CXCR4 Inhibition with BL-8040 in Combination with Nelarabine in Patients with Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia / Lymphoblastic Lymphoma

Background: The chemokine receptor, CXCR4, mediates the trafficking and retention of hematopoietic stem cells to the marrow through its interaction with the chemokine, CXCL12. CXCR4 is the most highly expressed chemokine receptor on T-ALL cells, and preclinical data demonstrate that CXCR4 is critical for the growth and survival of T-cell acute lymphoblastic lymphoma (T-ALL). Genetic loss or pharmacologic blockade of CXCR4 signaling suppresses T-ALL cell growth and leukemia initiating activity in murine models. BL-8040 is a novel synthetic peptide antagonist of the chemokine receptor, CXCR4. Compared to other CXCR4 inhibitors, BL-8040 is a more potent mobilizer of normal HSCs with sustained occupancy and inhibition of CXCR4. We previously reported that BL-8040 potently suppresses T-ALL cell growth in xenotransplantation models of T-ALL. To test the efficacy of BL-8040 in T-ALL by conducting a multicenter, open label pilot study of BL-8040 in combination with nelarabine in patients with relapsed or refractory disease (ClinicalTrials.gov: NCT0276338).

Methods: Adults with relapsed or refractory T-ALL/LBL, age ≥18 years and ECOG PS ≤2, were eligible for the study. A peripheral blood lymphoblast count ≤50,000/mm³ was required prior to starting treatment. During cycle 1, subjects received daily subcutaneous administration of BL-8040 1.5 mg/kg from Day 1 to Day 6 with nelarabine 1,500 mg/m2 intravenously over 2 hours on Days 2, 4 and 6. In subsequent 21-day cycles, BL-8040 1.5 mg/kg was administered daily on days 1-5 with nelarabine 1,500 mg/m² given on days 1, 3 and 5. Up to 4 cycles of treatment was allowed.

Results: Nine patients with median age of 29 years (range 20-75) have been enrolled in the study out of which including fout patients were in untreated 1^st relapse, one in 2^nd relapse, two with relapsed and refractory disease, and two primary refractory patient. Two patients had failed prior allogeneic hematopoietic cell transplant. The rate of complete remission is 56% (5/9) with all responses occurring after 1 cycle of treatment. Adverse events occurred in 2 subjects requiring dose modification. Consistent with the known mechanism of BL-8040, one subject developed G3 leukocytosis after BL-8040 administration with the peripheral WBC increasing from 5.3 to 273 h/mm³ with evidence of spontaneous tumor lysis requiring interruption of BL-8040 and leukapheresis. A second patient developed injection site pain requiring omission of the final dose of BL-8040. Peripheral blood analyzed at baseline and 24 hours after the first dose of BL-8040 (prior to nelarabine) showed the following: 1) sustained blockade of CXCR4 on leukemic blasts; 2) mobilization of leukemic blasts into the blood; and 3) no induction of leukemia blast apoptosis as measured by activated caspase 3 expression.

Conclusions: BL-8040 can be combined with nelarabine in subjects with relapsed or refractory T-ALL with encouraging CR rates. Evidence of on target effects on CXCR4 has been observed in this study with sustained CXCR4 receptor occupancy at 24 hours after administration along with tumor mobilization of ALL blasts into the peripheral circulation.