A Phase I Study of a Novel Human Monoclonal Antibody (mAb216) with Chemotherapy for the Treatment of Patients with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia.

BACKGROUND: Despite improvements in front-line therapy for adult ALL, most patients eventually relapse and do not tolerate or respond to reinduction therapy. Novel targeted therapies are needed that have both activity against adult ALL and a toxicity profile distinct from conventional chemotherapy. MAb216 is a naturally occurring human IgM monoclonal antibody derived from the VH4-34 (variable heavy chain) gene. It has shown promise as a novel therapy for B-ALL in preclinical studies. In vitro, mAb216 specifically binds and is cytotoxic to normal human B-lymphocytes and B-progenitor lymphoblasts from patients with ALL. Binding of mAb216 to its linear lactosamine ligand leads to formation of large membrane pores resulting in cell lysis. This non-classical apoptosis occurs in the absence of complement fixation but the cytotoxicity is enhanced by complement. The membrane pores may also facilitate entry of chemotherapeutic drugs into the leukemic blast providing an explanation for the enhanced cell killing that is seen when mAb216 is combined with vincristine.

METHODS: The primary aims of the study are to determine the maximum-tolerated dose, and dose-limiting toxicities of mAb216 as a single agent and in combination with vincristine in patients with relapsed or refractory B-ALL. Secondary aims are to characterize the pharmacokinetic behavior of mAb216 and to preliminarily assess clinical efficacy. Binding of mAb216 to the patient’s leukemic blasts is confirmed prior to enrollment. Two treatment courses of mAb216 are given with the same dose of antibody administered on days 0 and 7. In case of a suboptimal response (< 75% reduction in peripheral blood blasts) after the first dose of mAb216, the second dose is given in combination with vincristine. Five mAb216 dose levels are planned using a starting dose of 1.25 mg/kg and a standard 3+3 dose-escalation design. Clinical response is assessed by measuring the peripheral blood blast count weekly and by bone marrow biopsy if no blasts are present in the peripheral blood.

RESULTS: Nine of 10 patients screened exhibited binding of mAb216 to their blasts and were enrolled in the study (median age 27; range 10–73). Four patients had relapsed after allogeneic bone marrow transplantation, four patients had relapsed after a median of four (range 2–5) prior therapies, and one patient had primary refractory disease. In these patients, doses up to 2.5 mg/kg of mAb216 have been well tolerated. At a dose of 1.25 mg/kg one patient experienced vomiting and grade 3 epistaxis three days after the infusion. At 2.5 mg/kg one patient developed hives during the infusion that resolved with diphenhydramine and hydrocortisone. MAb216 has not induced immune complex formation. The median half-life is 1.76 h (range 0.78–9.3 h) and strongly correlates with the binding affinity of mAb216 to the blasts. 7/9 patients experienced a reduction of their peripheral blast count between 8–61% after infusion of mAb216 alone. 7/9 patients received the second dose of mAb216 in combination with vincristine on day 7 or earlier. All seven patients, who had failed previous treatment with regimens containing vincristine, achieved a reduction of their peripheral blast count of 50–100%. One patient had a hypocellular bone marrow with no residual blasts on day 21.

CONCLUSIONS: These results indicate that mAb216 alone and in combination with vincristine is a promising treatment for relapsed/refractory B-ALL. Patient recruitment and dose-escalation is ongoing.