(NCCN Guidelines®) Non-Hodgkin's Lymphomas

NCCN Guidelines Index NHL Table of Contents Discussion

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) Non-Hodgkin’s Lymphomas Version 2.2015

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DIAGNOSIS WORKUP DIAGNOSTIC CATEGORYd

a ESSENTIAL: ESSENTIAL: · Complete H&P examination, including complete · b See First-Line HTLV-1 serology: ELISA and confirmatory western skin exam Therapy for blot if ELISA is positive. If western blot is · Electrolytes, BUN, creatinine, serum calcium, Chronic/ indeterminate, then HTLV-1 PCR can be performed. serum LDH c Smoldering · CBC and peripheral blood smear for atypical cells: · Chest/abdominal/pelvic/neck CT scan Subtype lymphocytosis (ALC >4000/μL in adults) in acute and · Pregnancy testing in women of child-bearing age d (ATLL-2) chronic subtypes (if chemotherapy planned) · Flow cytometry on peripheral bloode See First-Line USEFUL IN SELECTED CASES: USEFUL IN CERTAIN CIRCUMSTANCES: · Upper gastrointestinal endoscopy Therapy for · Biopsy of lymph nodes (excisional), skin biopsy, GI · Skeletal survey in symptomatic patients Acute Subtype f tract, or bone marrow biopsy is required if: · Stool examination for parasites (strongyloides is (ATLL-3) > Diagnosis is not established on peripheral blood, or most likely) > Ruling out an underlying infection (tuberculosis, · PET-CT scan histoplasmosis, toxoplasmosis, etc.) · > If biopsy performed, the recommended panel for Central nervous system evaluation: CT scan, MRI See First-Line paraffin section immunohistochemistry:g,h CD3, and/or lumbar puncture in all patients with acute or Therapy for CD4, CD5, CD7, CD8, CD25, CD30 lymphoma subtypes or in patients with neurologic Lymphoma manifestations (ATLL-3) aThe diagnosis of ATLL requires histopathology and immunophenotyping of tumor lesion,or morphology and immunophenotying of peripheral blood, and HTLV-1 serology. b Seemap for prevalence of HTLV-1 by geographic region. e c Typical immunophenotype: CD2+ CD3+ CD4+ CD5+ CD7- CD8- CD25+ CD30-/+ Typical ATL cells (“flower cells”) have distinctly polylobated nuclei with ³ homogeneous and condensed chromatin, small or absent nucleoli, and TCRαβ +. Presence of 5% T-lymphocytes with an abnormal immunophenotype in agranular and basophilic cytoplasm, but multiple morphologic variations can be peripheral blood is required for diagnosis. f encountered. Presence of³ 5% atypical cells by morphology in peripheral blood Bone marrow involvement is an independent poor prognostic factor. g is required for diagnosis in the absence of other criteria. See Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature dShimoyama M and members of The Lymphoma Study Group. Diagnostic criteria B-Cell andNK/T-C ell Neoplasms (NHODG-A). h and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A Usually CD4+ T-cells with expression of CD2, CD5, CD25, CD45RO, CD29, T-cell report from the Lymphoma Study Group (1984-87). Br J Haematol 1991;79:428- receptorαβ, and HLA-DR. Most cases are CD7- and CD26- with low CD3 437. expression. Rare cases are CD8+ or CD4/CD8 double positive or double negative.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

ATLL SUBTYPEd FIRST-LINE THERAPYi INITIAL RESPONSE Consider prophylaxis for tumor (at 2 mo) lysis syndrome (See NHODG-B )

Clinical trial or Observation or Chronic/Smoldering Skin-directed therapies as clinically Continue treatment with indicated (See Mycosis Fungoides/ Respondersl zidovudine and interferon Sezary Syndrome [MFSS-A]) or Zidovudine and interferonj,k Clinical trial or Chemotherapy Non-respondersl (See Suggested Treatment Regimens [ATLL-B]) or Best supportive care

dShimoyama M and members of The Lymphoma Study Group. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol 1991;79:428-437. iSupportive care: anti-infectious prophylaxis with sulfamethoxazole/trimethoprim + strongyloidosis is recommended. jOutside of a clinical trial, if a patient is not responding or is progressing, treatment with zidovudine and interferon should be stopped. If there is evidence of clinical benefit, treatment should continue until best response is achieved. If life-threatening manifestations, treatment can be discontinued before the 2-month period. kSee references for zidovudine and interferon (ATLL-C). lSee Response Criteria for ATLL (ATLL-A). Responders include CR, uncertified PR, and PR.

ATLL SUBTYPEd FIRST-LINE THERAPYi INITIAL RESPONSE Consider prophylaxis for tumor (after 2 cycles) lysis syndrome (See NHODG-B) Continue prior therapy Clinical trial Respondersl or or Consider allogeneic stem cell transplant Zidovudine and interferonj,k Acutem or Clinical trial Chemotherapy or (See Suggested Treatment Best supportive care Regimens [ATLL-B]) or Alternate therapy not Non-respondersl previously treated with: Consider · SeeATLL-B or See TCEL-B allogeneic Respondersl for Second-line therapy stem cell or transplant · Zidovudine and interferon Continue chemotherapy Clinical trial Respondersl or or Consider allogeneic stem cell transplant m,n,o Chemotherapy Lymphoma Clinical trial (See Suggested Treatment or Regimens [ATLL-B]) Best supportive care l or Non-responders Chemotherapy (See Consider TCEL-B for Second- Respondersl allogeneic stem dShimoyama M and members of The Lymphoma Study Group. Diagnostic line therapy) cell transplant criteria and classification of clinical subtypes of adult T-cell leukaemia- lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol kSee References for zidovudine and interferon (ATLL-C). 1991;79:428-437. lSee Response Criteria for ATLL (ATLL-A). Responders include CR, uncertified iSupportive care: anti-infectious prophylaxis with sulfamethoxazole/trimethoprim PR, and PR. + strongyloidosis is recommended. mEfficacy of long-term treatment is limited. There are small series where jOutside of a clinical trial, if a patient is not responding or is progressing, transplant is beneficial. There is no defined treatment. treatment with zidovudine and interferon should be stopped. If there is evidence nAntiviral therapy is not effective. of clinical benefit, treatment should continue until best response is achieved. If oCNS prophylaxis: intrathecal chemotherapy is recommended (methotrexate and life-threatening manifestations, treatment can be discontinued before the 2- cytarabine and corticosteroids). month period.

RESPONSE CRITERIA FOR ATLLa

Lymph Extranodal Peripheral Response Definition Spleen, Liver Skin Bone Marrow Nodes Masses Blood

Complete Disappearance Normal Normal Normal Normal Normal† Normal remission* of all disease

Uncertified Stable residual ³75% ³75% complete mass in bulky Normal Normal Normal† Normal decrease‡ decrease‡ remission* lesion

Partial Regression of ³50% ³50% ³50% ³50% No increase Irrelevant remission* disease decrease‡ decrease‡ decrease decrease

Failure to attain complete/partial Stable No change No change No change No change remission and No change No change disease* in size in size in size in size no progressive disease

Relapsed New or disease or New or³ 50% New or³ 50% New or³ 50% ³50% New or³ 50% increased Reappearance progressive increase§ increase§ increase increase increase# lesions disease

*Required that each criterion be present for a period of at least 4 weeks. §Defined by³ 50% increase from nadir in the sum of the products of measurable †Provided that <5% of flower cells remain, complete remission is judged to have disease. been attained if the absolute lymphocyte count, including flower cells, # ³ 9 Defined by 50% increase from nadir in the count of flower cells and an absolute is <4 x 10 /L. lymphocyte count, including flower cells, of >4 x109 /L. ‡Calculated by the sum of the products of the greatest diameters of measurable disease. aTsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: A proposal from an international consensus meeting. J Clin Oncol 2009;27:453-459.

SUGGESTED TREATMENT REGIMENS (in alphabetical order)

· Chemotherapya > CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) > CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) > Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) > HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine

aThere are no published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the treatment of ATLL.

REFERENCES FOR ZIDOVUDINE AND INTERFERON

Zidovudine and interferon Bazarbachi A, Hermine O. Treatment with a combination of zidovudine and alpha-interferon in naive and pretreated adult T-cell leukemia/lymphoma patients. J Acquir Immune Defic Syndr Hum Retrovirol 1996;13 Suppl 1:S186-190.

Bazarbachi A, Plumelle Y, Carlos Ramos J, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010;28:4177-4183.

Hermine O, Allard I, Levy V, Arnulf B, Gessain A, Bazarbachi A. A prospective phase II clinical trial with the use of zidovudine and interferon- alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J 2002;3:276-282.

Hodson A, Crichton S, Montoto S, et al. Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma. J Clin Oncol 2011;29:4696-4701.

White JD, Wharfe G, Stewart DM, et al. The combination of zidovudine and interferon alpha-2B in the treatment of adult T-cell leukemia/lymphoma. Leuk Lymphoma 2001;40:287-294.

Adult T-cell Leukemia/Lymphoma The chronic subtype is characterized by absolute lymphocytosis (≥4 x 9 9 Adult T-cell leukemia/lymphoma (ATLL) is a type of peripheral T-cell 10 /L) with T-lymphocytes ≥3.5 x 10 /L, normal calcium level, LDH malignancy caused by a retrovirus, the human T-cell lymphotropic virus levels within 2 times upper normal limit, and no involvement of CNS, type I (HTLV-1), and is associated with a long period of latency (often bone or GI tract; lymphadenopathy and involvement of liver and spleen 6 manifesting several decades after exposure).1,2 ATLL is endemic to may be present. The lymphoma subtype is characterized by absence several regions, including southwest regions in Japan, the Caribbean, of lymphocytosis, ≤1% abnormal T-lymphocytes, and and parts of central Africa, owing to the distribution of HTLV-1.1-3 In the histologically-proven lymphadenopathy with or without extranodal International Peripheral T-cell Lymphoma (PTCL) Project, ATLL lesions. The acute subtype usually presents with leukemic manifestation comprised about 10% of the diagnosis for confirmed cases of PTCL or and tumour lesions, and represent cases that are not classified as any 6 NK/T-cell lymphomas (N=1,153).4 ATLL was rare in North America or of the other 3 subtypes above. The acute subtype is associated with a Europe (≤2%), but prevalent in Asia (25%), with all cases from Asia rapidly progressive disease course, and features including elevated originating in Japan. Among HTLV-1 carriers in Japan, the cumulative LDH levels, hypercalcemia (with or without lytic bone lesions), B life-time risk of developing ATLL is estimated to be 2.5%; the annual symptoms, generalized lymphadenopathy, splenomegaly, 1,2 incidence of ATLL in Japan is approximately 700.2 hepatomegaly, skin involvement, and organ infiltration.

ATLL can be associated with an aggressive disease course, with The smoldering and chronic subtypes have a more favorable prognosis median overall survival (OS) of 6 to 10 months among patients with the compared with the acute or the lymphoma subtypes. In the analysis of acute or lymphoma subtypes.4-6 The Lymphoma Study Group of the patients with ATLL (N=818; mean age 57 years) from the Lymphoma Japan Clinical Oncology Group (JCOG) have classified ATLL into four Study Group of JCOG, the estimated 4-year OS rates for patients with subtypes (smoldering, chronic, acute, or lymphoma) based on acute, lymphoma, chronic, and smoldering subtypes were 5%, 6%, 6 laboratory evaluations (e.g., serum lactate dehydrogenase [LDH], 27%, and 63%, respectively. The median OS was 6, 10, 24 months, calcemia, lymphocytosis) and clinical features of ATLL (e.g., and not yet reached, respectively. The maximum duration of follow-up 6 lymphadenopathy, hepatosplenomegaly, skin involvement).6 The was 7 years in this study. The analysis from the International PTCL smoldering and chronic subtypes are considered indolent forms of Project confirmed the poor outcomes of patients with acute or 4 ATLL. Both subtypes are usually characterized by 5% or more abnormal lymphoma subtypes of ATLL, with a median OS of 10 months. In a T-lymphocytes in the peripheral blood and may have skin or pulmonary recent report from a long-term follow-up of patients with newly lesions (but no ascites or pleural effusion). In addition, the smoldering diagnosed indolent ATLL (N=90), the median OS was 4 years and the subtype is associated with a normal lymphocyte count, normal serum estimated 5-, 10-, and 15-year survival rates were 47%, 25%, and 14%, 7 calcium level, LDH levels within 1.5 times upper normal limit, and no respectively. In the subgroup analysis, the 15-year OS rate and median involvement of liver, spleen, CNS, bone, or gastrointestinal (GI) tract.6 OS tended to be higher for the chronic subtype (15% and 5 years, The expected median OS for this subtype generally exceeds 5 years.2 respectively) than the smoldering subtype (13% and 3 years,

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-253 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion respectively). These long-term outcomes appear poorer than expected Diagnosis for patients with indolent ATLL; the heterogeneity in outcomes among The diagnosis of ATLL requires histopathology and immunophenotyping patients with even the indolent subtype of the disease may be of tumor lesion, peripheral blood smear analysis for atypical cells, flow explained, in part, by differences in patient- and disease-related factors. cytometry on peripheral blood and HTLV-1 serology.9,10 The presence of ≥5% T-lymphocytes with an abnormal immunophenotype in the In patients with ATLL, poor performance status, elevated LDH level, ≥4 peripheral blood is required for the diagnosis of ATLL in patients without total involved lesions, hypercalcemia and age ≥40 years have been histologically proven tumor lesions.6 The cytological features of ATLL identified as major adverse prognostic factors based on data from a may be broad, but typical ATLL cells are characterized by so-called large number of patients.2,8 Among patients with the chronic subtype, ‘flower cells’, which show distinct polylobated nuclei with homogeneous factors such as poor performance status, ≥4 total involved lesions, bone and condensed chromatin, small or absent nucleoli, and agranular and marrow involvement, elevated LDH, elevated blood urea nitrogen, and basophilic cytoplasm.1,10 These cytological characteristics are most low albumin levels have been identified as potential prognostic factors evident in the acute subtype of the disease.2 HTLV-1 serology should for decreased survival.2,7 Further studies with a larger number of be assessed by ELISA, and if positive, a confirmed by western blot. If patients are needed to elucidate prognostic factors that may help to the result from western blot is indeterminate, then PCR analysis for further risk stratify patients with indolent ATLL. For patients with HTLV-1 can be performed. Monoclonal integration of HTLV-1 proviral aggressive subtypes of ATLL, the International PTCL Project recently DNA occurs in all cases of ATLL; HTLV-1 integration patterns have reported that the International Prognostic Index (IPI) was a useful model been reported to have clinical and prognostic implications for ATLL.11 for predicting outcomes.4 Based on univariate analysis, presence of B Bone marrow biopsy or aspiration is generally not required to establish symptoms, platelet count <150 × 109/L, and high IPI score (≥3) were the diagnosis of ATLL. However, bone marrow evaluation may be useful found to be associated with decreased OS. Based on multivariate as bone marrow involvement has been reported as an independent analysis, however, IPI score was the only independent predictor for OS predictor of poor prognosis in ATLL.12 If the diagnosis of ATLL is not outcomes.4 Recently, a report based on data from patients with ATLL in established on peripheral blood examination, bone marrow biopsy or North America (N=89; acute or lymphoma subtypes in 79%) found that biopsy of the lymph nodes or lesions in skin or GI tract should be IPI scores were not always predictive for ATLL outcomes, and proposed performed. Biopsy of the suspicious lesion may also help to rule out a new prognostic model.5 In this study, the investigators identified 3 certain underlying infections (e.g., tuberculosis, histoplasmosis, and prognostic categories based on the following factors: ECOG toxoplasmosis). Excisional biopsy is recommended instead of core performance status, Ann Arbor stage, age, and serum calcium level at needle biopsy for the lymph nodes.10 diagnosis.5 If a biopsy is performed, the immunophenotyping panel should at In the NCCN Guidelines, patients with ATLL are classified into 4 minimum include the following markers: CD3, CD4, CD7, CD8, and subtypes (chronic, smoldering, acute and lymphoma) according to the CD25. The typical immunophenotype in most patients with ATLL Shimoyama criteria.6

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-254 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion involves mature CD4-positive T cells with expression of CD2, CD5, Response Criteria 1,10 CD25, CD45RO, CD29, T-cell receptor  and HLA-DR. Most ATLL The current response criteria used for ATLL are based on modifications 10 cells lack CD7 and CD26 and have a dim CD3 expression. In the to the original 1991 JCOG response criteria as suggested at the Guidelines, the following is included as representative of a typical international consensus meeting. The modified response criteria reflect immunophenotype for ATLL: CD2+, CD3+, CD4+, CD7-, CD8-, CD25+, the widely used criteria for CLL and NHL, which were published in 1996 CD30-/+, TCR αβ+. and 1999, respectively.15,16 These response criteria are based on the normalization or reduction in the size of enlarged lymph nodes and The clinical features of ATLL differ by subtype and disease stage, but extranodal masses (as calculated by the sum of the products of the patients with the most common acute or lymphoma subtypes may greatest diameters of measurable disease), reduction in the size of frequently present with lymphadenopathy (77%), fatigue (32%), spleen or liver and decrease in the involvement of peripheral blood, anorexia (26%), skin eruptions (23%), abdominal pain (23%), bone marrow and skin.10 The response is categorized as a complete pulmonary complications (18%; due to leukemic infiltration and/or remission (CR; defined as complete disappearance of all clinical, infections), splenomegaly (13%), and hepatomegaly (10%).2,4 Bone microscopic, and radiographic evidence of disease and absolute marrow involvement (28%) and CNS involvement (10%) are also not lymphocyte count, including flower cells, <4 x 109/L in the peripheral uncommon.2,4 blood), partial remission (PR; defined as ≥50% reduction in the sum of Workup the products of the greatest diameters of measurable disease without the appearance of new lesions, no increase in spleen or liver size, The initial workup for ATLL should include a comprehensive physical ≥50% reduction in skin involvement, and ≥50% reduction in absolute examination with complete skin examination, and CT scans of the lymphocyte counts in peripheral blood), stable disease (SD; failure to chest, abdomen and pelvis. Most patients with acute ATLL have achieve CR or PR with no progressive disease) and relapsed disease or elevated LDH levels, and lymphocytosis is found in patients with the progressive disease (PD; new or ≥50% increase in lymph node lesions, acute or chronic type at presentation. Laboratory evaluations should extranodal mass, or splenomegaly/hepatomegaly, ≥50% increase in include a complete blood count (CBC) and metabolic panel (serum skin involvement, 50% increase from nadir in the count of flower cells electrolyte levels, calcium, creatinine and blood urea nitrogen), and and an increase in absolute lymphocyte count, including flower cells, of measurement of serum LDH levels. >4 x 109/L).10 Each of the criterion for the response categories should Upper GI tract endoscopy should be considered in selected cases since be observed for a minimal period of 4 weeks to qualify for the response GI tract involvement is frequently observed in patients with aggressive (e.g., CR, PR, SD). The response criteria also includes a category for ATLL.13 CNS evaluation using CT scan, MRI and/or lumbar puncture unconfirmed CR, defined as ≥75% reduction in tumor size but with a may also be useful for all patients with acute or lymphoma subtypes or residual mass after treatment, with an absolute lymphocyte count, 9 in patients with neurological manifestations.14 including flower cells, of <4 x 10 /L. The usefulness of PET or PET-CT

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-255 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion has not been evaluated in the response assessment of patients with first-line therapy (n=207), the 5-year OS rates were 46%, 20% and 12%, ATLL. respectively, for patients who received first-line antiviral therapy alone, chemotherapy alone and chemotherapy followed by antiviral therapy.23 Treatment Options The ORR was 66% (CR in 35%) among patients who received first-line The ATLL subtype is an important factor for predicting prognosis and antiviral therapy (n=62 evaluable) and 88% (CR in 25%) among those deciding appropriate treatment strategies. Smoldering and chronic who received first-line chemotherapy alone (n=48 evaluable). Among subtypes are considered indolent, and are usually managed similarly to patients who received chemotherapy followed by antiviral therapy (n=14 indolent NHL with watchful waiting until symptomatic disease. In evaluable), the ORR was 93% (CR in 50%).23 For all patients with contrast, the acute and lymphoma subtypes typically require immediate follow-up survival data (n=238), the median OS was 12 months and the therapy. 5-year OS rate was 23%. In the subgroup analysis by ATLL subtype, median OS was 6 months, 13 months, and not reached, respectively, in A number of small studies and cases have reported on the activity of patients with acute, lymphoma and indolent (chronic or smoldering) the combination of an anti-retroviral agent zidovudine and interferon subtypes; the 5-year OS rate was 15%, 16%, and 76%, respectively.23 17-22 (IFN)-alfa in patients with ATLL. Among patients with primarily In the subgroup analysis by first-line treatment regimen, antiviral treatment-naïve aggressive ATLL, antiviral therapy with zidovudine and therapy resulted in significantly longer median OS (17 months vs. 12 IFN-alfa resulted in overall response rate (ORR) of 58%-80% and CR months) and higher 5-year OS rate (46% vs. 14%) compared with 17-19 rates of 20%-50%. Outcomes with this therapy for previously treated chemotherapy (with or without maintenance antiviral therapy). patients with relapsed/refractory disease were poorer, with ORR 17%- Interestingly, only the patients with the acute and indolent subtype 21,22 67% (nearly all PRs). The results of a meta-analysis on the use of benefited significantly from first-line antiviral therapy, whereas patients zidovudine and IFN for patients with ATLL were recently reported by with the lymphoma subtype had worse survival with antiviral therapy 23 Bazarbachi et al (N=254). Most of the patients (n=207 evaluable) in and better outcomes with first-line chemotherapy (with or without this analysis had the acute (47%) or lymphoma (41%) subtypes, with maintenance antiviral treatment). Multivariate analysis showed that only the remaining patients presenting with indolent disease. Patients had the ATLL subtype and type of first-line treatment were significant been treated with first-line antiviral therapy alone (n=75; comprising a independent predictors for poorer OS.23 These data suggest that combination of zidovudine and IFN-alfa in 97% of cases), chemotherapy antiviral therapy with zidovudine and IFN-alfa is effective in patients with alone (n=77; CHOP [cyclophosphamide, doxorubicin, vincristine, leukemic ATLL, but not in the lymphoma subtype. A recent prednisone] in 86% of cases) or chemotherapy followed by retrospective analysis evaluated outcomes in patients with aggressive maintenance antiviral therapy (n=55). Among the patients who received ATLL (N=73; 60% had lymphoma subtype) treated with chemotherapy first-line antiviral therapy alone, 60% had the acute subtype; in contrast, alone (n=39; primarily with CHOP-containing regimens) or combined among the patients who received chemotherapy alone, 62% had the therapy with chemotherapy and antiviral agents (zidovudine and INF- lymphoma subtype. In patients with available survival data and recorded alfa; given concurrent or sequential to chemotherapy or deferred).24 The

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-256 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion median OS among patients with the acute and lymphoma subtypes was AIDS Malignancy Consortium in patients with aggressive ATLL (N=19) , 7.5 months and 10 months, respectively. The use of antiviral treatments EPOCH chemotherapy followed by antiretroviral therapy (zidovudine, (at any point on the study) was associated with significant OS benefit for lamivudine, IFN-alfa up to 1 year) resulted in an ORR of 58% (CR in both the subgroups with acute and lymphoma ATLL.24 Among patients 10.5%) and a median duration of response of 13 months.29 Although with the lymphoma subtype (n=32), treatment with first-line combination this regimen appeared to be active in this patient population, viral therapy (with chemotherapy and antiviral agents) or chemotherapy with reactivation during therapy coincided with disease progression, which deferred antivirals resulted in significant OS benefits compared with likely contributed to treatment failure.29 A phase II trial by JCOG chemotherapy alone.24 evaluated an intensive multidrug combination chemotherapy regimen comprising VCAP-AMP-VECP [vincristine, cyclophosphamide, In patients with ATLL, combination chemotherapy with CHOP has doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and 5,23,25 resulted in ORR of 64% to 88% and CR rates of 18% to 25%. prednisone (AMP), and vindesine, etoposide, carboplatin, and 23,25-27 Median OS in published reports ranges from about 8 to 12 months. prednisone (VECP)], supported by G-CSF, in patients with aggressive In the aforementioned meta-analysis of data from patients with ATLL ATLL (N=93).30 The ORR with this regimen was 81% with a CR in treated with first-line therapies, chemotherapy (primarily CHOP) alone 35.5% of patients. The median OS was 13 months and the estimated 2- resulted in median OS of 10 months and chemotherapy with or without year OS rate was 31%. Grade 4 neutropenia (65%) and 23 maintenance antiviral therapy resulted in median OS of 12 months. As thrombocytopenia (53%) were frequently observed despite the use of alluded to earlier in the discussion, patients with the lymphoma subtype G-CSF.30 Based on the promising results seen in this study, a appeared to benefit more from first-line therapy with CHOP or CHOP- randomized phase III trial was conducted by JCOG to evaluate first-line like chemotherapy (with or without maintenance antivirals) than with therapy with VCAP-AMP-VECP compared with biweekly CHOP (CHOP- antivirals alone. In the subgroup of patients with the lymphoma subtype, 14) in patients with aggressive ATLL (N=118).25 The CR rate was OS outcome was significantly improved with first-line chemotherapy significantly higher with VCAP-AMP-VECP compared with CHOP-14 (n=72; median OS 16 months; 5-year OS 18%) compared with first-line (40% vs. 25%; P=0.02) but the 1-year PFS rate (28% vs. 16%) and 3- antiviral treatment alone (n=13; median OS 7 months; 5-year OS 0%; year OS rate (24% vs. 13%) were not significantly different. Median 23 P=0.009). Several prospective studies have evaluated the role of more PFS (7 months vs. 5 months, respectively) and median OS (13 months intensive chemotherapy combination regimens. A phase II multicenter vs. 11 months, respectively) were not different between treatment study investigated the activity of CHOP followed by a regimen with arms.25 VCAP-AMP-VECP regimen was associated with higher etoposide, vindesine, ranimustine, mitoxantrone, and G-CSF in patients incidence of toxicities compared with CHOP-14, including grade 4 28 with ATLL (N=81). The ORR with this intensive regimen was 74% (CR neutropenia (98% vs. 83%), grade 4 thrombocytopenia (74% vs. 17%) in 36%) and the median duration of response was 8 months. The and grade 3-4 infections (32% vs. 15%). Recently, a very limited median OS for all patients remained rather short, at 8.5 months; the 3- number of ATLL cases have been treated with hyper-CVAD (hyper- 28 year OS rate was 13.5%. In a small phase II trial conducted by the fractionated cyclophosphamide, vincristine, doxorubicin, and

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-257 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion dexamethasone), a regimen more commonly used in the treatment of prospective studies have been conducted to evaluate the use of patients with aggressive B-cell NHL and adult acute lymphoblastic reduce-intensity conditioning (RIC) in allogeneic HSCT for patients leukemias.31 Promising outcomes in terms of durable CRs have been with ATLL.32,36 In a combined analysis from two clinical trials (N=29), reported with this regimen in two cases of ATLL31; however, prospective the 5-year OS rate with RIC allogeneic HSCT was 34%.32 The NRM evaluations are needed. rate was 27.5%; 11 patients died due to disease progression. Ten patients are alive at a median follow up of 82 months following Allogeneic HSCT (using myeloablative or non-myeloablative transplant.32 conditioning) may improve outcomes for some patients with ATLL,32-37 with suggestion of a graft-versus-leukemia effect.38,39 Studies with A recent retrospective study evaluated the role of myeloablative allogeneic HSCT (primarily using myeloablative conditioning) have conditioning and RIC allogeneic HSCT in a large group of patients with reported promising disease-free and OS outcomes in patients with ATLL in Japan (N=586).40 The majority of patients had either acute ATLL, with median leukemia-free survival exceeding 17 months and 3- (57%) or lymphoma (28%)subtypes. Patients who received RIC for year OS rate of about 45%.33,35,37 However, the transplant procedure HSCT were older than those who received myeloablative conditioning was associated with a high treatment-related mortality (TRM) rate of regimens (median age 57 years vs. 49 years). The median OS 40% to 63%.33,35,37 In a multicenter retrospective analysis that (survival measured from time of HSCT) was 9.5 months among evaluated outcomes in patients with aggressive ATLL who received patients who received myeloablative conditioning, with a 3-year OS of myeloablative allogeneic HSCT (N=40), the median OS for all patients 39%. For patients who received RIC, the median OS was 10 months, following transplant was about 10 months.33 Acute graft-versus-host with a 3-year OS of 34%. The 3-year cumulative incidence of TRM disease (GvHD) developed in 67% of patients. The estimated 3-year was 38% with myeloablative conditioning and 33% with RIC. The 3- relapse-free survival and OS rate was 34% and 45%, respectively. year cumulative incidence of ATLL-related death was 22.5% and 33%, The incidence of TRM was 42.5%, with early TRM (within 6 months of respectively.40 Based on multivariate analysis, older age (>55 years), transplant) occurring in 13 patients (32.5%).33 A large retrospective male sex, lack of CR at time of HSCT, poorer performance status (PS analysis was conducted in patients with ATLL who underwent ≥1), and unrelated donor HSCT were significant independent factors allogeneic HSCT (related or unrelated) (N=386).34 After a median associated with decreased OS outcomes. Older age (>55 years) was follow up of 41 months, the 3-year OS rate for this patient cohort was a significant independent factor for poorer OS among patients who 33%. Overall, the incidence of TRM was 43%, which was mainly due received myeloablative conditioning, but not for those who received to infectious complications and organ failure. Based on multivariate RIC. In multivariate analysis, significant independent factors for risk of analysis, patient age (>50 years), male sex, lack of a CR at the time of TRM included male sex, poorer performance status (PS ≥1), and transplant, and the use of unrelated or cord blood were identified as unrelated donor HSCT; significant independent factors influencing adverse prognostic factors for OS outcomes.34 In an effort to reduce risks for ATLL-related death included non-CR at time of HSCT, poor the high rate of TRM observed with allogeneic HSCT, small PS (PS ≥2), and RIC.40 This analysis suggested that use of

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-258 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion myeloablative conditioning or RIC resulted in similar outcomes with with anti-Strongyloides agents and prophylaxis with allogeneic HSCT, and that HSCT may offer long-term survival in some sulfamethoxazole-trimethoprim to prevent Pneumocystis jirovecii patients with ATLL. Prospective studies in larger groups of patients pneumonia are recommended for all patients undergoing treatment for are warranted to further evaluate the role of allogeneic HSCT (with ATLL.10 myeloablative conditioning or RIC) in the management of ATLL. Primary Therapy Patients with ATLL who relapse after allogeneic HSCT have poor For patients with chronic or smoldering ATLL subtypes, observation is a prognosis and very limited treatment options. In a retrospective valid option for asymptomatic cases since both of these subtypes are analysis of patients who progressed or relapsed after first allogeneic considered indolent diseases. Alternatively, if symptoms are present, HSCT (N=35), donor lymphocyte infusion (DLI) was reported to induce these patients can be managed with skin-directed therapies (as long-term remissions in a few patients.41 Most patients in this analysis recommend for patients with mycosis fungoides or Sézary syndrome received withdrawal of immunosuppression as the initial intervention. within this NCCN Guidelines for NHL) for skin lesions, as appropriate, or Among the patients who subsequently received DLI (n=9), the median with antiviral therapy with combination of zidovudine and IFN-alfa. As OS after relapsed/progression was 17 months; the 3-year OS was previously discussed, enrollment in suitable clinical trials is encouraged, 33%. Debulking of tumors (with dose-reduced CHOP or RT) prior to where available. DLI seemed to be associated with improved outcomes; response was achieved in 5 of 6 patients who underwent pre-DLI cytoreductive For patients with acute ATLL, treatment options include participation in therapy. DLI resulted in remission lasting more than 3 years in 3 of the clinical trials, antiviral therapy with zidovudine and IFN-alfa, or patients.41 Among the patients who did not receive DLI (n=26), the combination chemotherapy regimens (i.e., CHOP, CHOEP, dose- median OS was 4 months and the 3-year OS was 14%. The majority adjusted EPOCH, or hyper-CVAD; all based on limited data only). For of these patients were treated with chemotherapy regimens following patients with the lymphoma subtype, primary treatment options include initial withdrawal of immunosuppression.41 This analysis showed that participation in clinical trials or combination chemotherapy (as induction of graft-versus-ATLL effect via treatments such as DLI may mentioned above for acute ATLL); antiviral therapy alone is not 23 provide long-lasting remission in select patients with relapsed ATLL. considered effective for this group of patients. CNS prophylaxis (with However, prospective clinical trials are needed to confirm these intrathecal methotrexate and cytarabine and corticosteroids) is findings. recommended in patients with lymphoma subtype. No optimal treatment has been defined for these patients with aggressive ATLL and efficacy NCCN Recommendations of long-term treatment is limited. As discussed earlier, allogeneic HSCT There are no optimal standard treatment regimens for the management may be beneficial in some patients with ATLL. of ATLL. Thus, the NCCN Guidelines panel recommends enrollment in Outside of a clinical trial, if a patient is not responding or is progressing, clinical trials as one of the options for all patients with ATLL. Prophylaxis on antiviral treatment with zidovudine and IFN-alfa, treatment should be

Version 2.2015, 03/03/15 © National Comprehensive Cancer Network, Inc. 2015, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-259 NCCN Guidelines Version 2.2015 NCCN Guidelines Index NHL Table of Contents Non-Hodgkin’s Lymphomas Discussion stopped. If there is evidence of clinical benefit, treatment should or has disease progression at 2 months from start of treatment (non- continue until best response is achieved. The duration of initial therapy responders to initial therapy), options for additional therapy include is usually 2 months. If life threatening manifestations occur, however, participation in clinical trials, where available, or combination treatment can be discontinued before this period. chemotherapy regimens (i.e., CHOP, EPOCH, or hyper-CVAD) or best supportive care. Allogeneic HSCT should be considered for patients The optimal chemotherapy regimen for patients with ATLL is not yet with acute or lymphoma subtype. established. The regimens listed in the NCCN Guidelines are based on institutional preferences and include CHOP, CHOEP, dose-adjusted For patients with acute or lymphoma ATLL subtypes who achieve an EPOCH or hyper-CVAD. initial response to primary therapy, continuation of the prior therapy or allogeneic HSCT (if donor is available) are appropriate options. Patients Mogamulizumab (KW-0761) is a humanized monoclonal antibody with acute ATLL with persistent or progressive disease following approved for the treatment of patients with relapsed or refractory CCR4- primary therapy (non-responders) should be treated in the context of a positive ATLL in Japan. The approval was based on results of a clinical trial, where possible, best supportive care or an alternate multicenter phase II study for patients with relapsed, aggressive CCR4- regimen not previously used (under first-line therapy for ATLL, for 42 positive ATLL (N=28). The primary endpoint of the trial was ORR; the second-line therapy recommended in the Guidelines for PTCL, or secondary endpoints included PFS and OS outcomes. Patients were antiviral therapy with zidovudine and IFN). In non-responding patients treated with mogamulizumab IV 1 mg/kg once per week for 8 weeks, with lymphoma ATLL subtypes after first-line therapy, options for 43 which was the dose derived from the phase I study. The ORR among second-line therapy include treatment in the context of a clinical trial, 42 evaluable patients (n=26) was 50% (95% CI, 30–70%). The median best supportive care or second-line therapy options based on the PFS and OS were approximately 5 months and 14 months, recommendations for PTCL. In patients with acute or lymphoma ATLL respectively. The most common adverse events included infusion subtypes who achieve a response to second-therapy, allogeneic HSCT 42 reactions (89%) and skin rashes (63%). Mogamulizumab is an should be considered if a donor is available. investigational agent in the U.S. and has not been approved for any indication by the FDA. This agent is currently being evaluated in previously treated patients with ATLL in a multicenter open-label randomized study in the U.S. and elsewhere.

Response Assessment and Additional Therapy For patients with chronic or smoldering ATLL who achieve an initial response (at 2 months following start of treatment; responders include those with a CR, uncertified PR, or PR), continuation of zidovudine and IFN-alfa is recommended. If the patient presents with persistent disease

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43. Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I study of KW- 0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol 2010;28:1591-1598. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20177026.