Initial results from a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) ± rituximab (R) + tafasitamab (tafa) for adults with newly-diagnosed (ND) Philadelphia chromosome negative (Ph-) B lymphoblastic leukemia (B-ALL).

Abstract

6540 Background: For adults with ND Ph- B-ALL, treatment consists of intense multiagent chemotherapy, with outcomes linked to early measurable residual disease negativity (MRD-). The addition of blinatumomab to frontline chemotherapy improves survival, but regimens used are limited by toxicity and complexity. DA-EPOCH ± R is well-tolerated, effective (32% MRD- after cycle [C]1), and relatively simple to administer for ND B-ALL. Tafa is a CD19 monoclonal antibody with activity in B-cell lymphomas. We hypothesized that adding tafa to DA-EPOCH ± R in adults with ND Ph- B-ALL would improve rates of early MRD- without an increase in toxicity. Methods: This is a phase II investigator-initiated trial of DA-EPOCH ± R + tafa in adults with ND CD19+ Ph- B-ALL who are not candidates for pediatric-inspired therapy: age >40, unable to receive all care in specialized center, etc. (NCT05453500). The primary endpoint is MRD- (<0.01%) by multiparameter flow cytometry (MFC) after C1; secondary endpoints include rates of MRD- by C4, incidence of grade 3+ non-hematologic adverse events (AEs) by CTCAE v5, and event-free (EFS) and overall survival (OS). Exploratory endpoints include high-throughput sequencing (HTS)-based MRD detection in marrow and cerebrospinal fluid (CSF) by clonoSEQ. DA-EPOCH (+ R if CD20+) with intrathecal chemo given on days (D) 1-5 every 21 D for up to C8 (Cassaday, et al. Leuk Lymphoma , 2023). Tafa is given at 12 mg/kg IV on D 1, 8, and 15 in each C. Risk and response are assigned per NCCN. We used a Simon 2-stage design based on results with DA-EPOCH alone: if ≥5/15 pts (33%) achieved MRD- after C1, we would enroll up to 30 pts. Results: From 3/2023 to 1/2025, 17 pts have enrolled: 15 are evaluable (2 on treatment without sufficient time to categorize response), with 1 pt removed during C1 for AE (grade 4 AST elevation). Median age was 67 (range: 44-84), and 67% (12/16) had poor-risk cytogenetics. Six pts (38%) received R. In those with sufficient follow-up (f/u), complete response rate was 80% (12/15); MRD- by MFC after C1 was 40% (6/15) and 71% (10/14) by C4. In pts MRD- by MFC, 56% (5/9) were MRD- by HTS. Initial CSF evaluation demonstrated disease by MFC in 3 pts; HTS on CSF was positive in those pts, plus 3 more (6 total). There were 2 grade 4 AEs (reported as serious AEs): sepsis and intracranial hemorrhage. Grade 3 AEs seen in > 1 pt were fibrinogen decreased (5), infections (5), febrile neutropenia (4), hypotension (3), and syncope (2). With the longest f/u at 21 mo (range 0.6-21), 0 pts have relapsed. Four pts have died: 3 from non-relapse mortality unrelated to study treatment (2 following allogeneic transplantation) and 1 from refractory ALL. Conclusions: In a cohort of ND Ph- B-ALL, the addition of tafa to DA-EPOCH ± R led to rates of MRD- that are higher than historical rates, with similar toxicity. Since the target C1 MRD- rate was reached in part 1 of the 2-stage design, the trial is proceeding to part 2 and accrual will be completed. While f/u is short, no relapses have been seen. HTS is feasible on CSF and extends the level of detection beyond MFC. Clinical trial information: NCT05453500 .