A Phase I Study of the Combination of Azacitidine, Cyclophosphamide, Vincristine, and Rituximab in Relapsed and Refractory Lymphoma

Abstract 1624

Tumor suppressor gene silencing via mechanisms including DNA hypermethylation is a recognized event in lymphomagenesis and lymphoma recurrence and transformation. DNA methyltransferase inhibitor, azacitidine, reduces epigenetic methylation in lymphoma and numerous other tumor models. Given the poor outcome of patients with transformed or refractory lymphoma, there is an immediate need to find novel therapies.

We report the first results of an ongoing Phase I trial evaluating the maximal tolerated dose (MTD) of azacitidine given in a schedule intended to sensitize lymphoma to a regimen of oral cyclophosphamide, intravenous vincristine, and rituximab (for those patients whose lymphoma expresses CD20) for patients with recurrent or refractory lymphoma. Participants receive azacitidine (days 1–5, starting with 25 mg/m²) followed by oral cyclophosphamide (days 6–9, 300 mg/m²), vincristine (day 8, 1.4 mg/m², maximum of 2 mg), and rituximab (day 8, 375 mg/m²). All patients receive pegfilgrastim (day 10, 6 mg) with each cycle. Cycles are repeated every 21 days for up to eight cycles if participants continue to benefit from therapy.

To determine the MTD, a “3+3” design was employed. Dose limiting toxicity (DLT) is assessed during cycle 1. DLT is defined as the following: grade 3 or 4 non-hematologic toxicity (excluding emesis or isolated elevation of alkaline phosphatase); grade 4 neutropenia or thrombocytopenia of ≥7 days duration; increased serum creatinine > 2.0 times upper limit of normal; inability to receive all doses of azacitidine or cyclophosphamide within the first cycle or inability to initiate cycle 2 within two weeks of completing cycle 1 due to drug-related toxicity.

Of the first 10 patients enrolled (8 patients in 25 mg/m2 azacitidine cohort, and 2 patients in 50 mg/m2 cohort), median age was 56 years (range 39–73). Median number of prior lines of therapy was 3 (range 2–4). Lymphoma subtypes included diffuse large B cell lymphoma (DLBCL; n=4), follicular lymphoma (FL; n=3), Hodgkins lymphoma (HL; n=1), small lymphocytic lymphoma (SLL; n=1), and cutaneous T-cell lymphoma (CTCL; n=1).

A median of 2 cycles (range 1–6) have been received. The MTD has not yet been reached. One patient experienced thrombocytopenia as a DLT. The DLT criteria were subsequently revised to allow grade 4 thrombocytopenia of < 7 days after initially noting that some patients experienced asymptomatic grade 4 thrombocytopenia lasting only a short duration. An additional three patients were accrued to the first dose level after this adjustment to the current DLT, with no additional patients experiencing a DLT. Grade 3–4 toxicities during any cycle of therapy were as follows: neutropenia (n=5); thrombocytopenia (n=4); anemia (n=2); and abscess, anorexia, bacteremia, hypoalbuminemia, and nausea (n=1 each). Additionally, grade 3 cardiac ischemia and deep venous thrombosis each occurred in one patient but were considered unrelated to treatment by the investigator. Of the 8 patients who have completed treatment, 1 patient with FL achieved a complete response (CR), 1 patient with FL achieved a partial response (PR), 2 had stable disease (SD), 2 experienced progressive disease (PD), and 2 were not evaluable (NE) for response. Interestingly, the CR was maintained for 7 months and the PR has been ongoing for 6 months since completion of therapy. These preliminary data suggest the therapeutic potential of this novel combination and enrollment remains ongoing to define the MTD. Additional correlative assessments of tumor and peripheral blood mononuclear cells are also underway.