Extended Follow-up of Dose-Adjusted EPOCH (DA-EPOCH) Plus Inotuzumab Ozogamicin (InO) in Adults with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL): A Safe and Effective Salvage Therapy

Introduction: Although salvage options for adults with R/R B-ALL have improved with the addition of CD19-directed immunotherapies (imtx) and InO (a CD22-directed antibody-drug conjugate), treatment of R/R disease remains limited by efficacy and toxicity. We have shown that DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) plus InO (DA-EPOCH-InO) elicits high response rates with a favorable safety profile in a phase I study in R/R B-ALL (Kopmar et al., JAMA Oncol, 2024). Here, we describe extended follow-up of all patients (pts) treated with DA-EPOCH-InO for R/R B-ALL at our center, including as a standard option off-protocol (SOC).

Methods: Pts treated on the prospective trial were ≥18 years old with R/R CD22+ B-ALL, acceptable organ function, and performance status. Pts treated per SOC were judged appropriate candidates using similar criteria. Pts on study gave written informed consent, while separate institutional approval was granted to review records retrospectively for those treated per SOC. Pts received DA-EPOCH-InO on trial between 10/2019 and 9/2022 (NCT03991884) vs 1/2023 until 5/2024 as SOC. DA-EPOCH was given in the conventional manner on days (D) 1-5. On trial, InO was given at 3 dose levels (DL): 0.3mg/m² on D8+15 (DL1); 0.6 on D8 and 0.3mg/m² D15 (DL2); and 0.6mg/m² on D8+15 (DL3) on a 28-day cycle; those treated as SOC received InO DL3. All pts received ursodiol and anti-infective prophylaxis. Response assessment included bone marrow exam with morphology and multiparameter flow cytometry (MFC): complete remission (CR) was <5% marrow blasts by morphology; in cases of non-CNS extramedullary disease (EMD), responses were graded per NCCN criteria. Statistical analyses included Kaplan-Meier survival estimates for event-free survival (EFS: first occurrence of refractory disease, relapse, or death) or overall survival (OS), as well as descriptive statistics. Treatment-related adverse events (TRAEs) were graded per CTCAE.

Results: From 10/2019 to 5/2024, 33 pts were treated with ≥1 cycle of DA-EPOCH-InO; the first 24 pts were treated on-protocol. One additional pt began DA-EPOCH off-protocol with intent to receive InO but did not receive it due to ensuing complications and thus represented the only unevaluable pt (3% attrition). Among evaluable pts, the median age was 43 years; 24% were Ph+, and 68% of Ph- pts had adverse-risk cytogenetics per NCCN; 48% had prior allogeneic transplantation (HCT), and 18% had prior CAR-T therapy. The overall response rate [ORR; morphologic CR plus radiographic CR or partial response (PR)] was 82% (95% CI: 69%-94%). Of pts with ³5% blood/marrow blasts before treatment (n=26), the morphologic CR rate was 85%, of which 82% were MRD-negative by MFC. Among pts with EMD (n=8, 1 of whom also had ≥5% marrow blasts), the ORR was 75% (5 CRs; 1 PR). With a median follow-up among survivors of 21.7 months (m), the median OS was 17.0 m, and the median EFS was 10.0 m. Among responders, 18 (67%) received consolidative imtx while in remission (i.e., HCT, CAR-T, or blinatumomab), with HCT used in 12 pts (44%). Relapse was seen in 4 of 12 pts (33%) who underwent HCT vs 13 of 21 pts (62%) who did not. The most common grade ≥3 non-hematologic TRAEs were febrile neutropenia (12 pts); infections (11); oral mucositis (4); and syncope (3). Grade 3+ liver test abnormalities occurred in 2 pts (6%); all liver test abnormalities resolved. No additional cases of sinusoidal obstruction syndrome (SOS) were noted in the SOC cohort, yielding an updated rate of SOS of 3% (n=1). No deaths occurred on study; 1 pt died from disseminated Candidiasis on Day 22 of Cycle 1 of DA-EPOCH-InO as SOC for post-HCT relapse in the setting of active chronic GVHD. Ninety-six doses (91%) of InO occurred outpatient, including 21 as SOC (95% of SOC doses) where drug came from commercial supply.

Conclusions: With extended follow-up and additional pts, DA-EPOCH-InO has consistently demonstrated response rates among the highest ever reported in pts with R/R B-ALL. Additionally, this combination has a favorable safety profile (rare significant hepatotoxicity and only 1 case of SOS) and facilitated consolidation with HCT or CD19-directed imtx in most responders. It also allows administration of InO in an outpatient setting, an important practical consideration. Overall, these data support both the current use and further development (e.g., as frontline therapy) of this regimen for pts with B-ALL.