A Review of Selected Presentations From the 2019 ASCO Annual Meeting
• May 31-June 4, 2019 • Chicago, Illinois
Brentuximab Vedotin With Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma: Three-Year Update of the ECHELON-1 Study
A 3-year follow-up of the ECHELON-1 trial (A Frontline Therapy Trial in Participants With Advanced Classical Hodgkin Lymphoma) demonstrated sustained efficacy with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) as treatment for stage 3/4 classical Hodgkin lymphoma.1 The trial compared brentuximab vedotin plus AVD vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) among patients from 21 countries. The patients were randomly assigned to receive 6 cycles of brentuximab vedotin plus AVD (n=664) or ABVD (n=670) intravenously on days 1 and 15 of each cycle. Patients were assessed by computed tomography (CT)/PET scans before and after treatment. PET status at the end of cycle 2 (PET2) was considered negative among patients with a Deauville score of 1, 2, or 3 and positive among those with a score of 4 or 5.
Initial results from the phase 3 ECHELON-1 trial showed that brentuximab vedotin plus AVD improved outcomes, with a hazard ratio (HR) for modified progression-free survival (PFS) of 0.77 (95% CI, 0.60-0.98).2 The 3-year follow-up study evaluated both investigator-assessed PFS among the intention-to-treat (ITT) population as well as safety, with particular attention to peripheral neuropathy.1 At a median follow-up of 37.1 months, the PFS rate was 83.1% with brentuximab vedotin plus AVD vs 76.0% with ABVD. Treatment with brentuximab vedotin plus AVD reduced the risk of progression or death at 3 years by 30% compared with ABVD (HR, 0.704; 95% CI, 0.550-0.901; P=.005; Figure 1). Subgroup analyses based on age, International Prognostic Score, PET2 status, and stage of disease also reflected superior PFS with brentuximab vedotin plus AVD compared with ABVD.
In the initial trial results, peripheral neuropathy was reported among 67% of patients receiving brentuximab vedotin plus AVD and 43% of those receiving ABVD (Figure 2).2 By the 3-year analysis, these cases improved completely or partially in 78% vs 83%, respectively. Among the patients with complete resolution of peripheral neuropathy, the median time to resolution was 28 weeks after the end of treatment with brentuximab vedotin plus AVD and 14 weeks after ABVD. For those patients with partial improvement, the median time to improvement was 40 weeks vs 32 weeks, respectively.
The study showed that initial treatment of advanced classical Hodgkin lymphoma with 6 cycles of brentuximab vedotin plus AVD provided strong, sustained benefits in all subgroups. Notably, brentuximab vedotin plus AVD improved PFS for both PET2-positive and PET2-negative patients. The study authors concluded that the 30% reduction in disease progression or death at 3 years, along with improvement in peripheral neuropathy over time, suggests that brentuximab vedotin plus AVD has a more favorable benefit/risk profile compared with ABVD.
References
1. Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma: three-year update of the ECHELON-1 study [ASCO abstract 7532]. J Clin Oncol. 2019;37(suppl 15).
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.
Umbralisib Monotherapy Demonstrates Efficacy and Safety in Patients With Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open Label, Registration Directed Phase II Study
Umbralisib has shown evidence of activity in patients with relapsed or refractory hematologic malignancies. This next-generation phosphoinositide 3-kinase delta (PI3Kδ) inhibitor may have improved selectivity and a distinct safety profile compared with earlier agents.1,2 A phase 1 trial showed a lower rate of colitis.2
The multicenter, multicohort phase 2b UNITY-NHL trial (Study to Assess the Efficacy and Safety of Ublituximab + TGR-1202 With or Without Bendamustine and TGR-1202 Alone in Patients With Previously Treated Non-Hodgkins Lymphoma) investigated the efficacy and safety of umbralisib alone and in various combinations in patients with relapsed or refractory non-Hodgkin lymphoma. Dr Felipe Samaniego presented results for patients with marginal zone lymphoma, who received single-agent umbralisib at an oral daily dose of 800 mg until progressive disease or unacceptable toxicity.1 The primary endpoint of the study was the overall response rate (ORR). The secondary endpoints were duration of response, PFS, time to response, and safety.
The trial enrolled 72 patients with marginal zone lymphoma. The interim efficacy analysis included 42 patients who received 9 or more treatment cycles, with a median duration of 10.1 months (range, 0.7-15.7). Their median age was 67 years (range, 34-81). Among these patients, 45% had received 1 prior line of therapy, and 55% had received 2 or more prior lines of therapy.
The median follow-up duration was 12.5 months (range, 8.3-18.5 months), with 55% of patients still receiving treatment at the time of the report. The cause of treatment discontinuation included progressive disease in 10 patients and treatment-related adverse events (AEs) in 5 patients.
The ORR was 52% with umbralisib, according to investigator assessment and independent review. The clinical benefit rate—a composite of partial response (PR), complete response (CR), and stable disease—was 88%.
According to independent review, umbralisib had activity across subtypes. The ORR was 57% in patients with extranodal marginal zone lymphoma, 42% in those with nodal marginal zone lymphoma, and 43% in those with splenic marginal zone lymphoma. ORR was 53% among patients who had received prior chemoimmunotherapy, 38% among those who were refractory to their most recent line of therapy, and 44% in those who had relapsed after 2 or more prior lines of therapy.
The median duration to initial response with umbralisib was 2.7 months. A reduction in tumor burden occurred in 86% of patients (Figure 3). The median duration of response with umbralisib was not reached among 22 evaluable patients. The median PFS was also not reached among 42 evaluable patients. The estimated rate of 12-month PFS was 66%.
AEs were evaluated in 69 patients, who had received umbralisib for a median of 6.9 months. Umbralisib was generally well tolerated. No deaths or cases of colitis were reported. Dose reductions owing to AEs were required by 9% of patients, and another 14% of patients discontinued umbralisib because of AEs that were possibly related to treatment. Diarrhea was the most common AE, ranging from grades 1 to 3. The prevalence of grade 3 diarrhea was 10%. Grade 3 elevations of the liver enzymes aspartate aminotransferase and alanine aminotransferase (ALT) each occurred in 9% of patients. Increases in liver enzymes mostly diminished throughout the course of the study, with only 1 patient showing an elevated ALT after 6 cycles. After 6 months, no patients discontinued umbralisib owing to a treatment-related AE.
References
1. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: a multicenter, open label, registration directed phase II study [ASCO abstract 7506]. J Clin Oncol. 2019;37(suppl 15).
2. Burris HA III, Flinn IW, Patel MR, et al. Umbra-lisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486-496.
Response to Brentuximab Vedotin by CD30 Expression: Results From Five Trials in PTCL, CTCL, and B-Cell Lymphomas
Treatment with brentuximab vedotin has been studied in several types of lymphoma.1 A component of brentuximab vedotin, the antimitotic drug monomethyl auristatin E (MMAE), acts upon cells expressing the CD30 cell surface antigen.2 However, there are additional possible explanations for the activity of brentuximab vedotin against tumor cells.1 These may include macrophage-mediated cellular phagocytosis, cellular immune response, and a bystander-killing effect.3-5 Additionally, responses to brentuximab vedotin have not consistently reflected levels of CD30 expression.6-10 A study examined the results of 5 prospective clinical trials to identify any association between CD30 expression and the efficacy of brentuximab vedotin.1 This study analyzed the results of 5 prospective clinical trials evaluating brentuximab vedotin for relapsed/refractory lymphoma. The analysis included 275 patients who received brentuximab vedotin monotherapy for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The 5 trials were the phase 2 SGN35-012 trial (parts A and C), the phase 2 35-IST-030 trial, the phase 3 ALCANZA trial (Brentuximab Vedotin or Physician’s Choice in CD30-Positive Cutaneous T-Cell Lymphoma), the phase 2 35-IST-001 trial, and the phase 2 35-IST-002 trial.
CD30 expression was quantified through immunohistochemistry. Patients were grouped by CD30 expression levels of greater than or equal to 10%, less than 10%, and undetectable. These levels were compared with data for the ORR and duration of response. For some patients in the ALCANZA and 35-IST-002 trials, more than 1 measurement of CD30 expression was available. When CD30 expression was calculated using averaged values in the ALCANZA and 35-IST-002 studies, expression was less than 10% in 140 patients, including 60 patients with undetectable expression. When the analysis included the lowest measured CD30 values from these studies, the number of patients with less than 10% expression was 153, of whom 80 had undetectable expression.
The analysis found that ORR values did not consistently correspond to CD expression.1 Only one comparison, among patients with CTCL in the ALCANZA trial, suggested a possible trend between higher ORR and high CD30 expression. However, the 95% CIs for ORR overlapped with each other across all categories. Among patients with B-cell NHL in the SGN35-012 study, no discernible trend appeared between the level of CD30 expression and ORR.
The level of CD30 expression did not correspond to the median duration of response across the studies. For patients with CTCL in the ALCANZA trial, based on averaged CD30 expression levels, the median duration of response was 15.1 months among those with 10% or higher CD30 expression and 16.6 months among those with a level below 10% (P=.46; Figure 4). Among patients with B-cell NHL in the SGN35-012 study, the median duration of response was 3.9 months in those with 10% or higher CD30 expression, 8.3 months in those with expression below 10%, and 11.6 months in those with undetectable expression (P=.78).
The study investigators concluded that the response and duration of response seen with brentuximab vedotin did not appear to be associated with levels of CD30 expression. They suggested that further elucidation of this drug’s mechanisms of action may help to improve outcomes.
References
1. Jagadeesh D, Horwitz SM, Bartlett NL, et al. Response to brentuximab vedotin by CD30 expression: results from five trials in PTCL, CTCL, and B-cell lymphomas [ASCO abstract 7543]. J Clin Oncol. 2019;37(suppl 15).
2. Sutherland MS, Sanderson RJ, Gordon KA, et al. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem. 2006;281(15):10540-10547.
3. Oflazoglu E, Stone IJ, Gordon KA, et al. Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. Blood. 2007;110(13):4370-4372.
4. Müller P, Martin K, Theurich S, et al. Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res. 2014;2(8):741-755.
5. Li F, Emmerton KK, Jonas M, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76(9):2710-2719.
6. Kim YH, Tavallaee M, Sundram U, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: a multi-institution collaborative project. J Clin Oncol. 2015;33(32):3750-3758.
7. Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. 2015;33(32):3759-3765.
8. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123(20):3095-3100.
9. 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.
10. Bartlett NL, Smith MR, Siddiqi T, et al. Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leuk Lymphoma. 2017;58(7):1607-1616.
Sintilimab for Relapsed/Refractory Extranodal NK/T-Cell Lymphoma: A Multicenter, Single-Arm, Phase 2 Trial (ORIENT-4)
The fully human antibody sintilimab targets programmed death 1 (PD-1) with high affinity and receptor occupancy.1-3 The single-arm phase 2 ORIENT-4 trial (Efficacy and Safety Evaluation of IBI308 in Patients With Relapsed/Refractory Extranodal NK/T Cell Lymphoma, Nasal Type: A Multicenter, Single Arm, Phase 2 Study) evaluated sintilimab in relapsed or refractory extranodal NK/T-cell lymphoma (ENKTL).1 Sintilimab was administered at 200 mg every 3 weeks until disease progression, death, unacceptable toxicity, or withdrawal from the trial. At the time of data cutoff, 28 patients with relapsed or refractory ENKTL received sintilimab, although the planned enrollment had allotted for 60 patients. Tumor response was evaluated with PET/CT and CT/magnetic resonance imaging (MRI) with contrast. After week 24, only CT/MRI with contrast was used.
The patients’ median age was 39.8 years (range, 19-65 years). Most patients (60.7%) were male. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 10.7%, 1 in 85.7%, and 2 in 3.6%. The median time from initial diagnosis was 22.0 months. The median number of prior lines of chemotherapy was 3.0, and 78.6% of patients had received prior radiotherapy. Two patients (7.1%) had undergone prior autologous stem cell transplant (SCT). Disease was refractory to asparaginase-based therapy in 12 patients (42.9%). Sixteen patients had relapsed disease (57.1%).
Sintilimab showed clinical activity among patients with relapsed or refractory ENKTL. The ORR was 67.9% (95% CI, 47.6-84.1). Two patients (7.1%) had a CR, and 17 patients (60.7%) had a PR. The ORR included 4 patients who developed pseudoprogressive disease before their response. Stable disease occurred in 5 patients (17.9%), and disease progression was seen in 3 (10.7%). One patient was not evaluable. The disease control rate of 85.7% included 5 patients who experienced pseudoprogressive disease before developing stable disease or responding to treatment. The study authors noted that early disease progression did not correlate with poor outcome.
The median time to response was 1.3 months (range, 1.2-5.5), and the median duration of response was 4.1 months. A total of 19 patients were still receiving sintilimab at the time of the report. At a median follow-up of 15.4 months, the median overall survival (OS) was not reached. The 1-year rate of OS was 82.1%. A subgroup analysis showed that a superior ORR was associated with Epstein-Barr virus negativity, absence of B symptoms, normal lactate dehydrogenase, and negative bone marrow involvement (Figure 5). In a subgroup analysis, the absence of bone marrow involvement was associated with a higher OS (HR, 0.17; P=.016). No association with OS was seen with relapsed vs refractory disease (HR, 0.604; P=.557).
Most treatment-related AEs were grade 1 or 2. There were no grade 4 or 5 treatment-related AEs. The most common all-grade treatment-related AEs were decreased lymphocyte count (46.4%) and fever (42.9%). The patients’ quality of life significantly improved from baseline (Figure 6).
References
1. Tao R, Fan L, Song Y, et al. Sintilimab for relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL): a multicenter, single-arm, phase 2 trial (ORIENT-4) [ASCO abstract 7504]. J Clin Oncol. 2019;37(suppl 15).
2. Xu JM, Jia R, Wang Y, et al. A first-in-human phase 1a trial of sintilimab (IBI308), a monoclonal antibody targeting programmed death-1 (PD-1), in Chinese patients with advanced solid tumors [ASCO abstract e15125]. J Clin Oncol. 2018;36(suppl 15).
3. Shi Y, Su H, Song Y, et al. Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2019;6(1):e12-e19.
Response to A+CHP by CD30 Expression in the ECHELON-2 Trial
The antibody-drug conjugate brentuximab vedotin selectively interacts with the CD30 cell surface antigen associated with some lymphoproliferative disorders.1,2 A component of brentuximab vedotin, MMAE, exhibits antimitotic activity.3 However, brentuximab vedotin may also exert antitumor activity through additional mechanisms of action, and the association between response and levels of CD30 expression is not confirmed.1,4-6
In the phase 3 ECHELON-2 trial (A Comparison of Brentuximab Vedotin and CHP With Standard-of-Care CHOP in the Treatment of Patients With CD30-Positive Mature T-Cell Lymphomas), brentuximab vedotin plus cyclophosphamide, dox-o-rubicin, and prednisone (CHP) was superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in treatment-naive patients with CD30-expressing PTCL.7 A follow-up analysis evaluated whether treatment response was related to CD30 expression among patients with angioimmunoblastic T-cell lymphoma (AITL; n=29)
or PTCL not otherwise specified (PTCL-NOS; n=28) who had received brentuximab vedotin plus CHP.1
The level of CD30 expression was measured with immunohistochemistry. Among the patients with AITL, 90% had a CD30 expression level of 10% to 30%, with a mean level of 20% and a median of 18%. The patients with PTCL-NOS had a wider range of CD30 expression. Their mean CD30 expression level was 41%, and their median level was 25%.
Patient responses to brentuximab vedotin plus CHP were broadly distributed across the range of CD30 expression levels. Among patients with AITL who had achieved a CR, 8 had levels of CD30 expression above the median for AITL, and 8 had levels at or below the median (P=.84; Figure 7). Among the patients with lower expression, 5 had a CD30 expression level of 10%. Among patients with AITL who had a PR, 1 had a CD30 expression level above the median, and 3 had levels at or below the median.
Among patients with PTCL-NOS who achieved a CR, 8 had CD30 expression above the median for this subtype, and 10 had CD30 expression at or below the median (P=.44). Four patients had a CD30 expression level of 10%. PRs were reported in 2 patients with CD30 expression above the median, and in 2 patients below the median (at 10% expression). The duration of CR appeared unrelated to CD30 expression levels for both AITL (P=.30) and PTCL-NOS (P=.90).
This analysis therefore suggested that levels of CD30 expression did not correspond to response to treatment with brentuximab vedotin plus CHP.1 CRs were reported even in patients with a CD30 expression of 10%. The study authors recommended evaluation of CD30 expression below 10%, a level that was not assessed in this analysis.
References
1. Advani RH, Horwitz SM, Iyer SP, et al. Response to A+CHP by CD30 expression in the ECHELON-2 trial [ASCO abstract 7538]. J Clin Oncol. 2019;37(suppl 15).
2. Sabattini E, Pizzi M, Tabanelli V, et al. CD30 expression in peripheral T-cell lymphomas. Haematologica. 2013;98(8):e81-e82.
3. Sutherland MS, Sanderson RJ, Gordon KA, et al. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem. 2006;281(15):10540-10547.
4. Oflazoglu E, Stone IJ, Gordon KA, et al. Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. Blood. 2007;110(13):4370-4372.
5. Müller P, Martin K, Theurich S, et al. Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res. 2014;2(8):741-755.
6. Li F, Emmerton KK, Jonas M, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76(9):2710-2719.
7. Horwitz S, O’Connor OA, Pro B, et al; ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240.
Polatuzumab Vedotin + Obinutuzumab and Lenalidomide in Patients With Relapsed/Refractory Follicular Lymphoma: Interim Analysis of a Phase Ib/II Trial
Polatuzumab vedotin is a first-in-class antibody-drug conjugate that targets CD79b, which is expressed in follicular lymphoma and diffuse large B-cell lymphoma (DLBCL).1 After polatuzumab vedotin binds to CD79b on tumor cells, it is internalized. It then disrupts cellular division, triggering apoptosis. Dr Catherine Diefenbach and colleagues presented an interim analysis of an open-label, single-arm phase 1b/2 trial of polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma. The patients were initially enrolled in a dose-escalation cohort.2 They received escalating doses of polatuzumab vedotin at 1.4 mg/kg or 1.8 mg/kg and lenalidomide at 10 mg, 15 mg, or 20 mg. Obinutuzumab was administered at a standard fixed dose of 1000 mg. The recommended phase 2 doses were 20 mg of lenalidomide and 1.4 mg/kg of polatuzumab vedotin.
In both phases, all patients initially received induction treatment consisting of 6 cycles of polatuzumab vedotin, obinutuzumab, and lenalidomide. The primary efficacy endpoint was CR at the end of induction, as assessed by independent review. Patients with a CR, PR, or stable disease could receive maintenance treatment with lenalidomide (administered on a 28-day cycle for up to 1 year) and obinutuzumab (administered every 2 months for up to 24 months).
The trial enrolled patients ages 18 years or older with relapsed or refractory follicular lymphoma of grades 1 to 3a. Patients had histologically confirmed CD20-positive tumors and 1 or more bidimensionally measurable lesions reaching at least 1.5 cm in 1 direction. They had an ECOG performance status of 0 to 2. Exclusion criteria were 3b disease; previous allogeneic SCT transplant; relapse within 100 days of autologous SCT; peripheral neuropathy of grade 2 or higher; resistance to lenalidomide; insufficient hematologic, renal, or hepatic function; or a positive test for hepatitis.
The interim analysis population consisted of 52 patients who had completed induction therapy and were evaluable for safety. In the dose-escalation portion, 16 patients received treatment at the phase 2 dose. In the dose-expansion portion, 36 patients were treated at the phase 2 dose. Among the patients treated at the recommended phase 2 dose, 18 were evaluable for efficacy.
The patients’ median age was 58 years in the efficacy population and 62 years in the safety population. These patients were heavily pretreated; at least 3 prior lines of therapy were reported by 61% of the efficacy population and 58% of the safety population. In each population, 50% of patients were refractory to their most recent prior therapy.
The ORR for the efficacy population was 89%.2 The CR by independent review was 67% by modified Lugano criteria and 78% by Lugano 2014 criteria. The study authors attributed this discrepancy to 3 patients with bone marrow–positive disease who had PET/CT results that were negative at the end of induction, but then did not undergo follow-up bone marrow assessment. According to the modified Lugano criteria, these patients are considered CR unconfirmed and categorized as PRs. An additional 6% of patients had stable disease.
At a median duration of follow-up of 16.6 months, the median PFS was not reached (Figure 8). The 12-month PFS rate was 90%. Among the 17 responders, 2 patients developed disease progression.
In the safety population, grade 3 to 4 AEs occurred in 75% of patients. Most of these events consisted of myelosuppression, particularly neutropenia. Serious AEs were reported in 40% of patients. The most common all-grade AEs were infection (56%), neutropenia (52%), thrombocytopenia (37%), infusion-related reaction (35%), pyrexia (35%), anemia (33%), diarrhea (29%), and rash (21%). Peripheral neuropathy was reported in 17% of patients, but all cases were grade 1 to 2 and reversible. The most common grade 3/4 AE was neutropenia, occurring in 46% of the safety population. Febrile neutropenia occurred in 4% of patients. In 31% of patients, an AE required a reduction in the dose of lenalidomide. Treatment with lenalidomide was interrupted in 52% of patients and discontinued in 15% owing to AEs.
References
1. Polson AG, Yu SF, Elkins K, et al. Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood. 2007;110(2):616-623.
2. Diefenbach C, Kahl B, Banerjee L, et al. Polatuzumab vedotin (pola) + obinutuzumab (G) and lenalidomide (len) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL): interim analysis of a phase Ib/II trial [ASCO abstract 7505]. J Clin Oncol. 2019;37(suppl 15).
First-Line Therapy of T-Cell Lymphoma: Allogeneic or Autologous Transplantation for Consolidation—Final Results of the AATT Study
The prospective, randomized AATT trial (Autologous or Allogeneic Transplantation in T-Cell Lymphoma) evaluated clinical outcomes in patients with T-cell lymphoma who underwent autologous SCT or allogeneic SCT as consolidation therapy. Dr Norbert Schmitz presented the results.1 The trial recruited more than 100 patients from 44 sites in Germany and France to receive frontline chemotherapy and subsequent consolidation with autologous SCT or allogeneic SCT. Patients who were randomly assigned to autologous SCT underwent peripheral blood stem cell harvest. The study enrolled patients ages 18 to 60 years, with an ECOG performance status between 0 and 3. The most common types of T-cell lymphoma included AITL in 38%, PTCL-NOS in 29%, and anaplastic lymphoma kinase–negative anaplastic large-cell lymphoma in 14%. The remaining patients had enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma, and subcutaneous panniculitis-type T-cell lymphoma.
The hypothesis was that allogeneic SCT would improve 3-year event-free survival from 35% to 60%. The trial design designated enrollment of 140 patients to detect an alpha of 5% with 80% power. A planned interim analysis showed a probability of approximately 10% to detect a difference of 25% in event-free survival, so a data safety monitoring committee stopped the study after accrual of 104 patients.2
Among the 54 patients in the autologous SCT arm, 57% were male. The allogeneic SCT arm had 49 patients, 69% of whom were male.1 The median age across both treatment arms was 50 years (range, 24-60 years). An elevated lactate dehydrogenase level was reported in 61% of patients. An ECOG performance status of higher than 1 was seen in 20% of patients, stage III/IV disease was reported in 88%, and 61% had more than 1 extranodal site of disease.
A total of 65% of patients completed the study as per protocol (63% of the autologous SCT arm and 67% of the allogeneic SCT arm). Fifty-eight patients underwent SCT. Among the patients who left the study before SCT, 28% did so because of progressive disease. Notably, 7 patients randomly assigned to allogeneic SCT underwent an autograft transplant. Six of these patients lacked a fully matched donor, and the allogeneic SCT arm was closed before 1 patient could undergo the procedure.
The 3-year rate of event-free survival was 38% in the autologous SCT arm and 43% in the allogeneic SCT arm, a difference that was not significant (P=.583; Figure 9).1 Among the patients who underwent transplant, the 3-year event-free survival rate was 61% in the autologous SCT arm and 65% in the allogeneic SCT arm, a difference that was also not significant (P=.430). Although no significant differences were observed, Dr Schmitz noted that the Kaplan-Meier curve for the patients who underwent allogeneic SCT appeared more stable.
Among the ITT cohort (n=103), the rate of 3-year OS was 70% with autologous SCT and 57% with allogeneic SCT, which was not significantly different (P=.408).1 Dr Schmitz suggested that this lack of a significant difference might be attributed to the fact that one-third of the patients randomly assigned to treatment could not proceed to SCT, in most cases because of refractory disease or early relapse. Significant differences in clinical outcome might have been observed had the analysis been limited to patients who had undergone SCT. The rate of 3-year OS was significantly improved among patients with an International Prognostic Index score of 0 or 1 vs a score of 2 or 3 (P=.012).
Across the entire trial, the rate of CR/unconfirmed CR was 45%. This rate was 39% in the autologous SCT arm and 51% in the allogeneic SCT arm. The overall rate of PR was 13%, with rates of 17% in the autologous arm and 8% in the allogeneic arm. In the ITT population, death from lymphoma was reported in 13 patients vs 11 patients, respectively. Among the 58 patients who underwent SCT, deaths occurred in 8 patients in the autologous group and 9 patients in the allogeneic group.
References
1. Schmitz N, Truemper L, Ziepert M, et al. First-line therapy of T-cell lymphoma: allogeneic or autologous transplantation for consolidation—final results of the AATT study [ASCO abstract 7503]. J Clin Oncol. 2019;37(suppl 15).
2. Schmitz N, Nickelsen M, Altmann B, et al. Allogeneic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: results of the interim analysis of the AATT trial [ASCO abstract 7503]. J Clin Oncol. 2015;33(suppl 15).
Lisocabtagene Maraleucel (Liso-Cel) Treatment of Patients With Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma and Secondary CNS Lymphoma: Initial Results From TRANSCEND NHL 001
The safety and efficacy of lisocabtagene maraleucel were investigated in the phase 1 TRANSCEND-NHL-001 trial (Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-Cell Non-Hodgkin Lymphoma).1 The study enrolled patients with relapsed or refractory NHL with secondary central nervous system lymphoma. They had either DLBCL (n=8) treated with at least 2 prior therapies, or mantle cell lymphoma (n=1) treated with at least 1 prior therapy.
Following lymphodepletion, pat-ients were treated with lisocabtagene maraleucel at 50 × 106 CAR+ T cells (n=3) or 100 × 106 CAR+ T cells (n=6). The study permitted a second dose of treatment for patients who developed progressive disease after an initial CR.
The patients’ median age was 60 years, and they had received a median of 3 lines of prior therapy.1 The time to peak CAR+ T-cell expansion occurred at a median of 11 days (range, 7-112). Among the 6 patients with DLBCL who received only 1 dose of lisocabtagene maraleucel, best responses included a CR in 4 and progressive disease in 2. Two patients received an additional dose of lisocabtagene maraleucel after progressive disease. The second dose did not lead to an additional response.
The median follow-up was 24.1 months (95% CI, 12.3-24.1) for the 6 patients with DLBCL receiving initial lisocabtagene maraleucel. The median PFS for these patients was 2.9 months (95% CI, 0.2 to not reached; Table 1). The median OS was 10.7 months (95% CI, 0.5 to not reached). Two patients were still in response at the time of the analysis. For the patient with mantle cell lymphoma, the best response was stable disease.
Death from disease progression occurred in 4 patients receiving initial lisocabtagene maraleucel, and in the 2 patients who received a second course of treatment. All patients in this study developed treatment-emergent AEs, and these events were grade 3 or 4 in most cases. No dose-limiting toxicities occurred, and no patients died from treatment-related causes.
Reference
1. Abramson JS, Palomba ML, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel) treatment of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) and secondary CNS lymphoma: initial results from TRANSCEND NHL 001 [ASCO abstract 7515]. J Clin Oncol. 2019;37(suppl 15).
Rituximab Maintenance for Patients With Diffuse Large B-Cell Lymphoma in First Complete Remission: Results From a Randomized HOVON-Nordic Lymphoma Group Phase III Study
In the phase 3 HOVON 84 NHL trial (Randomized Phase III Study on the Effect of Early Intensification of Rituximab in Combination With 2-Weekly CHOP Chemotherapy Followed by Rituximab Maintenance in Elderly Patients [66-80 Years] With Diffuse Large B-Cell Lymphoma), maintenance with rituximab did not provide an advantage vs observation following induction therapy with rituximab plus CHOP (R-CHOP) in patients with DLBCL.1 The trial consisted of 2 stages. The first examined rituximab intensification during induction therapy, and showed no benefit in CR or PFS with this approach compared with standard R-CHOP induction therapy.1-3 Throughout the induction stage, the 3-year and 5-year rates of PFS did not differ substantially between the treatments. OS also did not differ between the treatment arms, and no subgroups benefited from rituximab intensification.
The patients in the maintenance stage of the trial had been in a CR for at least 4 weeks following their last cycle of R-CHOP.1 Patients in the maintenance stage were randomly assigned to an observation arm with no therapy (n=195) or a maintenance arm consisting of intravenous rituximab given every 8 weeks for 12 doses or until relapse (n=191).1,2 In the rituximab maintenance arm, 6 enrolled patients went off-protocol before treatment began. The primary endpoint of the maintenance stage of the trial was disease-free survival (DFS), based on either relapse or death, measured from the time of randomization to maintenance or observation.
Patients received rituximab maintenance for a median of 22.5 months. At a median follow-up of 79.9 months, the median DFS was not reached. The 5-year rate of DFS was 79% in patients receiving rituximab maintenance vs 74% in those undergoing observation (HR, 0.83; 95% CI, 0.57-1.19; P=.31; Figure 10). Based on competing risk regression analysis, there were also no significant differences in time to relapse (HR, 0.82; 95% CI, 0.52-1.31; P=.42) or time to death (HR, 0.87; 95% CI, 0.48-1.59; P=.66) between the study arms. Univariate analyses revealed no patient subgroups in which rituximab maintenance improved DFS. The rate of OS was similar for patients receiving rituximab maintenance or observation (HR, 0.87; 95% CI, 0.57-1.31; P=.50).1 However, the rate of 5-year OS among patients in first CR after R-CHOP was high, at 84%.
A total of 149 patients (81%) completed maintenance therapy with rituximab. Most treatment discontinuations were in response to toxicity (n=15) or relapse (n=14).1 Grade 3/4 AEs occurred in 23% of patients who received rituximab maintenance.1 Serious AEs occurred in 36 patients receiving rituximab (19%); these events were considered potentially related to the study medication in 15 patients.
References
1. Lugtenburg EJ, de Nully Brown P, van der Holt B, et al. Rituximab maintenance for patients with diffuse large B-cell lymphoma in first complete remission: results from a randomized HOVON-Nordic Lymphoma Group phase III study [ASCO abstract 7507]. J Clin Oncol. 2019;37(suppl 15).
2. Netherlands Trial Register. Trial NL986 (NTR1014). https://www.trialregister.nl/trial/986. Accessed July 1, 2019.
3. Lugtenburg PJ, de Nully Brown P, van der Holt B, et al. Randomized phase III study on the effect of early intensification of rituximab in combination with 2-weekly CHOP chemotherapy followed by rituximab or no maintenance in patients with diffuse large B-cell lymphoma: results from a HOVON-Nordic Lymphoma Group study [ASCO abstract 7504]. J Clin Oncol. 2016;34(suppl 15).
Highlights in Lymphoma From the 2019 American Society of Clinical Oncology Annual Meeting: Commentary
Alex F. Herrera, MD
At the 2019 American Society of Clinical Oncology annual meeting, several presentations provided insight into the management of a range of lymphomas, including non-Hodgkin (NHL) and Hodgkin lymphomas. Studies were presented on stem cell transplant, as well as novel therapies, including antibody-drug conjugates, such as brentuximab vedotin and polatuzumab vedotin; targeted therapies, such as umbralisib and ibrutinib; and immunotherapies, such as sintilimab.
Brentuximab Vedotin
Dr David Straus presented a 3-year follow-up analysis of the ECHELON-1 study.1 This study compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) among patients with advanced-stage Hodgkin lymphoma.2 The current analysis evaluated standard progression-free survival (PFS), as opposed to the modified PFS that was the primary endpoint of the original study. Modified PFS encompassed the time to progression, death, or use of subsequent anticancer therapy following less than a complete response. The 3-year analysis also evaluated PFS according to whether the patient’s positron emission tomography (PET) scan was positive or negative. The important overall conclusion from the 3-year analysis is that remissions obtained with A+AVD appeared to be durable. At 2 years, the rate of PFS was 84%, compared with 83.1% at 3 years. There were few PFS events during the most recent year of follow-up. Among patients with a negative PET scan at the end of cycle 2 (PET2), the 3-year PFS was 87.2%. A striking finding was that among patients who were PET2-positive and young (<60 years), 3-year traditional PFS was 69.2% in those who continued with A+AVD vs 54.7% among those treated with ABVD. The data from this PET2 analysis are compelling. The outcomes seen with continuation of A+AVD compare favorably with those reported when treatment is changed to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escBEACOPP) in patients with a positive PET2 scan after 2 cycles of ABVD, a strategy used in the S0816 study and the RATHL trial.3,4 An appealing aspect of using A+AVD is that it obviates the need for dose escalation to BEACOPP, which is a regimen that can be associated with myelosuppression, infertility, and secondary malignancies.
The ECHELON-2 trial showed a superior outcome with the combination of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone as compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).5 Dr Ranjana Advani and colleagues analyzed data from this trial to determine the association between response and degree of CD30-positivity in patients with angioimmunoblastic T-cell lymphoma or peripheral T-cell lymphoma (PTCL) not otherwise specified.6 The ECHELON-2 study enrolled patients with CD30 expression of 10% or higher. In the analysis by Dr Advani, patients were stratified according to whether their level of CD30 expression was above or below the median.
A previous study of patients with relapsed or refractory T-cell lymphoma showed that CD30 expression did not correspond to response.7 The study by Dr Advani confirmed this finding, showing no association between response and degree of CD30 expression.6 These data suggest that patients with CD30 expression of 10% or higher should receive brentuximab vedotin, regardless of the degree of CD30 expression.
Novel Treatments and Regimens
Traditionally, treatments for patients with marginal zone lymphoma (MZL) have been limited to standard chemotherapies. Several novel therapies have been evaluated for patients with MZL. The US Food and Drug Administration recently approved the Bruton tyrosine kinase (BTK) inhibitor ibrutinib for relapsed/refractory disease and lenalidomide combined with rituximab for previously treated MZL.
A study by Dr Felipe Samaniego and coworkers evaluated the phosphoinositide 3-kinase (PI3K) inhibitor umbralisib in relapsed or refractory MZL.8 Most patients had received prior chemoimmunotherapy. According to an independent review committee, umbralisib produced an overall response rate of 52%. Stable disease was reported in 36% of patients. Investigator assessment of the interim efficacy population found that the estimated 12-month PFS was 66%.
Overall, umbralisib appeared to have activity in MZL, and the treatment was well tolerated. There was some gastrointestinal toxicity, including diarrhea and nausea, as well as mild myelosuppression. The options for MZL are expanding beyond standard chemoimmunotherapy to include BTK inhibitors and now, potentially, PI3K inhibitors.
Sintilimab is an anti–programmed death 1 (PD-1) antibody developed in China, where it was approved for Hodgkin lymphoma in 2018. Anti–PD-1 antibodies are effective in natural killer/T-cell lymphomas.9 A study from Dr Rong Tao evaluated sintilimab in extranodal natural killer/T-cell lymphoma (ENKTL).10 This study was performed in Asia, where the incidence of ENKTL is much higher than in the West. In smaller preliminary studies, the anti–PD-1 antibody pembrolizumab was associated with response rates of 57% to 100%.11,12 This larger study enrolled 28 patients who had received a median of 3 lines of prior therapy. All patients had received previous treatment with an L-asparaginase–containing regimen. ENKTL is an aggressive disease, and patients with relapsed or refractory disease traditionally have a poor prognosis. In the study by Dr Tao, the overall response rate in patients with relapsed/refractory ENKTL was 68%, which is a promising outcome in this high-risk population.10 The disease control rate was 86%. The rate of 1-year overall survival was 82%, and the median overall survival was not reached. As a comparison, the study authors cited a median overall survival of 4.8 months in a retrospective Chinese study of 46 patients with relapsed/refractory ENKTL treated with various standard salvage chemotherapy regimens.10 In the study by Dr Tao, benefits were more pronounced among patients with nodal disease, rather than bone marrow involvement, with excellent survival in this subgroup. The side effect profile of sintilimab was consistent with that of other anti–PD-1 antibodies. This larger study confirmed that most patients with relapsed/refractory ENKTL respond to PD-1 blockade.
A study presented by Dr Catherine Diefenbach evaluated polatuzumab vedotin, obinutuzumab, and lenalidomide in patients with relapsed or refractory follicular lymphoma.13 Lenalidomide is an effective therapy for the treatment of patients with previously untreated or relapsed/refractory follicular lymphoma. A recent study showed similar outcomes with first-line chemoimmunotherapy vs rituximab plus lenalidomide in the first-line treatment of follicular lymphoma.14 Studies have also demonstrated that the combination of lenalidomide plus obinutuzumab was effective in patients with follicular lymphoma.15 In the study by Dr Diefenbach, most patients had advanced-stage disease, had received 3 or more prior lines of treatment, and were refractory to their most recent prior therapy.13
Among the 18 patients treated, the early data on efficacy were promising, with a complete response rate of 78% and an overall response rate of 89% according to the 2014 Lugano classification.13 After a median follow-up of 16 months, 2 of 17 patients who responded to treatment had developed disease progression. The 12-month rate of PFS was 90%. These data are preliminary, but promising for a group of patients who were mostly refractory to their last treatment and had received a median of 3 prior lines of therapy.
The combination regimen did not show any unexpected safety signals. The most common side effects were neutropenia and thrombocytopenia, which were expected because lenalidomide and polatuzumab vedotin are each associated with cytopenias. Infections were relatively common. There were some gastrointestinal toxicities, including diarrhea. Infusion-related reactions were seen, as would be expected with obinutuzumab. Grade 3 or 4 adverse events were primarily hematologic; neutropenia was the most common.
Dr Jason Westin presented results of the Smart Start study, which evaluated lead-in treatment with rituximab, lenalidomide, and ibrutinib, following by administration of this triplet in combination with chemotherapy, among patients with newly diagnosed non–germinal center B-cell subtype (non-GCB) diffuse large B-cell lymphoma (DLBCL).16 Patients with non-GCB DLBCL typically have poorer outcomes after standard R-CHOP treatment. The response rate after the lead-in period with the triplet of rituximab, lenalidomide, and ibrutinib was 86%, with a complete response rate of nearly 40%. At the end of treatment with the triplet plus chemotherapy, among 49 evaluable patients, the complete response rate was 96%, which is very high for patients with non-GCB DLBCL. Among the 19 patients with double-expresser DLBCL, PFS was 94% at 1 year.
After 1 year of follow-up, there were 3 progression events. More time will be needed to assess the long-term durability of the excellent responses to this regimen. One patient who had received corticosteroids before starting the triplet lead-in regimen developed central nervous system aspergillosis. A study amendment then prohibited the prephase use of corticosteroids, and no other fungal infections were seen. There were no major toxicity signals, aside from rash, which is known to occur with the combination of lenalidomide and ibrutinib. There was a reasonably high rate of grade 4 neutropenia, which could be expected given that chemotherapy was combined with lenalidomide and ibrutinib, which are both associated with myelosuppression. Febrile neutropenia occurred in nearly one-quarter of patients, a higher rate than might be expected with standard chemotherapy. Therefore, the promising outcomes corresponded to some degree of increased toxicity. However, these results are extremely promising, and they could potentially inform the design of a larger, more definitive study. Results from longer-term follow-up are eagerly awaited.
Allogeneic vs Autologous Transplant
A randomized study presented by Dr Norbert Schmitz compared allogeneic vs autologous transplant as frontline therapy for younger patients with PTCL, a lymphoma subtype associated with a poor prognosis.17 Patients first received 4 cycles of CHOP plus etoposide. They then received 1 cycle of dexamethasone, cytarabine, and cisplatin. Patients who were randomly assigned to autologous transplant underwent harvesting for stem cells. Patients who were randomly assigned to allogeneic transplant proceeded to treatment. An important issue with this study concerns the selection of myeloablative conditioning for the patients undergoing allogeneic stem cell transplant. In recent years, reduced-intensity conditioning has been increasingly utilized in patients with NHL. Rates of event-free survival were similar between the arms in the intention-to-treat population. Among the patients who underwent transplant, there was no statistically significant difference in the rates of event-free survival or overall survival between the treatments. Transplant-related mortality reached 16% in the allogeneic transplant arm vs 0% in the autologous arm. The number of deaths from lymphoma was similar in both groups. There were more cases of relapsed disease in the autologous group vs the allogeneic group, but this difference was mitigated by the higher rates of transplant-related morbidity and mortality in the allogeneic transplant group. For patients with PTCL who respond to initial therapy, the typical treatment has been consolidative autologous stem-cell transplant in patients who achieved a first response. This study confirmed this practice, showing that the morbidity and mortality associated with allogeneic stem-cell transplant are unacceptably high, without a concomitant improvement in outcomes in this setting.
Disclosure
Dr Herrera is a consultant for Bristol-Myers Squibb, Genentech, Merck & Co, Kite Pharma/Gilead, Seattle Genetics, and Adaptive Biotechnologies. Dr Herrera has received research funding/grants from Genentech, Bristol-Myers Squibb, Immune Design, AstraZeneca, Merck & Co, Pharma-cyclics, Seattle Genetics, Kite Pharma, and Gilead Sciences.
References
1. Straus DJ, Długosz-Danecka M, Alekseev S, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma: three-year update of the ECHELON-1 study [ASCO abstract 7532]. J Clin Oncol. 2019;37(suppl 15).
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. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374(25):2419-2429.
4. 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 fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
5. Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240.
6. Advani RH, Horwitz SM, Iyer SP, et al. Response to A+CHP by CD30 expression in the ECHELON-2 trial [ASCO abstract 7538]. J Clin Oncol. 2019;37(suppl 15).
7. Horwitz SM, Advani RH, Bartlett N, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123(20):3095-3100.
8. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: a multicenter, open label, registration directed phase II study [ASCO abstract 7506]. J Clin Oncol. 2019;37(suppl 15).
9. Kwong Y-L, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing L-asparaginase. Blood. 2017;129(17):2437-2442.
10. Tao R, Fan L, Song Y, et al. Sintilimab for relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL): a multicenter, single-arm, phase 2 trial (ORIENT-4) [ASCO abstract 7504]. J Clin Oncol. 2019;37(suppl 15).
11. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129(17):2437-2442.
12. Li X, Cheng Y, Zhang M, et al. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol. 2018;11(1):15.
13. Diefenbach C, Kahl B, Banerjee L, et al. Polatuzumab vedotin (pola) + obinutuzumab (G) and lenalidomide (len) in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL): interim analysis of a phase Ib/II trial [ASCO abstract 7505]. J Clin Oncol. 2019;37(suppl 15).
14. Morschhauser F, Fowler NH, Feugier P, et al; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947.
15. Fowler NH, Neelapu SS, Samaniego F, et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: results of a phase I/II study [ASCO abstract 7531]. J Clin Oncol. 2017;35(suppl 15).
16. Westin J, Nastoupil LJ, Fayad L, et al. Smart Start: final results of rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma [ASCO abstract 7508]. J Clin Oncol. 2019;37(suppl 15).
17. Shmitz N, Nickelsen M, Altmann B, et al. Allogeneic or autologous transplantation as first-line therapy for younger patients with peripheral T-cell lymphoma: results of the interim analysis of the AATT trial [ASCO abstract 7503]. J Clin Oncol. 2015;33(suppl 15).