Phase I Study of Bendamustine in Refractory Leukemia.

Alkylating agents are active in leukemia. Examples are cyclophosphamide, chlorambucil, melphalan, busulfan, and others. Bendamustine, a rationally designed drug that incorporates alkylating agent properties plus an adenosine-like ring structure, may be active in leukemia. Fractionated doses of alkylators may improve efficacy (e.g. fractioned cyclophosphamide in ALL).

We initiated a phase I-II study of bendamustine in patients with refractory leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndromes. Starting dose was 50mg/m2 IV BID over 1-2 hours for 4 days every 4 weeks (3 pts.) with escalation to 75mg (3 pts.), and 100mg (6 pts). Three additional patients were treated at 50mg/m2 once that dose was declared safe as allowed by study design. Diagnoses were AML 12, ALL 2, MDS 1. Median age was 48 (range 22 to 88). All patients were refractory or had relapsed after multiple courses of chemotherapy. The median number of prior therapies was 3 (range 1 to 9). Five patients had chromosome 5, 7, or 8 abnormalities, 6 patients had miscellaneous abnormalities, 4 patients were diploid.

Toxicity – Grade 1-2 expected toxicities of nausea, vomiting, diarrhea, and transient transaminase elevations were seen at all dose levels. At the 75 mg/m2 dose level grade 3 transaminase elevation was seen in 1 pt. which occurred with rash and diarrhea, was thought to be related to GVHD and all subsided with dose increase of tacrolimus. One patient who began therapy with a creatinine of 1.8 had creatinine increase to 3.3 mg/DL. At the 100mg/m2 dose level 2/3 patients developed creatinine increase to 3.2 and 2.6 mg/DL. The creatinine increase occurred on day 7 and subsided by day 11 in both pts. An additional 3 pts. were treated at this dose level with no increase in creatinine to >2 mg/DL.

Response – Antileukemic activity was encouraging: 8/15 patients with peripheral blasts had >90% reduction of the leukemic cells; 2 patients had >50% reduction of marrow blasts % (90 to 10, 86 to 40).

Bendamustine has shown activity in this heavily pretreated refractory leukemia group. While the creatinine elevations were not severe (grade 3-4 NCI CTC) they were consistent to consider a bendamustine dose schedule of 50-75 mg/m2 IV BID x 4 days as a reasonable phase II schedule to explore in better prognosis patients, particularly in adult ALL in phase II studies.

Ravandi:Cephalon: Consultancy, Honoraria. Kantarjian:Cephalon: Research Funding.