabetes or hypertension requiring pharmacological therapy* Low-risk ET** Patients under 40 years lacking any of the above markers of high-risk disease
Intermediate risk ET** patients 40-60 years lacking any of the above markers of high-risk disease International Prognostic Score for ET - IPSET A novel risk stratification based upon histopathologically defined ET3
Risk factors Age ≥60 years (2 points) Leukocyte count ≥11x10 9/L (1 point) Prior thrombosis (1 point) Risk categories were Low (sum of scores = 0) Intermediate (sum of scores = 1 or 2) High (sum of scores = 3 or 4)
1Predicts thrombosis but not tested prospectively; 2Predicts thrombosis; 3Predicts thrombosis and overall survival but not ET-MF. *These risk factors are more controversial and have not been fully agreed, e.g. what degree of leukocytosis or grade of reticulin. **These categories are contentious and some recommend low- and high-risk only, or classify individuals with cardiovascular risk factors as intermediate-risk.
Continued on next page
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 267 | 19 th Congress of the European Hematology Association
especially pegylated forms, due to a potential disease pies may be attractive. Options for management in the face moderating effect. Pioneering studies with IFN were of HU resistance would include adjusting therapeutic tar - reported by Silver in 1988. 26 Subsequently, reports of both gets (e.g. to a platelet count of 600x10 9/L) or to switch to high levels of complete hematologic response rates, and an alternative agent either alone or in combination. In this good tolerance of Pegasys ( Peginterferon alfa-2a ), partic - regard, it is important to consider that HU, when used with 27-29 ularly when started at low doses. Of note, there appears or succeeded by agents such as busulfan, will significantly to be preferential targeting of the JAK2V617F mutated increase long-term risks of leukemia. For this reason, non- 30 clone in this context. Pegasys may, therefore, be effec - leukemogenic agents such as IFN or anagrelide are more tive when other therapies have failed or not been tolerated, appropriate in this setting. 15 and it may challenge the position of hydroxyurea (HU) as first-line therapy. The answer will require large random - ized trials with comprehensive evaluation for long-term Impact of JAK inhibitors and other novel therapies side-effects and late disease-related complications; such trials are currently underway. A further novel formulation A significant number of JAK inhibitors are now at vary - of IFN is also of interest in this context with provisional ing stages of clinical evaluation with most data available results approximately equivalent to that for other formula - for patients with myelofibrosis (see below). There is infor - tions of IFN; 25,31 a phase III clinical study (PROUD-PV) mation supporting their ability to control myeloprolifera - with this agent opened in 2013. tion in patients with PV and ET but not yet to prevent Regarding treatment targets, European LeukemiaNet has thrombosis or affect the probability of accelerated/more produced consensus criteria for response; these are designed aggressive disease. The study by Moliterno and colleagues for clinical trials and include reference to bone marrow mor - who treated 39 patients (n=12 ET, n=27 PV) with CEP 701 36 phology and molecular markers. 32 The same group also pro - (Cephalon) is salutary. Here, marked gastrointestinal duced criteria for resistance or intolerance to HU 33,34 which side-effects occurred, and whilst there were responses in provide useful guidance, although these could perhaps be splenomegaly, pruritus, and phlebotomy requirements broadened to include thrombotic events and persistence of (after 6 months), treatment was not associated with a disease-related symptoms despite therapy. reduction in either leukocytosis or thrombosis, and five The phenomenon of HU resistance is important and thrombotic events occurred on therapy. In an initial report identifies a group of patients with a poor prognosis 35 who of the study using ruxolitinib in 39 ET and 34 PV patients, require a change of treatment and for whom novel thera - there were similar rates of reduction of splenomegaly and
Table 1. Continued from previous page.
PRIMARY MYELOFIBROSIS IPSS prognostic score 12 Prognostic variables 01 Age in years < 65 > 65 WBC count x10 9/L < 25 > 25 Hemoglobin g/dL <10 Peripheral blast % < 1 > 1 Constitutional symptoms No Yes Risk assignment: Low = 0, Intermediate 1 = 1, Intermediate 2 = 2 High = 3+. Median survivals are 135, 95, 48 and 27 months, respectively.
DIPSS prognostic score 13 Prognostic variables 012 Age in years < 65 > 65 WBC count x10 9/L < 25 > 25 Hemoglobin g/dL <10 Peripheral blast % < 1 > 1 Constitutional symptoms No Yes Risk assignment: Low = 0; Intermediate 1 = 1 or 2; Intermediate 2 = 3 or 4; High = 5 or 6. Median survival: not reached, 14.2, 4, and 1.5 years, respectively. DIPSS plus prognostic score 14 Points from DIPSS 0123 DIPSS prognostic group points Low-risk 0 Intermediate-1 Intermediate-2 2 High-risk 3 To the DIPSS prognostic group add one point each for Platelet count x10 9/L < 100 Red cell transfusion required No Yes Unfavorable karyotype* No Yes Risk assignment number of points: Low = 0; Intermediate 1 = 1; Intermediate 2 = 2 or 3; High = 4 to 6. Corresponding median survival estimates: 185, 78, 35 and 16 months. *Unfavorable karyotype includes +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-. 11q23 rearrangements and complex karyotypes.
| 268 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 symptom scores, but here all patients achieved leukocyte tory agents. 43,44 There are several prognostic scores to sup - counts less than 10x10 9/L, and 41% achieved CR with port the management of MF. These include the platelets less than 400x10 9/L; no thrombotic events were International Prognostic Scoring System (IPSS), and dur - reported. 37 This study was up-dated, but only for the PV ing the course of disease, dynamic IPSS (DIPSS) and cohort 38 who received ruxolitinib for a median 152 weeks; DIPSS plus. However, these have only been validated only hematocrit less than 45% without phlebotomy was for PMF. 12-44 DIPSS plus, which incorporates karyotype, achieved in 97% by week 24 with only one patient requir - permits the identification of particularly both low- and ing a phlebotomy after week 4. Among patients with pal - high-risk patients when compared with the IPSS or pable splenomegaly at baseline, 44% and 63%, respective - DIPSS. A likely modification to these scores will incorpo - ly, achieved non-palpable spleen at weeks 24 and 144. rate screening for mutations in the following genes: Improvements in pruritus, night sweats, and bone pain ASXL1 , EZH2 , IDH1/2 , and SRSF2 (that were associated were observed within four weeks and maintained with with worse survival outcomes with a greater likelihood of continued treatment. Thrombocytopenia of grade 3 or transformation to acute leukemia in a recent study) or over, or anemia of grade 3 or over occurred in 3 patients indeed CALR with ASXL 1. 45-47 At present, however, each (9%) (1 patient had both) and were managed with screening for such mutations is neither routine practice nor dose modification. Two large phase III commercially incorporated into prognostic scores. sponsored studies of ruxolitinib are fully recruited and the The most common cause of death for patients with MF results are awaited. There is one ongoing academic study is acute myeloid leukemia (20%). However, most patients of ruxolitinib in ET and PV patients resistant or refractory die from other disease-related events, such as progression to HU. without transformation, severe constitutional symptoms Meanwhile, HDAC inhibitors such as vorinostat 39 and and cachexia, portal hypertension, and thrombotic or car - givinostat 40,41 have been used in ET/PV patients though diovascular events. 12 toxicities are variable, and for vorinostat, lead to high dis - continuation rates. The oral telomerase inhibitor imetelstat JAK inhibitors for the treatment of myelofibrosis: was investigated in ET, demonstrating molecular respons - es but also significant rates of hematologic toxicity. 42 current data Further studies of sufficient duration to permit the evalua - tion of the safety and efficacy of this and other novel Ruxolitinib is the first JAK inhibitor to gain approval; agents are certainly needed. To receive reimbursement, this followed phase III trials known as the Controlled any novel agents in PV and ET need studies incorporating Myelofibrosis Study with Oral JAK Inhibitor Treatment health economics assessments and long-term safety, and (COMFORT) trials. These included MF patients with biologically meaningful end points beyond control of intermediate-2– or high-risk disease as assessed by IPSS, blood counts are likely to be required. splenomegaly (5 cm minimum below the costal margin) and platelet count more than 100x10 9/L. 48,49 The COM - FORT trials also demonstrated that, in addition to the pro - Management of myelofibrosis found effects on splenomegaly, ruxolitinib provided statis - tically significant and very rapid improvements in Until recently, therapeutic options for patients with MF, patients’ symptoms and quality of life. Increasingly these including PMF, PPV- and PET-MF, consisted of allogeneic trials also provide strong evidence for a survival benefit hematopoietic stem cell transplantation (alloHSCT), associated with ruxolitinib therapy, at least in the popula - cytoreductive agents, splenectomy or splenic irradiation, tion of patients matching those from the COMFORT trials. and management of anemia with transfusions, erythro - In analyses reported at ASH 2013, the survival benefit poiesis-stimulating agents, androgens, or immunomodula - across both studies was assessed in the pooled patient pop -
Table 2. Recommendations for therapy in essential thrombocytopenia and polycythemia vera.
POLYCYTHEMIA VERA - ALL patients assess for and manage cardiovascular risk factor; screen for disease-related symptoms - TREAT WITH low-dose aspirin (unless contraindicated); venesection to target PCV 0.45. - HIGH-RISK PATIENTS* >60* years hydroxycarbamide or interferon second-line consider clinical trial or interferon**, if >75 years busulfan or 32P <60* years interferon** second-line consider clinical trial or hydroxyurea, or anagrelide**, *** ESSENTIAL THROMBOCYTHEMIA - ALL patients assess and manage cardiovascular risk factor; screen for disease-related symptoms - TREAT WITH low-dose aspirin (unless contraindicated). - HIGH-RISK PATIENTS* >60* years hydroxycarbamide second-line consider clinical trial or interferon**, anagrelide*** alone or in combination; if > 75 years busulfan or 32P**** - <60* years hydroxycarbamide or interferon** second-line consider clinical trial; line interferon**, anagrelide*** alone or in combination
*Treatment recommendations made for high-risk patients only, high-quality clear evidence for low- or intermediate-risk ET or PV management is unclear. **Not currently licensed for this indication. ***Current British Guidelines recommend regular monitoring of patients treated with anagrelide for the development of fibrosis.13,25 ****Rarely used and associated with significant risk of AML.
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 269 | 19 th Congress of the European Hematology Association
ulation; the effect of cross-over was accommodated using Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or the Rank-Preserving Structural Failure Time (RPSFT) Post-Essential Thrombocythemia Myelofibrosis; PER - analysis. Here, the hazard ratio for survival for ruxolitinib SIST-1) and recruitment is going well. versus control (placebo + best available therapy) was 0.65 Momelotinib (CYT387): a JAK1/JAK2 inhibitor, has (95%CI: 0.46-0.90; P=0.01) and for ruxolitinib versus completed evaluation in a phase I/II trial of patients with control (RPSFT-corrected for cross-over) it was 0.29 MF. The striking and potentially unique aspect of this ther - (95%CI: 0.13-0.63). 50 Intriguingly, this pooled analysis apy is that transfusion dependence appears to be amelio - across the COMFORT studies suggests that incrementally rated. For example, 49 of 72 transfused patients at baseline larger spleen volume is associated with worse outcome; achieved transfusion independence for at least 12 weeks, for every 5 dL of spleen volume risk of death increased by and median duration of transfusion independence/anemia 9%. This is the first link between spleen size and progno - response was not reached. 58 A phase III study of momelo - sis. Survival advantage showed a weak correlation with tinib is under way, and it will be important to determine degree of spleen response to ruxolitinib only to the same whether these encouraging results are confirmed in this degree as did female sex, higher hemoglobin, platelet setting. count and PET or PPV-MF versus PMF. A comparison Other JAK inhibitors: these include BMS-911543 59 and between the DIPSS cohort of patients and the COMFORT- NS-018, 60,61 and intriguingly INCB 039110 a selective II cohort demonstrated that the risk of death is halved by JAK1 inhibitor. In MF patients, this reduced symptoms in introducing ruxolitinib in the treatment of PMF patients. 51 up to 75% and in spleen volume in up to 14%. 62 Potential reasons for this survival advantage include improved performance status, reduced proinflammatory How safe is JAK inhibition? cytokines, improved nutritional status, and better overall physical functioning. Does ruxolitinib treatment result in improved survival Three important safety concerns have recently arisen due to an effect upon the underlying disease process? Only with regard to JAK inhibition: those of a ‘withdrawal syn - a modest reduction of mutant allele burden has also been drome’, neurological toxicity, and, lastly, risk of infec - reported in a proportion of the COMFORT-II ruxolitinib tions. treated patients. 52 Recent data do not clarify this, suggest - Early reports suggested an apparent risk of a severe inflammatory syndrome with poor outcome after ruxoli - ing that ruxolitinib therapy may be associated with reduc - 63 tion, stabilization or progression of marrow fibrosis in a tinib withdrawal. After three years of follow up, no con - proportion of patients. 53,54 Continued careful assessment is sistent pattern of AEs has been observed that would sug - gest a severe inflammatory syndrome after ruxolitinib dis - thus required. 52,64 Overall, from the COMFORT studies, anemia and continuation from the COMFORT trials. Nonetheless, thrombocytopenia were the most frequently reported it is important to be aware that spleen size and symptoms adverse events (AEs) with ruxolitinib treatment, Hb levels will revert to baseline (or worse if the patient has pro - reached a nadir (approx. 10% reduction) at week 12 and gressed during ruxolitinib therapy) and, therefore, careful then stabilized at an average reduction of approximately dose tapering or concomitant steroids are considered when 10 g/L below baseline at week 24, and platelet counts drop discontinuing ruxolitinib therapy. (~40%) and remain stable. Anemia and thrombocytopenia The recent withdrawal of fedratinib due to a constella - rarely led to treatment discontinuation (<1% of patients in tion of features resembling Wernicke’s encephalopathy in any treatment group) and were manageable with dose a series of patients, and of XL109 due to neurological tox - modification. Rates of grade 3/4 non-hematologic AEs icity, have raised questions as to whether this is a class were low in both COMFORT studies. However, an emer - effect, although, certainly for ruxolitinib, this seems most gent low-level signal is the risk of infection with JAK unlikely, and the compounds still in development will inhibition and we will return to this later. need to be scrutinized. It will also be important to under - stand whether there is an effect of JAK/STAT inhibition upon thiamine metabolism or critical neurological path - Other JAK inhibitors ways which rely upon JAK/STAT. Low rates of infections were noted at a slightly higher Several other JAK inhibitors are in various stages of level in ruxolitinib-treated patients from the COMFORT development. studies. However, a number of case reports have highlight - Fedratinib (SAR302503): this agent recently completed ed a number of severe infectious complications arising in a phase III study (JAKARTA-1) with positive outcome, JAK inhibitor-treated patients, including individual and a phase II study (JAKARTA-2) for ruxolitinib intoler - reports of Cryptococcus neoformans pneumonia, bilateral ant or resistant patients is fully recruited with positive toxoplasma retinitis, and Hepatitis B reactivation 65-67 and interim results. 55,56 However, its development has been one case of progressive multifocal leukoencephalopathy halted due to the development of a number of cases of (PML). 68 In the COMFORT-II study, one case of TB was Wernicke’s encephalopathy. reported and, indeed, 2 cases of TB lymphadenitis were Pacritinib (SB1518): is a JAK2 and FLT3 inhibitor, and recently reported out of 20 patients treated within a study its therapeutic use was associated with minimal myelosup - of ruxolitinib for MF in a TB endemic country. 69 Clues pression and no new onset of anemia or new transfusion regarding the potential mechanism for this comes from requirements in early clinical studies. 57 A phase III study several pieces of recently published work showing that the of pacritinib in patients with low platelets and sympto - development, activation and migration of monocyte- matic splenomegaly is currently open (Oral Pacritinib derived dendritic cell, as well as T-cell development and Versus Best Available Therapy in Patients with Primary differentiation, were significantly impaired following
| 270 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 exposure to ruxolitinib. 70-76 Whether this potential tional and/or experimental agents. However, the challenge immunomodulatory effect of JAK inhibition is a class lies in understanding how to assess the benefits of such effect or dependent upon the specificity of the inhibitor pilot approaches since observation of a survival benefit or compound needs to be elucidated and is currently being leukemia-free survival would require very large trials con - studied. ducted over a long period. Spleen volume response has almost become the standard end point in MF and may be selected as a primary end point, but other measures may be Non-JAK inhibitor therapies for MF more appropriate. Further efforts may help us to identify surrogate markers of response that could enable more In addition to JAK/STAT, other related pathways have rapid advancement in the selection of novel therapies or been found to be dysregulated in MF, and some examples combinations, e.g. allele burden, CD34 +, fibrosis grade, are discussed below. and/or other genetic signatures. Interferon: in early MF, interferon has been reported to Preliminary results in a small number of patients in induce molecular responses and improve marrow histol - 77,78 combination studies have been reported. Panobinostat ogy. combined with ruxolitinib has been well tolerated, and Everolimus: in a phase I/II study with this mTOR reductions in spleen size and improvement of MF-related inhibitor, 69% and 80% of patients experienced complete symptoms have been observed, even at doses below the resolution of systemic symptoms and pruritus, respective - therapeutic dosage of each agent as monotherapy. 94 ly. The response rate was 60% when European Ruxolitinib with Pegasys induced rapid molecular Myelofibrosis Network criteria were applied (n=8 major, response and was well tolerated. 96 An additional potential n=7 moderate, n=3 minor responses) or 23% when combination strategy is to utilize JAK inhibition to ensure IWGMRT criteria were used (n=1 partial response, n=6 79 patients are more likely to undergo alloSCT, a highly clinical improvements). attractive and logical approach since massive Panobinostat (LBH589): after 16 months of therapy splenomegaly and poor performance status are major bar - with this pan-deacetylase inhibitor one patient achieved a 80 riers to this therapy in MF. Two trials are under way, and near complete response. one of these (the JAK-ALLO study in France) recently Pomalidomide: used for anemia, pomalidomide was 81 suggested that there may be risks in using JAK inhibition successful in a phase II trial. However, the phase III trial with ruxolitinib prior to alloSCT. A preliminary report (RESUME) showed no significant transfusion independ - 82 highlighted unexpected SAEs, namely tumor lysis syn - ent response between the drug and placebo with negative drome (n=3) and cardiogenic shocks (n=3); this should be results, though some striking responses for thrombocy - carefully considered in other prospective trials and clinical topenia. practice. 97 Hedgehog signaling: there is an increasing awareness that the hedgehog signaling pathway is abnormal in hema - tologic malignancy. 83 In mouse models of myelofibrosis, Challenges ahead in the management of primary abnormalities in hedgehog signaling, as well as transform - myelofibrosis, essential thrombocythemia and poly - ing growth factor (TGF)- β1, mTOR and p53 were cythemia vera observed. 84 Improved efficacy of combinations of JAK2 and Hedgehog inhibitors was also recently reported in It is encouraging to witness the recent developments in mouse models, and a clinical trial with Erismodegib the understanding and treatment of MPN and observe the 85 (LDE225) together with ruxolitinib is ongoing. benefits that these new options can provide to patients. Lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) However, as we have seen, it will be important to assess agents: these amine oxidases catalyse crosslinking of col - the long-term safety and efficacy of new treatments. A fur - 86 lagen and elastin. Abnormal expression in MPN, in par - ther challenge in the introduction of novel therapies is ticular MF, was reported Targeting of LOXL2 with a determining both the current prevalence of disease and the 90 monoclonal antibody AB-0023, has been shown to be true societal cost of both the disease and its treatments, efficacious in rodent models of cancer, 91 and Simtuzumab which is poorly understood for MPN, and efforts should (GS-66214), a humanized version of AB-0023, 88 is consid - focus here. ered safe and well tolerated in liver disease, 92 and is cur - In terms of translational research, if the events surround - rently undergoing phase II trials in pulmonary and hepatic ing either progression in MF or transformation in post- fibrosis. ET/post-PV MF were better understood, more biologically Imetelstat: imetelstat (GRN163L), a telomerase relevant targets may be identified. Equally, a greater inhibitor, increased telomerase activity is detected in understanding of biological aspects of the disease will myelofibrosis. 93,94 Imetelstat was associated with an over - hopefully lead to better defined surrogate markers, for all response in 9 of 22 myelofibrosis patients; 4 had rever - which patients may be in need of novel therapies, and once sal of fibrosis and megakaryocyte abnormal morphology. they are on these agents, to identify which patients are These results, however, were accompanied by significant truly responding the best. myelosuppression and further data are awaited. 95
Using therapies in combination for the manage - References ment of myelofibrosis 1. Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, et al. Philadelphia-negative classical There is significant interest in improving patient out - myeloproliferative neoplasms: critical concepts and manage - comes using the combination of JAK inhibitors and tradi - ment recommendations from European LeukemiaNet. J Clin
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 271 | 19 th Congress of the European Hematology Association
Oncol. 2011;29(6):761-70. tosis on fibrotic or leukemic disease transformation and vascu - 2. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, lar complications. Leukemia. 2010;24(9):1574-9. Wedge DC, et al. Somatic CALR mutations in myeloprolifer - 23. Rumi E, Harutyunyan AS, Pietra D, Milosevic JD, Casetti IC, ative neoplasms with nonmutated JAK2. N Engl J Med. Bellini M, et al. CALR exon 9 mutations are somatically 2013;369(25):2391-405. acquired events in familial cases of essential thrombocythemia 3. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi or primary myelofibrosis. Blood. 2014 Feb 19 [Epub ahead of E, Milosevic JD, et al. Somatic mutations of calreticulin in print] myeloproliferative neoplasms. N Engl J Med. 2013;369(25): 24. Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi 2379-90. A, Pieri L, et al. Impact of Calreticulin Mutations on Clinical 4. Barbui T, Thiele J, Vannucchi AM, Tefferi A. Problems and and Hematological Phenotype and Outcome in Essential pitfalls regarding WHO-defined diagnosis of early/prefibrotic Thrombocythemia. Blood. 2013 Dec 26 [Epub ahead of print] primary myelofibrosis versus essential thrombocythemia. 26. Silver RT. Recombinant interferon-alpha for treatment of Leukemia. 2013;27(10):1953-8. polycythaemia vera. Lancet. 1988;2(8607):403. 5. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, 27. Gowin K, Thapaliya P, Samuelsson J, Harrison C, Radia D, Patrono C, et al. Efficacy and safety of low-dose aspirin in Andreasson B, et al. Experience with pegylated Interferon polycythemia vera. N Engl J Med. 2004;350(2):114-24. alpha-2a in advanced myeloproliferative neoplasms in an 6. Harrison C, Barbui T. Aspirin in low-risk essential thrombo - international cohort of 118 patients. Haematologica. cythemia, not so simple after all? Leuk Res. 2011;35(3):286- 2012;97(10):1570-3. 9. 28. Quintas-Cardama A, Kantarjian H, Manshouri T, Luthra R, 7. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes Estrov Z, Pierce S, et al. Pegylated interferon alfa-2a yields and venous haematocrit in primary proliferative poly - high rates of hematologic and molecular response in patients cythaemia. Lancet. 1978;2(8102):1219-22. with advanced essential thrombocythemia and polycythemia 8. Di Nisio M, Barbui T, Di Gennaro L, Borrelli G, Finazzi G, vera. J Clin Oncol. 2009;27(32):5418-24. Landolfi R, et al. The haematocrit and platelet target in poly - 29. Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, cythemia vera. Br J Haematol. 2007;136(2):249-59. Roussel M, et al. Pegylated interferon-alfa-2a induces com - 9. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, plete hematologic and molecular responses with low toxicity Cilloni D, et al. Cardiovascular events and intensity of treat - in polycythemia vera. Blood. 2008;112(8):3065-72. ment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. 30. Kiladjian JJ, Masse A, Cassinat B, Mokrani H, Teyssandier I, 10. McMullin MF, Harrison CN, Kiladjian JJ. Treatment target in le Couedic JP, et al. Clonal analysis of erythroid progenitors polycythemia vera. N Engl J Med. 2013;368(16):1554-5. suggests that pegylated interferon alpha-2a treatment targets 11. Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, JAK2V617F clones without affecting TET2 mutant cells. Rodeghiero F, et al. Survival and prognosis among 1545 Leukemia. 2010;24(8):1519-23. patients with contemporary polycythemia vera: an internation - 31. Gisslinger H, Buxhofer-Ausch V, Greil R, Thaler J, Schloegl al study. Leukemia. 2013;27(9):1874-81. E, Gastl GA, et al. Analysis Of Molecular Responses and 12. Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Chromosomal Aberrations In Patients With Polycythemia Morra E, et al. New prognostic scoring system for primary Vera Treated With Peg-Proline-Interferon Alpha-2b myelofibrosis based on a study of the International Working (AOP2014/P1101) In The Peginvera Study. Blood. 2013;122 Group for Myelofibrosis Research and Treatment. Blood. (21):1589. 2009;113(13):2895-901. 25. Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, Wolf D, 13. Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Kralovics R, et al. Efficacy and Safety Of AOP2014/P1101, a Pereira A, et al. A dynamic prognostic model to predict sur - Novel, Investigational Mono-Pegylated Proline-Interferon vival in primary myelofibrosis: a study by the IWG-MRT Alpha-2b, In Patients With Polycythemia Vera (PV): Update (International Working Group for Myeloproliferative On 51 Patients From The Ongoing Phase I/II Peginvera Study. Neoplasms Research and Treatment). Blood. 2010;115(9): Blood. 2013;122(21):4046. 1703-8. 32. Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, 14. Gangat N, Caramazza D, Vaidya R, George G, Begna K, Lengfelder E, et al. Revised response criteria for polycythemia Schwager S, et al. DIPSS plus: a refined Dynamic vera and essential thrombocythemia: an ELN and IWG-MRT International Prognostic Scoring System for primary myelofi - consensus project. Blood. 2013;121(23):4778-81. brosis that incorporates prognostic information from kary - 33. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison otype, platelet count, and transfusion status. J Clin Oncol. C, Hasselbalch H, et al. A unified definition of clinical resist - 2011;29(4):392-7. ance and intolerance to hydroxycarbamide in polycythaemia 15. Harrison CN, Bareford D, Butt N, Campbell P, Conneally E, vera and primary myelofibrosis: results of a European Drummond M, et al. Guideline for investigation and manage - LeukemiaNet (ELN) consensus process. Br J Haemat. ment of adults and children presenting with a thrombocytosis. 2010;148(6):961-3. Br J Haematol. 2010;149(3):352-75. 34. Barosi G, Besses C, Birgegard G, Briere J, Cervantes F, 16. Passamonti F. How I treat polycythemia vera. Blood. Finazzi G, et al. A unified definition of clinical resistance/ 2012;120(2):275-84. intolerance to hydroxyurea in essential thrombocythemia: 17. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi results of a consensus process by an international working E, et al. Development and validation of an International group. Leukemia. 2007;21(2):277-80. Prognostic Score of thrombosis in World Health Organization- 35. Hernandez-Boluda JC, Alvarez-Larran A, Gomez M, Angona essential thrombocythemia (IPSET-thrombosis). Blood. A, Amat P, Bellosillo B, et al. Clinical evaluation of the 2012;120(26):5128-33; quiz 252. European LeukaemiaNet criteria for clinicohaematological 18. Passamonti F, Thiele J, Girodon F, Rumi E, Carobbio A, response and resistance/intolerance to hydroxycarbamide in Gisslinger H, et al. A prognostic model to predict survival in essential thrombocythaemia. Br J Haematol. 2011;152(1):81- 867 World Health Organization-defined essential thrombo - 8. cythemia at diagnosis: a study by the International Working 36. Moliterno AR, Hexner E, Roboz GJ, Carroll M, Luger S, Group on Myelofibrosis Research and Treatment. Blood. Mascarenhas J, et al. An Open-Label Study of CEP-701 in 2012;120(6):1197-201. Patients with JAK2 V617F-Positive PV and ET: Update of 39 19. Campbell PJ, MacLean C, Beer PA, Buck G, Wheatley K, Enrolled Patients. ASH Annual Meeting Abstracts. Kiladjian JJ, et al. Correlation of blood counts with vascular 2009;114(22):753-. complications in essential thrombocythemia: analysis of the 37. Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, prospective PT1 cohort. Blood. 2012;120(7):1409-11. Levy R, et al. Durable Responses with the JAK1/ JAK2 20. Abdulkarim K, Ridell B, Johansson P, Kutti J, Safai-Kutti S, Inhibitor, INCB018424, In Patients with Polycythemia Vera Andreasson B. The impact of peripheral blood values and (PV) and Essential Thrombocythemia (ET) Refractory or bone marrow findings on prognosis for patients with essential Intolerant to Hydroxyurea (HU). ASH Annual Meeting thrombocythemia and polycythemia vera. Eur J Haematol. Abstracts. 2010;116(21):313-. 2011;86(2):148-55. 38. Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, 21. Wilkins BS, Erber WN, Bareford D, Buck G, Wheatley K, Rumi E, et al. A phase 2 study of ruxolitinib, an oral JAK1 and East CL, et al. Bone marrow pathology in essential thrombo - JAK2 inhibitor, in patients with advanced polycythemia vera cythemia: interobserver reliability and utility for identifying who are refractory or intolerant to hydroxyurea. Cancer. disease subtypes. Blood. 2008;111(1):60-70. 2014;120(4):513-20. 22. Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, 39. Andersen CL, McMullin MF, Ejerblad E, Zweegman S, et al. A prospective study of 338 patients with polycythemia Harrison C, Fernandes S, et al. A phase II study of vorinostat vera: the impact of JAK2 (V617F) allele burden and leukocy - (MK-0683) in patients with polycythaemia vera and essential
| 272 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014
thrombocythaemia. Br J Haematol. 2013;162(4):498-508. (MF) and Platelet Counts ≤100,000/µl. Blood. 40. Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, 2013;122(21):395. Specchia G, et al. A phase II study of Givinostat in combina - 58. Gotlib J, Gupta V, Roberts AW, Wadleigh M, Sirhan S, tion with hydroxycarbamide in patients with polycythaemia Bavisotto LM, et al. Update On The Long-Term Efficacy and vera unresponsive to hydroxycarbamide monotherapy. Br J Safety Of Momelotinib, a JAK1 and JAK2 Inhibitor, For The Haematol. 2013;161(5):688-94 Treatment Of Myelofibrosis. Blood. 2013;122(21):108. 41. Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari 59. Roberts AW, Seymour JF, Burbury K, Verstovsek S, ML, Guglielmelli P, et al. A pilot study of the Histone- Kantarjian HM, Begna K, et al. BMS-911543, A Selective Deacetylase inhibitor Givinostat in patients with JAK2V617F JAK2 Inhibitor: A Multicenter Phase 1/2a Study In positive chronic myeloproliferative neoplasms. Br J Myelofibrosis. Blood. 2013;122(21):664. Haematol. 2010;150(4):446-55. 60. Ma L, Clayton JR, Walgren RA, Zhao B, Evans RJ, Smith 42. Baerlocher GM, Leibundgut EO, Ayran C, Blaney M, MC, et al. Discovery and characterization of LY2784544, a Burington B, Morfeld D, et al. Imetelstat Rapidly Induces and small-molecule tyrosine kinase inhibitor of JAK2V617F. Maintains Substantial Hematologic and Molecular Responses Blood Cancer J. 2013;3:e109. in Patients with Essential Thrombocythemia (ET) Who Are 61. Mesa RA, Salama ME, Giles JLK, Pitou C, Zimmermann AH, Refractory or Intolerant to Prior Therapy: Preliminary Phase II Price GL, et al. Phase I Study Of LY2784544, a JAK2 Results. ASH Annual Meeting Abstracts. 2012;120(21):179-. Selective Inhibitor, In Patients With Myelofibrosis (MF), 43. Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Polycythemia Vera (PV), and Essential Thrombocythemia Griesshammer M, et al. Philadelphia-negative classical (ET). Blood. 2013;122(21):665. myeloproliferative neoplasms: critical concepts and manage - 62. Talpaz M, Gupta V, Savona M, Coughlin P, Winton E, Hunter ment recommendations from European LeukemiaNet. J Clin D, et al. An Open-Label, Phase II Study Of The JAK1 Oncol. 2011;29(6):761-70. Inhibitor INCB039110 In Patients With Myelofibrosis. Blood. 44. Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, 2013;122(21):663. Duncombe A, et al. Guideline for the diagnosis and manage - 63. Tefferi A, Pardanani A. Serious adverse events during ruxoli - ment of myelofibrosis. Br J Haematol. 2012;158(4):453-71. tinib treatment discontinuation in patients with myelofibrosis. 45. Biamonte F, Pieri L, Rotunno G, Paoli C, Fjerza R, Tagliafico Mayo Clin Proc. 2011;86(12):1188-91. E, et al. Impact Of Prognostically Detrimental Mutations 64. Verstovsek S, Gotlib J, Levy RS, Gupta V, Dipersio JF, (ASXL1, EZH2, SRSF2, IDH1/2) On Outcomes In Patients Catalano JV, et al. Long-Term Outcomes Of Ruxolitinib With Myelofibrosis Treated With Ruxolitinib In COMFORT- Therapy In Patients With Myelofibrosis: 3-Year Update From II. Blood. 2013;122(21):107. COMFORT-I. Blood. 2013;122(21):396. 46. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, 65. Caocci G, Murgia F, Podda L, Solinas A, Atzeni S, La Nasa G. Pardanani A, Pereira A, et al. Mutations and prognosis in pri - Reactivation of hepatitis B virus infection following ruxoli - mary myelofibrosis. Leukemia. 2013;27(9):1861-9. tinib treatment in a patient with myelofibrosis. Leukemia. 47. Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, 2014;28(1):225-7. Mannarelli C, et al. CALR and ASXL1 mutations-based 66. Wysham NG, Sullivan DR, Allada G. An opportunistic infec - molecular prognostication in primary myelofibrosis: an inter - tion associated with ruxolitinib, a novel janus kinase 1,2 national study of 570 patients. Leukemia. 2014 Feb 5 [Epub inhibitor. Chest. 2013;143(5):1478-9. ahead of print] 67. Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis 48. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio retinitis associated with ruxolitinib. N Engl J Med. JF, et al. A double-blind, placebo-controlled trial of ruxolitinib 2013;369(7):681-3. for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 68. Wathes R, Moule S, Milojkovic D. Progressive multifocal 49. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman leukoencephalopathy associated with ruxolitinib. N Engl J R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib ver - Med. 2013;369(2):197-8. sus best available therapy for myelofibrosis. N Engl J Med. 69. Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immuno - 2012;366(9):787-98. suppressive compound: is it time for anti-infective prophylax - 50. Hagop K, Kiladjian J-J, Gotlib J, Cervantes F, Mesa RA, is? Blood. 2013;122(23):3843-4. Barosi G, et al. A Pooled Overall Survival Analysis of The 70. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, COMFORT Studies: 2 Randomized Phase 3 Trials of Kurts C, et al. The JAK-inhibitor ruxolitinib impairs dendritic Ruxolitinib For The Treatment of Myelofibrosis. Blood. cell function in vitro and in vivo. Blood. 2013;122(7):1192- 2013;122(21):2820. 202. 51. Passamonti F, Maffioli M, Cervantes F, Vannucchi A, Morra E, 71. Rudolph J, Cornez I, Brossart P, Wolf D. The JAK1/JAK2 Barbui T, et al. Impact of ruxolitinib on the natural history of Inhibitor Ruxolitinib Substantially Affects NK Cell Biology. primary myelofibrosis: a comparison of the DIPSS and the Blood. 2013;122(21):16. COMFORT-2 cohorts. Blood. 2014;123(12):1833-5. 72. Wolschke C, Alchalby H, Ayuk F, Heinzelmann M, Triviai I, 52. Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik Badbaran A, et al. The Pan-JAK Inhibitor Ruxolitinib Impairs A, Stalbovskaya V, et al. Three-year efficacy, safety, and sur - T-Cell Activation, Cytokine Production and Proliferation In vival findings from COMFORT-II, a phase 3 study comparing Vivo and In Vitro. Blood. 2013;122(21):2001. ruxolitinib with best available therapy for myelofibrosis. 73. Campanelli R, Fois G, Poletto V, Villani L, Bonetti E, Catarsi Blood. 2013;122(25):4047-53. P, et al. Decrease Of T Regulatory Cells In Patients With 53. Wilkins BS, Radia D, Woodley C, El Farhi S, Keohane C, Myelofibrosis Receiving Ruxolitinib. Blood. 2013;122(21): Harrison CN. Resolution of bone marrow fibrosis in a patient 4057. receiving JAK1/JAK2 inhibitor treatment with ruxolitinib. 74. Cornez I, Heine A, Brossart P, Wolf D. CD4+ T Cell Functions Haematologica. 2013;98(12):1872-6. Are Potently Suppressed By The Janus Kinase 1/2 54. Thiele J, Bueso-Ramos CE, Sun W, Cortes JE, Kantarjian HM, (JAK1/JAK2) Inhibitor Ruxolitinib. Blood. 2013;122(21): Verstovsek S. Effects Of Five-Years Of Ruxolitinib Therapy 2281. On Bone Marrow Morphology In Patients With Myelofibrosis 75. Massa M, Rosti V, Campanelli R, Fois G, Barosi G. Rapid and and Comparison With Best Available Therapy. Blood. long-lasting decrease of T-regulatory cells in patients with 2013;122(21):4055. myelofibrosis treated with ruxolitinib. Leukemia. 55. Schaap NP, Zweegman S, Jourdan E, Kiladjian J-J, Cervantes 2014;28(2):449-51. F, Niederwieser D, et al. Efficacy and Safety Of Fedratinib 76. Kordasti SY, Seidl T, Abellan PP, Thomas NSB, Mufti GJ, (SAR302503/TG101348) In Patients With Intermediate- Or Harrison CN, et al. JAK Inhibition Reduces CD25 high High-Risk Myelofibrosis (MF), Post-Polycythemia Vera (PV) CD27+ FOXp3+ T Regulatory Cells and Causes a Silencing MF, Or Post-Essential Thrombocythemia (ET) MF Previously Of T Effector Cells In Patients With Myeloproliferative Treated With Ruxolitinib: Interim Results From a Phase II Neoplasms Whilst Promoting a TH17 Phenotype. Blood. Study (JAKARTA-2). Blood. 2013;122(21):661. 2013;122(21):4092. 56. Harrison CN, Cortes JE, Cervantes F, Mesa RA, Milligan D, 77. Ianotto JC, Boyer-Perrard F, Gyan E, Laribi K, Cony-Makhoul Masszi T, et al. Results Of a Randomized, Double-Blind, P, Demory JL, et al. Efficacy and safety of pegylated-interfer - Placebo-Controlled Phase III Study (JAKARTA) Of The on alpha-2a in myelofibrosis: a study by the FIM and GEM JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients French cooperative groups. Br J Haematol. 2013;162(6):783- With Myelofibrosis (MF). Blood. 2013;122(21):393. 91. 57. Dean JP, Cernohous P, Komrokji RS, Seymour JF, Mesa RA, 78. Tefferi A, Elliot MA, Yoon SY, Li CY, Mesa RA, Call TG, et Campbell MS, et al. Pacritinib, a Dual JAK2/FLT3 Inhibitor: al. Clinical and bone marrow effects of interferon alfa therapy An Integrated Efficacy and Safety Analysis Of Phase II Trial in myelofibrosis with myeloid metaplasia. Blood. Data In Patients With Primary and Secondary Myelofibrosis 2001;97(6):1896.
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 273 | 19 th Congress of the European Hematology Association
79. Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli 89. Papadantonakis N, Matsuura S, Ravid K. Megakaryocyte A, Tozzi L, et al. Safety and efficacy of everolimus, a mTOR pathology and bone marrow fibrosis: the lysyl oxidase con - inhibitor, as single agent in a phase 1/2 study in patients with nection. Blood. 2012;120(9):1774-81. myelofibrosis. Blood. 2011;118(8):2069-76. 90. Rodriguez HM, Vaysberg M, Mikels A, McCauley S, Velayo 80. Mascarenhas J, Mercado A, Rodriguez A, Lu M, Kalvin C, Li AC, Garcia C, et al. Modulation of lysyl oxidase-like 2 enzy - X, et al. Prolonged Low Dose Therapy with a Pan-Deacetylase matic activity by an allosteric antibody inhibitor. J Biol Chem. Inhibtor, Panobinostat (LBH589), in Patients with 2010;285(27):20964-74. Myelofibrosis. ASH Annual Meeting Abstracts. 2011;118(21): 91. Barry-Hamilton V, Spangler R, Marshall D, McCauley S, 794-. Rodriguez HM, Oyasu M, et al. Allosteric inhibition of lysyl 81. Tefferi A, Verstovsek S, Barosi G, Passamonti F, Roboz GJ, oxidase-like-2 impedes the development of a pathologic Gisslinger H, et al. Pomalidomide is active in the treatment of microenvironment. Nat Med. 2010;16(9):1009-17. anemia associated with myelofibrosis. J Clin Oncol. 92. Talal AH, Feron-Rigidon M, Madere J, Subramanian GM, 2009;27(27):4563-9. Bornstein JD. Simtuzumab, an antifibrotic monoclonal anti - 82. Passamonti F, Barbui T, Barosi G, Begna K, Cazzola M, body against lysyl oxidase-like 2 (LOXL2) enzyme, appears Cervantes F, et al. Phase 3 Study Of Pomalidomide In safe and well tolerated in patients with liver disease of diverse Myeloproliferative Neoplasm (MPN)-Associated etiology. J Hepatol. 2013;58:s532. Myelofibrosis With RBC-Transfusion-Dependence. Blood. 93. Bock O, Serinsoz E, Schlue J, Kreipe H. Different expression 2013;122(21):394. levels of the telomerase catalytic subunit hTERT in myelopro - 83. Irvine DA, Copland M. Targeting hedgehog in hematologic liferative and myelodysplastic diseases. Leuk Res. malignancy. Blood. 2012;119(10):2196-204. 2004;28(5):457-60. 84. Zingariello M, Martelli F, Ciaffoni F, Masiello F, Ghinassi B, 94. Florena AM, Tripodo C, Di Bernardo A, Iannitto E, Guarnotta D'Amore E, et al. Characterization of the TGF-beta1 signaling C, Porcasi R, et al. Different immunophenotypical apoptotic abnormalities in the Gata1low mouse model of myelofibrosis. profiles characterise megakaryocytes of essential thrombo - Blood. 2013;121(17):3345-63. cythaemia and primary myelofibrosis. J Clin Pathol. 2009;62 85. Keller MD, Rampal RK, Shank K, de Stanchina E, Rose K, (4):331-8. Amakye D, et al. Improved Efficacy Of Combination Of 95. Begna K, Laborde RR, Patnaik MM, Lasho TL, Zblewski D, JAK2 and Hedgehog Inhibitors In Myelofibrosis. Blood. Finke C, et al. Imetelstat, a Telomerase Inhibitor, Induces 2013;122(21):666. Morphologic and Molecular Remissions In Myelofibrosis and 86. Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, et al. Reversal Of Bone Marrow Fibrosis. Blood. 2013;122(21):662. Structural and functional diversity of lysyl oxidase and the 96. Bjørn ME, de Stricker K, Kjær L, Ellemann K. Rapid LOX-like proteins. Biochim Biophys Acta. 2003;1647(1- Clearance Of JAK2 V617F Allele Burden In Patient With 2):220-4. Advanced Polycythemia Vera (PV) During Combination 87. Tadmor T, Bejar J, Attias D, Mischenko E, Sabo E, Neufeld G, Therapy With Ruxolitinib and Peg-Interferon Alpha-2a. et al. The expression of lysyl-oxidase gene family members in Blood. 2013;122(21):5241. myeloproliferative neoplasms. Am J Hematol. 2013;88(5): 97. Francois S, Huynh A, Cassinat B, Bay J-O, Cornillon J, 355-8. Rolland V, et al. Ruxolitinib Before Allogeneic Hematopoietic 88. Zaffryar-Eilot S, Marshall D, Voloshin T, Bar-Zion A, Stem Cell Transplantation (HSCT) In Patients With myelofi - Spangler R, Kessler O, et al. Lysyl oxidase-like-2 promotes brosis: a Preliminary Descriptive Report Of The JAK ALLO tumour angiogenesis and is a potential therapeutic target in Study, a Phase II Trial Sponsored By Goelams-FIM In angiogenic tumours. Carcinogenesis. 2013;34(10):2370-9. Collaboration With The Sfgmtc. Blood. 2013;122(21):306.
| 274 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1)