A phase I trial of dose-adjusted EPOCH plus inotuzumab ozogamicin (InO) in adults with relapsed/refractory (R/R) B lymphoblastic leukemia/lymphoma (B-ALL).
Authors: Kopmar Noam Edward , Quach Kim , Gooley Ted , Martino Christen , Cherian Sindhu , Percival Mary-Elizabeth M. , Halpern Anna B. , Ghiuzeli Cristina Maria , Oehler Vivian G. , Abkowitz Janis , Walter Roland B. , Estey Elihu , Cassaday Ryan Daniel 
Published: June 2023

7007 Background: Outcomes for adults with R/R B-ALL remain poor, with existing options limited by efficacy and safety. InO has been combined with low-intensity chemotherapy, the benefit of which is unclear. DA-EPOCH is safe and active as frontline therapy in adults with ALL, so we combined this with InO in adults with R/R B-ALL (NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible patients (pts) were adults with R/R CD22+ B-ALL with ≥5% blood or marrow (BM) blasts or ≥1 site of measurable extramedullary disease (EMD); other eligibility criteria included ECOG ≤2 and no history of sinusoidal obstructive syndrome (SOS) or chronic liver disease. DA-EPOCH was given on days (d) 1-5 with GCSF. After cycle 1, dose adjustments to EPOCH were made based on hematologic nadirs from the prior cycle. Three dose levels (DL) of InO were studied, with InO given on d 8 + 15 as follows (respectively): 0.3 + 0.3 mg/m2 (DL1); 0.6 + 0.3 mg/m2 (DL2); and 0.6 + 0.6 mg/m2 (DL3). Up to 4 28-d cycles were given. The MTD was the highest DL of InO that yielded ≤33% rate of dose limiting toxicity (DLT), defined as grade 4+ non-heme treatment-related adverse events (TRAEs), any SOS regardless of timing, unable to complete 1 cycle due to TRAE, and treatment delays > 3 weeks. After the first 5 pts received DL1, a Bayesian Optimal Interval Design was used. Target accrual was 24 pts. BM and EMD response was assessed by NCCN criteria, with measurable residual disease (MRD) evaluated by multiparameter flow cytometry (MFC) and clonoSEQ. Results: 24 pts were screened: all were enrolled and evaluable for DLT and response. Median age was 46 (range: 28-76) years; median prior lines of therapy was 3 (range: 1-16); 13 pts (54%) had previously received allograft (HCT). 5 pts were enrolled at DL1, 8 pts at DL2, and 11 pts at DL3. There were 4 total DLTs: 1 at DL1 (grade 4 sepsis) and 3 at DL3 (grade 4 hyponatremia; delay for pancytopenia; grade 5 SOS after post-study HCT). DL3 was thus determined to be the MTD. No deaths occurred on study. Three pts (12%) had Grade 3 AST/ALT elevation; the SOS rate was 4%. Other grade 3+ non-heme TRAEs seen in >1 pt included infections (6 pts; 9 events), neutropenic fever (7; 8), and oral mucositis (3; 4). In the pts with ≥5% blood/BM blasts (n=20), the CR/CRi rate was 85%. By MFC, 70% achieved MRD- (45% after 1 cycle); using clonoSEQ, 33% were MRD-. Of the 6 pts with EMD, 83% responded (4 CR; 1 PR). The per-protocol and intent-to-treat (ITT) overall response rate was 83%. With median follow-up of 12 months (m), the median overall and relapse-free survival were 19 m and 12 m. Nine (38%) pts received post-study HCT. Conclusions: The addition of InO to DA-EPOCH in adults with heavily-pretreated R/R B-ALL is safe, with ITT response rates among the highest reported to date. Many pts proceeded to HCT. Further investigation of this combination is warranted. Clinical trial information: NCT03991884 .