Southwest Oncology Group Study S0910: A Phase 2 Trial of Clofarabine/ Cytarabine/ Epratuzumab for Relapsed/ Refractory Acute Lymphocytic Leukemia.

Pts were treated at SWOG institutions from August 2010 through July 2012. Clo was supplied by Genzyme, E was supplied by Immunomedics, and an IND was approved by the FDA. The protocol was reviewed and approved by each institution's review board. Eligibility criteria included: age ≥ 16 years, ≥ 20% marrow and or peripheral blood lymphoblasts expressing CD22, R/R precursor B-ALL (excluding Burkitt, mixed lineage leukemia, or Ph+ ALL). Flow cytometry was used to assess marrow involvement with disease at diagnosis and post-treatment (MRD) on Days 33–40 in pts who consented. MRD was performed using 6-color flow cytometry and the following antibody combinations: CD20 FITC/ CD10 PE/ CD38 PerCP-Cy5.5/ CD19 PE-Cy7/ CD58 APC/ CD45 APC-H7 and CD9 FITC / CD13+ CD33 PE / CD34 PerCP-Cy5.5/ CD19 PE-Cy7/ CD10 APC / CD45 APC-H7. In cases in which these antibody combinations were not informative, additional markers were employed. All pts received one cycle of treatment with Clo (40 mg/m²/d, Days 2–6), Cy (1 g/m²/d, Days 1–5), and E (360 mg/m²/d Days 7, 14, 21, and 28). Triplicate EKGs were performed pre-treatment, prior to E on Day 14, and after E on Day 28. CR was defined as < 5% marrow blasts, neutrophils ≥ 1000/ μL, platelets ≥ 100,000/ μL and no evidence of extramedullary disease. CRi was defined the same as CR but without recovery of neutrophil and/ or platelet counts. Pts were accrued in two stages. If at least 2 CR/ CRis were observed in the first 20 pts, an additional 15 pts were to be accrued (87% power to conclude that an agent with a response rate of 30% warrants further study).

The study proceeded to the second stage and closed to accrual on July 1, 2012 after meeting the protocol-defined criterion for a positive study. Thirty-five pts were enrolled. Three pts were ineligible and were excluded from the analysis. Of the 32 evaluable pts, the median age was 41 years (range 20–69), 24 pts (75%) were male, and the median WBC at registration was 5300/ μL (range 200-108,700). The median time from initial diagnosis to registration was 16 months (range 0–211 months). Nineteen pts (59%) were in first relapse, 8 (25%) in second relapse, 1 (3%) not yet reported, and 4 (13%) refractory. Four pts had received prior allogeneic hematopoietic stem cell transplant. Eighteen pts have died with 3 deaths occurring during treatment and attributed to sepsis (1) and cardiac arrest (2). Of the 29 pts evaluated for toxicity, 5 additional pts had Grade 4 non-hematologic toxicities including hypercalcemia, elevated transaminases, febrile neutropenia, acute kidney injury, hepatic failure, pneumonia, hypoxia, and respiratory failure. No allergic reactions to E were reported. No significant changes in the mean QTc interval occurred. The response rate was 45% (95% CI 26–64%), including 8 CRs and 5 CRis (among 29 eligible pts evaluated). The null response rate in this protocol was 10%, and the p-value comparing 45% to 10% is 0.000001. Of the 29 eligible pts with follow-up information, the median overall survival is 4 months. Only 5 pts who achieved CR/ CRi had MRD assessments. Of these, only 1 achieved a significant MRD response (< 0.01%), and this pt is still alive at 4.2 months.

The CR/ CRi rate in this study was encouraging, given the poor risk population and warrants further testing. Given previous results with Clo/ Cy in a similar population, these data suggest that the addition of E may be beneficial to combination chemotherapy in adult pts with R/R precursor B-ALL.

Advani:Genzyme: Honoraria, Research Funding; Immunomedics: Research Funding. Wood:Genzyme: Research Funding.