Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) yields durable remissions and survival in adults with newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL): Long-term follow-up of a prospective trial

Abstract

Abstract BACKGROUND Treatment for adult ALL historically introduces toxicity and complexity that can be prohibitive for some patients (pts). Recently, antigen-targeted agents and tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome (Ph)+ disease have demonstrated sufficient activity to reduce or omit cytotoxic chemotherapy. These regimens yield 3-5-year (yr) overall survival (OS) rates of ~50-80%. However, they may be limited to well-resourced centers due to complexity and cost of administration. DA-EPOCH is familiar to most oncologists and administratively simpler. In a single-arm Phase II trial we conducted, DA-EPOCH ± rituximab (R) ± TKI yielded comparable morphologic (morph) and measurable residual disease (MRD)- remissions with less toxicity than seen in a comparable cohort of patients receiving hyperCVAD. This study completed accrual in 2021, before routine upfront incorporation of immunotherapy and ponatinib (if Ph+). Here, we describe long-term outcomes and explore factors that may predict outcomes to this approach. METHODS Details of this study have been reported (Cassaday, et al. Leuk Lymphoma, 2023; NCT03023046). Adults with newly-diagnosed ALL were eligible if not candidates for pediatric-inspired therapy (e.g., Ph+, age ≥40). Imatinib or dasatinib was added if Ph+, and R if CD20+. Response was determined by bone marrow aspirate morph, multiparameter flow cytometry (MFC), high-throughput sequencing (HTS; clonoSEQ) and (for Ph+) BCR::ABL1 RT-PCR. Up to 8 cycles could be given followed by maintenance (POMP±TKI) or allogeneic transplant (HCT). The primary endpoint was rate of MRD- by MFC within 4 cycles. The current analysis focused on OS, relapse-free survival (RFS), and event-free survival (EFS) from treatment start using the Kaplan-Meier method. Events were defined as inability to achieve MRD- by MFC, disease recurrence, or death. RFS was only assessed among pts who achieved remission by morph. RESULTS 53 pts were evaluable, all of whom had ≥1 high-risk feature (ie, age ≥35, high WBC, or cytogenetics per NCCN). Median age was 55 (range: 19-79). 28 pts (53%) are still alive at a median follow-up of 69 months (mo; range: 50-98 mo). Only 2 pts died in remission within 1 yr of treatment start. Of 20 relapses, 8 (15%) involved the CNS, 3 of which were limited to CNS. There was no association between risk of CNS relapse and baseline cerebrospinal fluid testing by morph or MFC. 11 pts underwent HCT directly after DA-EPOCH, and 6 (55%) relapsed, range of 2-43 mo post-HCT. Among Ph+ pts (n=28), median OS was not reached (NR), median RFS was NR, and median EFS was 15 mo; 5-yr estimates (95% confidence interval [CI]) were 68% (53-88%), 56% (40-78%), and 36% (22-59%) for OS, RFS, and EFS, respectively. For the Ph- cohort (n=25), median OS was 52 mo, median RFS was NR, and median EFS was 15 mo; 5-yr estimates were 44% (28-68%), 56% (37-84%), and 24% (12-48%), for OS, RFS, and EFS, respectively. Among pts age ≥55, survival reflected that of the overall population: for Ph+ (n = 15), median OS was NR, median RFS was 24 mo, and median EFS was 19 mo; 5-yr estimates were 53% (33-86%), 50% (30-84%), and 33% (16-68%), for OS, RFS, and EFS, respectively. For age ≥55 Ph- (n = 12), median OS was 58 mo, median RFS was NR, and median EFS was 13 mo; 5-yr estimates were 50% (28-88%), 67% (42-100%), and 25% (9-67%), for OS, RFS, and EFS, respectively. In univariate Cox models, neither age (continuous or categorical with age 55 as a cutpoint), WBC, cytogenetic risk, LDH, nor use of R had statistically significant associations with OS, RFS, or EFS. When comparing outcomes by MRD status after 4 cycles across assay types, the only significant association was between MRD- status by HTS and EFS (hazard ratio [HR] 0.30, 95% CI 0.13-0.70, p = 0.005); however, 17 of 31 (55%) not MRD- by HTS also did not reach MRD- by MFC, which itself defined an event. Pts received a median of 4 cycles of DA-EPOCH (interquartile range: 3-6). 8 pts (15%) switched to blinatumomab when MRD+ after DA-EPOCH, with none receiving it when MRD-. CONCLUSIONS DA-EPOCH±R±TKI yields durable remissions, with survival comparable to immunotherapy-based strategies for ALL. Unlike many other approaches, outcomes for older pts were similar to the general study population. These results support DA-EPOCH±R±TKI as a curative-intent option, particularly in resource-limited settings. They also validate DA-EPOCH as an effective backbone to which new agents for ALL may be added.