Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

in JAMA oncology by Noam E Kopmar, Kim Quach, Ted A Gooley, Christen H Martino, Sindhu Cherian, Mary-Elizabeth M Percival, Anna B Halpern, Cristina M Ghiuzeli, Vivian G Oehler, Janis L Abkowitz, Roland B Walter, Ryan D Cassaday

TLDR

  • This study looked at a new way to treat a type of blood cancer called B-ALL. The study found that adding a drug called InO to a treatment called DA-EPOCH was safe and effective for adults with relapsed or refractory B-ALL. The study also found that many patients were able to proceed to poststudy treatments, such as allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. The study's findings suggest that this combination may be a viable option for patients who have failed prior treatments, and future studies should investigate its long-term efficacy and safety.

Abstract

Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. ClinicalTrials.gov Identifier: NCT03991884.

Overview

  • The study aimed to assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. The study was a single-center, single-arm, nonrandomized, phase 1 dose-escalation trial that included 24 participants with a median age of 46 years and a median number of lines of prior therapy of 3. DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%.

Comparative Analysis & Findings

  • The study found that adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. The morphologic complete response rate was 84%, and the overall response rate was 83%. Median overall survival, duration of response, and event-free survival were 17.0 months, 15.0 months, and 9.6 months, respectively. The study also found that many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy.

Implications and Future Directions

  • The study's findings suggest that adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL is a promising approach that warrants further investigation. The study's high response rates and low incidence of sinusoidal obstructive syndrome suggest that this combination may be a viable option for patients who have failed prior treatments. Future studies should investigate the long-term efficacy and safety of this combination, as well as its potential to improve outcomes in patients with more advanced disease. Additionally, future studies should explore the use of InO in combination with other therapies, such as chimeric antigen receptor T-cell therapy, to further improve outcomes for patients with relapsed or refractory B-ALL.
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