A Review of Selected Presentations From the 2015 American Society of Hematology Annual Meeting and Exposition • December 5-8, 2015 • Orlando, Florida
Special Reporting on:
• Five-Year Survival Data Demonstrating Durable Responses From a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients With Relapsed or Refractory Hodgkin Lymphoma
• Post Transplant Outcome of a Multicenter Phase II Study of Brentuximab Vedotin as First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT
• Targeted BEACOPP Variants in Patients With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Final Analysis of a Randomized Phase II Study
• TARC Predicts PET-Normalization and Event Free Survival in Relapsed/Refractory Hodgkin Lymphoma Patients Treated With Brentuximab Vedotin
• First Multicenter, Randomized Phase 3 Study in Patients (Pts) With Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL): Alisertib (MLN8237) Versus Investigator’s Choice (LUMIERE trial; NCT01482962)
• Brentuximab Vedotin in Combination With Dacarbazine or Bendamustine for Frontline Treatment
of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study
• Randomized Phase 2 Open-Label Study of R-CHOP ± Bortezomib in Patients (Pts) With Untreated Non-Germinal Center B-Cell-like (Non-GCB) Subtype Diffuse Large Cell Lymphoma (DLBCL): Results From the Pyramid Trial (NCT00931918)
• Updated Efficacy and Safety Data From the AETHERA Trial of Consolidation With Brentuximab Vedotin After Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse
PLUS Meeting Abstract Summaries
With Expert Commentary by:
Robert W. Chen, MD
Assistant Professor
Department of Hematology and Hematopoietic Cell Transplantation
City of Hope
Duarte, California
Five-Year Survival Data Demonstrating Durable Responses From a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients With Relapsed or Refractory Hodgkin Lymphoma
Approximately half of Hodgkin lymphoma (HL) patients who receive salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (SCT) will develop relapsed or progressive disease. Brentuximab vedotin is an antibody-drug conjugate that selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to CD30-positive cells. In a pivotal phase 2 trial of 102 patients with relapsed or refractory HL after autologous SCT, brentuximab vedotin yielded an overall response rate (ORR) of 75%, with complete responses (CRs) observed in 34% of patients.1,2 The most common treatment-related adverse event (AE) was peripheral sensory neuropathy, which occurred in 42% of patients. Other treatment-related AEs included nausea (35%), fatigue (34%), neutropenia (19%), diarrhea (18%), pyrexia (14%), vomiting (13%), arthralgia (12%), pruritus (12%), myalgia (11%), peripheral motor neuropathy (11%), and alopecia (10%). The toxicity profile was considered manageable.
Final results of this trial incorporating 5-year follow-up were reported at the 2015 American Society of Hematology (ASH) meeting.3 The median observation time for all enrolled patients from the first dose of brentuximab vedotin was 35.1 months (range, 1.8-72.9 months). The patients received a median of 9 cycles of brentuximab vedotin (range, 1-16).
The estimated 5-year overall survival (OS) was 41% (95% CI, 31%-51%), and median OS was 40.5 months (95% CI, 28.7-61.9 months; Figure 1). Median progression-free survival (PFS) was 9.3 months (95% CI, 7.1-12.2 months).
By the end of the study, 15 patients remained in remission, with a median observation time of 69.5 months (range, 66.5-72.9 months). Among the patients still in remission by the end of the study, 13 achieved a CR as best response. The ORR was 72%, with 33% CRs. The 34 patients who achieved a CR had received a median of 13.5 cycles of brentuximab vedotin. Thirteen of these patients (38%) remained in remission at study end. The median response duration was not reached in the patients who achieved a CR, and ranged from 2 to 71.6+ months. Thirteen of the 34 CR patients (38%) remained in remission at the time of study closure. Among the 6 CR patients who proceeded to allogeneic SCT as consolidation, 4 patients (67%) remained in CR. In the remaining 28 CR patients who did not receive allogeneic SCT as consolidation, 9 patients (32%) remained in CR with no subsequent therapy.
The most common treatment-related AEs were peripheral sensory neuropathy, fatigue, nausea, neutropenia, and diarrhea. Peripheral neuropathy occurred in 55% of patients; it resolved completely in 73% and improved in 14%. There were ongoing symptoms of grade 1 peripheral neuropathy in 20% and grade 2 in 7%. No patients experienced ongoing symptoms of grade 3 or higher. The most common grade 3 or higher AEs included neutropenia (20%), peripheral sensory neuropathy (8%), thrombocytopenia (8%), and anemia (6%).
References
1. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
2. 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.
3. Chen R, Gopal AK, Smith SE, et al. Five-year survival data demonstrating durable responses from a pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 2736]. Blood. 2015;126(suppl 23).
Post Transplant Outcome of a Multicenter Phase II Study of Brentuximab Vedotin as First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT
Dr Robert Chen presented the preliminary results from a prospective, multicenter, phase 2 trial investigating brentuximab vedotin as first-line salvage therapy prior to SCT in HL patients who failed induction chemotherapy.2 Eligible patients were ages 10 years or older with histologically documented, CD30-positive HL at relapse or after a failed response to induction chemotherapy. Radiographically measurable disease and adequate organ function were also required. The study excluded patients who had received any second-line salvage therapy and those with prior autologous or allogeneic hematopoietic SCT.
Patients initially received 2 cycles of brentuximab vedotin (1.8 mg/kg) with 3 weeks between cycles followed by positron emission tomography (PET) or computed tomography imaging. Patients with a CR, partial response (PR), or stable disease received 2 more cycles of brentuximab vedotin. Patients who achieved a CR then underwent stem cell mobilization followed by transplant. Patients with stable disease or progressive disease received further salvage chemotherapy. Patients with a PR were given the option of proceeding to SCT or receiving further salvage chemotherapy. The primary endpoint was ORR.
The 37 patients had a median age of 34 years (range, 11-67 years). Sixty-five percent of patients had primary refractory disease, and 35% had relapsed within 7 months of induction chemotherapy. Induction chemotherapy for 92% of the patients was doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), and 24% had received prior radiation.
After treatment with brentuximab vedotin, the ORR was 68% and included 35% CRs (Table 1). Univariate analysis did not reveal any differences in outcomes based on age, sex, disease stage, response to induction, or the presence of B symptoms or bulky disease. Among the 18 patients who did not achieve a CR after treatment with brentuximab vedotin and who subsequently received salvage chemotherapy, the ORR was 89%, with a CR rate of 56%. Among the 32 patients who proceeded to stem cell mobilization and autologous SCT, 72% had a CR, 25% had a PR, and 3% had stable disease. Salvage regimens included brentuximab vedotin only (47%), and brentuximab vedotin followed by either chemotherapy (50%) or radiation (3%).
Median follow-up for the 32 patients was 20.9 months (range, 10.1-41.1 months). At 18 months, the OS rate was 96.9% and the PFS rate was 71.9%. Nonrelapse mortality at day 100 was 3.1%. Twenty-five patients were treated at the City of Hope National Medical Center. These patients had a longer median follow-up of 24.2 months (range, 10.1-39.6 months). At 2 years, OS was 89.1% and PFS was 68.0% (Figure 2). Nonrelapse mortality at day 100 was 4%. The PFS rates were 76.5% for patients who achieved a CR prior to SCT vs 50.0% for those who did not (P=.047). Patients who received brentuximab vedotin alone as first-line salvage therapy had a PFS of 84.6%, whereas patients who received brentuximab vedotin plus chemotherapy had a PFS of 54.5% (P=.036).
All toxicities were grade 1 or 2. The most common AEs were stomatitis (60%), gastrointestinal toxicity (44%), and hepatic toxicity (24%). The combination of brentuximab vedotin plus bleomycin has been associated with an increase in pulmonary toxicity. In the current study, the only pulmonary toxicity events were grade 1, and they occurred in 8% of patients.
References
1. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
2. Chen R, Palmer J, Martin P, et al. Post transplant outcome of a multicenter phase 2 study of brentuximab vedotin as first line salvage therapy in relapsed/refractory HL prior to AHCT [ASH abstract 519]. Blood. 2015;126(suppl 23).
Targeted BEACOPP Variants in Patients With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Final Analysis of a Randomized Phase II Study
Escalated BEACOPP chemotherapy consists of bleomycin, vincristine, procarbazine, and prednisolone plus increased doses of etoposide, doxorubicin, and cyclophosphamide. The regimen has significantly improved tumor control and OS in patients with advanced-stage HL, with a recent study yielding an OS of 95.3% after 6 courses of escalated BEACOPP followed by PET-guided radiotherapy.1 However, the regimen is associated with severe treatment-related morbidity in approximately 60% of patients. AEs include hematologic toxicities, such as severe infections and the need for transfusions, and nonhematologic toxicities, particularly of the nervous system. A primary objective of the German Hodgkin Study Group (GHSG) has been to reduce the intensity of BEACOPP while maintaining its efficacy.
Brentuximab vedotin has demonstrated efficacy and tolerability in HL. A phase 2 study of 102 heavily pretreated patients with relapsed or refractory HL yielded an ORR of 72%, including a CR rate of 33%, following treatment with brentuximab vedotin monotherapy for up to 16 cycles.2 After a median observation time of 35.1 months (range, 1.8-72.9 months), the estimated 5-year OS rate was 41%, and the median OS was 40.5 months. These positive outcomes prompted the evaluation of brentuximab vedotin in combination with chemotherapy regimens derived from BEACOPP.3 The BEACOPP variants were adjusted to minimize toxicity by eliminating vincristine and bleomycin. Both MMAE and vincristine interfere with microtubule formation, and vincristine is also associated with neuropathy. Brentuximab vedotin has been associated with neurotoxicity. Bleomycin was omitted based on the potential for severe pulmonary toxicity when combined with brentuximab vedotin.4
The regimen known as BrECAPP included etoposide, doxorubicin, and cyclophosphamide plus brentuximab vedotin, procarbazine, and prednisone. The BrECADD regimen eliminated procarbazine and prednisone while retaining dacarbazine and dexamethasone and adding brentuximab vedotin. These regimens were evaluated in a randomized phase 2 study. Results from the final analysis were presented by Dr Peter Borchmann. The study’s primary objective was the CR rate at the end of treatment. Enrolled patients were ages 18 to 60 years and had advanced-stage HL. Patients were randomized to 2 cycles of BrECAPP or BrECADD and underwent interim staging by PET or computed tomography. After interim staging, patients with progressive disease were removed from the study. Patients with stable disease or better received 4 more cycles of the same regimen, and those with a positive PET scan then received radiotherapy.
The study then randomly assigned 49 patients to BrECAPP and 52 to BrECADD. The CR rates were 86% for BrECAPP and 88% for BrECADD. Estimates of 18-month PFS were 95.0% for BrECAPP and 88.6% for BrECADD. To compare the BEACOPP variants with escalated BEACOPP, the researchers provided data from the GHSG HD15 trial. The full dose at cycle 6 was given to 60% of patients in the BrECAPP arm and 69% of patients in the BrECADD arm. In comparison, 50% of patients received the full dose of escalated BEACOPP at cycle 6 in the GHSG HD15 trial. The proportions of patients receiving the lowest dose at cycle 6 were 17% for BrECAPP, 8% for BrECADD, and 15% for escalated BEACOPP. Brentuximab vedotin was reduced or stopped in cycle 5 or cycle 6 in 8% of patients.
Grade 3/4 hematologic toxicities were reported in 80% of the BrECAPP arm and 83% of the BrECADD arm. In comparison, grade 3/4 hematologic toxicities were reported in 93% of patients receiving escalated BEACOPP in the GHSG HD18 trial. Grade 3/4 nonhematologic toxicities were observed in 8% and 2% of patients receiving BrECAPP or BrECADD, respectively, vs 14.7% of patients who received 6 cycles of escalated BEACOPP in trial HD18. One patient in the BrECADD arm experienced a grade 3 event that resolved completely, accounting for the 2% rate of grade 3/4 nonhematologic toxicity.
An analysis of grade 4 hematologic toxicities suggested that the regimens containing brentuximab vedotin were associated with fewer complications than escalated BEACOPP (Table 2). In patients who received BrECAPP, BrECADD, or escalated BEACOPP, grade 4 anemia occurred in 6%, 0%, and 10.2%, respectively, and grade 4 thrombocytopenia occurred in 40%, 29%, and 47%. Grade 4 infection occurred in 2% of patients in all 3 treatment groups. Among patients receiving the BEACOPP variants, there were no reports of grade 4 neuropathy. Grade 1 to 3 sensory neuropathy occurred in 23% of the BrECAPP arm and 9% of the BrECADD arm, vs 1% of the escalated BEACOPP patients in HD18. All treatment-related neuropathy resolved completely, as did a single report of grade 3 motor neuropathy. A new trial, HD21, will compare 6 cycles of BrECADD vs 6 cycles of escalated BEACOPP in patients with advanced HL.
References
1. Engert A, Haverkamp H, Kobe C, et al; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.
2. Chen R, Gopal AK, Smith SE, et al. Five-year survival data demonstrating durable responses from a pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 2736]. Blood. 2015;126(suppl 23).
3. Borchmann P, Eichenauer DA, Pluetschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: final analysis of a randomized phase II study [ASH abstract 580]. Blood. 2015;126(suppl 23).
4. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348-1356.
TARC Predicts PET-Normalization and Event Free Survival in Relapsed/Refractory Hodgkin Lymphoma Patients Treated With Brentuximab Vedotin
The cysteine-cysteine thymus and activation-related chemokine (TARC), which is also known as CCL17, binds to chemokine receptors CCR4 and CCR8 and is normally produced by antigen-presenting cells.1 In HL, the chemokine is secreted by Reed-Sternberg cells and attracts TH2 T cells to the microenvironment. Based on its high expression levels in Reed-Sternberg cells, TARC is promising as a biomarker for predicting response to treatment in HL patients. In an analysis of serum samples of patients from several GHSG studies, lower baseline TARC was associated with a higher rate of PET negativity after 2 cycles of treatment, whereas a high level was associated with primary refractory disease.2 The findings support those of a prospective study that described a correlation between TARC levels in plasma and response to treatment.3 In another study, circulating CD163 (a marker of tumor-associated macrophages) and TARC were predictive of disease extent and response to treatment in newly diagnosed HL.4 Other biomarkers of interest in HL include interleukin (IL) 1, IL-6, IL-10, IL-2R, and soluble CD30.5-8
Dr Alison Moskowitz presented updated results from a nonrandomized, open-label, single-center, phase 2 study that aimed to increase the proportion of negative PET scans before autologous SCT in HL patients who had failed first-line therapy.9,10 Enrolled patients had relapsed or refractory HL and had failed 1 prior doxorubicin-containing chemotherapy regimen. All patients received brentuximab vedotin (1.2 mg/kg on days 1, 8, and 15) for two 28-day cycles. Patients with a negative PET scan proceeded to high-dose therapy and autologous SCT. Patients with a positive PET scan received 2 cycles of an augmented regimen of ifosfamide, carboplatin, and etoposide (ICE). Patients who received augmented ICE received a second PET scan and either proceeded to high-dose therapy plus autologous SCT or further treatment to address persistent PET abnormalities. A negative PET scan was defined as a Deauville score of 1 or 2.
The updated results incorporated a median posttransplant follow-up of 33 months (range, 20-43 months) for the 45 treated patients. In 76% of patients, PET scans were negative. The rate of event-free survival was highest for patients who were PET-negative after receiving brentuximab vedotin plus augmented ICE and was slightly lower for patients who were PET-negative after brentuximab vedotin alone (Figure 3). Patients who had persistent abnormalities on a PET scan after receiving brentuximab vedotin plus ICE showed the lowest rate of event-free survival, at approximately 50%.
Serum samples were collected at baseline and after 2 cycles of brentuximab vedotin. TARC decreased by approximately 82% from a baseline median level of 8250 pg/mL to a median of 1027 pg/mL after 2 cycles of brentuximab vedotin. A greater reduction in TARC following 2 cycles of brentuximab vedotin was associated with an increased likelihood of PET normalization (odds ratio, 5.82). The median serum level of TARC was 1027 pg/mL after 2 cycles of brentuximab vedotin. Among the 6 patients with progressive disease, all had TARC serum levels above the median after receiving brentuximab vedotin. One patient with a TARC level below the median after treatment died from infection.
Serum TARC levels below 1027 pg/mL correlated with an increased likelihood of event-free survival (2-year event-free survival rates: 94% vs 67%; P=.044). The highest rates of event-free survival were seen in patients with negative PET scans before SCT and in patients with a positive PET scan and a TARC serum level below 1027 pg/mL. A low level of serum TARC appeared to offset the negative predictive value of a positive PET scan before SCT.
This study also included an analysis of cytokines and chemokines (Table 3). Elevated baseline interferon γ and IL-10 correlated with the presence of extranodal disease. Elevated IL-10 and tumor necrosis factor α correlated with an increased likelihood of B symptoms.
References
1. Hnátková M, Mociková H, Trnený M, Zivný J. The biological environment of Hodgkin’s lymphoma and the role of the chemokine CCL17/TARC. Prague Med Rep. 2009;110(1):35-41.
2. Sauer M, Plütschow A, Jachimowicz RD, et al. Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma. Am J Hematol. 2013;88(2):113-115.
3. Plattel WJ, van den Berg A, Visser L, et al. Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin’s lymphoma. Haematologica. 2012;97(3):410-415.
4. Jones K, Vari F, Keane C, et al. Serum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma. Clin Cancer Res. 2013;19(3):731-742.
5. Reynolds GM, Billingham LJ, Gray LJ, et al. Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of ‘B’ symptoms and failure to achieve complete remission in patients with advanced Hodgkin’s disease. Br J Haematol. 2002;118(1):195-201.
6. Marri PR, Hodge LS, Maurer MJ, et al. Prognostic significance of pretreatment serum cytokines in classical Hodgkin lymphoma. Clin Cancer Res. 2013;19(24):6812-6819.
7. Casasnovas RO, Mounier N, Brice P, et al; Groupe d’Etude des Lymphomes de l’Adulte. Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin’s lymphoma: a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2007;25(13):1732-1740.
8. Rautert R, Schinköthe T, Franklin J, et al. Elevated pretreatment interleukin-10 serum level is an International Prognostic Score (IPS)-independent risk factor for early treatment failure in advanced stage Hodgkin lymphoma. Leuk Lymphoma. 2008;49(11):2091-2098.
9. 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.
10. Moskowitz AJ, Cho S, Fleisher M, et al. TARC predicts PET-normalization and event free survival in relapsed/refractory Hodgkin lymphoma patients treated with brentuximab vedotin [ASH abstract 180]. Blood. 2015;126(suppl 23).
First Multicenter, Randomized Phase 3 Study in Patients (Pts) With Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL): Alisertib (MLN8237) Versus Investigator’s Choice (LUMIERE trial; NCT01482962)
Alisertib is an investigational, orally administered, selective inhibitor of Aurora A kinase.1-3 In phase 2 trials, alisertib monotherapy demonstrated antitumor activity with favorable tolerability in peripheral T-cell lymphoma (PTCL), yielding an ORR of 30%.4,5 Dr Owen O’Connor presented results from the international, multicenter, open-label, phase 3 LUMIERE (Alisertib [MLN8237] or Investigator’s Choice in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma) study, which investigated the efficacy and safety of alisertib monotherapy in adult patients with relapsed or refractory PTCL.6 Patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Demographic and baseline characteristics were well balanced between the 2 treatment arms. The median age was 63 years (range, 19-86 years), and two-thirds were male. Patients had received treatment with at least 1 prior conventional systemic cytotoxic therapy but not with the study drugs. The study randomly assigned 138 patients to alisertib and 133 to the comparator arm.
Alisertib was administered at 50 mg twice daily on days 1 to 7 in 21-day cycles. Patients in the comparator arm received 1 of 3 therapies—pralatrexate, gemcitabine, or romidepsin—as selected by their physician. (Gemcitabine is currently not approved for use in hematologic malignancies.) Treatment continued until disease progression or unacceptable toxicity. Patients with stable disease or better could continue treatment for up to 2 years. The primary endpoints were ORR and PFS. Secondary endpoints were OS, CR rate, duration of response, and safety.
The study design included adaptive sample size reassessment with 2 interim analyses and a final analysis. For the first interim analysis, ORR was evaluated for the first 74 patients. The second interim analysis of ORR included the first 146 patients.
The ORRs were 35% (19% CRs) for alisertib vs 46% (28% CRs) for the comparator arm. The comparator treatments of pralatrexate (n=45), gemcitabine (n=22), and romidepsin (n=18) yielded ORRs of 44%, 36%, and 61%, respectively. Median PFS was 115 days for the alisertib arm vs 104 days for the comparator arm (hazard ratio [HR], 0.87; 95% CI, 0.64-1.16; P=.177; Figure 4). After elimination of patients who did not meet eligibility criteria based on central pathology review, the PFS rates were 120 days in the alisertib arm vs 104 days in the comparator arm. Median OS was 13.6 months for alisertib vs 12.1 months for comparator treatment (HR, 0.96; 95% CI, 0.70-1.33; P=.338). Estimated 2-year OS was 35% for both arms.
Treatment-related AEs were 88% in the alisertib arm vs 94% in the comparator arm. Treatment-related AEs of grade 3 or higher were reported in 70% vs 68% of patients, respectively. Treatment-related serious AEs were reported in 34% vs 32%. AEs leading to discontinuation were observed in 9% vs 14% of patients. On-study deaths occurred in 8% vs 12%. In the alisertib arm, anemia, neutropenia, and diarrhea were the most common AEs of any grade and of grade 3 or higher.
References
1. Gallop-Evans E. The role of alisertib in treatment of peripheral T-cell lymphomas. Future Oncol. 2015;11(18):2515-2524.
2. Nikonova AS, Astsaturov I, Serebriiskii IG, Dunbrack RL Jr, Golemis EA. Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci. 2013;70(4):661-687.
3. Niu H, Manfredi M, Ecsedy JA. Scientific rationale supporting the clinical development strategy for the investigational aurora A kinase inhibitor alisertib in cancer. Front Oncol. 2015;5:189.
4. Barr PM, Li H, Spier C, et al. Phase II Intergroup trial of alisertib in relapsed and refractory peripheral T-cell lymphoma and transformed mycosis fungoides: SWOG 1108. J Clin Oncol. 2015;33(21):2399-2404.
5. Friedberg JW, Mahadevan D, Cebula E, et al. Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. J Clin Oncol. 2014;32(1):44-50.
6. O’Connor OA, Özcan M, Jacobsen ED, et al. First multicenter, randomized phase 3 study in patients (pts) with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL): alisertib (MLN8237) versus investigator’s choice (LUMIERE trial; NCT01482962) [ASH abstract 341]. Blood. 2015;126(suppl 23).
Brentuximab Vedotin in Combination With Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study
Older patients with HL have an inferior outcome.1 Dr Christopher Yasenchak presented interim results from a multicohort phase 2 study of brentuximab vedotin in HL patients ages 60 years or older.2 Results from a monotherapy arm (cohort A) were published previously.3 Brentuximab vedotin monotherapy yielded an ORR of 92%, including 73% CRs, among 27 patients. All patients achieved stable disease or better. Median PFS was 10.5 months (range, 2.6+ to 22.3+ months). The therapy was generally well tolerated, with serious AEs observed in 22% of patients. No deaths occurred within 30 days of treatment cessation.
The current analysis provided data evaluating brentuximab vedotin in combination with dacarbazine or bendamustine.2,4 Patients in cohort B received brentuximab vedotin (1.8 mg/kg, day 1) for up to 16 cycles, plus dacarbazine (375 mg/m2, day 1) for up to 12 cycles. Cohort C also received brentuximab vedotin (1.8 mg/kg, day 1) for up to 16 cycles, plus bendamustine (90 mg/m2, days 1 and 2) for up to 6 cycles. Additional cycles of brentuximab vedotin were permitted for patients showing a clinical benefit. After 9 patients in cohort C received treatment, the protocol was amended to reduce the starting dose of bendamustine from 90 mg/m2 to 70 mg/m2.
Enrolled patients had treatment-naive classical HL and were ages 60 years or older. They were ineligible for first-line conventional combination therapy or had declined it. Patients had measurable disease of at least 1.5 cm and an ECOG performance status of 0 to 3. Patients enrolled in cohort C had a creatinine clearance rate of at least 40 mL/min. At the data cutoff, 27 patients had been treated in cohort A, and all were off treatment. Among the 22 patients treated in cohort B, 2 remained on treatment. Among the 20 patients treated in cohort C, 11 continued treatment with brentuximab vedotin monotherapy. Tolerability of bendamustine did not meet the study goals, and use of the drug was discontinued.
The median ages were 78 years in cohort A, 69 years in cohort B, and 75 years in cohort C. In all cohorts, most patients had an ECOG performance status of 0 or 1 and stage III/IV disease. Bulky disease was present in 22% of cohort A, 9% of cohort B, and 5% of cohort C. B symptoms were present in 33%, 41%, and 50%, respectively, and conventional chemotherapy was contraindicated in 52%, 86%, and 85%. Significant comorbidities and impaired functional status were noted in all 3 cohorts.
The ORRs were 92% in cohort A and 100% in cohorts B and C. Rates of CR were 73%, 67%, and 81%, respectively. With median observation times of 23.1 months for cohort A and 13.4 months for cohort B, estimates of 12-month PFS were 38% and 66%, respectively (Figure 5). The observation time for cohort C was only 4.6 months, precluding meaningful estimates of PFS.
In cohort A, patients received a median 8 cycles of treatment. In cohort B, patients received a median 12.5 cycles of brentuximab vedotin and a median 12 cycles of dacarbazine. In cohort C, patients received a median 3.5 cycles of brentuximab vedotin and a median 3.5 cycles of bendamustine. The most common reason for treatment discontinuation was an AE, as reported in 41% of cohorts A and B and 25% of cohort C. Other reasons for discontinuation in cohorts A, B, and C included progression after a CR or PR (41%, 14%, 0%, respectively), investigator decision (4%, 18%, 5%), and patient decision (11%, 18%, 15%).
All patients in the study experienced an AE. Rates of serious AEs were 22% in cohort A, 9% in cohort B, and 60% in cohort C. Treatment-related AEs of grade 3 or higher were reported in 48%, 36%, and 65% of patients in cohorts A, B, and C, respectively. AEs leading to treatment discontinuation were reported in 41% of patients in cohorts A and B and 25% of patients in cohort C. Brentuximab vedotin plus bendamustine was associated with more types of AEs and more grade 3/4 AEs compared with brentuximab vedotin plus dacarbazine. Peripheral neuropathy was more frequent in cohort B compared with cohort C; however, patients in cohort B had received more cycles of brentuximab vedotin (median 12.5 cycles vs 3.5 cycles). Within the 30-day safety period, 2 deaths occurred, both in cohort C and both considered unrelated to study treatment.
References
1. Evens AM, Hong F, Gordon LI, et al. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013;161(1):76-86.
2. Yasenchak CA, Forero-Torres A, Cline-Burkhardt VJM, et al. Brentuximab vedotin in combination with dacarbazine or bendamustine for frontline treatment of Hodgkin lymphoma in patients aged 60 years and above: interim results of a multi-cohort phase 2 study [ASH abstract 587]. Blood. 2015;126(suppl 23).
3. Forero-Torres A, Holkova B, Goldschmidt J, et al. Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015;126(26):2798-2804.
4. LaCasce A, Bociek RG, Matous J, et al. Brentuximab vedotin in combination with bendamustine for patients with Hodgkin lymphoma who are relapsed or refractory after frontline therapy [ASH abstract 293]. Blood. 2015;126(suppl 23).
Randomized Phase 2 Open-Label Study of R-CHOP ± Bortezomib in Patients (Pts) With Untreated Non-Germinal Center B-Cell-like (Non-GCB) Subtype Diffuse Large Cell Lymphoma (DLBCL): Results From the Pyramid Trial (NCT00931918)
Dr John Leonard presented results from the PYRAMID (Study to Assess the Effectiveness of RCHOP With or Without VELCADE in Previously Untreated Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma Patients) trial, an open-label, randomized phase 2 study that evaluated efficacy and safety of the standard regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) vs R-CHOP plus bortezomib (VR-CHOP) in patients with treatment-naive non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).1 Enrolled patients had centrally or locally confirmed non-GCB DLBCL based on the Hans immunohistochemistry method.2 Patients had measurable disease and an ECOG performance status of 0 to 2. Their median age was 64 years (range, 10-85 years). The study’s primary endpoint was PFS, with secondary endpoints of OS, ORR, CR, and toxicity. The study randomly assigned 91 patients to R-CHOP and 92 patients to VR-CHOP. At least 6 treatment cycles were completed by 86% of the R-CHOP arm and 85% of the VR-CHOP arm. The median follow-up was 34 months for both arms.
The ORR was 98% in the R-CHOP arm vs 96% in the VR-CHOP arm, with CR rates of 49% vs 56%, respectively. Rates of negative 18F-fluorodeoxyglucose PET scans at the end of treatment were 53% with R-CHOP and 59% with VR-CHOP. The 2-year PFS rates were 78% for R-CHOP vs 82% for VR-CHOP (HR, 0.73; P=.611). Two-year OS probability was 88% with R-CHOP vs 93% with VR-CHOP (HR, 0.75; P=.763; Figure 6). Survival outcomes were similar when analyzed by International Prognostic Index (IPI) score.
No new safety signals emerged in the toxicity analysis of R-CHOP (n=100) vs VR-CHOP (n=101). AEs of grade 3 or higher occurred in 71% of the R-CHOP group and 79% of the VR-CHOP group. Drug-related AEs of grade 3 or higher occurred in 55% vs 68%, respectively. One patient died in each arm. Neutropenia occurred at similar rates in both arms, whereas thrombocytopenia and anemia were more common with VR-CHOP. The most common nonhematologic AEs of any grade in both arms were fatigue, nausea, peripheral neuropathy, alopecia, and constipation. The most common AE of grade 3 or higher was neutropenia, occurring in approximately 50% of patients in both arms. Grade 3 or greater thrombocytopenia and anemia were more common in patients who received treatment with bortezomib. The only grade 3 or higher nonhematologic AE was hypokalemia, occurring in approximately 10% of patients in each arm.
In the current study, patients who received standard R-CHOP performed better than expected, demonstrating a 2-year PFS of 78%. In a previous study, patients with activated B-cell DLBCL based on gene expression profiling had a 3-year PFS rate of only 40% after treatment with standard R-CHOP.3 However, in a more recent study of patients with non-GCB DLBCL, R-CHOP yielded a 2-year PFS rate of 77%.4 Dr Leonard concluded by suggesting that the prospective selection process may have inadvertently excluded patients likely to have less favorable outcomes.
References
1. Leonard JP, Kolibaba K, Reeves JA, et al. Randomized phase 2 open-label study of R-CHOP ± bortezomib in patients (pts) with untreated non-germinal center B-cell-like (non-GCB) subtype diffuse large cell lymphoma (DLBCL): results from the PYRAMID trial [ASH abstract 811]. Blood. 2015;126(suppl 23).
2. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.
3. Lenz G, Wright G, Dave SS, et al; Lymphoma/Leukemia Molecular Profiling Project. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313-2323.
4. Offner F, Samoilova O, Osmanov E, et al. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015;126(16):1893-1901.
Updated Efficacy and Safety Data From the AETHERA Trial of Consolidation With Brentuximab Vedotin After Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse
AETHERA (A Phase 3 Study of Brentuximab Vedotin [SGN-35] in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant) is a placebo-controlled, randomized phase 3 study that investigated consolidation treatment with brentuximab vedotin after autologous SCT in 329 HL patients at high risk of relapse or progression.1 The study met its primary endpoint by demonstrating improved PFS with brentuximab vedotin vs placebo by independent review (42.9 months vs 24.1 months; HR, 0.57; P=.001). The most common AEs in the brentuximab vedotin treatment arm were peripheral sensory neuropathy (56% vs 16% for placebo) and neutropenia (35% vs 12% for placebo).
Dr John Sweetenham presented updated safety and efficacy results from the AETHERA trial, reflecting approximately 3 years of follow-up.2 Patients had a median age of 33 years (range, 18-76 years). Approximately 60% of patients in both arms had refractory disease, and one-third had relapsed within 12 months of their prior treatment. Salvage therapy before autologous SCT was associated with a CR rate of 37% to 38%, a PR rate of 34% to 35%, and a stable disease rate of 28%. One-third of patients had extranodal involvement upon relapse before autologous SCT, and 24% to 28% had B symptoms after first-line therapy.
The PFS rate at 24 months was 65% (95% CI, 57%-72%) for brentuximab vedotin vs 45% (95% CI, 37%-52%) for placebo. At 36 months, the PFS rate was 61% (95% CI, 53%-68%) vs 43% (95% CI, 36%-51%), respectively (Figure 7). The median PFS had not been reached for the brentuximab vedotin arm and was 15.8 months for the placebo arm (HR, 0.52). Subgroup analyses showed superior PFS for brentuximab vedotin vs placebo among patients with a PR prior to autologous SCT (HR, 0.459; 95% CI, 0.272-0.773), those with stable disease before autologous SCT (HR, 0.390; 95% CI, 0.390-0.686), and those with 2 or more risk factors (HR, 0.412; 95% CI, 0.291-0.583; Figure 8).
Among patients receiving brentuximab vedotin, 112 developed peripheral neuropathy, for a rate of 67%. Peripheral neuropathy was grade 3 in 22 patients. There were no reports of grade 4. The peripheral neuropathy resolved or improved in 99 patients (88%), and completely resolved in 74 (66%). Secondary malignancies were reported in 3% of the brentuximab vedotin arm vs 1% of the placebo arm. Following subsequent poststudy treatment with brentuximab vedotin to treat relapse, the ORR was 86% for the 7 evaluable patients in the brentuximab vedotin arm and 67% for the 61 evaluable patients in the placebo arm. Patients in the AETHERA study remain in long-term follow-up, and final analysis for OS is planned for 2020.
References
1. 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.
2. Sweetenham J, Walewski J, Nademanee AP, et al. Updated efficacy and safety data from the AETHERA trial of consolidation with brentuximab vedotin after autologous stem cell transplant (ASCT) in Hodgkin lymphoma patients at high risk of relapse [ASH abstract 3172]. Blood. 2015;126(suppl 23).
Highlights in Lymphoma From the 2015 ASH Meeting: Commentary
Robert W. Chen, MD
Presentations at the 2015 American Society of Hematology (ASH) meeting provided insight into the management of several lymphoma subtypes, including Hodgkin lymphoma, peripheral T-cell lymphoma (PTCL), anaplastic large-cell lymphoma, and mantle cell lymphoma. Studies evaluated therapies such as brentuximab vedotin, bendamustine, bortezomib, venetoclax, and alisertib, and attempted to refine existing regimens.
Hodgkin Lymphoma
There were several presentations on brentuximab vedotin, which provided both updated analyses and results from new trials. I presented data from a 5-year follow-up analysis of the pivotal phase 2 study of brentuximab vedotin in relapsed Hodgkin lymphoma.1 The study was published in 2012, and showed an overall response rate of 75%.2 It led to accelerated approval from the US Food and Drug Administration (FDA).
In the original study, approximately 50% of patients developed peripheral neuropathy. After 5 years, the peripheral neuropathy resolved or improved in 88% of these patients. In 73% of patients, it resolved completely. Therefore, most of the neuropathies seen with brentuximab vedotin were reversible and did not interfere with a patient’s life after treatment.
The 5-year overall survival in this study was 41%, and the progression-free survival (PFS) was 22%. The median overall survival was 40.5 months. (In contrast, before brentuximab vedotin was available, the median overall survival among patients who had failed an autologous transplant was approximately 10 to 27 months.) Approximately a third of the patients obtained a complete remission, and these patients had even better outcomes. Their 5-year overall survival was 64%, and their 5-year PFS was 54%. It is encouraging to be able to tell patients who have achieved a complete response that their chance of being alive in 5 years is approximately 60%.
I presented results from a study evaluating the posttransplant outcome of brentuximab vedotin as frontline salvage therapy.3 This study in the pretransplant population was prompted by the exciting data from the pivotal study showing that brentuximab vedotin had a high response rate in posttransplant patients.2 Typical frontline salvage therapies include multiagent combination chemotherapy, such as ifosfamide, carboplatin, and etoposide (ICE). Although ICE has a high response rate, it is associated with significant toxicity. Brentuximab vedotin also has a high response rate, but with far less toxicity.
The dosage of brentuximab vedotin was 1.8 mg every 3 weeks given for a total of 4 cycles. Patients who achieved a complete response or a very good partial response went directly to transplant. Patients who achieved only stable disease, progressive disease, or a partial response received second-line salvage therapy, such as ICE. The overall response rate was 68%, with 35% complete responses, which is similar to the pivotal trial. Among the 37 patients, 32 were able to proceed to transplant. Among the patients who proceeded to transplant, 72% achieved complete remission at the time of transplant. It is known that patients who undergo transplant while in complete remission have a better outcome than patients not in complete remission.
Approximately half of the patients who proceeded to transplant were receiving brentuximab vedotin alone. Those patients were therefore spared the multiagent salvage chemotherapy strategy. In the study, the stem cell mobilization rate was unaffected, and engraftment was not delayed. We also presented data for 2 years after transplant. The 2-year overall survival posttransplant was 89%, and the PFS was 68%, which compares favorably with historical controls. Among the patients who proceeded to transplant while in complete remission, the 2-year PFS was even better, at 77%.
Before the study, concerns had been raised regarding whether a complete response achieved with brentuximab vedotin is equivalent to a complete response achieved with ICE chemotherapy, and whether the posttransplant outcome—specifically, PFS—would be affected if patients received brentuximab vedotin alone. In the study, patients who received brentuximab vedotin alone achieved a higher rate of 2-year PFS, at 85%. Patients who received brentuximab vedotin as a salvage regimen only and proceeded to transplant had a very good outcome posttransplant.
Dr Alison Moskowitz presented a study evaluating whether levels of cysteine-cysteine thymus and activation-related chemokine (TARC) predict PET normalization.4 As in the previous study, brentuximab vedotin was used as the first-line salvage regimen, but at a different dosage: 1.2 mg weekly (compared with 1.8 mg every 3 weeks). The response rates, including PFS, were similar to the ones we reported in the previous trial. The focus of this study, however, was to identify biologic correlates to response. TARC levels were measured before and after treatment with brentuximab vedotin. They found that a reduction in TARC levels was associated with the rate of PET-negative complete responses. In addition, a TARC level less than 1026.7 pg/mL at the end of brentuximab vedotin therapy was associated with improved event-free survival after transplant. These data have positive implications for the future. It would be useful to rely on a blood test, instead of imaging, to confirm complete remission or predict for a good outcome after transplant. A larger study is needed to confirm these results.
Dr John Sweetenham presented updated efficacy and safety data from the AETHERA trial, a randomized, placebo-controlled, phase 3 study evaluating consolidation with brentuximab vedotin after transplant in patients with Hodgkin lymphoma.5 When AETHERA was presented in 2014, it showed that brentuximab vedotin improved PFS.6 The analysis at the 2015 ASH meeting provided updated efficacy and safety data drawn from approximately 3 years of follow-up. The median PFS in the placebo arm was 15.8 months, and it was not yet reached in the brentuximab vedotin arm. The 3-year PFS was 61% with brentuximab vedotin vs 43% with placebo. Peripheral neuropathy was seen in 67% of patients receiving brentuximab vedotin. By the end of this follow-up period, the neuropathy improved in 88% and completely resolved in 55%.
To summarize, the Kaplan-Meier curves for PFS are plateauing and clearly separating, indicating that the improvement seen with brentuximab vedotin could possibly translate into an overall survival advantage. Any neuropathy usually resolves. Overall, these follow-up results are very promising.
Dr Christopher Yasenchak presented data from a study of brentuximab vedotin plus dacarbazine or bendamustine in frontline treatment of elderly patients (≥60 years) with Hodgkin lymphoma.7 The standard treatment, ABVD, is associated with poor outcomes in elderly patients. In a previous study of elderly patients, single-agent brentuximab vedotin was associated with a high overall response rate (92%) and complete response rate (73%).8 However, the PFS was only 10.5 months, and the 1-year PFS was 38%. The current study attempted to improve PFS by adding an additional agent.
In the brentuximab vedotin/dacarbazine arm, the overall response rate was 100%, and the complete response rate was 67%. The 1-year PFS was 66%. Therefore, the addition of dacarbazine to brentuximab vedotin improved 1-year PFS by 28%. The toxicity was well- tolerated. This promising combination merits further study as upfront treatment for elderly patients with Hodgkin lymphoma.
In the brentuximab vedotin/bendamustine arm, the dose of bendamustine was reduced from 90 mg/m2 to 70 mg/m2 based on toxicity. The overall response rate was 100%, and the complete response was 81%, higher than the dacarbazine combination. This arm started later than the other, and the duration of response was not available. Toxicity was common in the bendamustine arm, with 65% of patients experiencing a grade 3 or higher adverse event. There were 2 deaths on study within 30 days, although they were deemed unrelated to treatment. The toxicity led the authors to conclude, and I would agree, that the brentuximab vedotin/bendamustine combination was not suitable in this population at the tested dose.
Dr Peter Borchmann presented data for a study of targeted BEACOPP variants.9 In Germany, escalated BEACOPP is a standard regimen for patients with advanced Hodgkin lymphoma. In the United States, ABVD is the standard regimen because it is associated with less toxicity than escalated BEACOPP. The aim of the study by Dr Borchmann was to decrease toxicity while maintaining efficacy by substituting brentuximab vedotin for certain agents. They evaluated 2 different regimens in 104 patients. The BrECAPP regimen added brentuximab vedotin while removing vincristine and bleomycin. The BrECADD regimen added brentuximab vedotin, removed vincristine, bleomycin, procarbazine, and prednisone, and added dexamethasone and dacarbazine, which is associated with less gonadotoxicity than procarbazine.
The primary endpoint of the study, PET-negative complete response, was similar in both treatment arms, at 86% for BrECAPP and 88% for BrECADD. PFS at 18 months was 95.0% vs 88.6%, respectively.
The regimens differed in terms of toxicity. The rate of grade 3/4 hematologic toxicity was 80% with BrECAPP vs 83% with BrECADD. Grade 3/4 organ toxicities occurred in 8% vs 2% of patients, respectively. No patients in the BrECADD arm developed grade 4 anemia, whereas it occurred in 6% of patients in the BrECAPP arm. Grade 4 thrombocytopenia occurred in 40% of the BrECAPP arm and 29% of the BrECADD arm. In the BrECADD arm, no patients developed severe neurotoxicity, compared with 1 patient in the BrECAPP arm. The authors concluded that BrECADD was a safer regimen and the one to use in future studies. I agree that BrECADD is preferable to BrECAPP. However, the rate of grade 3/4 hematologic toxicity seen in the BrECADD arm was still very high, at 83%. In addition, only 69% of patients in the BrECADD arm received the full treatment dose by the end of the study. The overall toxicity seen with the BrECADD regimen is still high compared with ABVD, and it would not be a popular regimen to use in the United States.
Dr Ramon Garcia-Sanz presented results from a phase 1/2 study of brentuximab vedotin plus etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) in the first salvage setting.10 The primary endpoint was complete response rate at the time of transplant. The study population consisted of Hodgkin lymphoma patients who had an inadequate response to frontline treatment and required salvage therapy. The study used the standard ESHAP regimen. Brentuximab vedotin was added at 3 different doses: 0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg. The phase 1 portion of the study found no dose-limiting toxicity to brentuximab vedotin. Therefore, 1.8 mg/kg, the standard dose, was used in the phase 2 portion.
Among the 17 evaluable patients, the complete response rate was high, at 94%. There were no difficulties with stem cell collection. There were high rates of hematologic toxicity, but that was expected with the ESHAP regimen. The authors concluded that the combination of brentuximab vedotin and ESHAP was safe, can induce a high complete response rate, and has the typical hematologic toxicity expected with the ESHAP regimen.
Dr Ann LaCasce presented a study evaluating brentuximab vedotin plus bendamustine as first-line salvage therapy in Hodgkin lymphoma patients.11 An interesting aspect of this study is that the patients also received brentuximab vedotin as maintenance therapy while they were awaiting stem cell transplant. This study is the first to evaluate patients who received brentuximab vedotin before and after transplant.
The original rate of infusion reaction in this study was high, at 58%. Grade 3 reactions occurred in 32% of patients. This rate of infusion reaction is higher than that seen with brentuximab vedotin or bendamustine alone. When this complication became apparent, the study design was amended to add corticosteroids and antihistamines as premedication. This strategy reduced the rate of grade 3 reactions to 17%.
The brentuximab vedotin/bendamustine regimen was efficacious. The overall response rate was 93%, with 73% complete responses. At 18 months, the PFS was 75%. The study also provided outcome data for after transplant. The 18-month PFS was 83%. Stem cells were collected without incident in 95% of patients.
Dr Carmelo Carlo-Stella presented results of a study evaluating bendamustine plus gemcitabine and vinorelbine in the first salvage setting.12 Bendamustine, gemcitabine, and vinorelbine were given every 3 weeks for a total of 4 cycles in 59 patients. The response rate was good, with an overall response of 83% and 73% complete responses. The long-term outcome, however, was less positive. The 2-year PFS was 51%, which appears lower than what the historical control would be. The regimen was safe. Stem cell collection was not possible in only 3.5% of patients. There was no engraftment delay.
Dr Stephen Ansell presented an update to a previous phase 1 study evaluating the PD-1 inhibitor nivolumab in patients with Hodgkin lymphoma.13 As reported at the 2014 ASH meeting, the overall response was 87% in the heavily pretreated population. This follow-up analysis showed that the responses were very durable. The median PFS has not yet been reached. The response was fairly durable even among patients who discontinued treatment owing to remission or toxicity. Most of the immunologic toxicity—rash, diarrhea, and colitis—resolved after nivolumab was discontinued. There were poor outcomes, however, among the 5 patients who responded to nivolumab and then proceeded to allogeneic transplant. Three of these patients died from veno-occlusive disease (VOD) or graft-vs-host disease (GVHD). There appeared to be a higher incidence of VOD and acute GVHD.
T-Cell Lymphoma
Dr Owen O’Connor presented results from LUMIERE, a large, randomized, phase 3 study comparing the oral kinase A inhibitor alisertib vs pralatrexate, romidepsin, or gemcitabine in patients with treatment-naive PTCL.14 In a phase 2 trial, alisertib was associated with a good response rate in patients with relapsed T-cell lymphoma.15 LUMIERE had 2 different endpoints: overall response rate and PFS. The results were disappointing. The response rate was 35% for alisertib vs 46% for the other therapies. PFS was 120 days for alisertib and 104 days for the other therapies. The results from this study indicate that alisertib should not be used in the management of frontline peripheral T-cell lymphoma.
Dr Fredrik Ellin presented results from a retrospective, population-based study that added etoposide to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).16 Data were gathered from the Swedish and Danish Registry for patients with anaplastic large-cell lymphoma (ALCL). Among the 371 patients, one-third were ALK-positive. This study confirmed previous data showing that ALK-positive patients have better outcomes.17 The 5-year PFS was 64% for ALK-positive patients vs 32% for ALK-negative patients. Patients with a high score on the International Prognostic Index had a worse outcome. An interesting finding was that the addition of etoposide increased overall survival, with a hazard ratio of 0.48. This large study is the first to show this improvement. A caveat to consider is that this study was retrospective, not prospective.
A phase 1/2 study presented by Dr Ahmed Sawas evaluated the addition of brentuximab vedotin to bendamustine in a population of heavily pretreated patients with relapsed/refractory Hodgkin lymphoma or ALCL.18 The study evaluated brentuximab vedotin at doses of 1.2 mg/kg or 1.8 mg/kg and bendamustine at doses of 70 mg/m2, 80 mg/m2, or 90 mg/m2. No dose-limiting toxicities were found, so that at the end of the trial, the dose was 1.8 mg/kg for brentuximab vedotin and 90 mg/m2 for bendamustine.
The aim of the study, to show that the combination of brentuximab vedotin plus bendamustine was safe, was met. The overall response rate was 67%, and the complete response rate was 19%. These response rates are low, but it should be noted that the patients were heavily pretreated. Many patients had prior exposure to brentuximab vedotin.
Dr John Leonard presented a study that added bortezomib to R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL).19 It is known that patients with the ABC subtype of DLBCL have inferior outcomes to R-CHOP chemotherapy. The ABC subtype of DLBCL relies heavily on the NF-kappa-B pathway. Bortezomib is a proteasome inhibitor, but it also downregulates NF-kappa-B downstream. This study randomized patients with the ABC subtype to receive R-CHOP only or R-CHOP plus bortezomib. The goal was to show that PFS would be better for patients who received bortezomib. Unfortunately, the study did not meet this goal. The addition of bortezomib was associated with a nonsignificant improvement in complete response, at 59% vs 53%, and in PFS, at 82% vs 78%. Thrombocytopenia was more common in the bortezomib arm.
The rate of PFS among the patients who received R-CHOP without bortezomib was 78%, which is high for patients with the ABC subtype of DLBCL. The authors suggested that the improvement seen with bortezomib failed to meet significance because this prospective study was unable to enroll high-risk patients. Patients who had significant disease burden and disease kinetics were unable to wait for completion of study screening procedures and ultimately could not enroll in this trial.
Dr Christopher Yasenchak presented results from a study evaluating R-CHOP plus brentuximab vedotin in DLBCL.20 The 3-year PFS for patients receiving R-CHOP is approximately 70%.21 This rate is lower, at 55%, among patients who have a high-risk International Prognostic Index (IPI) score. In an attempt to improve this rate, the study added brentuximab vedotin to R-CHOP. A prior study showed that brentuximab vedotin, an anti-CD30 antibody-drug conjugate, was effective in CD30-negative patients in the relapsed/refractory setting.22 In the current study presented at ASH, the complete response rate was 76% in CD30-positive patients vs 63% in CD30-negative patients. The 50-month rate of PFS was 83% in CD30-positive patients vs 54% in CD30-negative patients. Therefore, the addition of brentuximab vedotin to R-CHOP appeared to increase complete response and PFS in CD30-positive DLBCL patients with a high-risk IPI score. These promising results have led to a larger, randomized phase 2 study comparing R-CHOP vs R-CHOP plus brentuximab vedotin.
Dr John Gericitano presented the results of a phase 1 trial evaluating the safety, tolerability, and response of the BCL2 inhibitor venetoclax in a variety of lymphoma subtypes, including DLBCL, mantle cell lymphoma, follicular lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma.23 The study found that venetoclax was well tolerated. Responses were seen at all dose levels in mantle cell lymphoma but at only the higher dose levels for DLBCL and follicular lymphoma. It worked particularly well in mantle cell lymphoma, where the overall response rate was 75%. The overall response rate was 100% in Waldenström macroglobulinemia and 67% in marginal zone lymphoma. In follicular lymphoma and DLBCL, however, a higher dose was needed to obtain a response. The overall response rates were 18% for DLBCL and 38% for follicular lymphoma. An interesting finding is that complete responses appeared to be durable, lasting several weeks to months. Venetoclax is an exciting agent, particularly for mantle cell lymphoma and marginal zone lymphoma. For DLBCL and follicular lymphoma, venetoclax will probably need to be combined with other agents to improve response rates. Since venetoclax is so well tolerated, it should work well in combination with other therapies.
Mantle Cell Lymphoma
Dr Jeanette Doorduijn presented results from the HOVON (Hemato-Oncologie voor Volwassenen Nederland) trial, which examined whether bortezomib administered posttransplant can increase event-free survival.24 The enrolled patients had untreated mantle cell lymphoma. They received 3 cycles of R-CHOP and 2 cycles of rituximab plus Ara-C. They underwent transplant with a BEAM regimen. They were then randomly assigned to receive placebo or bortezomib at 1.3 mg/m2 given intravenously once a week, every 2 weeks, for 2 years. Although the study began with 140 patients, the randomized group included 60 patients.
At the end of the study, for all patients, the 4-year PFS was 61%, and the overall survival was 78%. The 4-year event-free survival was similar for both arms, at 72% without bortezomib vs 71% with bortezomib. The overall survival was 90% vs 93%, respectively. The study therefore showed that bortezomib did not improve event-free survival. However, there were 2 limitations to this study. The first is that the treatment arms were not well balanced. In the placebo arm, 70% of patients had a low-risk MIPI score vs 50% in the bortezomib arm. Another limitation is that only half the patients in the bortezomib arm completed treatment. Therefore, it cannot be concluded based on this study alone that posttransplant bortezomib maintenance therapy is not effective.
I presented results from an interim analysis of a multicenter study evaluating whether bortezomib and rituximab can increase event-free survival after transplant in patients with mantle cell lymphoma.25 This study was not randomized. All patients received bortezomib at 1.3 mg/kg subcutaneously once a week for 4 weeks every 3 months and rituximab at 375 mg/m2 once a week for 4 weeks every 6 months. We also assessed minimal residual disease, by using intrapatient quantifiable CCND1 mRNA.
The interim analysis showed a 2-year event-free survival of 100%. The intrapatient quantifiable CCND1 messenger mRNA level did not vary by more than 5%, showing that this method provides reliable monitoring of minimal residual disease. Thus far, this treatment appears safe and promising. This study is the only one evaluating rituximab plus bortezomib maintenance posttransplant. More follow-up is needed.
Disclosure
Dr Chen is a consultant for Seattle Genetics, Millennium, and Genentech, and a member of their speakers bureaus. He has received research funding from Seattle Genetics and Millennium.
References
1. Chen R, Gopal AK, Smith SE, et al. Five-year survival data demonstrating durable responses from a pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 2736]. Blood. 2015;126(suppl 23).
2. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
3. Chen R, Palmer J, Martin P, et al. Post transplant outcome of a multicenter phase 2 study of brentuximab vedotin as first line salvage therapy in relapsed/refractory HL prior to AHCT [ASH abstract 519]. Blood. 2015;126(suppl 23).
4. Moskowitz AJ, Cho S, Fleisher M, et al. TARC predicts PET-normalization and event free survival in relapsed/refractory Hodgkin lymphoma patients treated with brentuximab vedotin [ASH abstract 180]. Blood. 2015;126(suppl 23).
5. Sweetenham J, Walewski J, Nademanee AP, et al. Updated efficacy and safety data from the AETHERA trial of consolidation with brentuximab vedotin after autologous stem cell transplant (ASCT) in Hodgkin lymphoma patients at high risk of relapse [ASH abstract 3172]. Blood. 2015;126(suppl 23).
6. Moskowitz CH, Nadamanee A, Masszi T, et al. The AETHERA trial: results of a randomized, double-blind, placebo-controlled phase 3 study of brentuximab vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin lymphoma [ASH abstract 673]. Blood. 2014;124
(suppl 21).
7. Yasenchak CA, Forero-Torres A, Cline-Burkhardt VJM, et al. Brentuximab vedotin in combination with dacarbazine or bendamustine for frontline treatment of Hodgkin lymphoma in patients aged 60 years and above: interim results of a multi-cohort phase 2 study [ASH abstract 587]. Blood. 2015;126(suppl 23).
8. Forero-Torres A, Holkova B, Goldschmidt J, et al. Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015;126(26):2798-2804.
9. Borchmann P, Eichenauer DA, Pluetschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: final analysis of a randomized phase II study [ASH abstract 580]. Blood. 2015;126(suppl 23).
10. Garcia-Sanz R, Sureda A, Alonso-Alvarez S, et al. Evaluation of the regimen brentuximab vedotin plus ESHAP (BRESHAP) in refractory or relapsed Hodgkin lymphoma patients: preliminary results of a phase I-II trial from the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO) [ASH abstract 582]. Blood. 2015;126(suppl 23).
11. LaCasce AS, Bociek G, Sawas A, et al. Brentuximab vedotin plus bendamustine: a highly active salvage treatment regimen for patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 3982]. Blood. 2015;126(suppl 23).
12. Santoro A, Mazza R, Pulsoni A, et al. Remarkable clinical efficacy, stem cell mobilization activity and good toxicity profile of the novel begev regimen (bendamustine, gemcitabine and vinorelbine) used as salvage therapy prior to autologous stem cell transplant for relapsed/refractory Hodgkin lymphoma [ASH abstract 581]. Blood. 2015;126(suppl 23).
13. Ansell S, Armand P, Timmerman JM, et al. Nivolumab in patients (pts) with relapsed or refractory classical Hodgkin lymphoma (R/R cHL): clinical outcomes from extended follow-up of a phase 1 study (CA209-039) [ASH abstract 583]. Blood. 2015;126(suppl 23).
14. O’Connor OA, Özcan M, Jacobsen ED, et al. First multicenter, randomized phase 3 study in patients (pts) with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL): alisertib (MLN8237) versus investigator’s choice (LUMIERE trial; NCT01482962) [ASH abstract 341]. Blood. 2015;126(suppl 23).
15. Barr PM, Li H, Spier C, et al. Phase II intergroup trial of alisertib in relapsed and refractory peripheral T-cell lymphoma and transformed mycosis fungoides: SWOG 1108. J Clin Oncol. 2015;33(21):2399-2404.
16. Cederleuf H, Pedersen MB, Jerkeman M, et al. Addition of etoposide to CHOP is associated with improved outcome in adult anaplastic large cell lymphoma patients: a Nordic Lymphoma Group study [ASH abstract 340]. Blood. 2015;126(suppl 23).
17. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504.
18. Sawas A, Connors JM, Kuruvilla JG, et al. The combination of brentuximab vedotin (Bv) and bendamustine (B) demonstrates marked activity in heavily treated patients with relapsed or refractory Hodgkin lymphoma (HL) and anaplastic large T-cell lymphoma (ALCL): results of an international multi center phase I/II experience [ASH abstract 586]. Blood. 2015;126(suppl 23).
19. Leonard JP, Kolibaba K, Reeves JA, et al. Randomized phase 2 open-label study of R-CHOP ± bortezomib in patients (pts) with untreated non-germinal center B-cell-like (non-GCB) subtype diffuse large cell lymphoma (DLBCL): results from the PYRAMID trial [ASH abstract 811]. Blood. 2015;126(suppl 23).
20. Yasenchak CA, Forero-Torres A, Cline-Burkhardt VJM, et al. Brentuximab vedotin in combination with dacarbazine or bendamustine for frontline treatment of Hodgkin lymphoma in patients aged 60 years and above: interim results of a multi-cohort phase 2 study [ASH abstract 587]. Blood. 2015;126(suppl 23).
21. Paszkiewicz-Kozik E, Romejko-Jarosinska J, Osowiecki M, et al. Immunochemotherapy RCHOP in patients with diffuse large B-cell lymphoma over 75 year old [ASCO abstract e19525]. J Clin Oncol. 2015(suppl 33).
22. Bartlett NL, Farber CM, Yasenchak CA, et al. Updated results of a phase II trial of brentuximab vedotin combined with R-CHOP in frontline treatment of patients (pts) with high-intermediate/high-risk diffuse large B-cell lymphoma (DLBCL) [ASCO abstract 8506]. J Clin Oncol. 2015;33(suppl).
23. Gerecitano JF, Roberts AW, Seymour JF, et al. A phase 1 study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma [ASH abstract 254]. Blood. 2015;126(suppl 23).
24. Doorduijn JK, Minnema MC, Kersten MJ, et al. Bortezomib maintenance therapy after induction with R-CHOP, ARA-C and autologous stem cell transplantation in newly diagnosed MCL patients, results of a multicenter phase II HOVON study [ASH abstract 339]. Blood. 2015;126(suppl 23).
25. Chen R, Palmer J, Holmberg L, et al. Interim analysis of a phase 2 study of bortezomib plus rituximab maintenance therapy in patients with mantle cell lymphoma status post autologous stem cell transplantation [ASH abstract 1961]. Blood. 2015;126(suppl 23).
ABSTRACT SUMMARY A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients With Relapsed/Refractory Non-Hodgkin Lymphoma
Venetoclax is an oral inhibitor of BCL-2, an antiapoptotic protein that is commonly overexpressed in non-Hodgkin lymphoma. An open-label, dose-escalation, multicenter, phase 1 study evaluated the safety, pharmacokinetics, and efficacy of venetoclax monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma (Abstract 254). In the dose-escalation cohorts, venetoclax was administered once daily in doses starting at 200 mg and reaching a maximum level of 1200 mg. For evaluation in a safety cohort that included 15 patients with follicular lymphoma and 21 with DLBCL, venetoclax was escalated stepwise from 400 mg to 800 mg, and then to 1200 mg. The most common grade 3/4 treatment-emergent AEs in all patients were anemia (16%), neutropenia (12%), thrombocytopenia (9%), and fatigue (6%). Thirty-three percent of patients experienced at least 1 serious AE. The maximum tolerated dose was not reached. Grade 3 and 4 neutropenia were the only dose-limiting toxicities, occurring in 2 DLBCL patients receiving 600 mg. The ORR for the 106 non-Hodgkin lymphoma patients at all doses was 47%, including 13% CRs. The ORR was 75% in mantle cell lymphoma, 38% in follicular lymphoma, and 18% in DLBCL patients. The responses in follicular lymphoma and mantle cell lymphoma were durable.
ABSTRACT SUMMARY Brentuximab Vedotin Plus Bendamustine: A Highly Active Salvage Treatment Regimen for Patients With Relapsed or Refractory Hodgkin Lymphoma
Brentuximab vedotin and bendamustine are safe and active when administered as monotherapy to patients with relapsed or refractory HL. A single-arm, 2-stage, open-label, phase 1/2 study investigated the safety and efficacy of brentuximab vedotin plus bendamustine in HL patients with primary refractory disease or in first relapse (Abstract 3982). Patients received 2 to 6 cycles of combination therapy and additional cycles of brentuximab vedotin for up to 16 total doses. Optional autologous SCT was permitted any time after cycle 2. The 55 treated patients had a median age of 36 years (range, 19-79 years). Infusion-related reactions were observed in 58% of the patients, a higher rate than expected. A protocol amendment requiring premedication with corticosteroids and antihistamines reduced the severity of infusion-related reactions. Forty patients underwent autologous SCT following successful stem cell collection, and 1 patient underwent bone marrow harvest owing to failure of granulocyte-colony stimulating factor. After approximately 15 months of follow-up from the first dose of study treatment and 13 months from autologous SCT, the 2-drug combination yielded an ORR of 93%, including 76% CRs. The estimated 18-month PFS rate was 75%. An early trend suggested a benefit from brentuximab vedotin consolidation therapy after autologous SCT.
ABSTRACT SUMMARY Initial Results of US Intergroup Trial of Response-Adapted Chemotherapy or Chemotherapy/Radiation Therapy Based on PET for Non-Bulky Stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)
To further refine the use of interim PET, the US Intergroup conducted a phase 2 clinical trial for patients with newly diagnosed, nonbulky, stage I or II HL (Abstract 578). The 164 enrolled patients received 2 cycles of ABVD followed by PET. A Deauville score of 1 to 3 was considered negative. PET-negative patients received 2 more cycles of ABVD. PET-positive patients received 2 cycles of escalated BEACOPP plus 3060 cGy of involved-field radiation therapy. After a median follow-up of 2.1 years, 8 of 131 PET-negative patients relapsed or progressed. The estimated 3-year PFS for these patients was 92%. Among the 13 patients with PET-positive disease, 3 patients relapsed and 1 committed suicide. For these patients, the estimated 3-year PFS was 66%. The authors projected that the trial was likely to meet its primary objective of a 3-year PFS of at least 85% for PET-negative patients, but was unlikely to meet its secondary objective of improving 3-year PFS for PET-positive patients.
ABSTRACT SUMMARY Brentuximab Vedotin With RCHOP As Frontline Therapy in Patients With High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL): Results From an Ongoing Phase 2 Study
A multicenter, randomized, phase 2 study investigated 6 cycles of R-CHOP plus brentuximab vedotin (1.2 or 1.8 mg/kg) as first-line therapy in patients with high-intermediate or high-risk DLBCL (Abstract 814). Tumors were assessed at baseline for CD30 expression. Among the 51 patients, 71% had stage IV disease, 37% were high risk, and 63% were high/intermediate risk. After the first 10 patients experienced significant neurotoxicity with 1.8 mg/kg of brentuximab vedotin, the remaining patients received the 1.2 mg/kg dose. The most common grade 3/4 AEs were neutropenia (33%), febrile neutropenia (31%), and anemia (24%). ORRs were similar in the CD30-negative and CD30-positive patients. Among the 25 evaluable patients with CD30-positive disease, 84% obtained an objective response, including 76% CRs. Median PFS for the CD30-negative patients was 18 months vs not reached for the CD30-positive patients. Estimated 12-month and 15-month PFS rates for CD30-positive patients were both 83%. For CD30-negative patients, these rates were 62% and 54%, respectively. ORR was not impacted by the presence of Epstein-Barr virus. The trial has been amended to add a cohort evaluating brentuximab vedotin plus R-CHP in order to eliminate the toxicity associated with vincristine.
ABSTRACT SUMMARY Addition of Etoposide to CHOP Is Associated With Improved Outcome in Adult Anaplastic Large Cell Lymphoma Patients: A Nordic Lymphoma Group Study
A population-based study was conducted to analyze outcome and risk factors in adult anaplastic large T-cell lymphoma (ALCL) patients from the Swedish and Danish Lymphoma Registries (Abstract 340). The analysis included 371 patients, with a median follow-up of 7.2 years. ALK-positive patients were younger than ALK-negative patients (median age, 44 vs 66 years; P<.001). Five-year OS rates were 78% for the ALK-positive patients vs 37% for those who were ALK-negative. Multivariate analysis revealed that treatment with CHOP, compared with CHOP plus etoposide, was an independent risk factor associated with reduced OS (HR, 1.85; 95% CI, 1.18-2.89; P=.007). An increasing IPI score was also associated with inferior OS (HR for each increment, 1.79; 95% CI, 1.52-2.12; P<.001). For the 108 patients who had received treatment with CHOP plus etoposide, multivariate analysis revealed 3 independent risk factors for OS: increased age (HR for ages 41-60 years, 2.71; 95% CI, 1.45-5.05; P=.001; HR for ages 61-75 years, 7.34; 95% CI, 2.10-25.5), ALK negativity (HR, 2.54; 95% CI, 1.12-5.76; P=.026), and elevated lactate dehydrogenase (HR, 2.24; 95% CI, 1.08-4.67; P=.031).
ABSTRACT SUMMARY Interim Analysis of a Phase 2 Study of Bortezomib Plus Rituximab Maintenance Therapy in Patients With Mantle Cell Lymphoma Status Post Autologous Stem Cell Transplantation
A multicenter, phase 2 trial evaluated bortezomib plus rituximab maintenance therapy in patients with mantle cell lymphoma in CR after autologous SCT (Abstract 1961). The primary endpoint was disease-free survival after 2 years of maintenance therapy. The study accrued 16 patients, and 15 were eligible for analysis. The 2-year disease-free survival was 100%, and the 2-year OS was 100%. No patients relapsed or died. The treatment was well tolerated. Grade 3/4 AEs potentially related to treatment included neutropenia in 4 patients, lymphopenia in 3, and pneumonia and skin infection, each in 1 patient. Grade 2 AEs potentially related to treatment included thrombocytopenia in 2 patients and neutropenia, anemia, arthralgia, peripheral sensory neuropathy, pruritus, and hypertension, each in 1 patient. Peripheral neuropathy toxicities included grade 1 sensory neuropathy in 4 patients, grade 1 motor neuropathy in 1, and grade 2 sensory neuropathy in 1. In an analysis of 12 patients for minimal residual disease (MRD), the relative CCND1 mRNA level never exceeded 12% of the control (JVM2), and the majority of the samples were below 5%. There were few intrapatient fluctuations.
ABSTRACT SUMMARY The Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) Demonstrates Marked Activity in Heavily Treated Patients With Relapsed or Refractory Hodgkin Lymphoma (HL) and Anaplastic Large T-Cell Lymphoma (ALCL): Results of an International Multi Center Phase I/II Experience
A multicenter phase 1/2 study investigated the addition of brentuximab vedotin to bendamustine in heavily pretreated patients with relapsed or refractory HL and ALCL (Abstract 586). Patients were enrolled at 3 centers from August 2012 to November 2015. In phase 1 of the trial, brentuximab vedotin (day 1) was escalated from 1.2 mg/kg to 1.8 mg/kg, and bendamustine (days 1 and 2) was escalated from
70 mg/m2 to 100 mg/m2 in 5 cohorts, with treatment administered in 21-day intervals for a maximum of 6 cycles. Phase 2 used the recommended doses from phase 1 (brentuximab vedotin 1.8 mg/kg [day 1] plus bendamustine 90 mg/m2 [days 1 and 2]). The trial enrolled 27 patients in phase 1 and 19 patients in phase 2. For the 46 patients, median age was 36 years (range, 30-70 years), and the majority of patients were male. Patients had received a median 6 prior therapies (range, 1-16). For all dose levels combined, the ORR was 69%, including 20% CRs. Responses were observed in more than 50% of patients who had received either agent separately prior to study enrollment. The preliminary duration of response was 4.4 months (range, 2.3-10.3 months). In the phase 1 vs phase 2 patients, the most common grade 3/4 AEs were neutropenia (15% vs 16%, respectively), anemia (22% vs 0%), thrombocytopenia (19% vs 0%), and lung infection (11% vs 21%).
ABSTRACT SUMMARY Updated Data for the PD-1 Inhibitors Nivolumab and Pembrolizumab
An ongoing phase 1 study is evaluating the efficacy of nivolumab in 23 patients with relapsed or refractory HL. Twenty-three HL patients received nivolumab in the dose expansion cohort (Abstract 583). The ORR was 87%, including 22% CRs and 65% PRs. After a median follow-up of 101 weeks, median PFS and median duration of response had not been reached. Median rates of OS were 91% at 1 year and 83% at 1.5 years. Treatment-emergent AEs of interest included 1 event each of grade 3 colitis and grade 3 pneumonitis. Three patients discontinued treatment owing to AEs, 2 of which were considered related to nivolumab treatment. Pembrolizumab was evaluated in the open-label, multicenter phase 1b KEYNOTE-013 (A Trial of Pembrolizumab [MK-3475] in Participants With Blood Cancers [MK-3475-013]) trial. Results from an expansion cohort study were presented at the 2015 ASH meeting (Abstract 584). Among the 31 patients with relapsed or refractory classical HL, the ORR was 65%, including 16% CRs. The size of target lesions was reduced in 90% of patients. At 24 weeks, PFS was 69%, and 71% of patients had a response duration of 24 weeks or longer. Treatment-related AEs of any grade occurred in 68% of patients, and treatment-related AEs of grade 3 occurred in 16%. Two patients discontinued treatment owing to an AE.
ABSTRACT SUMMARY Evaluation of the Regimen Brentuximab Vedotin Plus ESHAP (BRESHAP) in Refractory or Relapsed Hodgkin Lymphoma Patients: Preliminary Results of a Phase I-II Trial From the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)
A phase 1/2 trial was conducted to evaluate the dose-limiting toxicity, maximum tolerated dose, and ORR with brentuximab vedotin plus etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) chemotherapy as second-line treatment in patients with relapsed or refractory HL prior to autologous SCT (Abstract 582). Brentuximab vedotin was administered on day 1 at 0.9 mg/kg, 1.2 mg/kg, or 1.8 mg/kg in conjunction with ESHAP every 21 to 28 days followed by autologous SCT. After transplant, patients received brentuximab vedotin monotherapy. All 9 patients enrolled in the phase 1 portion of the trial had a CR. Severe AEs included nonneutropenic fever that resolved in 1 to 3 days, pneumothorax that resolved in 1 day, and febrile neutropenia that resolved in 7 days. Two AEs of grade 4 neutropenia and 1 of grade 4 thrombocytopenia occurred. No dose-limiting toxicity was observed, and the maximum tolerated dose of brentuximab vedotin was defined as 1.8 mg/kg every 21 days in combination with ESHAP. The phase 2 portion included 36 patients. Stem cells were collected in 24 patients, and no mobilization failures occurred. In the 24 patients evaluable for pretransplant response, the ORR was 96%, with 83% metabolic CRs. The majority of grade 3/4 AEs were hematologic, and toxicity was manageable.
ABSTRACT SUMMARY Bortezomib Maintenance Therapy After Induction With R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study
Maintenance therapy with bortezomib after autologous SCT in mantle cell lymphoma patients was investigated in a phase 2 study (Abstract 339). Patients with newly diagnosed mantle cell lymphoma received 3 cycles of R-CHOP followed by 2 cycles of high-dose cytarabine plus rituximab; then carmustine, etoposide, cytarabine, and melphalan (BEAM); and, for patients with a PR or CR, autologous SCT. Patients with a CR or PR after transplant with adequate platelet and neutrophil counts were randomized to maintenance bortezomib (1.3 mg/m2 once every 2 weeks for 24 months) or no further treatment. The patients had a median age of 57 years (range, 34-66 years), and 78% were male. Mantle cell lymphoma IPI scores were low in 57%, intermediate in 32%, and high in 10%. Sixty eligible patients were randomly assigned to receive bortezomib maintenance or no further treatment. Among the 30 patients who received bortezomib maintenance, 15 completed the 2 years of treatment. Reasons for discontinuation included excessive toxicity (n=6), disease progression or relapse (n=4), nonadherence (n=3), and second malignancy (n=1). With a median follow-up of 50 months, median 4-year event-free survival for all patients in the intent-to-treat population was 61%, and median 4-year OS was 78%. Median 4-year event-free survival was 72% without bortezomib vs 71% with bortezomib. Rates of 4-year OS were 90% vs 93%, respectively.