A Review of Selected Presentations From the 2018 American Society of Clinical Oncology Annual Meeting • June 1-5, 2018 • Chicago, Illinois
Special Reporting on:
• Brentuximab Vedotin Plus Chemotherapy in Patients With Newly Diagnosed Advanced-Stage Hodgkin Lymphoma: North American Results
• Randomized Phase III Study Comparing an Early PET-Driven Treatment De-Escalation to a Not PET-Monitored Strategy in Patients With Advanced-Stages Hodgkin Lymphoma: Final Analysis of the AHL2011 LYSA Study
• Improving Outcomes With Brentuximab Vedotin Plus Chemotherapy in Patients With Newly Diagnosed Advanced-Stage Hodgkin Lymphoma
• Activity and Tolerability of the First-in-Class Anti-CD47 Antibody Hu5F9-G4 With Rituximab Tolerated in Relapsed/Refractory Non-Hodgkin Lymphoma: Initial Phase 1b/2 Results
• Brentuximab Vedotin With Chemotherapy for Stage III or IV Hodgkin Lymphoma: Impact of Cycle 2 PET Result on Modified Progression-Free Survival
• Durability of Response in ZUMA-1, the Pivotal Phase 2 Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
• Long-Term Follow-Up of Brentuximab Vedotin ± Dacarbazine as First-Line Therapy in Elderly Patients With Hodgkin Lymphoma
• Cost-Effectiveness Analysis of Brentuximab Vedotin With Chemotherapy in Newly Diagnosed Stage III/IV Hodgkin Lymphoma
Brentuximab Vedotin Plus Chemotherapy in Patients With Newly Diagnosed Advanced-Stage Hodgkin Lymphoma: North American Results
Prespecified analyses were conducted to assess safety and efficacy results in North American treatment centers that participated in the ECHELON-1 trial (Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma).1 Eighty-five sites in the United States and Canada were included. The primary endpoint of ECHELON-1 was modified progression-free survival (PFS), which included time to progression, death, or noncomplete response based on independent review, plus use of subsequent therapy to treat Hodgkin lymphoma (HL). Overall survival (OS) was the key secondary endpoint. After a median follow-up of 24.6 months, 2-year modified PFS rates were 82.1% with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) vs 77.2% with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; hazard ratio [HR] for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60-0.98; P=.04).2 Based on the trial results, in March 2018, the US Food and Drug Administration (FDA) expanded the indication of brentuximab vedotin (in combination with chemotherapy) to include the treatment of adults with previously untreated stage III/IV classical HL.3
Modified PFS as assessed by an independent review facility in North America was a prespecified analysis. Exploratory analyses of the North American subgroup included investigator-determined modified PFS as well as PFS, with PFS defined as the time from randomization to disease progression or death from any cause. PFS and modified PFS were determined by Kaplan-Meier analysis. In North America, 250 patients were randomly assigned to receive brentuximab vedotin plus AVD and 247 to receive ABVD. Patient characteristics were well-balanced between the 2 arms. Patients underwent imaging with computed tomography/position emission tomography (PET).
The median follow-up was approximately 25 months. The modified PFS at 2 years as determined by independent review was 84.3% (95% CI, 78.7%-88.5%) with brentuximab vedotin plus AVD vs 73.7% (95% CI, 67.3%-79.1%) with ABVD (HR, 0.596; 95% CI, 0.395-0.899; P=.012; Figure 1). The modified PFS as assessed by investigators was 86.4% (95% CI, 81.3%-90.2%) with brentuximab vedotin plus AVD vs 73.6% (95% CI, 67.2%-78.9%) in the standard treatment arm (HR, 0.516; 95% CI, 0.339-0.786; P=.002). The investigator-assessed standard PFS at 2 years was 88.1% (95% CI, 83.1%-91.7%) vs 76.4% (95% CI, 70.1%-81.5%), respectively (HR, 0.500; 95% CI, 0.318-0.786; P=.002). Brentuximab vedotin plus AVD showed a benefit or a trend toward a benefit in most subgroups, including patients with baseline stage IV disease (HR, 0.554; 95% CI, 0.327-0.937), a high International Prognostic Score (HR, 0.396; 95% CI, 0.199-0.789), and B symptoms (HR, 0.664; 95% CI, 0.391-1.127).
Response rates were consistently superior with brentuximab vedotin plus AVD. The independent review yielded PET-negativity rates after treatment cycle 2 of 88% with brentuximab vedotin plus AVD vs 83% with ABVD, and the proportion of patients with a Deauville score of 2 or less after completion of first-line therapy was 85% vs 76%. The CR rates were 72% vs 67% (based on revised Cheson response criteria4). Grade 3 or higher adverse events (AEs) were more common among patients treated with brentuximab vedotin plus AVD (81% vs 67%), as were drug-related AEs of grade 3 or higher (77% vs 56%). AEs led to treatment discontinuation in 15% of the brentuximab vedotin plus AVD arm vs 24% in the ABVD arm. Peripheral neuropathy of any grade was more common in patients treated with brentuximab vedotin plus AVD (80% vs 56%), and included an increase in the rate of grade 3 peripheral neuropathy (17% vs <1%). Rates of pulmonary toxicity were higher in the ABVD arm (10% vs 3% for any grade; 6% vs 2% for grade 3 or higher). Among the 7 deaths in the ABVD arm, 6 were related to pulmonary toxicity. Two patients died in the brentuximab vedotin arm.
References
1. Ramchandren R, Advani RH, Ansell SM, et al. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results [ASCO abstract 7541]. J Clin Oncol. 2018;36(15 suppl).
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. N Engl J Med. 2018;378(4):331-344.
3. Adcetris [package insert]. Bothell, WA: Seattle Genetics, Inc; 2018.
4. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
Randomized Phase III Study Comparing an Early PET-Driven Treatment De-Escalation to a Not PET-Monitored Strategy in Patients With Advanced-Stages Hodgkin Lymphoma: Final Analysis of the AHL2011 LYSA Study
Treatment with 6 cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) can achieve long-term control of HL.1,2 Compared with ABVD, escalated BEACOPP improves PFS. It does not improve OS, however, and it can be associated with myelodysplastic syndrome/acute myeloid leukemia and infertility. The use of PET imaging to characterize early responses could enable de-escalation of treatment after escalated BEACOPP without sacrificing disease control.
The phase 3 AHL2011 LYSA trial (Advanced Hodgkin Lymphoma 2011 Lymphoma Study Association) evaluated whether altering therapy based on PET imaging after 2 or 4 cycles of escalated BEACOPP could improve outcome.3 Eligible patients were ages 16 to 60 years and had classical HL with high-risk stage IIB or stage III/IV disease. Before the 1:1 randomization, patients were stratified based on their International Prognostic Score and stage. PET imaging was performed after treatment cycles 2 (PET2) and 4 (PET4) in both arms. Patients in the standard treatment arm received 6 cycles of escalated BEACOPP. In the experimental arm, patients received 2 initial cycles of escalated BEACOPP. Patients who had a positive PET2 result continued treatment with escalated BEACOPP, whereas those with a negative result switched to 4 cycles of ABVD. In both arms, patients with a positive PET4 result switched to salvage therapy. The trial used a noninferiority 5-year PFS design that anticipated thresholds of 85% in the standard treatment arm and greater than 75% in the experimental arm (HR, 1.77).
The study enrolled 413 patients in the standard treatment arm and 410 in the experimental arm. The patients’ median age was 30 years (range, 16-60 years), and 63% were male. Sixty-eight percent of patients had B symptoms, 88% had stage III/IV disease, and 58% had an International Prognostic Score of 3 or higher. PET2 results were positive in 12% of patients in the standard treatment arm and 13% in the experimental arm. Thus, based on the intention-to-treat analysis, 84% of patients in the experimental arm received 2 cycles of escalated BEACOPP followed by 4 cycles of ABVD. After a median follow-up of 50.4 months, the estimated 5-year PFS was 86.2% in the standard treatment arm vs 85.7% in the experimental arm (HR, 1.084; 95% CI, 0.73-1.59; P=.68), thus demonstrating noninferiority. The estimated 5-year OS was also similar for the standard and experimental treatment arms (95.2% vs 96.4%, respectively; HR, 0.936; 95% CI, 0.42-2.05; P=.91). PET4 results were positive in 7% of patients in the standard treatment arm vs 4% in the experimental arm. PET results correlated with PFS. The estimated 5-year PFS was 90.9% for patients with negative PET2 and PET4 results vs 75.4% for patients with positive PET2 and negative PET4 results (P<.001; Figure 2). The estimated 5-year OS was superior in patients with negative PET results after 2 and 4 cycles of escalated BEACOPP (P<.04).
Nearly all patients in both arms experienced at least 1 grade 3/4 AE. Grade 3/4 AEs that occurred at higher rates in the standard treatment arm vs the experimental arm included anemia (69% vs 28%; P<.001), thrombocytopenia (66% vs 40%; P<.001), and febrile neutropenia (35% vs 23%; P<.001). Serious AEs were also more common in the standard treatment arm (27% vs 17%; P<.002), as were treatment-related serious AEs (47% vs 28%; P<.001). Treatment discontinuation owing to toxicity was noted in 6.8% of patients in the standard treatment arm vs 1% of those in the experimental arm (P<.00001). Secondary primary malignancies were observed in 2.4% vs 1.2% (P>.05).
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. Vassilakopoulos TP, Johnson PW. Treatment of advanced-stage Hodgkin lymphoma. Semin Hematol. 2016;53(3):171-179.
3. Casasnovas O, Brice P, Bouabdallah R, et al. Randomized phase III study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma: final analysis of the AHL2011 LYSA study [ASCO abstract 7503]. J Clin Oncol. 2018;36(15 suppl).
Improving Outcomes With Brentuximab Vedotin Plus Chemotherapy in Patients With Newly Diagnosed Advanced-Stage Hodgkin Lymphoma
The open-label, phase 3 ECHELON-1 trial compared 6 cycles of brentuximab vedotin plus AVD vs ABVD in patients with treatment-naive stage III/IV HL.1 Neutropenia of any grade occurred in 58% of patients treated with brentuximab vedotin plus AVD vs 45% of those treated with ABVD. Granulocyte-colony stimulating factor (G-CSF) was administered at the investigator’s discretion, with formal recommendations made by an independent data monitoring committee for patients treated with brentuximab vedotin plus AVD. Among these patients, administration of G-CSF as primary prophylaxis was associated with lower rates of grade 3 or higher neutropenia (29% vs 70%) and febrile neutropenia (11% vs 21%).
Dr David Straus presented results of exploratory analyses comparing outcomes in patients who received G-CSF primary prophylaxis vs those who did not.2 Among 662 patients treated with brentuximab vedotin plus AVD, 83 received G-CSF primary prophylaxis. The median time to first use of G-CSF was 0.3 weeks (range, 0.1-0.7 weeks). G-CSF primary prophylaxis was associated with reduced rates of hospitalization (29% vs 38%), neutropenia of grade 3 or higher (29% vs 70%), and febrile neutropenia of any grade (11% vs 21%; Figure 3). Among the 9 deaths in the brentuximab vedotin plus AVD arm, 7 were associated with neutropenia, and none of these patients had received G-CSF primary prophylaxis. Peripheral neuropathy was observed in 57% of patients who received G-CSF primary prophylaxis vs 68% of those who did not. G-CSF prophylaxis reduced delays in the administration of brentuximab vedotin (35% vs 49%) and decreased
dosage reductions (20% vs 26%).
Patients treated with G-CSF primary prophylaxis before brentuximab vedotin plus AVD demonstrated a numerically reduced risk for modified PFS events, both in comparison with patients in the same arm who did not receive G-CSF primary prophylaxis (HR, 0.737; 95% CI, 0.396-1.372) and in comparison with patients in the ABVD arm (HR, 0.586; 95% CI, 0.317-1.081). The analysis is limited by the small number of patients who received G-CSF primary prophylaxis.
References
1. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
2. Straus DJ, Collins GP, Walewski JA, et al. Improving outcomes with brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma [ASCO abstract 7534]. J Clin Oncol. 2018;36(15 suppl).
Activity and Tolerability of the First-in-Class Anti-CD47 Antibody Hu5F9-G4 With Rituximab Tolerated in Relapsed/Refractory Non-Hodgkin Lymphoma: Initial Phase 1b/2 Results
Macrophages remove pathogens and unwanted cells by detecting specific cell-surface molecules that induce a signal to commence phagocytosis. Macrophages are also abundant in most tumors and may invoke phagocytosis in response to cancer cells. CD47 is an immunoglobulin-like protein that can interact with SIRPα, a regulatory membrane glycoprotein that is expressed on macrophages.1 The interaction of CD47 with its receptor on macrophages inhibits phagocytosis; thus, cancer cells may evade phagocytosis through expression of CD47. CD47 expression has been shown to enable a human acute myeloid leukemia cell line to engraft into immunocompromised mice, and increased CD47 expression is associated with a worse prognosis in multiple subtypes of non-Hodgkin lymphoma (NHL), including B-cell NHL.2 An anti-CD47 monoclonal antibody that enables phagocytosis was evaluated in combination with rituximab for the treatment of mice engrafted with the human NHL cell line. The antibody combination showed synergistic efficacy, eliminating NHL cells in 60% of mice in a disseminated engraftment model and in 86% of mice in a localized engraftment model. Similar results were obtained using xenograft models that were transplanted with primary diffuse large B-cell lymphoma (DLBCL) cells.
A humanized anti-CD47 antibody, Hu5F9-G4 (5F9), binds to CD47 with 8 nM affinity.3 The antibody induced potent macrophage-mediated phagocytosis of primary human acute myeloid leukemia cells in vitro and eradicated primary human acute myeloid leukemia xenografts in a mouse model. The humanized anti-CD47 antibody also showed synergistic activity with rituximab in a mouse xenograft model of NHL. The synergy is believed to arise from the prophagocytic signals provided by rituximab through its Fc receptor, combined with the ability of 5F9 to intercept CD47.
The combination of 5F9 plus rituximab was evaluated in a phase 1b/2 dose-escalation and expansion study in patients with relapsed or refractory B-cell NHL who required treatment after standard therapies.4 The trial used a 3 + 3 dose-escalation design. To mitigate anemia and other on-target toxicities, patients received a priming dose of 5F9 at 1 mg/kg, plus higher weekly maintenance doses that ranged from 10 mg/kg to 30 mg/kg. Rituximab was administered at 375 mg/kg weekly for cycle 1, then monthly for cycles 2 to 6. The trial’s primary endpoint was the safety, tolerability, and recommended phase 2 dose of the antibody combination.
The trial enrolled 22 patients with DLBCL and 7 with follicular lymphoma. Their median age was 59 years (range, 44-82 years), and 68% had stage III/IV disease. The median number of prior therapies was 4 (range, 2-10), and 95% of patients were refractory to their prior rituximab regimen. Thirteen patients were treated at the highest dose level of 5F9, and the maximum tolerated dose was not reached. Therefore, the recommended phase 2 dose in combination with rituximab was a priming dose of 1 mg/kg, followed by a maintenance dose of 30 mg/kg given weekly for cycle 1 and every 2 weeks for subsequent cycles.
The objective response rate (ORR) was 50% (according to Lugano criteria). The change in tumor burden is shown in Figure 4. Complete responses (CRs) were seen in 43% of patients with follicular lymphoma and 33% of those with DLBCL. Efficacy was observed among patients who were refractory to a prior rituximab-containing regimen. Most responses were observed within the first 2 months of treatment. After a median follow-up of 6 to 8 months, 11 patients had responded and 1 had developed progressive disease. In 2 DLBCL patients, response improved over time, from stable disease to a CR in one and from a partial response (PR) to a CR in the other. The median duration of response was not reached, and the longest observed duration of response exceeded 14 months.
Most AEs were grade 1 or 2. The most common AEs of any grade were, as anticipated, on-target anemia, infusion reactions, and related symptoms. Three patients developed dose-limiting toxicities. Two of these patients were successfully rechallenged and continued treatment, with resolution of the AE. One patient discontinued treatment owing to an AE. No autoimmune AEs were observed. There were no late safety signals, and treatment lasted for more than 18 months in some patients.
Depending on their age, red blood cells express proteins that may induce or inhibit phagocytosis and lead to on-target anemia. Older red blood cells lose expression of CD47 and gain expression of molecules that activate phagocytosis. Use of an initial priming dose of 5F9 results in a temporary, mild decline in hemoglobin caused by clearance of aged red blood cells and temporary compensatory reticulocytosis. In the current study, hemoglobin and reticulocyte levels returned to baseline with continued 5F9 treatment, after approximately 8 weeks. The recommended phase 2 dose is supported by data showing a CD47 receptor occupancy of nearly 100% on day 1 of cycle 2, combined with 5F9 tissue penetration observed via immunohistochemical staining. 5F9 recently received Fast Track designation by the FDA for both DLBCL and follicular lymphoma. Phase 2 studies of 5F9 plus rituximab are ongoing.5
References
1. Jaiswal S, Jamieson CH, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271-285.
2. Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142(5):699-713.
3. Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10(9):e0137345.
4. Advani RH, Flinn IW, Popplewell L, et al. Activity and tolerability of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: initial phase 1b/2 results [ASCO abstract 7504]. J Clin Oncol. 2018;36(15 suppl).
5. ClinicalTrials.gov. Trial of Hu5F9-G4 in combination with rituximab in relapsed/refractory B-cell non-Hodgkin’s lymphoma. Identifier: NCT02953509. https://clinicaltrials.gov/ct2/show/NCT02953509. Accessed June 28, 2018.
Brentuximab Vedotin With Chemotherapy for Stage III or IV Hodgkin Lymphoma: Impact of Cycle 2 PET Result on Modified Progression-Free Survival
The ECHELON-1 trial compared 6 cycles of brentuximab vedotin plus AVD vs ABVD in patients with treatment-naive, stage III/IV HL.1 Interim PET imaging has been validated for response assessment in HL patients. A Deauville score of 3 or lower was considered PET-negative, and a score of 4 or 5 was PET-positive.2-4 In a previous study of ABVD chemotherapy, PET2-positivity was prognostic for a reduced PFS.5
A post-hoc analysis of results from the ECHELON-1 trial evaluated clinical characteristics and modified PFS outcomes based on PET2 results as determined by an independent review facility.6 Patients with a Deauville score of 5 at PET2 were allowed to switch to an alternative therapy at the physician’s discretion. Rates of PET2 negativity were 89% (588/664) with brentuximab vedotin plus AVD and 86% (577/670) with ABVD. A positive PET2 result was seen in 7% of patients (47/644) treated with brentuximab vedotin plus AVD and in 9% (58/670) of those treated with ABVD. PET2 status was not available for 64 patients, and 5 patients had a Deauville score of 5 and switched to a different therapy. Patient characteristics were generally similar in both arms, regardless of PET2 status.
Among patients treated with brentuximab vedotin plus AVD, the estimated 2-year modified PFS was 85.2% for those who were PET2-negative vs 57.5% for those who were PET2-positive (HR, 3.382; 95% CI, 2.033-5.625; P<.001). In the ABVD arm, the estimated 2-year modified PFS was 80.9% for PET2-negative patients vs 42.0% for PET2-positive patients (HR, 4.793; 95% CI, 3.229-7.118; P<.001). The modified PFS was numerically superior with brentuximab vedotin plus AVD vs ABVD among PET2-negative patients (85.2% vs 80.9%; P=.070) and PET2-positive patients (57.5% vs 42.0%; P=.089; Figure 5), but the comparisons did not reach statistical significance.
References
1. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
2. Barrington SF, Kirkwood AA, Franceschetto A, et al. PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study. Blood. 2016;127(12):1531-1538.
3. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048-3058.
4. Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009;50(8):1257-1260.
5. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to International Prognostic Score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol. 2007;25(24):3746-3752.
6. Chen RW, Ansell SM, Gallamini A, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin lymphoma (HL): impact of cycle 2 PET result on modified progression-free survival (mPFS) [ASCO abstract 7539]. J Clin Oncol. 2018;36(15 suppl).
Durability of Response in ZUMA-1, the Pivotal Phase 2 Study of Axicabtagene Ciloleucel in Patients With Refractory Large B-Cell Lymphoma
Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy designed to increase the T-cell response against tumor cells.1 The CAR construct consists of an anti-CD19 single-chain variable domain, a CD28 transmembrane domain, a CD28 costimulatory domain, and the CD3ζ T-cell receptor signaling domain. CD19 is a transmembrane glycoprotein that is expressed on the vast majority of normal and neoplastic B cells. The phase 1/2 ZUMA-1 trial (A Phase 1-2 Multi-Center Study Evaluating Axicabtagene Ciloleucel in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma) evaluated CAR T-cell therapy in patients with refractory NHL, including DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma. The phase 1 portion of the study included 7 patients and yielded an ORR of 71% and a CR rate of 57%.2
The phase 2 portion of the trial enrolled 101 patients into 2 cohorts: those with refractory DLBCL (n=77) and those with refractory transformed follicular lymphoma or primary mediastinal B-cell lymphoma (n=24). Key eligibility criteria included aggressive B-cell lymphoma; no response to the most recent chemotherapy, or relapse within 12 months of an autologous stem cell transplant (SCT); and prior treatment with an anti-CD20 monoclonal antibody and an anthracycline. Patients received 3 days of a conditioning regimen consisting of cyclophosphamide (500 mg/m2) plus fludarabine (30 mg/m2). The axicabtagene ciloleucel dose was 2 × 106 CAR T cells/kg. CAR T cells were successfully manufactured for 99% of enrolled patients, and 91% of enrolled patients received treatment. Among the 108 patients in phase 1 or 2 of ZUMA-1 (at a data cutoff of August 17, 2017), the minimum follow-up was 12 months and the median follow-up was 15.4 months.3 The long-term follow-up analysis showed an ORR of 82% and a CR rate of 58%, with ongoing responses in 42% of patients. The median OS was not reached. The median duration of response was 11.1 months (95% CI, 3.9 months to not reached). Grade 3 or higher AEs of interest included cytokine release syndrome (12%) and neurologic events (31%).
A retrospective analysis of the phase 2 ZUMA-1 data was conducted to evaluate whether the time to response and PR and CR at month 3 after treatment were prognostic factors for PFS.4 The study was prompted by the fact that over half of the progression events in ZUMA-1 had occurred by month 3 after the CAR T-cell infusion. Among the 84 patients who had a PR or CR, the median time to response was 1 month (range, 0.8-14.8 months) overall, and 1 month (range, 0.8-12.3 months) for patients who achieved a CR (Figure 6). Among the 44 patients with a PR, 18 (42%) converted to a CR. Although many of the patients with a PR converted to a CR by month 3, conversions from a PR to a CR were observed up to 12 months after the CAR T-cell infusion.
Among the 101 patients in the phase 2 study, the median age was 58 years (range, 23-76 years), two-thirds were male, and 85% had stage III/IV disease. Most patients (69%) had received 3 or more prior therapies. Among the patients with a response at 3 months, 9 had a PR and 42 had a CR. Patients with a PR or CR shared similar characteristics, including the median number of prior therapies and the tumor burden. Kaplan-Meier analysis was conducted to determine the PFS rate for patients with a PR vs those with a CR at month 3 after treatment. The analysis yielded similar PFS rates for both groups. For patients with a CR at month 3, the median PFS was not reached (95% CI, not reached to not reached). For patients with a PR at month 3, the median PFS was also not reached (95% CI, 4.4 months to not reached). Among the patients with a PR or CR at month 3, the likelihood of maintaining that response at month 12 was 78% (95% CI, 36%-94%) and 79% (95% CI, 63%-88%), respectively.
Rates of grade 3 or higher AEs were 100% in patients who achieved a PR at month 3 after CAR T-cell infusion and 93% in those with a CR at this time. In comparison, the rate was 97% in the overall study population. Cytokine release syndrome of grade 3 or higher occurred in 0% of the PR group, 12% of the CR group, and 12% of the 101 patients included in the phase 2 portion of the trial. Neurologic events of grade 3 or higher were observed in 33% of patients with a PR at month 3, 36% of those with a CR at month 3, and 29% of the overall study population. The safety results led to the adoption of guidelines that recommend earlier intervention for cytokine release syndrome.5
References
1. Jain MD, Bachmeier CA, Phuoc VH, Chavez JC. Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma. Ther Clin Risk Manag. 2018;14:1007-1017.
2. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
4. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma [ASCO abstract 3003]. J Clin Oncol. 2018;36(15 suppl).
5. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62.
Long-Term Follow-Up of Brentuximab Vedotin ± Dacarbazine as First-Line Therapy in Elderly Patients With Hodgkin Lymphoma
Clinical trials of treatment-naive HL patients commonly exclude those who are ages 60 years or older. Compared with younger patients, elderly patients have an inferior prognosis, with a shorter survival and inferior outcome after first-line treatment. Dr Jonathan Friedberg presented 3-year follow-up results from a nonrandomized, open-label, phase 2 study that evaluated brentuximab vedotin (1.8 mg/kg,
day 1) for up to 16 cycles with or without dacarbazine (375 mg/m2, day 1) for up to 12 cycles.1 The trial enrolled patients with classical HL, but excluded those with nodular lymphocyte-predominant HL. Patients were treatment-naive and ages 60 years or older. They had measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 3. Patients were ineligible for conventional first-line combination therapy or declined this treatment. The primary endpoint was the ORR.2
In this study, 49 patients received at least 1 dose of brentuximab vedotin, either as monotherapy (n=27) or with dacarbazine (n=22). In the monotherapy arm, 52% of patients were ineligible for conventional chemotherapy, 63% had stage III/IV disease, and 22% had extranodal involvement. Among patients in the combined treatment arm, 86% were ineligible for conventional chemotherapy, 73% had stage III/IV disease, and 41% had extranodal involvement. Comorbidities and functional status were generally similar in both arms.
The median observation time was 42.6 months (range, 4.6-56.3 months) for the monotherapy patients and 37.8 months (range, 14.8-44.8 months) for the combination therapy patients. The estimated 3-year PFS was 34% (95% CI, 16%-53%) vs 52% (95% CI, 26%-73%), respectively (Figures 7 and 8). The estimated 3-year OS was 71% (95% CI, 49%-85%) with monotherapy vs 90% (95% CI, 65%-97%) with the combination.
The median time to resolution of associated symptoms was 15.0 weeks with monotherapy vs 3.6 weeks with the combination. However, peripheral neuropathy symptoms improved more quickly in the monotherapy arm (8.9 vs 14.0 weeks).
The median number of treatment cycles was 8 (range, 3-23) in the brentuximab vedotin monotherapy arm vs 12.5 (range, 2-27) in the combination arm. Treatment-emergent peripheral neuropathy events of any grade were observed in 89% vs 86%, respectively.3,4 Grade 3 peripheral neuropathy events occurred in 27% to 30% of patients in the 2 arms, and no grade 4 events were reported.
References
1. Friedberg JW, Forero-Torres A, Holkova B, et al. Long-term follow-up of brentuximab vedotin ± dacarbazine as first line therapy in elderly patients with Hodgkin lymphoma [ASCO abstract 7542]. J Clin Oncol. 2018;36(15 suppl).
2. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
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. 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.
Cost-Effectiveness Analysis of Brentuximab Vedotin With Chemotherapy in Newly Diagnosed Stage III/IV Hodgkin Lymphoma
In the ECHELON-1 trial, AVD plus brentuximab vedotin improved survival and response outcomes vs standard ABVD, while also reducing rates of pulmonary toxicity.1 A Markov decision-analytic model based on data from ECHELON-1 evaluated whether substitution of brentuximab vedotin for bleomycin in the ABVD regimen is cost-effective for patients with newly diagnosed stage III/IV HL.2 Patients with previously untreated stage III/IV HL were included in a transition state model, which used 3-month length cycles, a lifetime horizon, and standard 3% future discounting. Transition probabilities and utilities were assessed using data from ECHELON-1 and previously published studies. The 2017 Medicare fee schedule and pertinent peer-reviewed medical literature were used to estimate baseline medical costs. Quality-adjusted life-years, incremental cost-effectiveness ratios, and lifetime direct health care costs were calculated for brentuximab vedotin plus AVD vs ABVD from a societal perspective within the United States. Drug calculations accounted for unused drug by rounding up to the next full single-use vial. The robustness of conclusions was tested using 1-way, probabilistic, and scenario analyses. The model was used to estimate brentuximab vedotin price reductions that would lead to cost-effectiveness with indication-specific pricing.
The model showed improved long-term clinical outcomes with brentuximab vedotin plus AVD compared with ABVD, and an average gain of 1.34 life-years. Treatment with the brentuximab vedotin combination was associated with an incremental cost-effectiveness ratio of $317,254 per quality-adjusted life-year gained. Eliminating the need for growth factor support with brentuximab vedotin plus AVD yielded an incremental cost-effectiveness ratio of $249,640 per quality-adjusted life-year. Lifetime costs were estimated at $184,291 for ABVD and $361,137 for brentuximab vedotin plus AVD. The analysis assumed a current price of $6970 per 50 mg vial of brentuximab vedotin. With indication-specific pricing, the acquisition costs for brentuximab vedotin used for first-line treatment would have to be reduced by 56% (to $3023 per vial) to achieve a cost of $150,000 per quality-adjusted life-year and by 73% (to $1848 per vial) to reduce the cost to $100,000 per quality-adjusted life-year (Figure 9). Limitations to the study included the fact that, as in ECHELON-1, the model did not include alterations to first-line therapy based on interim PET results. In addition, the analysis evaluated only direct health care costs, without addressing the potential economic benefits that result from improved survival in a relatively young population.
References
1. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344.
2. Huntington SF, Von Keudell GR, Davidoff AJ, et al. Cost-effectiveness analysis of brentuximab vedotin with chemotherapy in newly diagnosed stage III/IV Hodgkin lymphoma [ASCO abstract 6609]. J Clin Oncol. 2018;36(15 suppl).
Highlights in Lymphoma From the 2018 American Society of Clinical Oncology Annual Meeting: Commentary
Robert W. Chen, MD
Assistant Professor, Department of Hematology and Hematopoietic Cell Transplantation
City of Hope
Duarte, California
The 2018 American Society of Clinical Oncology annual meeting featured sev-eral imp-ortant abstracts on the man-age-ment of lymphoma. Analyses of the ECHELON-1 trial (Phase 3 Front-line Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma) provided further insight into the use of brentuximab vedotin plus chemotherapy. Other studies eval-uated the use of positron emission tomography (PET) to deescalate therapy after bleomycin, etoposide, dox-orubicin, cyclophosphamide, vin–cris-tine, procarbazine, and pred-ni-sone (BEACOPP) and provided new data on chimeric antigen receptor (CAR) T-cell therapy and novel treatments.
Hodgkin Lymphoma
ECHELON-1
Dr Radhakrishnan Ramchandren presented an analysis of the North Amer-ican population in the ECHELON-1 trial, which eval-uated brentuximab vedotin plus chem-o-therapy in patients with newly diag-nosed Hodgkin lymphoma.1 Overall results from the trial, published in 2017, showed a modified progression-free survival (PFS) of 82.1% with brentuximab vedotin plus chemotherapy vs 77.2% with the control treatment of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), a difference of 4.9% (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60-0.98; P=.04).2 ECHELON-1 enrolled approximately 1300 patients, of whom 500 lived in North America. Among these patients, half were treated with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) and the other half received ABVD. The arms were well-balanced in terms of stage 3 or 4 disease, age, and International Prognostic Score. The analysis showed that the patients in North America did much better with brentuximab vedotin. The 2-year modified PFS, as assessed by an independent review facility, was 84.3% in patients receiving brentuximab vedotin plus AVD vs 73.7% in those receiving ABVD. This difference of 11.6% was statistically significant and dramatically different from that seen in the overall study population. Another important finding was the rate of 2-year PFS as assessed by the investigators, which was 88.1% with brentuximab vedotin plus AVD vs 76.4% with ABVD, a statistically significant difference of 11.7%. The presentation did not offer speculation as to why patients in North America did much better with brentuximab vedotin plus AVD vs ABVD.
I presented another subanalysis of the ECHELON-1 study. These data focused on the impact of cycle 2 PET (PET2) results on modified PFS in patients with stage 3 or 4 Hodgkin lymphoma treated with brentuximab vedotin plus chemotherapy.3 It is known that patients treated with ABVD who are PET-positive after 2 cycles of therapy will not do well.4 In ECHELON-1, outcomes to 6 cycles of ABVD according to PET2 results were similar to historical rates. The modified 2-year PFS was 42.0% among PET-positive patients vs 80.9% for PET-negative patients. After 2 cycles of brentuximab vedotin plus AVD, the modified 2-year PFS was 57.5% in the PET-positive group vs 85.2% in the PET-negative patients. Although this difference was not statistically significant, there appears to be an advantage to brentuximab vedotin plus AVD in PET2-positive patients.
Previously, one way to improve outcome in PET2-positive patients was to escalate therapy from ABVD to escalated BEACOPP after PET2. However, BEACOPP is associated with significant hematologic and infectious toxicities.5 In a trial from the Southwest Oncology Group (SWOG), escalation of therapy resulted in a 2-year PFS of approximately 60%.6 Based on this analysis of the ECHELON-1 trial, it may be possible to avoid escalated BEACOPP after PET2 by starting therapy with brentuximab vedotin plus AVD.
Another analysis of the ECHELON-1 trial, presented by Dr David Straus, evaluated the use of granulocyte-colony stimulating factor (G-CSF) prophylaxis among patients treated with brentuximab vedotin.7 The design of ECHELON-1 did not mandate prophylactic G-CSF at initiation. Treatment with traditional ABVD also does not require primary G-CSF prophylaxis. During the trial, however, increased rates of febrile neu-tropenia in the experimental arm led to the recommendation of primary G-CSF prophylaxis. Eighty-three patients rec-eived primary G-CSF pro-phyl-axis, and 453 did not. Most patients received the short-acting, nontabulated formulation. After institution of pri-mary G-CSF pro-phylaxis, the rate of neutropenia decreased from 73% to 35%, and the rate of grade 3 or higher neutropenia dropped from 70% to 29%. Grade 4 neutropenia decreased from 51% to 22%. Most importantly, febrile neutropenia decreased from 21% to 11%. During cycle 1, febrile neutropenia decreased from 11% to 1%.
An interesting observation was that patients who received primary G-CSF prophylaxis had far fewer dose delays of brentuximab vedotin plus AVD compared with patients without prophylaxis, at 35% vs 49%. This difference could explain the improvement in PFS seen with primary G-CSF prophylaxis. The 2-year modified PFS was 84.6% with primary G-CSF prophylaxis vs 81.7% without. (In comparison, the 2-year modified PFS was 77.2% in the ABVD arm.) Patients who received primary G-CSF prophylaxis had fewer dose delays and experienced less toxicity, and therefore they could tolerate more treatment administered on time, possibly leading to better outcomes.
Use of PET Scans to Deescalate BEACOPP
Dr Olivier Casasnovas presented the final analysis of the AHL2011 LYSA trial (Advanced Hodgkin Lymphoma 2011 Lymphoma Study Association), which evaluated whether results from PET scans can be used to deescalate therapy after escalated BEACOPP.8 Outside the United States, one standard treatment for patients with advanced-stage Hodgkin lymphoma is escalated BEACOPP.9 The associated toxicity,5 however, has prompted evaluation of other strategies. In the AHL2011 LYSA trial, patients who were PET-negative after 2 cycles of escalated BEACOPP could downgrade to ABVD. In the standard arm, the interim PET result did not impact treatment; patients received 6 cycles of escalated BEACOPP. The Deauville score was used to categorize the scans, with scores of 1, 2, or 3 as negative and scores of 4 or 5 as positive. Overall, the PET2-negative rate was 87%. The 4-year PFS was 87.1% among patients in the experimental arm, in which the PET result was used to deescalate therapy, vs 87.4% in the standard arm, in which patients received 6 cycles of escalated BEACOPP. There was also no significant difference between the rates of 4-year overall survival, which were 97.1% vs 96.9%, respectively. The study therefore showed that deescalation of therapy based on a PET scan did not reduce PFS or overall survival. As expected, safety improved in the PET-driven arm, with decreased rates of anemia, feb-rile neutropenia, thrombocytopenia, infec-tion, and sepsis. These patients also showed improvement in the rates of serious adverse events and secondary primary malignancies.
Non-Hodgkin Lymphoma
Polatuzumab Vedotin
Polatuzumab vedotin is an antibody drug conjugate targeting lymphomas that express CD79b, such as follicular lymphoma and DLBCL. A phase 1 trial showed high response rates with this drug as a single agent in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia.10 Dr Laurie Sehn reported the results of a randomized phase 2 trial evaluating the addition of polatuzumab vedotin to bendamustine and rituximab in patients with refractory follicular lymphoma or diffuse large B-cell lymphoma (DLBCL).11 The primary endpoint was the rate of complete response as assessed by an independent review facility. The addition of polatuzumab vedotin did not improve outcome among patients with follicular lymphoma. Improvement was seen, however, in the DLBCL cohort. The overall response rate was 45% with the addition of polatuzumab vedotin vs 18% with bendamustine and rituximab alone. The complete response rate was also higher with polatuzumab vedotin, at 40%, vs 15% with bendamustine and rituximab alone. The median PFS was 6.7 months vs 2.0 months, respectively, and the overall survival was 11.8 months vs 4.7 months. Based on these data, polatuzumab vedotin received breakthrough therapy designation and priority medicine designation by the US Food and Drug Administration (FDA) and European Medicines Agency for relapsed/refractory DLBCL. This agent could soon become an option for these patients.
A phase 1b study presented by Dr Ranjana Advani evaluated the first-in-class, anti-CD47 antibody known as 5F9 in combination with rituximab in patients with relapsed/refractory NHL.12 CD47 is a “do not eat me” signal on cancer cells that prevents macrophages, a component of the innate immune system, from destroying the cells. When macrophages encounter CD47, they leave the cell intact. Among patients with DLBCL, those with low CD47 expression have better outcomes than those with high expression.13
Preclinical studies of NHL xenograft models found synergy between 5F9 and rituximab in inducing remissions.13,14 This phase 1 trial evaluated 3 different doses of 5F9 in combination with rituximab. Patients had relapsed/refractory DLBCL or follicular lymphoma. The study found that 5F9 was safe through cohort 3, which evaluated a priming dose of 1 mg/kg, followed by a 30 mg/kg maintenance dose weekly for cycle 1, and then every 2 weeks for cycle 2 and subsequent treatment. This regimen became the recommended phase 2 dose.
The treatment was well-tolerated. Most adverse events were grade 1 or 2. The most common adverse events were, as expected, on-target anemia and infusion reaction. For all patients, the overall response rate was 50%, with a complete response rate of 36%. These rates were 40% and 33%, respectively, in the DLBCL cohort, and 71% and 43% in those with follicular lymphoma. Some durable responses were seen. 5F9 has received fast-track designation by the FDA for both DLBCL and follicular lymphoma.
Acalabrutinib
Dr Roger Owen presented results from a phase 2 trial of acalabrutinib in patients with relapsed/refractory or treatment-naive Waldenström mac-ro-globulinemia.15 Acalabrutinib is a newer-generation Bruton tyrosine kinase (BTK) inhibitor with highly selective, potent activity. It is more selective for BTK than ibrutinib, an approved BTK inhibitor with demonstrated activity in Waldenström macroglobulinemia. In the study by Dr Owen, the overall response rate was 93%, and 80% of patients had a major response (defined as a partial response or better). In the treatment-naive population, the overall response rate was 93%, with a major response rate of 79%. The median duration of response was not reached. At 24 months, responses were maintained in 82% of the relapsed/refractory patients and 90% of the treatment-naive population. The 24-month PFS was 82% vs 90%, respectively.
Acalabrutinib was well-tolerated, with no unexpected toxicities. Most adverse events were grade 1 or 2, and the most common included headaches, diarrhea, contusions, dizziness, and fatigue. A key event of clinical interest was atrial fibrillation, which occurred in 4 patients with relapsed/refractory disease and 1 patient with treatment-naive disease. During treatment, patients’ hemoglobin improved and immunoglobulin M decreased, which would be expected. In conclusion, acalabrutinib monotherapy was highly effective in patients with relapsed/refractory or treatment-naive Waldenström macroglobulinemia. The responses appeared to be durable.
Rituximab Maintenance
Dr Mathias Rummel presented data from a study of patients with marginal zone lymphoma who were treated with rituximab and bendamustine, and then randomly assigned to placebo or rituximab maintenance.16 Maintenance rituximab improved PFS compared with placebo, with a hazard ratio of 0.33 and a P value of .00005. Previous studies showed that rituximab maintenance improved PFS in patients with follicular lymphoma,17 and this new trial now provides data for marginal zone lymphoma.
Axicabtagene Ciloleucel
The ZUMA-1 trial (A Phase 1-2 Multi-Center Study Evaluating Axicabtagene Ciloleucel in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma) evaluated the CAR T-cell therapy axicabtagene ciloleucel in patients with relapsed/refractory DLBCL. The trial met its primary endpoint, with an objective response rate of 82%.18 The complete response rate was 54%. Based on these results, axicabtagene ciloleucel was approved by the FDA in this setting. Dr Frederick Locke presented a long-term analysis of ZUMA-1.19 It was known that patients with a complete response did well. In contrast, among patients with a partial response, the response was not durable. In some cases, a partial response converted to a complete response. The long-term analysis found that 42% of patients had ongoing responses. The study also found that the PFS at 3 months is a predictor of long-term outcome; the response can be durable in patients who maintain a response at 3 months. Patients who do not have a response at 3 months are unlikely to stay in remission. This analysis therefore introduces 3-month PFS as an important clinical marker for these patients.
Disclosure
Dr Chen is a member of the speakers bureau of Seattle Genetics and a consultant for Seattle Genetics and Acerta.
References
1. Ramchandren R, Advani RH, Ansell SM, et al. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results [ASCO abstract 7541]. J Clin Oncol. 2018;36(15 suppl).
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. N Engl J Med. 2018;378(4):331-344.
3. Chen RW, Ansell SM, Gallamini A, et al. Bren-tuximab vedotin with chemotherapy for stage III or IV Hodgkin lymphoma (HL): impact of cycle 2 PET result on modified progression-free survival (mPFS) [ASCO abstract 7539]. J Clin Oncol. 2018;36(15 suppl).
4. Sher DJ, Mauch PM, Van Den Abbeele A, LaCasce AS, Czerminski J, Ng AK. Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin’s lymphoma: the importance of involved-field radio-therapy. Ann Oncol. 2009;20(11):1848-1853.
5. Behringer K, Mueller H, Goergen H, et al. Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol. 2013;31(2):231-239.
6. Press OW, Li H, Schöder H, et al. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluor-odeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
7. Straus DJ, Collins GP, Walewski JA, et al. Improving outcomes with brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma [ASCO abstract 7534]. J Clin Oncol. 2018;36(15 suppl).
8. Casasnovas O, Brice P, Bouabdallah R, et al. Ran-domized phase III study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma: final analysis of the AHL2011 LYSA study [ASCO abstract 7503]. J Clin Oncol. 2018;36(15 suppl).
9. Mounier N, Brice P, Bologna S, et al; Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥ 4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014;25(8):1622-1628.
10. Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16(6):704-715.
11. Sehn LH, Kamdar M, Herrera AF, et al. Ran-domized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL [ASCO abstract 7507]. J Clin Oncol. 2018;36(15 suppl).
12. Advani RH, Flinn IW, Popplewell L, et al. Activity and tolerability of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/refractory non-Hodgkin lymphoma: initial phase 1b/2 results [ASCO abstract 7504]. J Clin Oncol. 2018;36(15 suppl).
13. Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142(5):699-713.
14. Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10(9):e0137345. doi:10.1371/journal.pone.0137345.
15. Owen R, McCarthy H, Rule S, et al. Acalabrutinib in patients with Waldenström macroglobulinemia [ASCO abstract 7501]. J Clin Oncol. 2018;36(15 suppl).
16. Rummel MJ, Koenigsmann M, Chow KU, et al. Two years rituximab maintenance vs observation after first-line treatment with bendamustine plus rituximab in patients with marginal zone lymphoma: results of a prospective, randomized, multicenter phase 2 study (the StiL NHL7-2008 MAINTAIN trial) [ASCO abstract 7515]. J Clin Oncol. 2018;36(15 suppl).
17. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51.
18. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
19. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma [ASCO abstract 3003]. J Clin Oncol. 2018;36(15 suppl).