A Review of Selected Presentations From the 2017 American Society of Hematology Annual Meeting and Exposition • December 9-12, 2017 • Atlanta, Georgia
Brentuximab Vedotin Plus Doxorubicin, Vinblastine, and Dacarbazine as Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients With Previously Untreated Stage III or IV Hodgkin Lymphoma: The Phase 3 ECHELON-1 Study
More than 65,000 new cases of Hodgkin lymphoma are diagnosed annually worldwide, and approximately 40% are stage III or stage IV at presentation.1,2 The chemotherapy combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was originally developed in the 1970s and has been the standard of care for patients with Hodgkin lymphoma for decades.3,4 However, ABVD is associated with major toxicities, including myelosuppression and pulmonary events that arise from the use of bleomycin. For patients who relapse after primary therapy, standard treatment consists of high-dose chemotherapy plus autologous stem cell transplant.5,6 Brentuximab vedotin is an antibody-drug conjugate consisting of an antibody that binds to CD30 joined to monomethyl auristatin E by a protease-cleavable linker.7-10 After internalization, the monomethyl auristatin E moiety is released and disrupts microtubule assembly. The combination of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) was evaluated in a phase 1 dose-escalation trial.11,12 The combination was generally well-tolerated and yielded a complete response (CR) rate of 96%, a 5-year failure-free survival rate of 92%, and a 5-year overall survival (OS) rate of 100%.
The open-label, randomized, phase 3 ECHELON-1 trial (Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma) evaluated the combination of brentuximab vedotin plus AVD vs ABVD as first-line therapy in patients with stage III/IV classical Hodgkin lymphoma.13,14 Patients were randomly assigned to treatment with 6 cycles of ABVD or brentuximab vedotin (1.2 mg/kg on days 1 and 15) plus AVD. Imaging was performed following cycle 2, after which patients with a Deauville score of 5 could be switched to the other treatment arm. The primary endpoint was modified progression-free survival (PFS) by independent review. This endpoint referred to the time to progression, death from any cause, or a position emission tomography scan showing a Deauville score of 3, 4, or 5 after completion of frontline therapy followed by additional anticancer therapy, whether or not there was a defined histologic progression. The secondary endpoint was OS.
The study enrolled 664 patients into the brentuximab vedotin plus AVD arm and 670 into the ABVD arm. Approximately one-third of the patients had stage III disease, 59% had B symptoms, 23% had bone marrow involvement, and 29% had more than 1 site of extranodal involvement. After a median follow-up of 24.9 months, the 2-year modified PFS rate by independent review was 82.1% (95% CI, 78.7%-85.0%) in the brentuximab vedotin plus AVD arm vs 77.2% (95% CI, 73.7%-80.4%) in the ABVD arm (hazard ratio [HR] for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60-0.98; P=.035; Figure 1). Modified PFS was superior with the brentuximab vedotin combination among most subgroups, as evidenced by preplanned analysis. Interim analysis of OS was conducted at the same time as the primary endpoint, at which time 67 deaths had occurred (HR, 0.72; 95% CI, 0.44-1.17; P=.19). The final OS analysis will be conducted after 112 deaths.
The most common clinically im–portant treatment-emergent adverse events (AEs) of any grade were neutropenia (58%), constipation (42%), and vomiting (33%) in the brentuximab vedotin plus AVD arm, and neutropenia (45%), constipation (37%), and fatigue (32%) in the ABVD arm. The most common AEs of grade 3 or higher in the brentuximab vedotin plus AVD arm were neutropenia, occurring in 54% (vs 39% in the ABVD arm), and febrile neutropenia, occurring in 19% (vs 8% in the ABVD arm). Among the 83 patients in the brentuximab vedotin plus AVD arm who received prophylactic treatment with granulocyte-colony simulating factor, the rate of febrile neutropenia was 11%, vs 21% among patients who did not receive prophylaxis (n=579). Peripheral neuropathy was observed in 67% of patients in the brentuximab vedotin plus AVD arm vs 43% in the ABVD arm. In the brentuximab vedotin arm, peripheral neuropathy had resolved completely or had improved by at least 1 grade in 67% of patients by the last follow-up visit. Interstitial lung disease of grade 3 or higher was observed in less than 1% of patients in the brentuximab vedotin plus AVD arm vs 3% of patients in the ABVD arm. Among the 9 deaths that occurred in the brentuximab vedotin plus AVD arm, 7 were associated with neutropenia. Eleven of 13 deaths in the ABVD arm were related to pulmonary toxicity.
References
1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide IARC Cancer Base No. 11. International Agency for Research on Cancer. http://globocan.iarc.fr. Accessed January 3, 2018.
2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review (CRS), 1975-2014. National Cancer Institute. https://seer.cancer.gov/csr/1975_2014. Posted April 2017. Accessed January 15, 2017.
3. Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE, Ansell SM. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol. 2005;23(30):7614-7620.
4. Vakkalanka B, Link BK. Neutropenia and neutropenic complications in ABVD chemotherapy for Hodgkin Lymphoma. Adv Hematol. 2011;2011:656013.
5. Ansell SM. Hodgkin lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(4):434-442.
6. Carde P, Karrasch M, Fortpied C, et al. Eight cycles of ABVD versus four cycles of BEACOPPescalated plus four cycles of BEACOPPbaseline in stage III to IV, international prognostic score ≥3, high-risk Hodgkin lymphoma: first results of the phase III EORTC 20012 Intergroup trial. J Clin Oncol. 2016;34(17):2028-2036.
7. Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;
21(7):778-784.
8. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4):1458-1465.
9. Wahl AF, Klussman K, Thompson JD, et al. The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin’s disease. Cancer Res. 2002;62(13):3736-3742.
10. Okeley NM, Miyamoto JB, Zhang X, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res. 2010;16(3):888-897.
11. Connors JM, Ansell SM, Fanale M, Park SI, Younes A. Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma. Blood. 2017;130(11):1375-1377.
12. 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.
13. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 ECHELON-1 study [ASH abstract 6]. Blood. 2017;130(suppl 1).
14. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma [published online December 10, 2017]. N Engl J Med. 2017. doi:10.1056/NEJMoa1708984.
Brentuximab Vedotin With R-CHP Chemotherapy as Frontline Treatment for Patients With CD30-Positive Primary Mediastinal Large B-Cell, Diffuse Large B-Cell, and Grey Zone Lymphomas: Results of a Phase I/II Multisite Trial
CD30 is expressed in approximately 20% of diffuse large B-cell lymphomas (DLBCLs), 80% of primary mediastinal large B-cell lymphomas (PMBLs), and 100% of gray zone lymphomas. PMBL is a rare form of lymphoma with molecular and clinical features that resemble classical Hodgkin lymphoma.1 Current first-line regimens include rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), with or without radiation; and dose-adjusted etoposide and doxorubicin, plus cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R).2,3 With R-CHOP, rates of event-free survival and PFS are less than 80%, and most patients receive treatment with radiation, which is associated with long-term negative effects.3,4 DA-EPOCH-R is an intense, infusional regimen, and real-world and pediatric data have shown lower PFS rates compared with the initial study by Dunleavy and colleagues.2,5-7
Brentuximab vedotin has shown activity in patients with relapsed or refractory PMBL and was evaluated as first-line treatment in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (R-CHP) in a phase 1/2 study.8-10 Elig-ible patients had treatment-naive, his-tologically confirmed, CD30-pos-itive PMBL, DLBCL, or gray zone lymphoma of any stage and an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 3. Brentuximab vedotin was administered at 1.8 mg/kg concurrently with R-CHP on day 1, once every 3 weeks for 6 cycles. Responses were measured via fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). Granulocyte-colony stim-ulating factor was allowed, and con-solidative radiation was permitted after posttreatment imaging.
The 31 patients had a median age of 37 years (range, 18-76 years), and 42% had stage III/IV disease. Among the 23 patients with PMBL, 91% had bulky tumors that were 7.5 cm or longer. Grade 3/4 AEs that were possibly related to study treatment were observed in 87% of patients. They included hematologic events (reported in 74% of patients) and nonhematologic events (in 35%). Grade 3 febrile neutropenia was observed in 23% of patients. Two patients discontinued treatment. A reduction in the dose of brentuximab vedotin was required in 2 patients owing to AEs. One patient developed acute myeloid leukemia at 2 years after completion of therapy. Among 6 patients treated with brentuximab vedotin in combination with R-CHP, no dose-limiting toxicities were observed.
The dose was expanded for the phase 2 portion of the study. Among 29 patients in the phase 1/2 study population, the overall response rate (ORR) was 100%, with a CR rate of 86%. All of the PRs occurred in patients with PMBL. After a median follow-up of 17 months (range, 7-44 months), median PFS and median OS were not reached (Figure 2). The 1-year PFS was 92% (95% CI, 73%-98%), and 1-year OS was 100%. In the cohort of 22 PMBL patients, median PFS and median OS were also not reached. At 1 year, PFS was 89% (95% CI, 64%-97%) and OS was 100%. No differences were observed between the 14 patients who received radiotherapy and the 8 patients who did not (P=.47). The PMBL patients showed a high rate of thromboembolic events, including deep vein thrombosis (23%) and pulmonary embolism (14%).
References
1. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851-862.
2. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408-1416.
3. Rieger M, Osterborg A, Pettengell R, et al; MabThera International Trial (MInT) Group. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011;22(3):664-670.
4. Gleeson M, Hawkes EA, Cunningham D, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) in the management of primary mediastinal B-cell lymphoma: a subgroup analysis of the UK NCRI R-CHOP 14 versus 21 trial. Br J Haematol. 2016;175(4):668-672.
5. Burke GAA, Gross TG, Pillon M, et al. Results of Inter-B-NHL Ritux 2010—phase II study of DA-EPOCH-R for children and adolescents with primary mediastinal large B-cell lymphoma (PMLBL) on behalf of European Intergroup for Childhood Non Hodgkin’s Lymphoma (EICNHL) and Children’s Oncology Group (COG) [ASH abstract 4124]. Blood. 2017;130(suppl 1).
6. Giulino-Roth L, O’Donohue T, Chen Z, et al. Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Br J Haematol. 2017;179(5):739-747.
7. Shah NN, Szabo A, Huntington SF, et al. R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis [published online December 19, 2017]. Br J Haematol. doi:10.1111/bjh.15051.
8. Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(9):1394-1402.
9. Zinzani PL, Pellegrini C, Chiappella A, et al. Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma: results from a phase 2 clinical trial. Blood. 2017;129(16):2328-2330.
10. Svoboda J, Landsburg DJ, Nasta SD, et al. Brentuximab vedotin with R-CHP chemotherapy as frontline treatment for patients with CD30 positive primary mediastinal large B-cell, diffuse large B-cell, and grey zone lymphomas: results of a phase I/II multisite trial [ASH abstract 191]. Blood. 2017;130(suppl 1).
In Vitro, In Vivo, and Parallel Phase I Evidence Support the Safety and Activity of Duvelisib, a PI3K-δ,γ Inhibitor, in Combination With Romidepsin or Bortezomib in Relapsed/Refractory T-Cell Lymphoma
Duvelisib is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta and PI3K-gamma that has shown encouraging efficacy in a phase 1 study, with ORRs of 50% in peripheral T-cell lymphoma and 32% in cutaneous T-cell lymphoma.1 Responses have been linked to constitutive activation of phosphorylated Akt in T-cell lymphoma cell lines (P=.024). Based on its encouraging activity in T-cell lymphoma, duvelisib was evaluated in combination with romidepsin or bortezomib in 2 parallel phase 1 studies in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma.2 The studies followed a 3 + 3 design with dose expansion at the maximum tolerated dose. A lead-in cohort of patients treated with duvelisib monotherapy prior to the combination was included to learn more about this agent’s mechanism of action and to improve patient sel-ection.
In arm A, duvelisib was administered twice daily at 25 mg, 50 mg, or 75 mg in combination with romidepsin. No dose-limiting toxicities were observed, and the maximum tolerated dose was established as romidepsin at 10 mg/m2 on days 1, 8, and 15 plus duvelisib at 75 mg twice daily. Across all cohorts, the most common AEs observed with the combination treatment were grade 1/2 fatigue, nausea, and altered taste (Figure 3). The most common grade 3/4 event was neutropenia. Two deaths occurred that were unrelated to study treatment, including 1 from diffuse alveolar hemorrhage following allogeneic stem cell transplant and 1 from sepsis in the setting of disease progression. Across the 3 dose cohorts, 9 patients (60%) achieved a response. CRs occurred in 4 patients (27%) and PRs in 5 (33%). PRs were observed in 2 of 4 patients with cutaneous T-cell lymphoma (50%). Among the 11 patients with peripheral T-cell lymphoma, 7 achieved a response (64%), including 4 CRs (36%) and 3 PRs (27%).
In arm B, duvelisib was administered twice daily at 25 mg, 50 mg, or 75 mg in combination with bor-tezomib. One patient experienced a dose-limiting toxicity of pneumonia at the lowest duvelisib dose level, and the maximum tolerated dose was iden-ti-fied as duvelisib at 25 mg, twice daily, plus bor-tezomib at 1.0 mg/m2 on days 1, 4, 8, and 11. Across all cohorts, the most common treatment-related AE of any grade was diarrhea/colitis, observed in 12 of 17 patients (71%). The most common treatment-related grade 3/4 AE was elevated levels of alanine and/or aspartate transaminase, observed in 6 patients (35%), followed by high alkaline phosphatase levels, rash, and neutropenia, each observed in 2 patients (12%). Serious grade 3/4 AEs occurred in patients treated with the higher doses of duvelisib, leading to expansion with the lowest-dose combination. One death occurred in a patient who developed Stevens-Johnson syndrome. Among 17 patients treated in the 3 dose cohorts, 6 (35%) achieved a response, half of which were CRs. Among 7 patients with cutaneous T-cell lymphoma, only 1 patient (14%) achieved a PR. There were no CRs. Among 10 patients with peripheral T-cell lymphoma, the ORR was 50% and included 3 patients with CRs.
The rate of liver function abnormalities was higher with duvelisib plus bortezomib compared with duvelisib plus romidepsin. Similarly, a previous study of duvelisib monotherapy in 210 patients showed high rates of abnormal liver function.3 Elevated alanine aminotransferase of any grade was observed in 39% of patients treated with duvelisib alone, including 20% with grade 3/4 elevations. Elevated aspartate transaminase of any grade was observed in 38% of patients, including 15% with grade 3/4 elevations. In contrast, among the 16 patients treated with duvelisib and romidepsin, grade 1/2 elevations in alanine or aspartate transaminase each occurred in 13% of patients, with no grade 3/4 elevations. The addition of romidepsin to duvelisib appeared to confer a protective effect with regard to toxicity. Further expansion of the duvelisib plus romidepsin cohort is planned.
References
1. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase I trial and preclinical models of T-cell lymphoma [published online December 12, 2017]. Blood. doi:10.1182/blood-2017-08-802470.
2. Moskowitz A, Koch R, Mehta-Shah N, et al. In vitro, in vivo, and parallel phase I evidence support the safety and activity of duvelisib, a PI3K-δ,γ inhibitor, in combination with romidepsin or bortezomib in relapsed/refractory T-cell lymphoma [ASH abstract 819]. Blood. 2017;130(suppl 1).
3. Flinn IW, O’Brien S, Kahl B, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies [published online November 30, 2017]. Blood. doi:10.1182/blood-2017-05-786566.
Results From a Phase 1/2 Study of Brentuximab Vedotin in Combination With Nivolumab in Patients With Relapsed or Refractory Hodgkin Lymphoma
Nivolumab and brentuximab vedotin have demonstrated single-agent activity among patients with relapsed or refractory Hodgkin lymphoma.1,2 A study was conducted to evaluate the combination of brentuximab vedotin plus nivolumab as an alternative to chemotherapy in patients with relapsed or refractory Hodgkin lymphoma.3 The open-label, multicenter, phase 1/2 trial enrolled 62 adults with relapsed or refractory classical Hodgkin lymphoma after first-line chemotherapy. Responses were assessed using the 2014 Lugano classification.4 The primary endpoints were safety, including AE incidence and severity, and the CR rate following completion of study treatment. Patients received treatment every 3 weeks for up to 4 cycles. For cycle 1, patients received brentuximab vedotin on day 1 and nivolumab on day 8, with both therapies administered on day 1 for subsequent cycles. Blood samples for biomarker analyses were taken throughout the study and at the end of treatment. After completing the end-of-treatment response assessment, patients were eligible for autologous stem cell transplant. AEs were recorded from the start of treatment through 100 days after the last dose of nivolumab.
The 62 enrolled patients had a median age of 36 years (range, 18-69 years), and 39% had stage III/IV disease. Sixty-one patients received at least 1 dose of the study drug, and 58 patients completed all 4 cycles of brentuximab vedotin plus nivolumab. There were 4 treatment discontinuations during the study: 2 based on patient decisions not involving an AE, 1 owing to grade 3 peripheral neuropathy, and 1 owing to the investigator’s decision. Nearly all patients experienced an AE of any grade, and 31% had an AE of grade 3 or higher. The most common AEs of any grade were nausea (49%), infusion-related reactions (44%), and fatigue (41%). Grade 3 AEs occurred in 17 patients (28%). Grade 4 AEs were observed in 2 patients (3%), including 1 case each of thrombocytopenia and increased lipase enzymes.
Infusion-related reactions occ-urred in 27 patients (44%), including 25 patients (41%) who experienced a reaction during infusion with brentuximab vedotin. Pretreatment with a low-dose corticosteroid and an antihistamine did not affect the frequency or severity of infusion-related reactions. Although no patient discontinued treatment owing to an infusion-related reaction, the event led to interruption of the infusion in 26 patients (26%). Excluding any infusion-related reactions, potential immune-related AEs occurred in 50 patients (82%). Five patients were treated with a systemic corticosteroid for an immune-related AE; these cases consisted of grade 4 colitis and grade 4 pneumonitis, grade 4 pneumonitis, grade 3 diarrhea and grade 2 colitis, grade 3 transaminase elevation, and grade 2 pneumonitis. AEs did not lead to any treatment discontinuations.
Among 60 patients evaluable for efficacy, the ORR was 83% (95% CI, 72%-92%). The CR rate was 62% (95% CI, 48%-74%). Patients with a Deauville score of 1 or 2 accounted for 29 of the CRs (78%). One patient with a Deauville score of 5 achieved a CR. Among the 13 patients (22%) with a PR (95% CI, 12%-34%), all had a Deauville score of 4 or 5. Among the 60 patients who were evaluable for efficacy, 54 ultimately proceeded to autologous stem cell transplant, including 42 who proceeded to transplant directly after completing study treatment and 12 who proceeded to transplant after receiving subsequent salvage therapy. Treatment with brentuximab vedotin and nivolumab did not appear to affect yields of stem cell mobilization and collection or engraftment. After a median follow-up of 8 months, the median duration of response was not reached. Six-month PFS was 89% (95% CI, 75%-95%). The changes in standardized uptake value are shown in Figure 4.
Populations of T cells decreased after administration of brentuximab vedotin and increased after administration of both brentuximab vedotin and nivolumab, with the most dramatic changes in cell count observed for T-regulatory cells (Figure 5). The activated and dividing CD4-positive T-cell populations followed a similar pattern, decreasing after infusion of brentuximab vedotin on day 1 of cycle 1, and then significantly increasing after administration of both antibodies during cycle 2. Although T-cell receptor clonality did not change with dual antibody treatment, preexisting T-cell clones in the periphery expanded. After patients received brentuximab vedotin on day 1 of cycle 1, cytokine and chemokine profiles were consistent with innate immune system activation. In contrast, after coadministration of both antibodies on day 1 of cycle 2, the cytokine and chemokine profile was consistent with activation of the adaptive immune response. Baseline levels of interferon-gamma inducible protein 10 were significantly lower in patients who achieved a CR (P=.0178). Thymus- and activation-regulated chemokine levels were also lower in patients who achieved a CR, both at baseline and afterward. According to ex vivo testing of peripheral blood samples with major histocompatibility complex 1 and 2 antigen peptides, there was an increase in interferon-gamma expression from effector memory CD8-positive T cells. The greatest stimulation was observed at day 15 of cycle 1, which is consistent with activation of the immune system after treatment with both antibodies.
References
1. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311-319.
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. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 649]. Blood. 2017;130(suppl 1).
4. 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.
High Complete Response Rates With Pembrolizumab in Combination With Rituximab in Patients With Relapsed Follicular Lymphoma: Results of an Open-Label, Phase II Study
Tumors associated with follicular lymphoma are infiltrated with antitumor T cells. These T cells are functionally impaired, however, owing to PD-1 expression and pathway activation, and the tumor cells continue to reproduce.1 Pembrolizumab is an anti–PD-1 antibody that restores antitumor T-cell function, and rituximab is an anti-CD20 antibody that induces tumor cell killing through antibody-directed cellular cytotoxicity. Combining these antibodies could provide synergistic antitumor activity by activating both the innate and adaptive immune systems. The combination of pembrolizumab and rituximab was evaluated in an open-label, 1-arm, single-institution, phase 2 trial of adults with grade 1 to 3a follicular lymphoma who had rituximab-sensitive disease and had rel-apsed after treatment with at least 1 prior therapy.2 Eligible patients had an ECOG performance status of 0 to 1.
Patients were treated with 4 weekly doses of ruxolitinib at 375 mg/m2 on days 1, 8, 15, and 22. Treatment with pembrolizumab began on day 2 in a flat dose of 200 mg, and was continued every 3 weeks for up to 16 doses. Responses were assessed according to the Lugano Classification.3 The primary objective was ORR. It was anticipated that the 2-drug combination would improve ORR to 60%, from the 40% seen with rituximab monotherapy in historical controls.
The 30 evaluable patients had a median age of 64 years (range, 43-84 years), and 57% were male. The Follicular Lymphoma International Prognostic Index (FLIPI) score was low in 27% of patients, intermediate in 53%, and high in 20%. Sixty percent of patients had stage IV disease. The median PFS from the most recent prior line of therapy was 28 months (range, 3-162 months).
After a median follow-up of 13.8 months, the antibody combination yielded an ORR of 67%, with a CR rate of 50% (Figure 6). The median duration of response was 14.1 months. The median PFS was 11.4 months. In patients who experienced a PFS lasting beyond 1 year with their most recent therapy, median PFS was 13.8 months (95% CI, 8.5 months to not reached), whereas for patients who had experienced a PFS lasting 1 year or less, the median PFS with the antibody combination was 4.1 months.
The most common treatment-emergent AEs of any grade were fatigue (46%), diarrhea (40%), and nausea and vomiting (37%). Grade 3/4 AEs included nausea and vomiting (7%), diarrhea (3%), and transaminitis (3%). In addition, 1 patient (3%) experienced grade 3 aseptic meningitis. Six patients discontinued treatment owing to immune-related AEs, including grade 2/3 diarrhea (10%), grade 2 pneumonitis (7%), and grade 2 rash (3%).
Programmed death ligand 1 (PD-L1) was detected in the histiocytes of the 19 tumors tested. However, PD-L1 was not detected on tumor cells in 8 samples. Among the latter, 50% of patients responded, yielding 2 CRs and 2 PRs. Among the 11 tumor samples with PD-L1 expression, PD-L1 was present in 1% to 8% of tumor cells in 10 samples and in 20% of tumor cells in 1 sample. PD-L1 expression was not a significant predictor of response (P=.71). Analysis of immune cell gene signatures in baseline tumors of 18 patients showed an association between the presence of a high CD8-positive T-effector score and a CR.
For the overall study population, the ORR was 67% for patients with a high CD8-positive T-effector score and 63% in those with a low score. For patients who achieved a CR, 67% had a high score and 28% had a low score. Interferon-gamma has been proposed as a biomarker associated with response to pembrolizumab.4 Peripheral blood samples were available from 26 patients who received treatment with pembrolizumab plus rituximab. Among these patients, interferon-gamma–related scores correlated with response to the 2-drug combination based on a 10-gene score (P=.016) and a 28-gene score (P=.023).
References
1. Myklebust JH, Irish JM, Brody J, et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 2013;121(8):1367-1376.
2. Nastoupil L, Westin JR, Fowler J, et al. High complete response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: results of an open-label, phase II study [ASH abstract 414]. Blood. 2017;130(suppl 1).
3. 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.
4. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930-2940.
Sequential Brentuximab Vedotin Before and After Adriamycin, Vinblastine, and Dacarbazine for Older Patients With Untreated Classical Hodgkin Lymphoma: Final Results From a Multicenter Phase II Study
Patients with Hodgkin lymph-o-ma ages 60 years and older are consistently underrepresented in clinical trials, and their outcomes are inferior to those seen in younger pat-ients.1,2 In a prospective study that compared ABVD vs the Stanford V regimen in Hodgkin lymphoma, elderly patients had a significantly reduced 5-year failure-free survival (74% vs 48%; P=.002) and OS (90% vs 58%; P<.0001) compared with younger patients.3 In a study of 27 elderly patients with Hodgkin lymphoma (median age, 78 years), first-line treatment with brentuximab vedotin monotherapy yielded an ORR of 92% and a CR rate of 73%.4 However, 30% of the patients experienced grade 3 neuropathy and lost the ability to perform daily activities, such as bathing and eating. The median PFS was 10.5 months for all patients vs 11.8 months for patients who achieved a CR. Combining brentuximab vedotin with dacarbazine or bendamustine led to a longer median PFS of 17.94 months.5 The ORR was 100% and the CR rate was 62%. However, the PFS for patients with a CR was only 10.78 months. Grade 3 neuropathy occurred in 27% of patients, and 2 patients died from toxicity.
An investigator-initiated study evaluated the incorporation of brentuximab vedotin into frontline therapy followed by AVD in elderly patients with Hodgkin lymphoma.6 Eligible patients were ages 60 years or older and had treatment-naive, advanced-stage Hodgkin lymphoma. Enrolled patients initially received 2 cycles of brentuximab vedotin (1.8 mg/kg every 3 weeks) and then 6 cycles of AVD, followed by 4 cycles of brentuximab vedotin consolidation. The study used a Simon 2-stage design, with a planned enrollment of 48 patients. The primary endpoint was the CR rate after AVD treatment. Responses were assessed using the Lugano criteria based on FDG-PET/CT with Deauville criteria.7 Benchmarks for evaluating the CR rate ranged from 46% to 78%.3,8,9
The 48 patients had a median age of 69 years (range, 60-88 years), and 63% were male. One-fourth of patients had classical Hodgkin lymphoma histology. Eighty-two percent of patients had stage III/IV disease, 23% had bone marrow involvement, and the median Cumulative Illness Rating score was 6. Among 7 patients who were not evaluable for response after the final AVD cycle, 1 died from pancreatitis,10 4 withdrew owing to toxicities (2 each from brentuximab vedotin induction or AVD in cycle 1), and 2 patients withdrew consent, both owing to diarrhea from brentuximab vedotin induction. The median Cumulative Illness Rating score of these 7 patients was 13 (range, 10-19) vs 5 (range, 0-20) for the evaluable patients (P=.001).
After 2 cycles of brentuximab vedotin and 6 cycles of AVD, the ORR in 41 evaluable patients was 95%, with a CR rate of 90%. The CR rate increased to 93% after 4 cycles of brentuximab vedotin consolidation. In the intent-to-treat population of 48 patients, the ORR was 88%, with a CR rate of 81% after the final AVD treatment cycle.
Serious AEs were observed in 42% of patients. Grade 2 peripheral neuropathy occurred in 33% of patients, but most cases were reversible. The most common grade 3/4 serious AE was infection (15%). Only 4% of patients experienced grade 3/4 peripheral neuropathy. Approximately half of patients (52%) completed all treatment cycles. Discontinuation was attributed to withdrawal of consent in 9% and no response or progressive disease in 6%. A total of 33% of patients withdrew from the study owing to toxicity, including grade 2 peripheral neuropathy in 12%.
After a median follow-up of 31 months, the intent-to-treat population had a 2-year PFS of 85% and a 2-year OS of 94% (Figure 7). The univariate analysis showed that increasing age, female sex, and increasing Cumulative Illness Rating score corresponded to inferior PFS (P≤.05 for each). Multivariate analysis showed that increasing age after 60 years was associated with an inferior PFS (HR, 1.19 for each year; 95% CI, 1.02-1.37; P=.02).
References
1. Stark GL, Wood KM, Jack F, Angus B, Proctor SJ, Taylor PR; Northern Region Lymphoma Group. Hodgkin’s disease in the elderly: a population-based study. Br J Haematol. 2002;119(2):432-440.
2. Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692-695.
3. 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.
4. 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.
5. Friedberg JW, Forero-Torres A, Bordoni RE, et al. Frontline brentuximab vedotin in combination with dacarbazine or bendamustine in patients aged ≥60 years with HL. Blood. 2017;130(26):2829-2837.
6. Evens AM, Advani RH, Fanale M, et al. Sequential brentuximab vedotin (BV) before and after adriamycin, vinblastine, and dacarbazine (BV-AVD) for older patients with untreated classical Hodgkin lymphoma (cHL): final results from a multicenter phase II study [ASH abstract 733]. Blood. 2017;130(suppl 1).
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.
8. Böll B, Bredenfeld H, Görgen H, et al. Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood. 2011;118(24):6292-6298.
9. Proctor SJ, Wilkinson J, Jones G, et al. Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study. Blood. 2012;119(25):6005-6015.
10. Gandhi MD, Evens AM, Fenske TS, et al. Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event. Blood. 2014;123(18):2895-2897.
Nivolumab in Classical HL: Results From the Phase 2 CheckMate 205 Study
In the phase 2 CheckMate 205 study, patients with relapsed or refractory classical Hodgkin lymphoma after autologous stem cell transplant received treatment with nivolumab (3 mg/kg every 2 weeks).1,2 The trial yielded an ORR of 69%, with durable responses, an acceptable safety profile, and a potential benefit in patients with stable or progressive disease. Studies of checkpoint inhibitors suggested that some patients with solid tumors may benefit from treatment after disease progression.3,4 As a result, the CheckMate 205 study was amended in July 2014 to allow patients with stable performance status and perceived clinical benefit to receive treatment beyond investigator-assessed disease progression.
The CheckMate 205 trial enrolled 243 patients with an ECOG performance status of 0 or 1 who required treatment after autologous stem cell transplant. The 63 patients in cohort A had no prior exposure to brentuximab vedotin. The 80 patients in cohort B had received brentuximab vedotin after autologous stem cell transplant. The 100 patients in cohort C had received brentuximab vedotin at some point for relapsed disease. Cohort D included 51 patients with newly diagnosed, advanced-stage classical Hodgkin lymphoma, and these patients were treated with nivolumab plus AVD.5 Disease progression occurred in 105 patients in cohorts A, B, and C. Among these patients, 70 were treated beyond disease progression and the remaining 35 were not.6 Patients were permitted to receive treatment beyond disease progression until they experienced an increase in overall tumor burden of 10% or more.
The 70 patients in the treatment-beyond-progression group had a median age of 37 years (range, 18-72 years), 67% were male, and 61% had an ECOG performance status of 0.6 The 35 patients who progressed and did not receive further treatment had a median age of 34 years (range, 23-63 years), 54% were male, and 34% had an ECOG performance status of 0. B symptoms were present in 20% of patients who received treatment beyond progression vs 34% of patients who did not receive treatment after progression. The most common cause of progression in the treatment-beyond-progression group was development of a new lesion (reported in 67%). Patients in the treatment-beyond-progression group received a median of 8 doses of nivolumab (range, 1-43 doses) after initial progression, and the median follow-up after initial progression was 4 months (range, <1-17 months). The rate of treatment-related AEs was similar in the treatment-beyond-progression group before and after progression. Drug-related AEs of any grade were observed in 64% of patients before progression and in 46% of patients afterward. These drug-related AEs were grade 3 or 4 in 9% vs 13%, respectively.
Before initial disease progression, the responses in the treatment-beyond-progression group included a CR rate of 7% and a PR rate of 44%.6 Stable disease was reported in 29% of patients, and 19% had progressive disease. (Responses were not evaluable in 1%.) Among patients who were not treated beyond progression, the CR rate was 23%, the PR rate was 34%, 26% had stable disease, 11% had progressive disease, and 6% were not evaluable. Among 51 patients in the treatment-beyond-progression group who were evaluable for response to treatment after initial disease progression, 53% showed some reduction in target lesions: 31% had a reduction of more than 25%, 14% had a reduction of more than 50%, and 2% had a reduction of 100%. The time from initial progression to next therapy was 8.8 months (95% CI, 5.5 months to not reached) in the treatment-beyond-progression group vs 1.5 months (95% CI, 0.6-3.3 months) in the non–treatment-beyond-progression group. Twelve-month OS was 93% (95% CI, 83%-97%) vs 80% (95% CI, 62%-90%), respectively (Figure 8).
The 51 patients in cohort D of the CheckMate 205 study were adults with newly diagnosed classical Hodgkin lymphoma of stage IIB, III, or IV.5 They had an ECOG performance status of 0 or 1. Patients initially received 4 doses of nivolumab (240 mg given every 2 weeks) followed by continued nivolumab plus AVD every 2 weeks. Patients had a median age of 18 years (range, 18-87 years), and 63% were male. B symptoms at diagnosis were reported in 80% of patients, 31% had bulky disease, and 49% had extranodal involvement.
More than half of patients experienced grade 3/4 treatment-related hematologic AEs, most commonly, grade 3/4 neutropenia (49%).5 Grade 3/4 nonhematologic treatment-related AEs included nausea (2%) and pyrexia (2%). No grade 5 treatment-related AEs occurred within 30 days of the final dose of study therapy. One patient died from study drug toxicity 38 days after the last cycle of nivolumab plus AVD. Grade 3/4 immune-mediated AEs included hepatitis (4%) and elevated transaminase (6%); all these cases resolved.
At the end of study therapy, the ORR was 84% according to both investigator and independent review and included CR rates of 80% vs 67%, respectively (Figure 9). Among the 46 evaluable patients, the ORR was 93%, and included CR rates of 74% by independent review vs 89% by investigator review. Modified 9-month PFS as assessed by independent review was 94% (95% CI, 82%-98%).
References
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. Fanale M, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classical Hodgkin lymphoma after autologous transplant: full results after extended follow-up of the phase 2 CheckMate 205 trial [ICML abstract 125]. Hematol Oncol. 2017;35(S2).
3. George S, Motzer RJ, Hammers HJ, et al. Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical trial. JAMA Oncol. 2016;2(9):1179-1186.
4. Long GV, Weber JS, Larkin J, et al. Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2 phase 3 clinical trials. JAMA Oncol. 2017;3(11):1511-1519.
5. Ramchandren R, Fanale M, Rueda A, et al. Nivolumab for newly diagnosed advanced-stage classical Hodgkin lymphoma: results from the phase 2 CheckMate 205 study [ASH abstract 651]. Blood. 2017;130(suppl 1).
6. Cohen JB, Engert A, Ansell SM, et al. Nivolumab treatment beyond investigator-assessed progression: outcomes in patients with relapsed/refractory classical Hodgkin lymphoma from the phase 2 CheckMate 205 study [ASH abstract 650]. Blood. 2017;130(suppl 1).
Highlights in Lymphoma From the 2017 American Society of Hematology Meeting: Commentary
Craig H. Moskowitz, MD
Steven A. Greenberg Chair in Lymphoma Research
Clinical Director, Division of Hematologic Oncology
Attending Physician, Lymphoma and Adult BMT Services
Member, Memorial Sloan Kettering Cancer Center
Professor of Medicine, Weill Medical College of Cornell University
New York, New York
The 2017 American Society of Hematology (ASH) meeting was marked by a presentation at the plenary session of data from the ECHELON-1 study (Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma), which compared brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for advanced-stage Hodgkin lymphoma. There were a number of other studies that focused on the brentuximab vedotin/AVD program. Data were also presented for treatments such as nivolumab; ofatumumab, bendamustine, and bortezomib; pembrolizumab combined with rituximab; pralatrexate with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and duvelisib in combination with romidepsin or bortezomib.
Hodgkin Lymphoma
Brentuximab Vedotin
Dr Joseph Connors presented results from the randomized, phase 3 ECHELON-1 study of brentuximab vedotin plus AVD vs ABVD in patients with advanced-stage Hodgkin lymphoma.1 Results of this trial were simultaneously published in the New England Journal of Medicine.2 There are approximately 66,000 cases of Hodgkin lymphoma worldwide. Approximately 40% of these patients have advanced-stage Hodgkin lymphoma. (The most common presentation is that of unfavorable early-stage Hodgkin lymphoma.) In the United States, for decades the standard treatment of advanced-stage Hodgkin lymphoma has been ABVD chemotherapy. From 70% to 75% of patients are cured with this approach. The ECHELON-1 study aimed to improve upon these results by replacing bleomycin in the ABVD regimen with brentuximab vedotin. Brentuximab vedotin has been approved in various settings for Hodgkin lymphoma management, including for palliation, as maintenance therapy after an autologous stem cell transplant (per the AETHERA study [A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant]3), and as second salvage chemotherapy prior to autologous stem cell transplant. ECHELON-1 is a registration trial that enrolled patients with advanced-stage Hodgkin lymphoma from more than 200 sites worldwide. Patients were randomly assigned 1-to-1 to either 6 cycles of ABVD or 6 cycles of brentuximab vedotin plus AVD. The dose of brentuximab vedotin was 1.2 mg/kg. An interim positron emission tomography (PET) scan was performed after cycle 2. The study used a new primary endpoint called modified progression-free survival (PFS), which was defined as the time to progression, death from any cause, or a position emission tomography scan showing a Deauville score of 3, 4, or 5 after completion of frontline therapy followed by additional anticancer therapy, whether or not there was a defined histologic progression. In my view, the modified PFS endpoint is a favorable one for a randomized study in lymphoma. However, this endpoint makes the results somewhat difficult to interpret because it is common to use consolidation radiotherapy for bulky disease in advanced-stage Hodgkin lymphoma. If used, this would be considered an event based upon this endpoint.
There were 664 patients in the brentuximab vedotin plus AVD arm and 670 patients in the ABVD arm. There was a male predominance. Most of the patients were young (<45 years), and most were treated in Europe. Two-thirds of the patients had stage IV disease. Only 25% of the patients had an International Prognostic Score of 4 to 7.
Use of brentuximab vedotin was associated with a 5% improvement in modified PFS. Progressive disease was seen in 90 patients treated with brentuximab vedotin plus AVD vs 102 patients treated with ABVD. There were 18 deaths in the brentuximab vedotin plus AVD arm and 22 deaths in the ABVD arm. The modified progression analysis showed that an additional 13 events were caused by either additional chemotherapy or radiotherapy.2 There was no difference in overall survival. The Forrest plot analysis showed that brentuximab vedotin plus AVD was superior in almost all subgroups. Interestingly, there was no difference between the arms among patients with stage 3 disease without extranodal involvement, which has implications for treatment. A somewhat surprising finding was that the outcome for the 186 patients older than 59 years was excellent in both arms.
As expected, the brentuximab vedotin plus AVD arm was more toxic than the ABVD arm in terms of neuropathy, infections, and febrile neutropenia. Unfortunately, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was not mandatory in all treatment centers worldwide. In the United States, where G-CSF was used routinely, there were fewer infectious complications. Interestingly, in the United States, there was also an improvement in modified PFS compared with that seen in other countries, by nearly 10%.
ECHELON-1 is the first study, outside of the BEACOPP programs,4 to show that ABVD was inferior to another treatment, based upon the endpoint of modified PFS. The study did not, however, provide a significant amount of information on subset analyses. Based on both the published article and the presentation at ASH, I would recommend that patients with stage 4 disease receive brentuximab vedotin plus AVD, if this regimen is approved. For patients with stage 3 disease, I see no reason for this treatment program to be used, pending other analyses.
There were several other presentations on Hodgkin lymphoma that may have an impact on patient management. Dr Andrew Evens presented results that support the use of brentuximab vedotin plus AVD in elderly patients.5 This study evaluated sequential brentuximab vedotin plus AVD chemotherapy followed by posttreatment brentuximab vedotin in elderly patients with Hodgkin lymphoma. These results were previously presented in a shorter format.6 The presentation by Dr Evens provided the final data. This study has the best results I have seen among patients with Hodgkin lymphoma who are ages 60 to 80 years and fit for chemotherapy. In fact, the results are no different from those seen with brentuximab vedotin plus AVD in the ECHELON-1 study, and the sequential regimen is probably easier to tolerate than concomitant brentuximab vedotin plus AVD. My institution participated in this study, and it is a long treatment program, lasting almost 9 months. An interesting result is that after 2 cycles of brentuximab vedotin, given initially as first treatment, nearly all patients responded to therapy. There were several complete responses. Posttreatment brentuximab vedotin was also fairly well-tolerated. Once this study is published, I expect that this regimen will become the standard treatment program for elderly patients with Hodgkin lymphoma. In this older patient population, the sequential treatment was better tolerated than concomitant brentuximab vedotin plus AVD.
Dr Anita Kumar presented the results of a study evaluating brentuximab vedotin plus AVD and 20 Gy of radiotherapy among patients with unfavorable early-stage Hodgkin lym-phoma.7 Results from patients in the first cohort, who were treated with 30 Gy of radiotherapy, were previously published in Blood.8 Nearly all of the patients in the first cohort did well and are currently alive and free of disease. For the second cohort, the dose of radiotherapy was reduced by 10 Gy. The presentation by Dr Kumar was well-received. All 29 patients in this cohort were progression-free. The follow-up for a third cohort is now nearly complete; these patients are being treated with residual site radiation therapy, which radiates only PET-negative residual lymph node sites. I anticipate that these data will be presented at the International Symposium on Hodgkin Lymphoma in Cologne, Germany, in October 2018.
Another brentuximab vedotin plus AVD program was presented by the Lymphoma Study Association (LYSA).9 The study aimed to determine if PET 2 could be a reasonable endpoint in patients with early-stage Hodgkin lymphoma and be used in random assignment trials. It was a fairly large study, enrolling 170 patients. Nearly 85% of the patients had a PET-2 negative response, which was the primary endpoint. One can imagine using this endpoint for potential PET-adapted therapy. It is unclear if patients do in fact require 12 doses of brentuximab vedotin plus AVD to achieve an 80% to 85% 3-year PFS. If the PET scan is negative after 2 cycles, it might be feasible to administer 4 doses of brentuximab vedotin plus AVD. If the PET scan is negative, then brentuximab vedotin may no longer be needed.
Dr Alex Herrera presented final results of a trial evaluating brentuximab vedotin in combination with nivolumab as salvage chemotherapy for patients with relapsed or refractory Hodgkin lymphoma.10 Previous results were presented earlier,11 and the final results were also published in Blood.12 Of note, more than 60% of the patients in this study had a PET-negative complete response prior to stem cell transplant. The treatment program was well-tolerated, with minimal immune-related adverse events. This treatment does not have a superior outcome compared with standard multiagent, platinum-based salvage chemotherapy, but it is given on an outpatient basis and is better tolerated. This regimen will likely be another option for this patient population.
Dr Robert Chen presented results from a phase 2 study of brentuximab vedotin plus ibrutinib in patients with relapsed or refractory Hodgkin lymphoma.13 Previous therapies included ABVD in 94% and brentuximab vedotin in 25%. The overall response rate was 75%, and the complete response rate was 37%. It was unclear if this combination is better than brentuximab vedotin alone. The combination was well-tolerated. Some of the patients had previously received brentuximab vedotin.
Nivolumab
Two studies of nivolumab in Hodgkin lymphoma management were notable. The CheckMate 205 study evaluated AVD plus nivolumab in untreated, advanced-stage patients (a similar population to that of ECHELON-11).14 The treatment program was well-tolerated. Nearly all patients had evidence of improvement at the end of therapy, and it appeared that the majority were in remission. It should be mentioned that this study used PET imaging, which is difficult to interpret in patients receiving checkpoint inhibitors because of the high false-positive rate. I recommend use of computed tomography as opposed to PET imaging in this setting.
Dr Jonathan Cohen presented an interesting study.15 Nivolumab was administered to patients after disease progression, as confirmed by imaging studies. Several patients had evidence of clinical benefit for 6 to 12 months, which implies that when fluorodeoxyglucose PET is used to determine response evaluation, it may be difficult to determine when treatment with a checkpoint inhibitor, either nivolumab or pembrolizumab, should be stopped. In my opinion, when using a checkpoint inhibitor for palliation, computed tomography should be used for initial evaluation. When there is evidence of tumor shrinkage, it is unclear if any further imaging studies are necessary. Treatment should continue unless there is obvious clinical progression.
Non-Hodgkin Lymphoma
Brentuximab Vedotin
Dr Jakub Svoboda presented results from a study evaluating the combination of brentuximab vedotin with rituximab plus cyclophosphamide, doxorubicin, and prednisone (R-CHP) chemotherapy as frontline treatment of patients with primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, and gray-zone lymphoma.16 All patients were CD30-positive; brentuximab vedotin binds to CD30. In this open-label study, brentuximab vedotin at a standard dose was substituted for vincristine. Growth factor support was administered to all patients. The study enrolled 31 patients at 3 centers. In general, the treatment program was well-tolerated. Sensory neuropathy was seen in 45% of patients, and motor neuropathy occurred in 10% of patients. The overall response rate in patients who underwent end-of-treatment evaluation was 100%. At a median follow-up of 17 months, the median PFS and overall survival had not been reached. This treatment program warrants further investigation in these patient populations.
Ofatumumab, Bendamustine, and Bortezomib
A randomized, phase 2 study from the Alliance for Clinical Trials in Oncology compared ofatumumab/bendamustine vs ofatumumab/bendamustine/bor-tezomib followed by maintenance therapy in untreated patients with high-risk follicular lymphoma.17 The results were disappointing. Unfortunately, there were no differences in the rates of complete response or overall response between the 2 treatment programs. Compared with bendamustine and rituximab, these more-complicated regimens offered no benefit.
Pembrolizumab and Rituximab
Dr Loretta Nastoupil presented data for pembrolizumab combined with rituximab in relapsed follicular lymphoma.18 In general, this was a favorable patient population. All 30 patients were sensitive to rituximab. The treatment regimen consisted of 4 weekly doses of rituximab, plus pembrolizumab given every 3 weeks for a year. After treatment, approximately 50% of the patients were still in a minimal disease state. However, there was a significant amount of immune-related adverse events with the combination, higher than that seen with single-agent rituximab in the same setting. Of note, high levels of CD8-positive T-cell effector scores, based on NanoString analysis, correlated with a complete response. Checkpoint inhibitors and rituximab, with or without other agents, are a platform in follicular lymphoma.
Pralatrexate and CHOP
Dr Andrei Shustov presented results from a phase 1 dose-escalation study evaluating pralatrexate in combination with CHOP in previously untreated patients with peripheral T-cell lymphoma.19 There is no standard upfront therapy for peripheral T-cell lymphoma, and many experts recommend investigational therapy. This standard, 3-plus-3, dose-escalation study evaluated pralatrexate administered at various doses along with standard CHOP chemotherapy. Antimicrobial prophylaxis, growth-factor support, and leucovorin rescue therapy were administered. Among the 31 patients enrolled in the study, 29 were evaluable for response. The maximum tolerated dose was not reached, and pralatrexate at 30 mg/m2 is the dose that will be used in the phase 2 study. The most common adverse events were fatigue and constipation. Approximately 10% of patients had grade 3/4 mucositis. The overall response rate was 90%, and the complete response rate was 66%, which is encouraging. I anticipate that these data will lead to a randomized study.
Duvelisib With Romidepsin or Bortezomib
A multicenter group reported on the results of a parallel, phase 1 study of duvelisib in combination with rom-ide-psin or bortezomib in patients with relapsed or refractory T-cell lym-phoma.20 There is no standard of care in this patient population. App-roximately 30 patients were treated during the study. There were 15 patients evaluable for response in the romidepsin/duvelisib arm and 17 pat-ients in the bortezomib/duvelisib arm. The overall response rates were 50% in the duvelisib/romidepsin arm and 35% in the bortezomib/duvelisib arm. Unfortunately, there was more toxicity in the bortezomib/duvelisib arm. The romidepsin/duvelisib arm will move forward into a phase 2 trial. Both treatment programs, however, are encouraging in the relapsed and refractory setting.
Disclosure
Dr Moskowitz has received research support from Seattle Genetics, Merck, and Pharmacyclics. He is a member of the Scientific Advisory Boards of Seattle Genetics, Merck, and Celgene.
References
1. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (HL): the phase 3 ECHELON-1 study [ASH abstract 6]. Blood. 2017;130(suppl 1).
2. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma [published online December 10, 2017]. N Engl J Med. 2017. doi:10.1056/NEJMoa1708984.
3. Moskowitz CH, Nademanee A, Masszi T, et al; AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
4. Viviani S, Zinzani PL, Rambaldi A, et al; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203-212.
5. Evens AM, Advani RH, Fanale M, et al. Sequential brentuximab vedotin (BV) before and after adriamycin, vinblastine, and dacarbazine (BV-AVD) for older patients with untreated classical Hodgkin lymphoma (cHL): final results from a multicenter phase II study [ASH abstract 733]. Blood. 2017;130(suppl 1).
6. Evens AM, Hamlin P, Nabhan C, et al. Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: initial results from a phase 2 multicentre study [ICML abstract 089]. Hematol Oncol. 2015;33(suppl 1).
7. Kumar A, Casulo C, Advani R, et al. A pilot study of brentuximab vedotin and AVD chemotherapy followed by 20 Gy involved-site radiotherapy in early-stage, unfavorable-risk Hodgkin lymphoma [ASH abstract 734]. Blood. 2017;130(suppl 1).
8. Kumar A, Casulo C, Yahalom J, et al. Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2016;128(11):1458-1464.
9. Fornecker L-M, Lazarovici J, Aurer I, et al. PET-based response after 2 cycles of brentuximab vedotin in combination with AVD for first-line treatment of unfavorable early-stage Hodgkin lymphoma: first analysis of the primary endpoint of BREACH, a randomized phase 2 trial of LYSA-FIL-EORTC Intergroup [ASH abstract 736]. Blood. 2017;130(suppl 1).
10. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 649]. Blood. 2017;130(suppl 1).
11. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ICML abstract 74]. Hematol Oncol. 2017;35(suppl S2).
12. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [published online December 17, 2017]. Blood. doi:10.1182/blood-2017-10-811224.
13. Chen R, Palmer J, Herrera A, et al. Phase II study of brentuximab vedotin plus ibrutinib for patients with relapsed refractory Hodgkin lymphoma [ASH abstract 738]. Blood. 2017;130(suppl 1).
14. Ramchandren R, Fanale M, Rueda A, et al. Nivolumab for newly diagnosed advanced-stage classical Hodgkin lymphoma: results from the phase 2 CheckMate 205 study [ASH abstract 651]. Blood. 2017;130(suppl 1).
15. Cohen JB, Engert A, Ansell SM, et al. Nivolumab treatment beyond investigator-assessed progression: outcomes in patients with relapsed/refractory classical Hodgkin lymphoma from the phase 2 CheckMate 205 study [ASH abstract 650]. Blood. 2017;130(suppl 1).
16. Svoboda J, Landsburg DJ, Nasta SD, et al. Brentuximab vedotin with R-CHP chemotherapy as frontline treatment for patients with CD30 positive primary mediastinal large B-cell, diffuse large B-cell, and grey zone lymphomas: results of a phase I/II multisite trial [ASH abstract 191]. Blood. 2017;130(suppl 1).
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20. Moskowitz A, Koch R, Mehta-Shah N, et al. In vitro, in vivo, and parallel phase I evidence support the safety and activity of duvelisib, a PI3K-δ,γ inhibitor, in combination with romidepsin or bortezomib in relapsed/refractory T-cell lymphoma [ASH abstract 819]. Blood. 2017;130(suppl 1).