Hydroxyurea's Leukemogenicity in Myeloproliferative Neoplasms: A Not Guilty Verdict
Published on: November 01, 2011
Dr. Gotlib indicated no relevant conflicts of interest.
Björkholm M, Derolf ÅR, Hultcrantz M, et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol. 2011;29:2410-2415.
Among patients who suffer from myeloproliferative neoplasms (MPNs), and for some doctors who treat them, an uncomfortable concern has lingered about hydroxyurea’s role in the risk of transformation into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to the inherent capacity of MPNs to transform into leukemia, prior studies have established the increased leukemogenic risk of alkylator therapies or radioactive phosphorus (32P). Data from several trials over the last 40 years suggest little of a conspiratorial role of hydroxyurea monotherapy but increased potential for leukemic evolution when the drug is combined with other cytotoxics. Because longer follow-up times have revealed a higher incidence of leukemia in MPN patients treated with myelosuppressive agents, apprehension over the use of hydroxyurea is particularly relevant to younger persons who may be exposed to the drug for decades.
To better define risk factors for transformation of MPNs, investigators from the Swedish Chronic Myeloproliferative Neoplasm Study Group and the National Cancer Institute harnessed data from an MPN cohort of 11,039 patients derived from Sweden’s centralized National Cancer Registry. A nested case-control study compared 162 MPN patients with transformation (153 to AML, 9 to MDS) with 242 matched MPN control patients without disease evolution. The overall incidence of AML transformation into MPNs was 35-fold compared with the general population, with the greatest risk in primary myelofibrosis (PMF), followed by polycythemia vera (PV) then essential thrombocythemia (ET). Of interest, 25 percent of MPN patients who developed AML or MDS were never exposed to hydroxyurea, alkylating agents, or 32P, and this is consistent with the intrinsic genetic instability of these disorders. There was no significant increased risk of AML/MDS development with prior exposure to hydroxyurea, irrespective of the cumulative dose level (e.g., 1-499 vs. 500-999 g vs. > 1,000 g). Patients who received relatively higher doses of 32P (> 1,000 MBq) and alkylators (> 1 g) exhibited a significantly increased odds ratio for leukemia development (e.g., 4.6- and 3.4-fold, respectively) compared with the 1.3-fold insignificant increase with the highest dose range of hydroxyurea. Treatment with two or more cytoreductive agents similarly increased the odds of leukemic transformation (2.9-fold) and was greater than any single treatment alone. Approximately 75 percent of patients treated with alkylating agents or 32P developed AML/MDS five years or later after their MPN diagnosis compared with ~40 percent of patients who received no treatment or hydroxyurea alone. Overall, only 2.6 percent of the 11,039 MPN patients converted to AML/MDS.
Despite the potential shortcomings related to a population-based analysis, this study’s large sample size and durable follow-up provide more compelling evidence for disease and non-treatment related factors in MPN transformation. However, the report also confirms the unambiguous risk associated with relatively high doses of alkylating agents and 32P, and the potentiating leukemogenic effect of multiple cytoreductive drugs. In conjunction with these data, given its experience in sickle cell disease and its lack of increased mutagenicity ex-vivo with cells from MPN patients,1 hydroxyurea should be considered a nominal risk in this patient population.
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- Hanft VN, Fruchtman SR, Pickens CV, et al. Acquired DNA mutations associated with in vivo hydroxyurea exposure. Blood. 2000;95:3589-3593.