Final Results of a Multicenter Pilot Study Evaluating Brentuximab Vedotin with Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (BV-CHEP) for the Treatment of Aggressive Adult T-Cell Leukemia/Lymphoma

Introduction: Aggressive adult T-cell leukemia/lymphoma (ATLL) is a type of non-Hodgkin lymphoma that is often fatal. ATLL is exceedingly rare in the United States (US), with most cases occurring in emigrants from human T-lymphotropic virus type 1 (HTLV-1) endemic regions. Studies focusing on ATLL in the US are sparse, and have shown poor response rates; because of this, there is no standard of care treatment approach.

Brentuximab vedotin (BV) is a CD30 targeting antibody-drug conjugate that is effective in treating many types of lymphoma, including CD30+ peripheral T-cell lymphomas. Studies have shown efficacy even in lymphomas with very low CD30 expression. We developed a prospective, multicenter pilot study evaluating BV in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for the treatment of ATLL. We report the final safety and efficacy analysis below.

Methods: Adult patients (pts) from 5 centers were enrolled from October 2017 through June 2022. Newly diagnosed ATLL pts were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Pts did not have to express CD30 to be enrolled; pts were considered CD30+ if there was >1% expression. Frontline consolidation with allogeneic stem cell transplant (alloSCT) was permitted at any time after 2 cycles of BV-CHEP. Transplant-ineligible pts completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance. Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Pts were treated with standard dosing every 21 days: BV 1.8 mg/kg on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 days 1-3, and prednisone 100mg days 1-5. All pts received GCSF support. The primary endpoint was CR by PET-CT (and peripheral blood for leukemic types) after at least 2 cycles of therapy per adapted Lugano and ATLL criteria. Secondary endpoints were safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS).

Results: 16 pts were enrolled and evaluable for the safety and efficacy analysis. All pts were HTLV-1 positive. Seven of 16 were the acute type, 8 were lymphomatous, and 1 was chronic unfavorable. Seven of 16 (43.75%) expressed CD30. The median age was 56 (range 34 to 69) and 12 of 16 (75%) were female. 14 of 16 pts identified as Black, 1 identified as Asian, and 1 was other. Countries of origin included: Antigua and Barbuda N=1, Colombia N=1, Haiti N=7, Jamaica N=2, Japan N=1, Liberia N=1, and the US N=3. All pts were advanced stage (12 of 16 stage IV; 4 stage III). Four had positive cerebrospinal fluid at baseline, which cleared with intrathecal (IT) treatments, and 10 were given IT prophylaxis. Nine pts had an ATL-PI score >3 (56.25%) with a median score of 3 (range 2-4). No subjects received prior antiretroviral therapy.

12 of 16 pts completed at least 4 cycles of treatment (median 4.5 cycles; range 2 to 6). Ten of 16 pts achieved a CR (62.5%) and 4 pts achieved a PR (ORR of 87.5%) after >2 cycles of BV-CHEP. The median duration of follow-up was 47.2 mo. The median PFS (mPFS) was 7.11 mo (3.93 to NR) and the median OS (mOS) was 12.2 mo (9.29 to NR) (Fig.1). Of pts who achieved a CR, the mPFS was 11.07 mo and the mOS was 15.7 mo. There was no significant difference in PFS or OS by CD30 status or by ATLL subtype. One pt received 3 cycles of maintenance BV. 5 pts received alloSCT consolidation and there was an OS benefit for this group ( p=0.007; Fig.2).

Grade 3 or higher toxicities included neutropenia (N=13), anemia (N=11), thrombocytopenia (N=9), febrile neutropenia (N=7), mucositis (N=6), colitis (N=3), infections (N=3; COVID19, thrush, clostridium difficile), hyponatremia (N=3), and vomiting (N=2). Nine of 16 patients had peripheral neuropathy (all grade 1/2). There were 11 pt deaths, 9 of which were disease-related and 2 were due to shock (hypovolemic and septic) off-treatment. No patients had to come off study due to toxicity and there were no treatment-related deaths.

Conclusions: In this final analysis, BV-CHEP was safe and effective for the treatment of aggressive ATLL. High ORR and CR rates were achieved regardless of CD30 status, and compare favorably to prior clinical trials. AlloSCT had an OS benefit with 4 of 5 pts achieving long-term remission. Toxicity was manageable and cytopenias were expected. Peripheral neuropathy was common, but low-grade.