ABSTRACT
Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult Tcell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOPequivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled;all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation;19 pts discontinued early-12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 1 .1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%;18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/-ASCT) followed by BV consolidation was tolerable and effective.
ABSTRACT
Background: Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder. After the STiL-1 trial (Rummel MJ. Lancet. 2013;381(9873):1203-1210) demonstrated significant benefit in a subgroup analysis as well as reduced toxicity using bendamustine and rituximab (BR) compared to R-CHOP (N=41 enrolled WM patients), BR became the preferred immunochemotherapy (IC) regimen for all patients with symptomatic treatment naïve (TN) WM in British Columbia (BC) since 2014. Prior to the introduction of BR, the combination of rituximab, cyclophosphamide, vincristine, and prednisone (RCVP), was the standard of care in BC for this population since 2004, given its widespread use across a broad range of indolent B-cell lymphomas. We report a population-based analysis evaluating outcomes in TN-WM patients comparing BR with RCVP. Methods: The BC Cancer Centre for Lymphoid Cancer Database was used to identify TN-WM patients treated with BR or RCVP as their first systemic therapy between August 1, 2004 - August 1, 2020. A period of observation but no prior to systemic therapy was permitted. All patients had clinicopathologically confirmed lymphoplasmacytic lymphoma and measurable monoclonal IgM. Event-free survival (EFS) was defined as time from start of IC to progression, relapse, initiation of alternative therapy, histologic transformation, or death due to any cause. Early progression (POD24) was defined as relapse or progression, death from lymphoma, or treatment toxicity within 24 months of initiation of systemic therapy. Outcomes were compared with a historical cohort of patients treated with frontline RCVP. Responding patients were eligible to receive maintenance rituximab (MR) every 3 months for 2 years since 2006;however this was discontinued in 2020 when a subgroup analysis of the MAINTAIN trial (Rummel MJ. Blood 2019;134 (Supplement_1): 343), showed a lack of PFS benefit after BR, coupled with safety and vaccine response concerns during the COVID-19 pandemic. Results: A total of 111 patients with WM were identified;57 treated with BR, 54 treated with RCVP. Median age was 69 years (range 33-89) and baseline characteristics (Table 1), were well-balanced. A higher proportion of RCVP-treated patients received >4 cycles of chemotherapy (81% vs 65%, p=0.049). After IC, 75 (68%) received MR, with 36 (63%) and 39 (72%) in the BR and RCVP groups respectively (p=0.3). Median follow-up from diagnosis for all living patients was 5.9 years (range 0.8-19.2), with median 4.4y vs 9.8y for BR and RCVP respectively. EFS estimates at 4-years achieved with BR were 57% (95% CI 40-71%) compared to RCVP 60% (95% CI 45-72%), p=0.5 (Figure 1). Median EFS was established for RCVP due to longer duration of follow up at 6.3 years (95% CI 3.6-11.8y). Overall survival (OS) estimates at 4-years were 74% (95% CI 57-85%) and 81% (95% CI 67-89%) for BR and RCVP patients respectively, p=0.6. Worse performance status (≥2) was the only pre-treatment factor identified as significant for inferior EFS. A sub-analysis limited to patients that received >4 cycles of IC also showed no clear difference in outcomes between BR and RCVP. Median time to transformation was 6.5y (5.5-13y), with only 3 late biopsy-proven events. Early progression (POD24) has occurred in 19 (18%) patients, with inferior survival observed in patients that had an early event compared with a reference cohort (2-years event free), however this did not reach statistical significance (p=0.3) (Figure 1). Conclusion: This population-based analysis of TN-WM patients treated with upfront IC confirms the excellent outcomes that can be achieved with a finite course of therapy. In contrast to prior studies, similar outcomes were observed with RCVP and BR. Further, regardless of front-line therapy, POD24 may be associated with inferior outcome but larger studies are needed. To our knowledge, this study is the first to make a direct comparison between BR and RCVP, and one of the largest restricted to IC-treated TN-WM. This data supports RCVP as a viable option, and should ser e to inform clinicians, patients, and policy makers in decision-making when considering upfront therapeutic options, and when considering indefinite alternative regimens such as BTK inhibitors. [Formula presented] Disclosures: Gerrie: AbbVie: Honoraria, Research Funding;Janssen: Honoraria, Research Funding;Astrazeneca: Honoraria, Research Funding;Sandoz: Honoraria;Roche: Research Funding. Savage: Servier: Consultancy, Honoraria;Astra-Zeneca: Consultancy, Honoraria;BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding;Seattle Genetics: Consultancy, Honoraria;Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding;Takeda: Other: Institutional clinical trial funding;AbbVie: Consultancy, Honoraria;Roche: Research Funding;Beigene: Other: Institutional clinical trial funding;Genentech: Research Funding. Villa: Roche: Honoraria;Janssen: Honoraria;Lundbeck: Honoraria;Celgene: Honoraria;Seattle Genetics: Honoraria;AbbVie: Honoraria;AstraZeneca: Honoraria;Gilead: Honoraria;NanoString Technologies: Honoraria. Scott: BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling–licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling.;Abbvie: Consultancy;Janssen: Consultancy, Research Funding;AstraZeneca: Consultancy;Rich/Genentech: Research Funding;Celgene: Consultancy;Incyte: Consultancy;NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling. Craig: Bayer: Consultancy. Slack: Seagen: Consultancy, Honoraria. Sehn: Debiopharm: Consultancy;Novartis: Consultancy;Genmab: Consultancy. Freeman: Amgen: Honoraria;Celgene: Honoraria;Sanofi: Honoraria, Speakers Bureau;Incyte: Honoraria;Abbvie: Honoraria;Teva: Research Funding;Roche: Research Funding;Bristol Myers Squibb: Honoraria, Speakers Bureau;Janssen: Honoraria, Speakers Bureau;Seattle Genetics: Honoraria.