phosphorus-radioisotopes and Myelodysplastic-Syndromes

Polycythemia vera, essential thrombocythemia, and primary myleofibrosis are chronic myeloproliferative neoplasms (MPNs) associated with an increased morbidity and mortality. MPNs are also associated with progression to acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The "true" rate of transformation is not known mainly due to selection bias in clinical trials and underreporting in population-based studies. The outcome after transformation is dismal. The underlying mechanisms of transformation are incompletely understood and in part remain an area of controversy. There is an intrinsic propensity in MPNs to progress to AML/MDS, the magnitude of which is not fully known, supporting a role for nontreatment-related factors. High doses of alkylating agents, P(32) and combined cytoreductive treatments undoubtedly increase the risk of transformation. The potential leukemogenic role of hydroxyurea has been a matter of debate due to difficulties in performing large prospective randomized trials addressing this issue. The main focus of this review is to elucidate therapy-related leukemic transformation in MPNs with a special focus on the role of hydroxyurea.

Topics: Antineoplastic Agents; Cell Transformation, Neoplastic; Disease Progression; Humans; Hydroxyurea; Janus Kinase 2; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Phosphorus Radioisotopes; Polycythemia Vera; Primary Myelofibrosis; Survival Analysis; Thrombocythemia, Essential

Between 1980 and 1992, 237 polycythaemic patients aged 65 or more, or with high vascular risk factors were treated with 32P according to a protocol using, or not, maintenance therapy with low-dose hydroxy-urea (500 mg/day). The present follow-up covers 1448 years/patient. Maintenance therapy was seldom discontinued because of blood toxicity or gastrointestinal intolerance, but it was stopped in 20 percent of the cases because monitoring was difficult in very old patients. Maintenance therapy reduced the mean annual 32P dose by at least 50 percent. However, the actual risk of malignant blood diseases (myelodysplasia, acute leukaemia, lymphoma) was similar in the two arms of the protocol: 14 percent at the 10th year. Compared with the French population of the same age-groups, there was no excess of epithelial cancers in both arms. Maintenance therapy did not control platelet counts perfectly. The risk of severe vascular events was identical in both arms; probably no higher than expected at that age and significantly lower than in previously published data. The actuarial survival curves in both groups showed a 50 percent survival of about 11 years, i.e. very near to that of the reference French population (12.5 years) of similar sex and age.

Topics: Age Factors; Aged; Carcinoma; Cardiovascular Diseases; Female; Humans; Hydroxyurea; Injections, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Phosphorus Radioisotopes; Polycythemia; Primary Myelofibrosis; Risk Factors

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).. 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.. 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.. 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.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Case-Control Studies; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Logistic Models; Male; Middle Aged; Myelodysplastic Syndromes; Phosphorus Radioisotopes; Polycythemia Vera; Primary Myelofibrosis; Risk Factors; Thrombocythemia, Essential

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by increased risk of thrombosis and/or hemorrhages. Cytotoxic drugs are mostly used in patients at high risk for thrombotic complications, while their use is still debated in low risk patients because of the risk of leukemia or secondary neoplasm. We discuss the leukemic risk of available treatment strategies in a large cohort of patients. Over a 12 years period we treated 23 patients with busulfan (BU), 1 with pipobroman (Pi), 6 with 32P, 48 with hydroxyurea (HU) in 62 cases associated with acetyl salicylic acid (ASA) while 77 patients received ASA alone and 33 did not receive any therapy. We observed 2 cases of acute leukemia (AL) and 1 of myelodysplastic syndrome (MDS). One of these patients had been treated with 32P and Pi these after with and the other two with BU and HU. They represented 23% of all patients treated with more than 1 cytotoxic agent, 16.6% of 32P treated subjects, 4% of those with HU and 6.4% of those with BU. The case of MDS occurred in a 81 years old female and represents 4% of cases of ET over the 70 years of age. No cases of AL or MDS were observed in patients not receiving cytotoxic therapy (with or without ASA). According to our experience the use of more than one cytotoxic agent in ET confirms the increase in the risk of leukemia in these cases. However, none of the patients treated with HU alone, even for more than 10 years (12 cases) developed AL. No treatment or therapy with ASA alone may be the best choice in young patients with ET with a low risk of thrombotic complications.

Topics: Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Busulfan; Fatal Outcome; Female; Humans; Hydroxyurea; Leukemia; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Phosphorus Radioisotopes; Pipobroman; Thrombocythemia, Essential

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Busulfan; Female; Follow-Up Studies; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Phosphorus Radioisotopes; Pipobroman; Retrospective Studies; Thrombocythemia, Essential