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Journal of the National Comprehensive Cancer Network Commentary Lessons From ASH 2010: A Focus on NHL

At the 52nd Annual Meeting and Exposition of ASH in December, some 881 abstracts included information on Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL), with at least 363 on chronic lymphocytic leukemia (CLL). This brief summary discusses some of the important findings that will begin to impact practice.

Follicular Lymphoma Overall survival (OS) for patients with follicular lymphoma (FL) has improved since Andrew D. Zelenetz, MD, the introduction of rituximab. Data have shown that for patients who need treatment, PhD rituximab added to chemotherapy improves overall response (OR) and complete 1–4 Andrew D. Zelenetz, MD, PhD, response (CR) rates, progression-free survival (PFS), and OS. is Chief of the Lymphoma In an update of the Primary RItuximab and MAintenance (PRIMA) trial, Salles Service, Division of Hematology/ et al.5 enrolled patients with untreated, high tumor-burden FL. Patients were treated Oncology, Memorial Sloan- Kettering Cancer Center. with 1 of 3 regimens (R-CHOP, R-CVP, or R-FCM) at the discretion of the treating His research focuses on physician. Patients with a partial response or CR were randomized to observation or improving clinical outcomes in maintenance with rituximab, 375 mg/m2, once every 8 weeks for 2 years. At a median lymphoma and on the molecular of 42 months after registration, the 36-month PFS was 75% in the maintenance mechanisms of non-Hodgkin lymphoma. arm versus 58% in the observation arm, which met the primary end point of a 45% Dr. Zelenetz received his BA and improvement in median PFS. The only safety issue was a slight increase in risk of PhD from Harvard University infection in the maintenance group. and his MD from Harvard In a subanalysis of the PRIMA study, Trotman et al.6 examined the role of FDG- Medical School. His internship and residency were completed PET imaging to predict outcome in FL. At diagnosis, 99% (119/120) of PET scans at Stanford University Medical were positive, demonstrating their utility for initial diagnosis. Among 124 patients Center. who underwent PET scans after completion of induction chemotherapy, patient Dr. Zelenetz is a member of ASH, characteristics were similar to those of the entire study population. Discordance ASCO, and the American College was noted between response assessments determined by CT and PET. The post- of Physicians. He participates in various committees: he is Vice induction PET was shown to be a better discriminator of outcome than the CT scan. Chairperson of the Cancer and At 3 years, patients with a positive PET scan had significantly inferior PFS (32% Leukemia Group B Lymphoma vs. 74%) and OS (88% vs. 97%). These findings showed that the updated Cheson Core Committee, Chair of the NCCN Non-Hodgkin’s Lymphoma response criteria, which include FDG-PET, are applicable to patients with FL. Panel, Board Member of the The updated results of the FIT trial,7 which examined consolidation with Leukemia and Lymphoma 90Y-ibrituomab tiuxetan radioimmunotherapy (RIT) after initial (immuno) Society, and a member of the chemotherapy for FL, were similar to those already published but provided more Lymphoma Research Foundation Scientific Advisory Board. He information about patients initially treated with rituximab-based therapy. Among has been the recipient of the those patient the CR and CR-unconfirmed (CRu) was improved with RIT Memorial Sloan-Kettering consolidation. A higher risk of secondary myelodysplastic syndromes (MDS)/acute Fellowship Teaching Excellence Award multiple times. myeloid leukemia in the RIT consolidation arm was concerning, but the difference Throughout his career, his was not quite statistically significant. Nonetheless, RIT consolidation provided a research has been published 3-year prolongation of PFS compared with observation. Available data do not directly in such journals as Blood, The address the choice between consolidation with RIT or maintenance with rituximab, Journal of Clinical Oncology, but both represent options to prolong PFS. Neither post-remission strategy has been and Clinical Cancer Research. shown to improve OS. Given the favorable impact of rituximab on OS in patients with FL, an international cooperative effort reexamined the role of observation in patients with low tumor burden.8 The trial objective was to determine if treatment with The ideas and viewpoints rituximab in asymptomatic advanced-stage FL significantly delayed chemotherapy expressed in this commentary are those of the author and do not or radiotherapy compared with observation. Patients were initially randomized to necessarily represent any policy, observation, rituximab weekly for 4 weeks, or rituximab weekly for 4 weeks followed position, or program of the NCCN.

Zelenetz

by rituximab maintenance, but an early analysis led to the showed that inclusion of cytarabine in the induction closure of the second arm. At a median follow-up of 32 regimen for MCL improved time to treatment failure, but months, a significant difference was seen in the initiation further follow-up is needed to determine impact on OS. of new therapy among the arms (44%, 23%, and 10%, respectively), which translated to significant differences in PFS in a pair-wise comparison. However, no difference Aggressive B-Cell Lymphoma was seen in OS. The major critique of this study is the Primary mediastinal B-cell lymphoma (PMBL) represents primary end point of starting new therapy. This benefit a unique entity in malignant lymphomas. Morphologically, may be important if sustained impact on quality of life is it is strikingly similar to diffuse large B-cell lymphoma; seen, but the analysis is still pending. Although OS is the however, gene expression profiling shows that it more ultimate end point, time to the start of second therapy closely resembles HL. Because PMBL is often seen in would provide a more balanced assessment among the young women, eliminating radiation therapy potentially study arms. reduces risk for late complications. In an analysis of This study8 left many physicians wondering how 54 patients (56% women) with PMBL treated with to select patients for observation, and an interesting sequential R-CHOP followed by ICE with no radiation preliminary report9 may shed light on this dilemma. A therapy, 5-year PFS was 78% and OS was 88%.12 Bulky study by Kedmi et al.9 used a quantitative image analysis disease did not impact outcomes. Interim FDG-PET after to determine the intrafollicular proliferative index (PI) R-CHOP did not predict for PFS. One patient developed and correlated the PI to outcome. The median PI was MDS and 10 experienced relapse, of whom 6 underwent found to be 28%, and therefore a cutoff of 30% was used to HDT/ASCR and 5 remain progression-free. These data analyze outcome. Among patients with asymptomatic low show that patients with PMBL can have an excellent tumor-burden FL who were initially observed, those with outcome without radiation therapy. a PI of 30% or less had a median time to start of therapy of approximately 5 years, compared with 18 months for patients with a PI greater than 30%. If these findings are Hodgkin Lymphoma confirmed in an independent dataset, intrafollicular PI The early favorable results of the Stanford V may be a valuable tool in selecting patients for observation. radiochemotherapy regimen for HL led to a U.S. 10 In a randomized prospective trial, Coiffer et al. Intergroup comparison of ABVD chemotherapy and randomized 676 patients with relapsed or progressive Stanford V radiochemotherapy. In this study, Gordon 2 FL to treatment with either bortezomib (1.6 mg/m on et al.13 randomized 812 patients to either ABVD, with 2 days 1, 8, 15, 22, cycles 1–5) and rituximab (375 mg/m involved-field radiation (IFRT) given only to those with on days 1, 8, 15, 22 of cycle 1 and day 1 of cycles 2–5) massive mediastinal disease, or the Stanford V regimen or rituximab alone on the same schedule. At a median (12 weeks of chemotherapy), followed by IFRT only given follow up of 34 months, median PFS was 11 months in the to those with nodal sites larger than 5 cm in transverse rituximab-alone arm versus 13 months in the rituximab/ dimension, to determine if the Stanford V regimen would bortezomib arm. A 5.4-month difference was seen in time result in a 33% reduction in failure-free survival (FFS) to next therapy. Although this difference is statistically hazard rate. The study was well balanced for the major significant, the clinical benefit of rituximab/bortezomib is prognostic factors, including International Prognostic unclear, and significantly greater neurotoxicity was seen Score (IPS). (17% vs. 1%). In this study, 40% of patients on the ABVD arm received radiation therapy compared with 73% on the Stanford V arm. No statistically significant difference was Mantle Cell Lymphoma seen in response rate. The 5-year FFS was 73% for ABVD In a prospective trial, Hermine et al.11 randomized 497 and 71% for Stanford V. In a subset of patents with IPS patients with mantle cell lymphoma (MCL) to induction of 3 or greater, ABVD showed a significant advantage in therapy with either R-CHOP or alternating R-CHOP/R- 5-year FFS (68% vs. 58%). Toxicity was similar in the arms, DHAP before high-dose therapy with autologous stem cell although more lymphopenia and neuropathy were seen in rescue (HDT/ASCR). The CR/CRu rate was significantly patients on the Stanford V regimen. higher in the alternating arm after induction, but this In a subset analysis of this study involving 237 patients difference was lost after HDT/ASCR. Time to treatment with bulky mediastinal stage I/II disease who had received failure favored the alternating arm. No difference in OS 36 Gy IFRT to the mediastinum, bilateral supraclavicular, was seen at a median follow- up of 32 months. This trial and hila, Advani et al.14 found no significant difference in

Focus on NHL

5-year FFS (ABVD, 85%; Stanford V, 78%; P = .18). This T-Cell Lymphoma was the third randomized comparative trial of Stanford Patients with aggressive T-cell lymphoma generally have V versus ABVD, and the results have been consistent. a poor outcome; however, systemic anaplastic T-cell ABVD remains the standard of care, and the Stanford lymphoma (sALCL) that expresses anaplastic kinase 1 V regimen an alternative for patients in whom a lower (AKL1) is generally viewed as an exception. In a large cumulative dose of doxorubicin or bleomycin is a clinical retrospective cohort of patients with sALCL taken from consideration. sequential GELA studies, the most important prognostic Age has long been recognized as an important factors were age older than 40 and beta-2 microglobulin. prognostic factor in HL, with about 20% of patients ALK1 expression was closely correlated with age and were not independent of each other in multivariant analysis.17 presenting over the age of 60. In an analysis of patients In patients younger than 40 years, ALK1 expression did older than 60 with early favorable disease or early not impact PFS or OS. However, younger patients with unfavorable disease treated with ABVD in the German beta-2 microglobulin less than 3 had a poorer outcome. 15 Hodgkin Lymphoma Study group trials, Böll et al. noted In patients older than 40 years, ALK1 expression was the relative dose intensity was lower for older patients as a associated with a marginally superior PFS and OS. consequence of dose reductions and delays attributable to Patients with relapsed or refractory sALCL were the 15 toxicity. This finding corresponded to a lower 5-year PFS subject of a phase II study of BV. In this study, Shustov compared with younger patients. In older patients, 5% et al.18 treated 58 patients with sALCL with the same of deaths were from HL and 5% from treatment-related regimen described previously for patients with HL.The toxicity. Although ABVD is effective for older patients OR and CR rates were 86% and 54%, respectively, with a with early-stage HL, care must be taken to reduce toxicity. median PFS of 41 weeks. Peripheral neuropathy was seen Brentuximab vedotin (BV) is an antibody drug in 38% of patients (10% grade 3, no grade 4). OR and CR conjugate that targets the antitubulin agent monomethyl were similar for ALK1-positive and -negative patients, auristatin E (MMAE) to CD30+ cells. After endocytosis and hematologic toxicity was minimal. Given the poor outcome for older patients with sALCL, it would be of the antibody drug conjugate, MMAE is released by very interesting to see if BV can safely and effectively be intra-lysosomal protease cleavage. The primary end combined with CHOP; however, overlapping peripheral point of a phase II study involving patients with relapsed neuropathy may be a challenge. or refractory HL was to establish OR and CR rates for Other forms of peripheral T-cell lymphoma (PTCL) 16 those who had previously undergone HDT/ASCR. remain a major clinical challenge. Pralatrexate was Patients were treated with the recommended dose of BV, recently approved for treatment of relapsed or refractory 2 1.8 mg/m , every 3 weeks for a maximum of 16 cycles disease, but additional agents and novel combinations (median, 9 treatments). CR was seen in 34% of patients. are also necessary. Romidepsin is a histone deacetylase Remarkably, 96 of 102 patients experienced some tumor inhibitor with pleiotropic effects altering gene expression, reduction. Median PFS was 25.1 weeks and median activating apoptosis, and inhibiting angiogenesis. The response duration was 29 weeks. final results of a multicenter phase II study of romidepsin 19 Interestingly, median PFS after BV was superior to confirmed early results from the NCI. In this study, the that of the prior treatment. However, 20% of patients OR rate was 26%, with a CR/CRu rate of 13%. Median time to progression was 6 months and median duration of discontinued the drug secondary to an adverse event. The response was 12 months. Similar response rates were seen most common adverse event was neuropathy (in 55%); for PTCL not otherwise specified, angioimmunoblastic however, only 8% had grade 3 neuropathy and none had T-cell lymphoma, and sALCL (ALK1-negative). The grade 4. Neuropathy improved or resolved in 68% of most common treatment-related toxicities were nausea, patients after the drug was discontinued. vomiting, diarrhea, infection, asthenia, thrombocytopenia, This study shows that BV is highly active in relapsed and neutropenia. Cardiac toxicity was minimal (6%). or refractory HL; however, the PFS is short. Because no treatments are currently approved for relapsed or refractory HL progression after HDT/ASCR, these data may provide Agents on the Horizon a basis for an investigational new drug application. Early-phase data emerged on several agents with early However, more data are needed to determine if this drug indications of clinical activity. For example, BTK is can improve second- and even first-line therapy and thus a tyrosine kinase downstream of the B-cell receptor. impact outcomes. Inhibition of BTK induces apoptosis. In a phase I study of

Zelenetz

PCI-32765, a BTK inhibitor, Fowler et al.20 evaluated the maintenance in follicular lymphoma patients responding to agent in patients with recurrent B-cell malignancies and iImmunochemotherapy [abstract]. Blood 2010;116:Abstract 1788. found it to be well tolerated with minimal hematopoietic 6. Trotman J, Fournier M, Lamy T, et al. Result of FDG PET-CT imaging after immunochemotherapy induction is a powerful and toxicity.20 The OR rates by intention-to-treat were 45% independent prognostic indicator of outcome for patients with and 55% among evaluable patients. A phase I trial was follicular lymphoma: an analysis from the PRIMA study [abstract]. also conducted in CLL,21 with similar manageable toxicity Blood 2010;116:Abstract 855. noted. Early indications are promising, with an OR rate of 7. Hagenbeek A, Radford J, Van Hoof A, et al. 90Y-Ibritumomab 64%. Interestingly, lymph nodes respond early, with a rise tiuxetan (Zevalin) consolidation of first remission In advanced- in peripheral clonal lymphocytosis, which then improves stage follicular non-Hodgkin’s lymphoma: updated results after with further therapy.22 a median follow-up of 66.2 months from the international, randomized, phase III First-Line Indolent Trial (FIT) in 414 CAL-101 is a class I PI3K inhibitor selective for the patients [abstract]. Blood 2010;116:Abstract 594. δ-isoform with expression restricted to hematopoietic 8. Ardeshna KM, Qian W, Smith P, et al. An Intergroup randomised cells. In knockout mice, lack of the δ-isoform results in a trial of rituximab versus a watch and wait strategy in patients with B-cell defect. In vitro CAL-101 results showed enhanced stage II, III, IV, asymptomatic, non-bulky follicular lymphoma apoptosis of B-cell lines. In a phase I study of CAL-101 in (grades 1, 2 and 3a). A preliminary analysis [abstract]. Blood 2010;116:Abstract 6. a heavily pre-treated population with CLL (median prior 9. Kedmi M, Hedvat CV, Maragulia J, Zelenetz AD. Low proliferation treatments, 5) including 36% of patients with del(17p), index may be associated with longer time to first therapy in low responses were seen at all dose levels.23 However, grade follicular lymphoma [abstract]. Blood 2010;116:Abstract worsening lymphocytosis was common, with an OR rate 4149. of 26%. Adverse events included grade 3 or 4 neutropenia, 10. Coiffier B, Osmanov E, Hong X, et al. A phase 3 trial comparing thrombocytopenia, anemia, and transaminitis. In a study bortezomib plus rituximab with rituximab alone in patients with of the same agent in patients with indolent NHL and relapsed, rituximab-naive or -sensitive, follicular lymphoma [abstract]. Blood 2010;116:Abstract 857. MCL,24 the toxicity profile was slightly different, with 11. Hermine O, Hoster E, Walewski J, et al. Alternating courses of more grade 3 or 4 transaminitis and less neutropenia. The 3x CHOP and 3x DHAP plus rituximab followed by a high dose OR rate was 63% in patients with indolent NHL and 48% ARA-C containing myeloablative regimen and autologous stem in those with MCL. cell transplantation (ASCT) is superior to 6 courses CHOP plus Preliminary data from a phase I combination of CAL- rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: results of the MCL Younger Trial 101 with rituximab or bendamustine in CLL and indolent of the European Mantle Cell Lymphoma Network (MCL net) NHL suggest that both agents can be safely combined [abstract]. Blood 2010;116:Abstract 110. 25 with CAL-101. However, efficacy of the combination 12. Moskowitz C, Hamlin PA Jr, Maragulia J, et al. Sequential dose- will only be evaluable in future phase II and III trials. dense RCHOP followed by ICE consolidation (MSKCC protocol 01-142) without radiotherapy for patients with primary mediastinal large B cell lymphoma [abstract]. Blood 2010;116:Abstract 420. 13. Gordon LI, Hong F, Fisher RI, et al. A randomized phase III trial References of ABVD Vs. Stanford V +/- radiation therapy in locally extensive 1. Fisher RI, LeBlanc M, Press OW, et al. New treatment options have and advanced stage hodgkin’s lymphoma: an Intergroup study changed the survival of patients with follicular lymphoma. J Clin coordinated by the Eastern Cooperatve Oncology Group (E2496) Oncol 2005;23:8447–8452. [abstract]. Blood 2010;116:Abstract 415. 2. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy 14. Advani R, Hong F, Fisher RI, et al. Randomized phase III trial with rituximab added to the combination of cyclophosphamide, comparing ABVD + radiotherapy and the Stanford V regimen in doxorubicin, vincristine, and prednisone (CHOP) significantly patients with stage I/II bulky mediastinal Hodgkin lymphoma: a improves the outcome for patients with advanced-stage follicular subset analysis of the US Intergroup trial E2496 [abstract]. Blood lymphoma compared with therapy with CHOP alone: results 2010;116:Abstract 416. of a prospective randomized study of the German Low-Grade 15. Boll B, Gorgen H, Fuchs M, et al. Feasibility and efficacy of ABVD Lymphoma Study Group. Blood 2005;106:3725–3732. in elderly Hodgkin lymphoma patients: analysis of two randomized 3. Liu Q, Fayad L, Cabanillas F, et al. Improvement of overall and prospective multicenter trials of the German Hodgkin Study Group failure-free survival in stage IV follicular lymphoma: 25 years of (HD10 and HD11) [abstract]. Blood 2010;116:Abstract 418. treatment experience at The University of Texas M.D. Anderson 16. Chen R, Gopal AK, Smith SE, et al. Results of a pivotal phase 2 Cancer Center. J Clin Oncol 2006;24:1582–1589. study of brentuximab vedotin (SGN-35) in patients with relapsed or 4. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP refractory Hodgkin lymphoma [abstract]. Blood 2010;116:Abstract compared with cyclophosphamide, vincristine, and prednisone 283. alone in patients with previously untreated advanced follicular 17. Sibon D, Fournier M, Briere J, et al. Prognostic factors and long term lymphoma. J Clin Oncol 2008;26:4579–4586. outcome of 138 adults with systemic anaplastic large-cell lymphoma: 5. Salles GA, Catalano J, Feugier P, et al. Updated results of a retrospective study by the Groupe d’Etude Des Lymphomes De the PRIMA study confirms the benefit of 2-years rituximab l’Adulte (GELA) [abstract]. Blood 2010;116:Abstract 322.

Focus on NHL

18. Shustov AR, Advani R, Brice P, et al. Complete remissions with 22. Ponader S, Buggy J, O’Brien S, et al. Bruton’s tyrosine kinase brentuximab vedotin (SGN-35) in patients with relapsed or inhibitor PCI-32765 abrogates BCR- and nurselike cell-derived refractory systemic anaplastic large cell lymphoma [abstract]. Blood activation of CLL cells in vitro and in vivo [abstract]. Blood 2010;116:Abstract 961. 2010;116:Abstract 45. 19. Coiffier B, Pro B, Prince HM, et al. Final results from a pivotal, 23. Furman RR, Byrd JC, Brown JR, et al. CAL-101, an isoform- multicenter, international, open-label, phase 2 study of romidepsin selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, in progressive or relapsed peripheral t-cell lymphoma (PTCL) demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia following prior systemic therapy [abstract]. Blood 2010;116:Abstract [abstract]. Blood 2010;116:Abstract 55. 114. 24. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in 20. Fowler N, Sharman JP, Smith SM, et al. The Btk inhibitor, PCI- a phase 1 study of CAL-101, an isoform-selective inhibitor 32765, induces durable responses with minimal toxicity in patients of phosphatidylinositol 3-kinase P110{delta}, in patients with with relapsed/refractory B-cell malignancies: results from a phase I relapsed or refractory non-Hodgkin lymphoma [abstract]. Blood study [abstract]. Blood 2010;116:Abstract 964. 2010;116:Abstract 1777. 21. Burger JA, O’Brien S, Fowler N, et al. The Bruton’s tyrosine kinase 25. Flinn IW, Schreeder MT, Wagner-Johnston N, et al. A phase 1 study inhibitor, PCI-32765, is well tolerated and demonstrates promising of CAL-101, an isoform-selective inhibitor of phosphatidylinositol clinical activity in chronic lymphocytic leukemia (CLL) and small 3-kinase P110{delta}, in combination with rituximab and/ lymphocytic lymphoma (SLL): an update on ongoing phase 1 or bendamustine in patients with relapsed or refractory B-cell studies [abstract]. Blood 2010;116:Abstract 57. malignancies [abstract]. Blood 2010;116:Abstract 2832.