Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study

Finazzi, Guido; Caruso, Vanesa; Marchioli, Roberto; Capnist, Giovanni; Chisesi, Teodoro; Finelli, Carlo; Gugliotta, Luigi; Landolfi, Raffaele; Kutti, Jack; Gisslinger, Heinz; Marilus, Raphael; Patrono, Carlo; Pogliani, Enrico Maria; Randi, Maria Luigia; Villegas, A; Tognoni, Gianni; Barbui, Tiziano

doi:10.1182/blood-2004-09-3426

Cited by 388 publications

(362 citation statements)

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“…[69][70][71][72] By contrast, a leukemogenic potential of hydroxyurea (HU) has not been shown in clinical trials, although there is evidence showing that the sequential use of HU and other cytoreductive drugs (alkylating agents, radioactive phosphorus) increases the risk of AL/MDS. [72][73][74][75] In addition, several retrospective studies did not find an increased risk of AL in PV and ET treated with HU alone, [76][77][78] and similar conclusions were drawn from a recent meta-analysis of HU therapy in sickle cell anemia. 79 Still, very long-term results of prospective studies in HU-treated MPN patients with more than 10 years of follow-up showed a cumulative incidence of AL/MDS of more than 10% beyond 12 years of follow-up, suggesting that the risk of leukemic evolution could be higher than reported earlier in studies with shorter follow-up.…”

Section: Ifn-a and Leukemic Evolutionsupporting

confidence: 55%

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

2008

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Interferon (IFN) was the first cytokine discovered 50 years ago, with a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities, that rapidly raised interest in its therapeutic use in malignancies. IFN-receptor characterization was also pivotal in the discovery of the JAK/STAT signaling pathway. Among the large IFN family, mainly one of the type I IFN, IFN-a2, is used in therapy. Many clinical trials have shown remarkable efficacy of IFN-a in bcr-abl-negative myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV), and essential thrombocythemia (ET). IFN-a induces about 80% of hematological responses in those diseases and is able to reduce splenomegaly, as well as relieve pruritus and other constitutional symptoms. Yet its use was limited by toxicity, leading to early treatment discontinuation in about 20% of the patients. However, its lack of leukemogenic potential and its possible use during pregnancy have already made IFN-a the drug of choice for younger MPN patients. In addition, several studies have shown a probably selective effect of IFN-a on PV and ET clones, as shown by cytogenetic remissions, reversions to polyclonal hematopoiesis, and more recently by induction of JAK2V617F complete molecular remissions in PV which may widen the indications of IFN-a in JAK2-mutated MPN.

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Section: Ifn-a and Leukemic Evolutionsupporting

confidence: 55%

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

2008

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“…There are, to date, no controlled studies that implicate either hydroxyurea or busulfan as being leukemogenic in either ET or PV. Similarly, the two largest non-controlled studies in ET [54] and PV [108] do not support the concern that leukemia might arise from the use of hydroxyurea and there is additional evidence to that effect from long-term studies of patients receiving hydroxyurea for sickle cell disease [123]. The evidence for busulfan leukemogenicity in the context of treatment for PV or ET is equally weak and inappropriately extrapolated from older patients with advanced phase disease and exposed to multiple cytoreductive drugs.…”

Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 99%

“…Similarly, the incidence of AML in patients treated with hydroxyurea, compared to a historical control treated with either chlorambucil or radiophosphorus, was significantly lower (5.9 % vs. 10.6% vs. 8.3%, respectively, in the first 11 years of treatment) [105]. Other studies have confirmed the low incidence of AML in PV patients treated with hydroxyurea (1-5.6%) [106][107][108].…”

Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 99%

“…The evidence for busulfan leukemogenicity in the context of treatment for PV or ET is equally weak and inappropriately extrapolated from older patients with advanced phase disease and exposed to multiple cytoreductive drugs. The recurrent flaw in data interpretation, when it comes to examining the relationship between leukemic drugs and leukemic transformation, is best illustrated by the largest prospective/retrospective study, to date, in PV (n 5 1638) [108]. At a median follow-up of 8.4 years from diagnosis, only 1.3% of the patients developed AML.…”

Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 99%

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Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management

2015

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Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life‐expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high‐risk is defined by the presence of age >60 years or presence of thrombosis history; low‐risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk‐adapted therapy: The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low‐dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon‐α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 90:163–173, 2015. © 2014 Wiley Periodicals, Inc.

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“…Thrombotic complications are the main cause of morbidity and mortality, occurring in more than one third of patients and causing 35-45% of deaths [5,6]. Other possible adverse events are the evolution into secondary myelofibrosis (MF) or acute myeloid leukemia (AML) occurring in 10-15% [4,[6][7][8] and 2-15% [4,[8][9][10][11][12][13][14][15][16] of patients, respectively, depending on treatments and with increased incidence with long-standing disease.…”

Section: Introductionmentioning

confidence: 99%