title: Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms.
abstract: OBJECTIVE
  Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU).
  
  
  METHODS
  On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk.
  
  
  RESULTS
  Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation.
  
  
  CONCLUSIONS
  The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.
authors.affiliation: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden. magnus.bjorkholm@karolinska.se
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: Asa R
authors.initials: AR
authors.lastname: Derolf
authors.forename: Malin
authors.initials: M
authors.lastname: Hultcrantz
authors.forename: Sigurdur Y
authors.initials: SY
authors.lastname: Kristinsson
authors.forename: Charlotta
authors.initials: C
authors.lastname: Ekstrand
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Goldin
authors.forename: Björn
authors.initials: B
authors.lastname: Andreasson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Birgegård
authors.forename: Olle
authors.initials: O
authors.lastname: Linder
authors.forename: Claes
authors.initials: C
authors.lastname: Malm
authors.forename: Berit
authors.initials: B
authors.lastname: Markevärn
authors.forename: Lars
authors.initials: L
authors.lastname: Nilsson
authors.forename: Jan
authors.initials: J
authors.lastname: Samuelsson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Granath
authors.forename: Ola
authors.initials: O
authors.lastname: Landgren
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000401:mortality; D007958:Leukocyte Count; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology* / Q000401:mortality; D010761:Phosphorus Radioisotopes / Q000009:adverse effects; D011087:Polycythemia Vera / Q000150:complications* / Q000628:therapy; D055728:Primary Myelofibrosis / Q000150:complications* / Q000628:therapy; D012307:Risk Factors; D013920:Thrombocythemia, Essential / Q000150:complications* / Q000628:therapy
chemical_list: D018906:Antineoplastic Agents, Alkylating; D010761:Phosphorus Radioisotopes