Busulfan Induces Hematologic and Molecular Responses in Polycythemia Vera (PV) Refractory to Multiple Drugs

Abstract 5068

Busulfan, a highly effective and established drug in polycythemia vera (PV), produces lasting clinical and hematologic responses. Its use as a first and second line therapy for PV recently diminished owing to largely unsubstantiated concerns of increased leukemogenicity. However, in a pivotal phase III trial of busulfan vs. P³² conducted by the EORTC in patients with PV, busulfan sustained long term clinical and hematologic responses as well as superior 10 year overall survival (70% vs. 55%). Toxicity was minimal and a low incidence of acute leukemia was reported (1% at 8 years).

Accordingly, we treated 5 PV patients with busulfan, 4 of whom were refractory to multiple drugs including hydroxyurea (HU), pegylated interferon alfa-2a (pIFN), imatinib, dasatinib, and anagrelide. Clinical and hematologic response was graded according to PVSG criteria and molecular response according to ELN criteria. JAK2^V617F allele burdens were determined by pyrosequencing, which quantifies mutant alleles more than 5%. If negative by pyrosequencing, we used an ARMS-PCR assay with a sensitivity of 0. 1%. Phlebotomy was performed to maintain the hematocrit (Hct) less than 45% for men and 42% for women. Treatment with busulfan was discontinued if patients experienced adverse side effects and/or had platelet counts less than 100, 000/mL while in clinical remission.

All 5 patients had complete hematologic responses (CHR) within 3 months of starting busulfan (table 1). Molecular responses (MR) were: 1 complete (CMR) after 6 months, 1 partial (PMR) after 6 months, and 3 with no response (NMR) after 3, 7, and 60 months of treatment respectively. The 2 patients who had MR were homozygous for JAK2^V617F, and the 3 who did not were heterozygous. Treatment was discontinued in the patient with CHR and CMR after 7 months due to thrombocytopenia; the patient has since maintained CHR and CMR for 3 years off treatment. The remaining 4 patients have maintained CHR on low doses of busulfan (table 1). No adverse events were observed over a median treatment duration of 15 months (range: 3–60 months).

The significant difference in molecular response between patients with homozygous and heterozygous JAK2 mutations receiving similar doses of busulfan is noteworthy. This suggests a susceptibility of homozygous JAK2V617F clones to busulfan, but not to other drugs including HU, IFNa, and anagrelide.

In summary, our 5 patients with multidrug refractory PV had rapid and sustained hematologic responses to busulfan at low doses, with favorable short and long term toxicity profiles. Two JAK2^V617F homozygous patients had the best MR. Our findings indicate the effectiveness of a safe, relatively inexpensive drug in inducing clinical outcomes not significantly different from that of costly drugs, such as JAK2 inhibitors. In addition, the high rates of MR we observed in patients with homozygous JAK2 mutations warrant further study of busulfan with respect to this parameter.