A Review of Selected Presentations From the 2016 American Society of Hematology Annual Meeting and Exposition
December 3-6, 2016 • San Diego, California
PLUS Meeting Abstract Summaries
With Expert Commentary by:
Steven M. Horwitz, MD
Associate Attending, Lymphoma Service
Memorial Sloan Kettering Cancer Center
New York, New York
Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients With CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician’s Choice (Methotrexate or Bexarotene): The Phase 3 ALCANZA Study
Cutaneous T-cell lymphoma (CTCL) is incurable with current therapies, and advanced-stage disease is associated with a poor prognosis. Standard-of-care therapies, such as methotrexate and bexarotene, rarely provide durable responses.1,2 The cell surface marker CD30 is commonly expressed on malignant T cells of mycosis fungoides and primary cutaneous anaplastic large cell lymphoma (ALCL). Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to monomethyl auristatin E, a microtubule disrupting agent.3 In two phase 2 studies of patients with CTCL, brentuximab vedotin showed an acceptable safety profile and significant clinical activity, with objective response rates (ORRs) of approximately 70%.4,5
The randomized, open-label, phase 3 ALCANZA trial (A Phase 3 Trial of Brentuximab Vedotin [SGN-35] Versus Physician’s Choice [Methotrexate or Bexarotene] in Patients With CD30-Positive Cutaneous T-Cell Lym-phoma) evaluated brentuximab ved-otin (1.8 mg/kg every 3 weeks) vs physician’s choice of methotrexate (5-50 mg weekly) or bexarotene (300 mg/m2 daily) in patients with previously treated CD30-positive mycosis fungoides or primary cutaneous ALCL.6 Patients were treated for up to sixteen 21-day cycles; among those receiving methotrexate or bexarotene, the goal was to achieve the maximum tolerated dose.
Patients were recruited from 52 centers in 13 countries. Enrolled patients were required to have expression of CD30 on at least 10% of either neoplastic cells or lymphoid infiltrate by central review of biopsy. Two biopsies were required for patients with mycosis fungoides. All mycosis fungoides patients had received at least 1 prior systemic therapy, and all primary cutaneous ALCL patients had received prior radiotherapy or at least 1 prior systemic therapy. The primary endpoint was the rate of objective response lasting at least 4 months (ORR4), with results assessed by independent review of global response using consensus guidelines published by the International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer.7 ORR4 was chosen as the primary endpoint in order to capture response rate and duration in a single measurement. Global response is a composite of skin evaluation, radiographic assessment, and Sézary cell enumeration. Secondary endpoints included progression-free survival (PFS), the rate of complete response (CR), and symptom burden as measured by the symptom domain of the Skindex-29 quality-of-life tool.8
The study randomly assigned 66 patients to the brentuximab vedotin arm and 65 to the comparator arm. Data from 64 patients in each arm were available for the intent-to-treat analysis. Baseline characteristics were generally well-balanced between the 2 arms. Patients had a median age of 59 to 62 years (range, 22-83 years), 52% to 58% were male, and nearly all patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Baseline biopsies showed a median baseline CD30 expression level of 31% to 33% (range, 3%-100%). Patients had received a median of 4 prior therapies overall (range, 0-15), and a median of 2 prior systemic therapies (range, 0-11). Approximately three-fourths of patients in each arm had mycosis fungoides, of whom 61% to 67% had advanced disease. In the brentuximab vedotin arm, 25% of patients had primary cutaneous ALCL vs 23% in the comparator arm. The brentuximab vedotin arm had a larger proportion of primary cutaneous ALCL patients with extracutaneous disease (44%
Median treatment duration was 36 weeks with brentuximab vedotin, 17 weeks with bexarotene, and 9 weeks with methotrexate. After a median follow-up of 17.5 months, the trial demonstrated a significant improvement in ORR4 with brentuximab vedotin vs physician’s choice of treatment (56.3% vs 12.5%; P<.0001). Brentuximab vedotin yielded a CR
rate of 15.6% vs 1.6% in the comparator arm (P=.0046), and the PFS was 16.7 months vs 3.5 months, respectively (HR, 0.270; 95% CI, 0.169-0.430; P<.0001; Figure 1). Brentuximab vedo-tin provided a superior reduction in skin symptoms, as assessed by
Skindex-29 symptom domain scores (-27.96 points vs -8.62 points; P<.0001; Figure 2). In the brentuximab vedotin arm, responses were observed across all stages of disease. Brentuximab vedotin was superior in subset analyses, demonstrating improved ORR4 in subgroups based on ECOG PS, sex, age, mycosis fungoides vs primary cutaneous ALCL, involvement of skin only vs other areas, and baseline tumor score.
The safety profile associated with brentuximab vedotin was generally similar to that observed in previous trials. An adverse event (AE) of grade 3 or higher was observed in 41% of the brentuximab vedotin arm vs 47% of the physician’s choice arm. A serious AE occurred in 29% of patients in each arm. AEs resulting in discontinuation of study treatment occurred in 24% vs 8% of patients, respectively. In the brentuximab vedotin arm, 6% of patients died within 30 days of the last dose vs 0 patients in the comparator arm. Among the 4 patients who died in the brentuximab vedotin arm, 3 died from causes considered unrelated to study treatment: lymphoma progression, pulmonary embolism, and sepsis. One patient with primary cutaneous ALCL died from multiple organ dysfunction syndrome attributed to tumor necrosis at visceral disease sites caused by brentuximab vedotin. The most common treatment-emergent AE of any grade was peripheral neuropathy, occurring in 67% of brentuximab vedotin patients vs 6% of patients receiving methotrexate or bexarotene, followed by nausea (36% vs 13%) and diarrhea (29% vs 6%). No grade 4 peripheral neuropathy was reported in the brentuximab vedotin arm. After a median 22.9 months of follow-up, peripheral neuropathy had improved or resolved in 82% of affected patients receiving brentuximab vedotin.
1. Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part II. Prognosis, management, and future directions. J Am Acad Dermatol. 2014;70(2):223.e1-223.e17.
2. Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M; ESMO Guidelines Working Group. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi149-vi154.
3. Zinzani PL, Bonthapally V, Huebner D, Lutes R, Chi A, Pileri S. Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: cutaneous T-cell lymphomas. Crit Rev Oncol Hematol. 2016;99:228-240.
4. Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. 2015;33(32):3759-3765.
5. Kim YH, Tavallaee M, Sundram U, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project. J Clin Oncol. 2015;33(32):3750-3758.
6. Kim YH, Whittaker S, Horwitz SM, et al. Brentuximab vedotin demonstrates significantly superior clinical outcomes in patients with CD30-expressing cutaneous T cell lymphoma versus physician’s choice (methotrexate or bexarotene): the phase 3 ALCANZA study [ASH abstract 182]. Blood. 2016;128(suppl 22).
7. Olsen EA, Whittaker S, Kim YH, et al; International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29(18):2598-2607.
8. Chren MM, Lasek RJ, Flocke SA, Zyzanski SJ. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases. Arch Dermatol. 1997;133(11):1433-1440.
Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients With Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study
Follicular lymphoma is considered incurable, and patients usually present with advanced disease at diagnosis.1,2 Median PFS for patients with advanced symptomatic follicular lymphoma is 6 to 8 years, and median survival is at least 12 years. Rituximab, an anti-CD20 monoclonal antibody, is a component of follicular lymphoma therapy during induction and maintenance and has played a key role in extending survival.3 Obinutuzumab (GA101) is a glycoengineered, humanized, type II, anti-CD20 monoclonal antibody that has demonstrated increased induction of direct cell death and antibody-directed cellular cytotoxicity, with reduced dependency on complement.4 Glycoengineering of the Fc region of the antibody was undertaken with the goal of enhancing immune effector functions.5 The glycoengineered antibody also showed a slower rate of internalization upon binding to SU-DHL4 cells and from cells in whole blood obtained from patients with chronic lymphocytic leukemia. In phase 2 clinical trials, obinutuzumab combined with lenalidomide or chemotherapy demonstrated activity in previously treated patients with follicular lymphoma or indolent non-Hodgkin lymphoma (NHL).6,7
The international, open-label, phase 3 GALLIUM study (A Study of Obinutuzumab [RO5072759] Plus Chemotherapy in Comparison With MabThera/Rituxan [Rituximab] Plus Chemotherapy Followed by GA101 or MabThera/Rituxan Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin’s Lymphoma) evaluated obinutuzumab plus chemotherapy vs rituximab plus chemotherapy in patients with treatment-naive, indolent B-cell NHL. Dr Robert Marcus presented results for 1202 patients with previously untreated follicular lymphoma of grade 1 to 3a.8 Patients had stage III/IV disease or bulky stage II disease, defined by a tumor diameter of at least 7 cm. All patients received induction chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine. In addition, patients were randomly assigned to receive treatment with either obinutuzumab or rituximab. Obinutuzumab (1000 mg) was administered on days 1, 8, and 15 of cycle 1. Thereafter, it was administered on day 1 of cycles 2 to 8 in patients receiving 3-week cycles of CHOP or CVP or on day 1 of cycles 2 to 6 in patients receiving 4-week cycles of bendamustine. Rituximab (375 mg/m2) was administered on day 1 of cycles 1 to 8 in patients receiving 3-week cycles of CHOP or CVP or on day 1 of cycles 1 to 6 in patients receiving 4-week cycles of bendamustine.
After induction, patients who achieved a CR or partial response (PR) continued to receive the same antibody treatment every 2 months as maintenance therapy. The study had an 80% power to detect a hazard ratio (HR) of 0.74 in follicular lymphoma patients. The primary endpoint was investigator-assessed PFS in follicular lymphoma patients. A preplanned interim efficacy analysis demonstrated a superior PFS in the obinutuzumab arm. As a result, the study was unblinded as recommended by the independent data monitoring committee, with a data cutoff of January 31, 2016.
At the end of induction, the ORR based on investigator assessment was 86.9% in the rituximab arm vs 88.5% in the obinutuzumab arm. CR rates were 23.8% vs 19.5%, respectively. After a median follow-up of 34.5 months, 3-year PFS was estimated at 73.3% with rituximab vs 80.0% with obinutuzumab, reflecting a 33% reduction in the risk of progression or death in patients treated with obinutuzumab (HR, 0.66; 95% CI, 0.51-0.85; P=.0012; Figure 3). PFS as assessed by an independent review committee confirmed obinutuzumab superiority (HR, 0.71; 95% CI, 0.54-0.93; P=.014). No significant difference was observed in overall survival (OS; P=.21). Discontinuation rates were 14.2% for patients receiving rituximab vs 16.3% for patients receiving obinutuzumab.
AEs of grade 3 or higher were observed in 67.9% of patients in the rituximab arm vs 74.9% of patients in the obinutuzumab arm, and included neutropenia in 37.9% vs 43.9%. Grade 3/4 febrile neutropenia occurred in 4.9% vs 6.9% of patients, respectively. Other grade 3/4 AEs of interest that were more frequent in the obinutuzumab arm included infections (15.6% vs 20.0%) and infusion-related reactions (6.7% vs 12.4%). Serious AEs were also more frequent with obinutuzumab (39.9% vs 46.1%). The rate of death was higher overall than anticipated (3.4% with rituximab vs 4.0% with obinutuzumab). In both treatment arms, the use of bendamustine was associated with a higher rate of death (5%) than CHOP or CVP.
1. Feugier P. A review of rituximab, the first anti-CD20 monoclonal antibody used in the treatment of B non-Hodgkin’s lymphomas. Future Oncol. 2015;11(9):1327-1342.
2. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055-2063.
3. Nastoupil LJ, Sinha R, Byrtek M, et al. The use and effectiveness of rituximab maintenance in patients with follicular lymphoma diagnosed between 2004 and 2007 in the United States. Cancer. 2014;120(12):1830-1837.
4. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12(10):2031-2042.
5. Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22):4393-
6. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013;122(7):1137-1143.
7. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015;33(30):3467-3474.
8. Marcus R, Davies A, Ando K, et al. Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study [ASH abstract 6]. Blood. 2016;128(suppl 22).
Preliminary Results From a Phase 1/2 Study of Brentuximab Vedotin in Combination With Nivolumab in Patients With Relapsed or Refractory Hodgkin Lymphoma
In Hodgkin lymphoma (HL), cure rates of 80% are achieved by combining chemotherapy and radiation treatments.1,2 However, long-term toxicities, such as secondary malignancies and cardiovascular effects, remain a concern.1,2 In a phase 2 study of 102 HL patients with relapsed or refractory disease following autologous stem cell transplant (SCT), durable remissions were achieved after treatment with brentuximab vedotin.3 Among the 34 patients who achieved a CR with brentuximab vedotin, 16 (47%) remained progression-free after a median follow-up of 53 months. Nivolumab is a fully human monoclonal antibody that targets the programmed death 1 (PD-1) immune checkpoint pathway. PD-1 is expressed on T cells and serves as a checkpoint to limit the immune responses mediated by these cells. Tumor cells that express the PD ligands 1 (PD-L1) or 2 (PD-L2) inhibit the surveillance activity of T cells, thus allowing the tumor cells to evade immune detection. Classical HL is marked by the presence of malignant Reed-Sternberg cells surrounded by ineffective inflammatory and immune cells. PD-L1 and PD-L2 expression is often increased on Reed-Sternberg cells, and nivolumab yielded an ORR of 87% and acceptable tolerability in a study of 23 heavily pretreated patients with relapsed or refractory HL.4 In a single-arm, phase 2 trial of 80 HL patients whose disease had failed to respond to both autologous SCT and treatment with brentuximab vedotin, nivolumab monotherapy was associated with an ORR of 66%, including a 28% CR rate.5
A phase 1/2 study evaluated the safety and efficacy of brentuximab vedotin plus nivolumab in adults with HL whose disease had failed to respond to first-line therapy.6 Patients were excluded from this study if they had previously received more than 1 line of prior therapy; therapy with brentuximab vedotin; treatment with any agent that targets the pathways for PD-1, cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), or CD137; or autologous SCT. Patients received treatment with the 2 antibodies in 21-day cycles for a maximum of 4 cycles. During cycle 1, brentuximab vedotin (1.8 mg/kg) was administered on day 1 and nivolumab (3 mg/kg) was administered on day 8. Thereafter, both drugs were administered on day 1 of each cycle. After completion of the final response assessment, patients were allowed to undergo autologous SCT. Investigator assessment of lymphoma response and progression was based on the Lugano Classification Revised Staging System for malignant lymphoma.7
The study enrolled 42 patients, with a median age of 37 years. Forty percent of patients had primary refractory disease, 33% had relapsed after a remission lasting no longer than 1 year, and 26% had relapsed after a remission duration of longer than 1 year. Twenty-six percent of patients had extranodal disease, and 10% had bulky disease. In 88% of patients, first-line therapy consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), and 12% had previously received radiation. At the time the study was reported, all patients had received at least 1 dose of the study drugs, 29% remained on treatment, and 67% had completed treatment.
The ORR in 29 evaluable patients was 90%, including a CR rate of 62% (Figure 4). Among the 18 patients who achieved a CR, 14 had a Deauville score of 1 or 2, and 3 had a Deauville score of 3. (The score was not reported for 1 patient.) Peripheral blood immunophenotyping was performed to determine the effect of treatment on various cell types. At baseline, a high percentage of regulatory T cells were shown to express CD30. After administration of single-agent brentuximab vedotin during cycle 1, no effect was observed on CD4-positive cells, but there was evidence of a decrease in immunosuppressive regulatory T cells. After administration of nivolumab on day 8 of cycle 1, the proportion of activated and dividing CD4-positive cells increased.
Nine patients were able to proceed to autologous SCT. There was no evidence that treatment with the combination of brentuximab vedotin plus nivolumab had any impact on stem cell mobilization or engraftment. The median number of apheresis sessions was 2 (range, 1-3), the median total number of CD34-positive cells harvested was 7.9 cells/kg (range, 4-26), the median time to neutrophil engraftment was 11.5 days (range, 9-15), and the median time to platelet engraftment was 16 days (range, 12-20).
Five percent of patients had discontinued before completing study treatment, 21% had initiated autologous SCT, and 5% had received an alternative salvage therapy prior to autologous SCT. Patients had received a median of 4 doses of the 2 antibodies (range, 1-4 doses). No patients discontinued treatment owing to an AE. Infusion-related reactions leading to dose interruption occurred in 26% of patients receiving brentuximab vedotin and 7% of those receiving nivolumab.
The most common treatment-emergent AEs of any grade were fatigue, nausea, infusion-related reactions, and pruritus, each occurring in approximately 30% to 40% of patients. All AEs observed in 10% or more of patients were grade 1 or 2, with the exception of 1 patient who experienced grade 3 urticaria. Infusion-related reactions were observed in 38% of patients, including 1 patient with a grade 3 reaction. The most common symptoms included flushing (14%), nausea (14%), chest discomfort (12%), dyspnea (12%), urticaria (12%), cough (10%), and pruritus (10%). The study protocol was amended to require premedication with low-dose corticosteroids and antihistamines at cycles 2 to 4, but the rate and severity of infusion-related reactions did not change. Potential immune-related AEs of any grade included infusion-related reaction (36%), rash (29%), diarrhea (26%), transaminase elevation (10%), and hypothyroidism (5%). All of these events were grade 1 or 2, with the exception of 1 patient (2%) who experienced a grade 3/4 transaminase elevation. There were no reports of pneumonitis or colitis. Four patients received topical corticosteroids for rash and infusion-related reactions. Five patients received systemic corticosteroids for infusion-related reactions, and 1 patient each received systemic corticosteroids for urticaria, rash, pruritus, ear itching, or elevated alanine transaminase.
1. Bhatt G, Maddocks K, Christian B. CD30 and CD30-targeted therapies in Hodgkin lymphoma and other B cell lymphomas. Curr Hematol Malig Rep. 2016;11(6):480-491.
2. Stathis A, Younes A. The new therapeutical scenario of Hodgkin lymphoma. Ann Oncol. 2015;26(10):2026-2033.
3. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(8):1236-1243.
4. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319.
5. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294.
6. Herrera AF, Bartlett NL, Ramchandren R, et al. Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 1105]. Blood. 2016;128(suppl 22).
7. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
BEACOPP Escalated Followed by Radiotherapy of Initial Bulk or Residual Disease in Advanced Stage Hodgkin Lymphoma: Long-Term Follow Up of the HD9 and HD12 Trials of the German Hodgkin Study Group
In trial HD9 from the German Hodgkin Study Group (GHSG), patients were randomly assigned to 1 of 3 chemotherapy regimens: 4 cycles of cyclophosphamide, vincristine, pro-carbazine, and prednisone alternating with ABVD (COPP-ABVD); 8 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (standard BEACOPP); or 8 cycles of escalated BEACOPP, which contains increased doses of etoposide, doxorubicin, and cyclophosphamide.1 When indicated, treatment was followed by local radiotherapy. Enrollment in the COPP-ABVD group was stopped in 1996 based on inferior results. The trial established 8 cycles of escalated BEACOPP followed by radiotherapy at sites of initial bulky disease or residual tumors as the standard of care for patients with advanced HL.
Subsequently, trial HD12 evaluated a reduced-intensity regimen in an effort to improve tolerability while maintaining efficacy.2 HD12 compared 8 cycles of escalated BEACOPP vs 4 cycles of escalated BEACOPP followed by 4 cycles of standard BEACOPP with concomitant radiotherapy (the 4 + 4 regimen), but with no radiotherapy at sites of initial bulk or residual disease. The trial enrolled 1670 patients between January 1999 and January 2003. After 5 years of follow-up, the reduced-intensity regimen did not substantially reduce rates of severe toxicity and may have yielded decreased efficacy compared with escalated BEACOPP.
Dr Bastian von Tresckow of the University of Cologne in Cologne, Germany presented long-term foll-ow-up from the GHSG HD9 and HD12 trials.3 After a median observation time of 141 months, the 15-year estimate of cumulative secondary malignancies was similar for patients treated with 4 cycles of COPP/ABVD (7.2%), 8 cycles of standard BEACOPP (9.1%), or 8 cycles of escalated BEACOPP (11.4%). The estimated 15-year PFS confirmed the initial finding that showed superior efficacy with escalated BEACOPP. Fifteen-year PFS estimates were 57.0% for patients treated with 4 cycles of COPP/ABVD, 66.8% for patients treated with 8 cycles of standard BEACOPP (HR vs 4 cycles of COPP/ABVD, 0.73), and 74.0% for patients treated with 8 cycles of escalated BEACOPP (HR vs 4 cycles of COPP/ABVD, 0.53). The difference in estimated 15-year PFS for 4 cycles of COPP/ABVD vs 8 cycles of escalated BEACOPP was 17.0%. The intensified regimen also yielded an improved OS. The estimated 15-year OS was 72.3% with 4 cycles of COPP/ABVD, 74.5% with 8 cycles of standard BEACOPP, and 80.9% with 8 cycles of escalated BEACOPP.
In HD12, patients with sites of initial bulk or residual disease were randomly assigned to receive radiotherapy or no further treatment. After a median observation time of 95 months to 100 months, the rates of secondary malignancies in the HD12 patients receiving 8 cycles of escalated BEACOPP were 9.2% with radiotherapy vs 6.3% without radiotherapy. These rates were 5.9% vs 6.1% for patients receiving the 4 + 4 regimen with or without radiotherapy, respectively. The standardized incident ratios ranged from 2.3 to 3.2 for the 4 treatment arms, with overlapping confidence intervals. Comparison of the 2 chemotherapy regimens yielded similar survival outcomes. After a median observation time of 105 months, the median estimated 10-year OS for treatment was 87.3% with 8 cycles of escalated BEACOPP vs 86.8% with the 4 + 4 regimen, with no difference in risk (HR, 1.0; 95% CI, 0.7-1.4).
In contrast, radiotherapy was associated with an improved PFS. After a median observation time of 97 months, median estimated 10-year PFS was 86.8% for patients who received radiotherapy vs 82.2% for patients who did not. The results were confounded by the fact that 229 patients in the radiotherapy group did not receive radiotherapy, and 69 patients in the no-radiotherapy group did receive radiotherapy. With a median observation time of 100 months, analysis of the patients based on actual radiotherapy exposure yielded median estimated 10-year PFS rates of 89.8% in patients without radiotherapy exposure vs 83.3% in patients with radiotherapy to initial bulk or residual tumors. Similarly, OS analysis based on actual treatment revealed a superior outcome with radiotherapy. With a median observation time of 107 months, the median estimated 10-year OS was 93.7% in patients treated with radiotherapy and 90.4% in patients without radiotherapy. In patients with residual lesions only, the difference in OS was even more pronounced. After a median observation time of 108 months, median estimated 10-year OS was 94.4% in patients who received radiotherapy vs 88.4% in patients who did not.
The long-term analysis confirmed earlier results observed in patients with advanced HL. Despite a potential increase in the rate of secondary cancers, escalated BEACOPP was superior to 4 cycles of COPP/ABVD in terms of PFS and OS. Eight cycles of escalated BEACOPP plus radiotherapy in patients with initial bulk or residual disease was associated with a 15-year PFS of 74% and a 15-year OS of 80.9%. Radiotherapy was particularly beneficial in patients with residual lesions after chemotherapy. The current GHSG strategy for this patient population is 6 cycles of escalated BEACOPP followed by radiotherapy of residual lesions based on imaging with positron emission tomography.
1. Diehl V, Franklin J, Pfreundschuh M, et al; German Hodgkin’s Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395.
2. Borchmann P, Haverkamp H, Diehl V, et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.
3. Kreissl S, von Tresckow B, Goergen H, et al. BEACOPPescalated followed by radiotherapy of initial bulk or residual disease in advanced stage Hodgkin lymphoma: long-term follow up of the HD9 and HD12 trials of the German Hodgkin Study Group [ASH abstract 923]. Blood. 2016;128(suppl 22).
A Phase I Study With an Expansion Cohort of the Combination of Ipilimumab and Nivolumab and Brentuximab Vedotin in Patients With Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412 Arms D and E)
The phase 1 E4412 trial was designed to test the hypothesis that targeting tumor cells with brentuximab vedotin and concomitantly activating immune cells in the tumor microenvironment would improve outcomes in HL patients.1 Eligible patients were adults with relapsed or refractory HL and measurable disease. Exclusion criteria included use of brentuximab vedotin during the prior 6 months, relapse within 6 months of receiving prior brentuximab vedotin, and prior nivolumab treatment. Three patients were initially enrolled in arm D (dose level 1), in which they received nivolumab at 3 mg/kg on day 1 of cycles 1 to 46 plus brentuximab vedotin at 1.2 mg/kg on day 1 of cycles 1 to 16, in 3-week cycles. Seven patients in arm E (dose level 2) received nivolumab as in arm D plus a higher dose of brentuximab vedotin, 1.8 mg/kg, given on day 1 of cycles 1 to 16. Arm F was the phase 1 expansion cohort, and 9 patients in this arm received the same treatment as patients in arm E. Brentuximab vedotin and nivolumab were administered on the same day, with brentuximab vedotin administered first, followed by 1 hour of observation, and subsequent administration of nivolumab. Responses were assessed by the investigator. A Deauville score of 1 or 2 was required for CR. Imaging was performed at study start and at 12 weeks, then every 3 months.
The primary objective of the study was to determine the maximum tolerated dose and dose-limiting toxicities of the regimen. Secondary objectives included response rates, clinical benefit, response duration, and survival. Correlative studies included tumor- specific T-cell immunity, systemic cytokine and T-cell specific profiles, and gene expression profiling to determine a response vs resistance signature.
The 19 enrolled patients had a median age of 40 years (range, 21-70 years), and 53% were male. Patients had a baseline ECOG PS of 0 (57%), 1 (32%), or 2 (11%). Twenty-six percent of patients had B symptoms, and the median number of prior systemic therapies was 3 (range, 1-7). Forty-two percent of patients had received prior SCT, and 21% had received prior treatment with brentuximab vedotin. One patient required a brentuximab vedotin dose reduction. In 2 patients, the dose of brentuximab vedotin was delayed. Nivolumab dose delays occurred in 2 patients.
In the population of 12 evaluable patients, the ORR was 100%, including 66% CRs (Figure 5). Two patients had received prior brentuximab vedotin, and both of these patients achieved a CR. After a median follow-up of 4.7 months, median PFS was 8.5 months (Figure 6). After a median follow-up of 3.5 months, median OS was not reached. The durability of responses will be evaluated when longer follow-up data are available, and correlative studies are continuing.
Treatment was generally well-tolerated. The most common AE of any grade was elevation of hepatic enzymes, which occurred primarily in cycle 1, consisted of grade 1/2 events, and was transient, with no impact on treatment. The second most common AE of any grade was grade 1/2 peripheral sensory neuropathy, observed most frequently in patients who had received prior brentuximab vedotin. Other common AEs of any grade included nausea, maculopapular rash, headache, and fever. Six grade 3 to 5 AEs were observed.
1. Diefenbach CS, Hong F, David KA, et al. A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN cancer research group (E4412 arms D and E) [ASH abstract 1106]. Blood. 2016;128(suppl 22).
Five-Year Survival Data From a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients With Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma
An open-label, multicenter, pivotal phase 2 study evaluated the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory systemic ALCL.1 Eligible patients had CD30-positive relapsed or refractory systemic ALCL, were at least 12 years old, had measurable disease, and had an ECOG PS of 0 or 1. The first patient was enrolled in June 2009, and all patients had completed treatment by June 2011. Patients received brentuximab vedotin (1.8 mg/kg) on day 1 of 21-day cycles for up to 16 cycles. The primary endpoint was ORR based on independent review, with a secondary endpoint of OS. Additional prespecified endpoints included PFS and ORR according to investigator review.
The study enrolled 58 patients with a median age of 52 years (range, 14-76 years). Fifty-seven percent of patients were male, and all but 1 patient had an ECOG PS of 0 or 1. Seventy-two percent of patients had anaplastic lymphoma kinase (ALK)-negative disease, 62% had disease that was refractory to first-line therapy, and 26% had previously undergone autologous SCT.
The initial ORR based on independent review was 86%, including 59% CRs.2 The most common AEs of grade 3 or higher were neutropenia (21%), peripheral neuropathy (17%), and thrombocytopenia (14%). Peripheral neuropathy occurred in 57% of patients; the majority of cases were grade 1 or 2. The peripheral neuropathy completely resolved in 67% of patients, and no grade 3 cases were evident at last follow-up. In 8 of 11 patients with ongoing peripheral neuropathy at last follow-up, the maximum severity was grade 1. In patients whose peripheral neuropathy resolved, the median time from onset to resolution was 14 weeks.
Five-year follow-up data were presented by Dr Barbara Pro.3 After a median observation time of 71.4 months, the estimated 5-year OS was 60% (Figure 7), the median OS was not estimable, and the median PFS was 20.0 months. The estimated 5-year OS rate was 61% in patients with ALK-negative disease vs 56% in those with ALK-positive disease. In the 38 patients who achieved a CR with brentuximab vedotin, response duration ranged from 0.9 months to 79.7+ months. The median response duration was not reached. Among the patients who achieved a CR, 16 subsequently underwent consolidative allogeneic or autologous SCT. Median OS and median PFS were not reached in these patients. In the 22 patients with CR who did not undergo consolidative SCT, the median OS was not reached (Figure 8), and the median PFS was 39.4 months. The ongoing phase 3 ECHELON-2 trial (A Comparison of Brentuximab Vedotin and CHP With Standard-of-Care CHOP in the Treatment of Patients With CD30-Positive Mature T-Cell Lymphomas) is evaluating brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone vs CHOP as first-line treatment for CD30-expressing peripheral T-cell lymphomas, including systemic ALCL.4
1. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-2196.
2. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-2196.
3. Pro B, Advani RH, Brice P, et al. Five-year survival data from a pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma [ASH abstract 4144]. Blood. 2016;128(suppl 22).
4. ClinicalTrials.gov. ECHELON-2: a comparison of brentuximab vedotin and CHP with standard-of-care CHOP in the treatment of patients with CD30-positive mature T-cell lymphomas (ECHELON-2). https://clinicaltrials.gov/ct2/show/NCT01777152. Identifier: NCT01777152. Accessed January 2, 2017.
CheckMate 205 Update With Minimum 12-Month Follow Up: A Phase 2 Study of Nivolumab in Patients With Relapsed/Refractory Classical Hodgkin Lymphoma
In patients with relapsed or refractory classical HL following autologous SCT, historical PFS data suggest that the durability of response to subsequent brentuximab vedotin corresponds with the depth of response. In a phase 2 study, 102 HL patients who had relapsed following autologous SCT were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of 16 cycles.1 The ORR was 75%, including 34% CRs. The median PFS for the entire study group was 5.6 months. Median response duration was 20.5 months for patients who achieved a CR and 6.7 months for patients who achieved a PR. Classical HL is characterized by malignant cells with alterations at the 9p24.1 locus that result in overexpression of the PD-1 ligands, PD-L1 and PD-L2, suggesting that silencing of the immune checkpoint pathway could enhance killing of malignant HL cells.2 Nivolumab targets PD-1 and is approved by the US Food and Drug Administration for treatment of classical HL that has relapsed or progressed after autologous SCT and posttransplant treatment with brentuximab vedotin. The Checkmate 205 (Study of Nivolumab in Patients With Classical Hodgkin’s Lymphoma) trial investigated the efficacy and safety of single-agent nivolumab (3 mg/kg) every 2 weeks in patients with classical HL after failure of autologous SCT.3 Cohort A included 63 patients who had no exposure to brentuximab vedotin after SCT and cohort B included 80 patients who received brentuximab vedotin after SCT. Patients in cohort A vs cohort B had a median age of 33 years (range, 18-65 years) vs 37 years (range, 18-72 years), respectively. All patients had an ECOG PS of 0 or 1. The median number of previous therapies was 2 (range, 2-8) in cohort A and 4 (range, 3-15) in cohort B. In cohort A, 32% of patients had received systemic cancer therapy or radiotherapy following autologous SCT. The primary endpoint was the ORR following a prespecified minimum follow-up period of 6 months, as assessed by independent review. Among 80 patients in cohort B, the primary endpoint analysis showed an ORR of 66%. The median PFS was 10 months, and the response duration was 8 months.
Dr John Timmerman presented initial findings from cohort A and updated findings from cohort B.4 Minimum follow-up was 9 months in cohort A vs 12 months in cohort B. In cohort A, 93% of 63 evaluable patients showed a reduction in tumor burden. The ORR was 68%, including 14 patients with a CR (Table 1). Responses generally occurred fairly quickly in the brentuximab vedotin–naive patients, with a median time to response of 2 months (range, 2-6 months). After a median follow-up of 14 months (range, 1-20 months), the median duration of response and the median PFS were not reached overall, nor in the subsets of patients who had achieved a CR or PR. Nine-month PFS was 68%, and 9-month OS was 97%.
Six patients in cohort A and 11 patients in cohort B proceeded to allogeneic hematopoietic SCT after nivolumab treatment. The median time from last nivolumab dose to transplant was 158 days (range, 27-411 days) in cohort A vs 38 days (range, 23-271 days) in cohort B. In cohort B, 4 patients experienced grade 2 to 4 graft-vs-host disease. There were no deaths from disease progression reported among patients who proceeded to allogeneic hematopoietic SCT, and no transplant-related mortality occurred. In cohort B, the median follow-up was 15 months (range, 2-19 months). The ORR was 68%, including 6 patients (7.5%) with a CR, and 95% of patients showed a reduction in tumor burden. The median duration of response was 13 months. Among patients who achieved a CR, the median duration of response was not reached. It was 13 months among patients who achieved a PR. Twelve-month OS was 95%.
At the time of this analysis, most patients remained on treatment (62% in cohort A vs 54% in cohort B). Reasons for discontinuing treatment included disease progression (25% in cohort A vs 24% in cohort B), nivolumab toxicity (3% vs 6%), and AEs unrelated to study drug (2% vs 1%). Toxicities leading to study drug discontinuation included hepatic-related events (n=4), pneumonitis (n=2), and syncope (n=1). In cohort A, the most common drug-related AEs of any grade included fatigue (29%), diarrhea (21%), rash (13%), and pruritus (13%). In cohort B, the most common drug-related AEs of any grade were fatigue (29%), infusion-related reaction (20%), rash (15%), and arthralgia (15%). Drug-related grade 3/4 AEs occurred in 11% of patients in cohort A and 30% in cohort B. Drug-related serious AEs were reported in 1 patient in each cohort. No treatment-related deaths occurred in either cohort.
1. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294.
2. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268-3277.
3. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294.
4. Timmerman JM, Engert A, Younes A, et al. Checkmate 205 update with minimum 12-month follow up: a phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma [ASH abstract 1110]. Blood. 2016;128(suppl 22).
Highlights in Lymphoma From the 2016 American Society of Hematology Annual Meeting and Exposition: Commentary
Steven M. Horwitz, MD
Memorial Sloan Kettering Cancer Center
New York, New York
Several abstracts presented at the 2016 American Society of Hematology (ASH) meeting provided data that may impact the management of patients with lymphoma. New and updated study data were presented for T-cell lymphoma, B-cell lymphoma, and classical Hodgkin lymphoma.
Two studies of newer therapeutic approaches in T-cell lymphoma, both in cutaneous T-cell lymphoma, were practice-changing or at least practice-informing.
The ALCANZA trial (A Phase 3 Trial of Brentuximab Vedotin [SGN-35] Versus Physician’s Choice [Methotrexate or Bexarotene] in Patients With CD30-Positive Cutaneous T-Cell Lymphoma) was one of the more impactful studies presented at the 2016 ASH meeting. Dr Youn Kim presented results from this phase 3, international study, which enrolled 131 patients with mycosis fungoides or anaplastic large cell lymphoma.1 ALCANZA is a randomized study, which is rare in this setting. The investigational arm was brentuximab vedotin, and the control arm was an investigator’s choice of either methotrexate or bexarotene. One audience question about this study concerned the selection of the therapies for the control arm. The choice was based primarily on the availability of standard agents at all of the participating centers, which included sites in Europe and Australia. Methotrexate and bexarotene are among the more commonly available and commonly used systemic therapies for cutaneous T-cell lymphoma worldwide.1 Several of the agents available in the United States, such as romidepsin and pralatrexate, are not available in some countries.
All patients with mycosis fungoides had received previous systemic treatment, and had a CD30 expression of at least 10% on tumor cells or the lymphoid infiltrate as assessed by central pathology review of at least 2 skin biopsies. Patients with anaplastic large cell lymphoma, which is always CD30-positive, had relapsed after prior systemic therapy or radiation therapy.
The ALCANZA trial used a novel primary endpoint known as overall response rate 4 (ORR4), which was defined as a global response (encompassing response in skin, lymph nodes, and blood) that lasted at least 4 months. In many studies of cutaneous T-cell lymphoma, because the disease is visible and very symptomatic, there is a tendency for patients with minimal response or stable disease to discontinue treatment and switch therapy before they develop defined progressive disease. Consequently, those patients who switch therapy without progression may be censored from assessment of progression-free survival (PFS), and/or their PFS may be impacted by subsequent therapy. To compensate for this occurrence, ORR4 was designed in consultation with the US Food and Drug Administration (FDA) and key experts to identify responses of sufficient degree and duration as to be clinically meaningful. Secondary endpoints included complete response rate and PFS.
The results showed that brentuximab vedotin was significantly better than the standard arm of methotrexate or bexarotene.1 The ORR4 was 56% for brentuximab vedotin vs 12.5% for the physician’s choice of treatment. The complete response rate was 15.6% for brentuximab vedotin and just 1.6% for physician’s choice. The median PFS was more than 16 months for brentuximab vedotin vs less than 4 months for physician’s choice. Quality-of-life assessments also showed significant benefit for brentuximab vedotin.
Historically, many systemic ther-apies for cutaneous T-cell lymphoma were associated with moderate res-ponse rates in phase 2 trials. It was difficult to know whether one agent was more active than another, and selection was based on factors such as toxicity, ease of administration, and cost. With ALCANZA, however, there is now a randomized study that clearly shows significantly better activity for one drug, brentuximab vedotin, over some standard therapies. These results will surely factor into the selection and sequencing of therapy for patients with cutaneous T-cell lymphoma.
One caveat to this new approach concerns cumulative toxicity. A common principle of management for this disease was to select milder therapies and give them until progression or intolerance. Many of the standard drugs used in this setting, such as bexarotene, methotrexate, vorinostat, and romidepsin, are not associated with cumulative toxicity.2 Brentuximab vedotin has neuropathy as a cumulative toxicity. It cannot be given indefinitely. In the ALCANZA trial, the average number of cycles was 12. Physicians will need to balance the benefits of the higher response rate, which correlated with quality-of-life improvement, against the cumulative toxicity of neuropathy, which often leads to treatment discontinuation.
A multicenter, phase 2 trial of pembrolizumab from the Cancer Immunotherapy Trials Network provided data on another new option for relapsed mycosis fungoides and Sézary syndrome. Dr Michael Khodadoust presented preliminary results.3 Treatments for mycosis fungoides and Sézary syndrome are associated with responses that have some durability, but they do not cure the disease. There is almost always a need for subsequent lines of therapy. In many of these patients, particularly those with Sézary syndrome, tumor cells express programmed death 1 (PD-1).4 Pembrolizumab inhibits PD-1. Data on checkpoint inhibitors in cutaneous T-cell lymphomas are limited. The minimal data available for these patients from the nivolumab studies showed mostly stable disease and few responses.5
The study enrolled 15 patients with Sézary syndrome and 9 with mycosis fungoides. Patients with mycosis fungoides had stage 1b or higher disease, and all had relapsed after prior systemic therapy.
The overall response rate was 38%.3 Responses were seen across all subgroups, including patients with Sézary syndrome and advanced-stage disease. Some of the responses were fairly durable. Although the follow-up was relatively short, there were ongoing responses beyond 6 months and beyond a year. Most of the responses occurred within the first 2 months of treatment.
Some patients developed red, inflamed skin that resembled progression of disease. However, biopsies showed this reaction to be a flare from the treatment, and some of these patients subsequently responded. The study is also analyzing immune correlates to identify predictors of response, but results are not yet available.
Pembrolizumab is currently FDA-approved for other settings, such as advanced melanoma, non–small cell lung cancer, and head and neck squamous cell cancer. This study will likely stimulate additional studies of checkpoint inhibition in cutaneous T-cell lymphoma and other T-cell lymphomas.
There were several abstracts in B-cell lymphoma. Two have the potential to change clinical practice.
The international, randomized, phase 3 GALLIUM study (A Study of Obinutuzumab [RO5072759] Plus Chemotherapy in Comparison With MabThera/Rituxan [Rituximab] Plus Chemotherapy Followed by GA101 or MabThera/Rituxan Maintenance in Patients With Untreated Advanced Indolent Non-Hodgkin’s Lymphoma) evaluated obinutuzumab in patients with previously untreated, indolent non-Hodgkin lymphoma. In the ASH plenary session, Dr Robert Marcus presented results for the follicular lymphoma cohort (n=1201).6 These patients had grade 1 to 3a disease that was advanced stage or bulky. Most of the patients had advanced-stage disease and high scores on the Follicular Lymphoma International Prognostic Index (FLIPI). Approximately half of the patients had bulky disease. These patients therefore had a high tumor burden and were an appropriate population to receive chemoimmunotherapy.
Patients were randomly assigned to receive induction therapy with obinutuzumab plus chemotherapy or rituximab plus chemotherapy. The chemotherapy regimen could consist of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); or bendamustine. Each institution involved in the study was permitted to preselect a chemotherapy regimen that was used by all of its enrolled patients. When interpreting the results, it is important to know that there was no individual bias impacting which patients received which regimen.
Patients who achieved a complete or partial response then went on to receive maintenance therapy. Those in the obinutuzumab induction arm received obinutuzumab maintenance, and those in the rituximab induction arm received rituximab maintenance.
At the end of induction therapy, the overall response was similar in both treatment arms, at 86.9% for patients receiving rituximab plus chemotherapy and 88.5% for patients receiving obinutuzumab plus chemotherapy.6 Differences, however, appeared after maintenance therapy. PFS was significantly improved with obinutuzumab and chemotherapy. The 3-year PFS was 80% for obinutuzumab plus chemotherapy vs 73% for rituximab plus chemotherapy (hazard ratio, 0.66). A similar benefit with obinutuzumab was seen in time to next therapy, another endpoint. At 3 years, 87.1% of the obinutuzumab group did not require therapy vs 81.2% of the rituximab group (hazard ratio, 0.68). There was no difference in terms of overall survival, at a median follow-up of just under 3 years. In this study, obinutuzumab plus chemotherapy appeared to provide similar response and better durability than rituximab plus chemotherapy.
There was a mild imbalance in terms of toxicity, with numerically higher instances of febrile neutropenia and infection in the obinutuzumab plus chemotherapy arm. Not surprisingly, infusion-related events were significantly higher in the obinutuzumab arm.
Another interesting and unexpected finding from this study that may impact practice was an increased number of fatal adverse events among patients treated with bendamustine. There were more grade 5 adverse events in the bendamustine-containing regimens, as compared with CHOP or CVP, regardless of whether patients also received obinutuzumab or rituximab. These deaths spanned a number of different etiologies, including pneumonia, respiratory and other infections, sepsis, and bacteremia. Some clinicians believe that this difference is an accurate reflection of increased toxicity and risk with bendamustine, whereas others view it as more of an isolated finding in this study alone.
The takeaways from this study are that obinutuzumab in combination with chemotherapy, when compared with rituximab in combination with chemotherapy, had superior activity in terms of PFS at the cost of some modest increase in toxicity, and that bendamustine as part of chemoimmunotherapy resulted in a higher number of toxicity-related deaths than CHOP or CVP. These findings have led some clinicians to reconsider using bendamustine as a standard chemotherapy for patients with follicular lymphoma. Use of bendamustine is particularly being questioned in younger patients who are likely to tolerate CHOP reasonably well.
R-CHOP vs Dose-Adjusted EPOCH-R
An important, and long-awaited, phase 3 trial from the US Intergroup, led by the Alliance for Clinical Trials in Oncology, randomly assigned patients with untreated diffuse large B-cell lymphoma to receive rituximab plus CHOP (R-CHOP) or rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH-R).7 This long-term study was based on preliminary data, largely from the National Cancer Institute, suggesting that dose-adjusted EPOCH-R may provide higher activity in these patients overall or in certain subsets. The study enrolled more than 500 patients.
There were no significant differences between the 2 treatments.7 Overall response rates were approximately 89% in each arm. Complete response rates were 62% for R-CHOP and 61% for dose-adjusted EPOCH-R. There were no significant differences in event-free survival and overall survival.
There was some increased toxicity, primarily hematologic events, in the dose-adjusted EPOCH-R arm. These patients experienced more high-grade thrombocytopenia, neutropenia, and febrile neutropenia. EPOCH is dose-adjusted based on the nadir counts, so it is expected that if the dose is escalated based on lack of a sufficient nadir, it will push more patients toward higher grades of hematologic toxicity. There was also more neuropathy in the dose-adjusted EPOCH-R arm.
In subset analyses, the study stratified patients according to International Prognostic Index scores, to see whether outcome varied according to low, intermediate, or high risk. The numbers are too small to draw any firm conclusions, but there was at least a possibility that higher-risk patients may have achieved benefit from dose-adjusted EPOCH-R. Confirmation of this observation will of course require further study. The study authors are performing subset analysis based on cell of origin to determine whether EPOCH-R might be better for certain subtypes of large B-cell lymphoma. Those data were not yet available.
There were updates on the use of checkpoint inhibitors in patients with Hodgkin lymphoma. Long-term analysis of the phase 2, single-agent studies of pembrolizumab and nivolumab continued to show high rates of activity and durability.8,9 There were patients with relapsed or refractory Hodgkin lymphoma who appear to have long-term disease control with pembrolizumab or nivolumab. The FDA approved nivolumab for relapsed/refractory classical Hodgkin lymphoma in May 2016. A similar approval is expected for pembrolizumab. These agents are finding a place among more standard therapy in the later-line relapsed/refractory setting and are being tested in earlier lines of therapy.
Brentuximab Vedotin Plus Nivolumab
Several ongoing studies are evaluating checkpoint inhibitors in earlier lines of therapy or as part of combinations. Dr Alex Herrera presented preliminary data for a phase 1/2 study of brentuximab vedotin plus nivolumab as second-line therapy in patients with relapsed or refractory classical Hodgkin lymphoma.10 All the patients responded to treatment and were able to proceed directly to autologous stem cell transplant. Half of the patients had complete responses. Interestingly, in studies of single-agent brentuximab vedotin as a second-line therapy, only about a third of patients had complete or near-complete responses to brentuximab vedotin alone that allowed them to proceed directly to transplant without additional chemotherapy.11,12
This chemotherapy-free second-line regimen appears quite active. At this early stage, however, I would not recommend use of this approach off-study. It will be of interest to see how these data mature. There will likely be many additional follow-up studies evaluating ways to incorporate checkpoint inhibitors into earlier lines of therapy for Hodgkin lymphoma.
Dr Horwitz has received research funding from Seattle Genetics, Takeda, and Celgene, and consulting fees from Seattle Genetics and Takeda.
1. Kim YH, Whittaker S, Horwitz SM, et al. Brentuximab vedotin demonstrates significantly superior clinical outcomes in patients with CD30-expressing cutaneous T cell lymphoma versus physician’s choice (methotrexate or bexarotene): the phase 3 ALCANZA study [ASH abstract 182]. Blood. 2016;128(suppl 22).
2. Poligone B, Heald P. Menus for managing patients with cutaneous T-cell lymphoma. Semin Cutan Med Surg. 2012;31(1):25-32.
3. Khodadoust M, Rook AH, Porcu P, et al. Pembrolizumab for treatment of relapsed/refractory mycosis fungoides and Sézary syndrome: clinical efficacy in a CITN multicenter phase 2 study [ASH abstract 181]. Blood. 2016;128(suppl 22).
4. Samimi S, Benoit B, Evans K, et al. Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol. 2010;146(12):1382-1388.
5. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698-2704.
6. Marcus R, Davies A, Ando K, et al. Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study [ASH abstract 6]. Blood. 2016;128(suppl 22).
7. Wilson WH, sin-Ho J, Pitcher BN, et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303 [ASH abstract 469]. Blood. 2016;128(suppl 22).
8. Moskowitz CH, Zinzani PL, Fanale MA, et al. Pembrolizumab in relapsed/refractory classical Hodgkin lymphoma: primary end point analysis of the phase 2 KEYNOTE-087 study [ASH abstract 1107]. Blood. 2016;128(suppl 22).
9. Timmerman JM, Engert A, Younes A, et al. Checkmate 205 update with minimum 12-month follow up: a phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma [ASH abstract 1110]. Blood. 2016;128(suppl 22).
10. Herrera AF, Bartlett NL, Ramchandren R, et al. Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 1105]. Blood. 2016;128(suppl 22).
11. Chen R, Palmer JM, Martin P, et al. Results of a multicenter phase II trial of brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2015;21(12):2136-2140.
12. Moskowitz AJ, Schöder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin’s lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284-292.
ABSTRACT SUMMARY Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination With CHP in the Frontline Treatment of Patients With CD30-Expressing Peripheral T-Cell Lymphomas
A phase 1 trial evaluated 6 cycles of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone followed by 10 cycles of brentuximab vedotin monotherapy as first-line treatment in 26 patients with peripheral T-cell lymphoma (Abstract 2993). Most of the patients (73%) had systemic ALCL, and most (73%) had stage III/IV disease. After a median observation time of 53 months (range, 4.6-58.3 months), 17 patients remained in the study. An AE led 23% of patients to discontinue study treatment. The most common grade 3/4 AEs were febrile neutropenia (31%), nonfebrile neutropenia (23%), anemia (15%), and pulmonary embolism (12%). Peripheral neuropathy was reported in 73% of patients, but resolved in most (with a median time to resolution of 5 months). No deaths occurred within 30 days of cessation of study treatment. The estimated 4-year PFS was 53% (95% CI, 31%-69%), and the estimated 4-year OS was 80% (95% CI, 59%-91%).
ABSTRACT SUMMARY Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303
The Alliance Intergroup compared rituximab plus CHOP (R-CHOP) vs dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (EPOCH-R) in patients with stage 2 or higher, newly diagnosed DLBCL (Abstract 469). The study was initiated in 2005. The efficacy analysis provided data for 233 patients in the R-CHOP arm and 232 patients in the dose-adjusted EPOCH-R arm. The baseline demographics and disease characteristics were well-balanced. Approximately 75% of patients had stage 3 or 4 disease. There were no significant differences in response between the 2 treatments. Overall response rates were approximately 89% in each arm. CR rates were 62% for R-CHOP vs 61% for dose-adjusted EPOCH-R. Event-free survival and OS did not significantly differ between the groups. More toxicity was seen with dose-adjusted EPOCH-R. Patients in this arm were more likely to discontinue treatment early (6.5% vs 1.5%; P=.004).
Safety and Activity of Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Initial Results of a Phase I/II Trial
A phase 1/2 study investigated the addition of brentuximab vedotin to ifosfamide, carboplatin, and etoposide (ICE) in patients with classical HL who had relapsed after first-line treatment or had primary refractory disease (Abstract 1834). Patients were excluded from the study if they had received prior treatment with brentuximab vedotin or recent treatment with chemotherapy. A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose of brentuximab vedotin in combination with ICE. Among the 16 patients who completed study treatment, 44% had advanced-stage disease at diagnosis, all had received first-line ABVD, 69% had achieved a CR with initial treatment, and 31% had received prior radiotherapy. One AE consisting of grade 4 sepsis was classified as a dose-limiting toxicity. The maximum tolerated dose was established as brentuximab vedotin at 1.5 mg/kg on days 1 and 8 plus ICE in two 21-day cycles. The ORR was 94%, including 88% CRs. After a median follow-up of 10.5 months, all patients were alive. All stem cell collection procedures were successful.
ABSTRACT SUMMARY Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Clinical Efficacy in a CITN Multicenter Phase 2 Study
A phase 2 trial from the Cancer Immunotherapy Trials Network evaluated pembrolizumab in 24 patients with relapsed/refractory mycosis fungoides or Sézary syndrome (Abstract 181). The ORR was 38%, consisting of 1 CR and 8 PRs. Among the patients who responded, 6 had 90% or greater improvement in skin disease. Stable disease was reported in an additional 38% of patients. The median time to response was 11 weeks (range, 8-41 weeks). Responses were durable, with 8 of 9 continuing at the time the study was reported. Responses were seen regardless of the patients’ disease stage, disease type, and number of prior systemic therapies. At the time of the analysis, the median PFS had not yet been reached, and the 1-year PFS was 69%. Skin tissue expression of PD-1, PD-L1, PD-L2, or infiltrating CD8-positive T cells did not impact treatment response.
Brentuximab Vedotin Plus ESHAP (BRESHAP) Is a Highly Effective Combination for Inducing Remission in Refractory and Relapsed Hodgkin Lymphoma Patients Prior to Autologous Stem Cell Transplant: A Trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)
A study from the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO) evaluated brentuximab vedotin plus etoposide (40 mg/m2) on days 1 to 4, methylprednisolone (250 mg) on days 1 to 4, high-dose cytarabine (2 g/m2) on day 5, and cisplatin (25 mg/m2) on days 1 to 4 (BRESHAP) in patients with relapsed or refractory HL. The phase 1 portion established 1.8 mg/m2 on day 1 as the appropriate dose of brentuximab vedotin (Garcia-Sanz R et al. 2015 ASH Abstract 582). Results for the phase 2 portion were presented at the 2016 ASH meeting (Abstract 1109). Among 66 patients, 61% had primary refractory disease, 41% had extranodal disease, 18% had received prior radiotherapy, and 30% had B symptoms. Following treatment, the ORR was 95%, including 71% CRs. The most common nonhematologic AEs of any grade were fever (27%), mucositis (27%), and pain (25%). Twenty-three serious AEs were reported, including fever (n=13), hypomagnesemia (n=3), and viral infection (n=2). One patient died from nonneutropenic abdominal sepsis, and 1 patient died from pulmonary embolism. There were no collection failures among the 64 patients who proceeded to stem cell transplant.
ABSTRACT SUMMARY Pembrolizumab in Relapsed/Refractory Classical Hodgkin Lymphoma: Primary End Point Analysis of the Phase 2 KEYNOTE-087 Study
The phase 2 KEYNOTE-087 study investigated the efficacy and safety of pembrolizumab, a PD-1 inhibitor, in patients with relapsed or refractory classical HL (Abstract 1107). The study enrolled 3 subtypes of patients: those who developed relapsed or refractory disease after autologous SCT and treatment with subsequent brentuximab vedotin (cohort 1); those who were ineligible for autologous SCT owing to chemoresistance and brentuximab vedotin therapy failure (cohort 2); and those with relapsed or refractory disease after autologous SCT who did not receive treatment with subsequent brentuximab vedotin (cohort 3). Based on blinded independent central review, the ORR for the entire study group of 210 patients was 69.0% (95% CI, 62.3%–75.2%), including 22.4% CRs. The ORR was 73.9% (95% CI, 61.9%–83.7%) in cohort 1, 64.2% (95% CI, 52.8%–74.6%) in cohort 2, and 70.0% (95% CI, 56.8%–81.2%) in cohort 3. The rate of CR in the 3 cohorts was 21.7%, 24.7%, and 20.0%, respectively. In patients with primary refractory vs relapsed disease, the ORR was 79.5% vs 67.8%, respectively. The fixed dose of pembrolizumab (200 mg) every 3 weeks was associated with an acceptable toxicity profile.
ABSTRACT SUMMARY A LYSA Phase II Study of Oral JAK1/2 Inhibitor Ruxolitinib in Advanced Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
Ruxolitinib, an oral inhibitor of JAK 1/2, was evaluated in a phase 2 study of patients with advanced relapsed or refractory HL (Abstract 4160). Ruxolitinib (20 mg) was administered twice daily for six 28-day cycles, with maintenance therapy allowed for patients exhibiting disease control. The 33 enrolled patients had received a median 5 prior lines of therapy (range, 1-16). Sixty-nine percent of patients had stage III/IV disease, and 82% were refractory to their most recent prior therapy. After induction, the ORR was 9.4%, with no CRs. The best ORR at any time during the study was 18.8%, and included 1 patient (3%) with a CR. The median duration of response was 7.7 months (95% CI, 1.8 months-not reached). Ruxolitinib did not meet the threshold level for activity based on the primary endpoint of response at 6 months. There were 40 AEs of any grade observed in 14 patients. Eighteen were of grade 3 or greater, and 8 AEs were serious. No AEs led to death.
ABSTRACT SUMMARY Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure: Long-Term Efficacy From the Phase 1b KEYNOTE-013 Study
The phase 1b KEYNOTE-013 study evaluated pembrolizumab (10 mg/kg) every 2 weeks in a cohort of patients with relapsed or refractory classical HL (Abstract 1108). Patients were required to have failed prior brentuximab vedotin and to have failed or be ineligible for treatment with autologous SCT. Of the 31 patients, 29% had bulky disease, 32% had B symptoms, and 74% had failed prior autologous SCT. The median number of prior lines of therapy was 5 (range, 2-15). After a median follow-up of 29 months, the most common treatment-related AEs of any grade were diarrhea (occurring in 19%), and hypothyroidism, pneumonitis, and nausea (each observed in 13% of patients). Treatment-related grade 3/4 AEs were observed in 19% of patients. Based on blinded independent central review, the ORR was 58%, with 19% CRs. In the 13 patients with primary refractory disease, the ORR was 62%, and the CR rate was 31%. In the 18 patients without primary refractory disease, the ORR was 56%, with 11% CRs.