Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea

Alvarez‐Larrán, Alberto; Martínez-Avilés, Luz; Hernández‐Boluda, Juan Carlos; Ferrer‐Marín, Francisca; Antelo, María Luisa; Burgaleta, Carmen; Mata, María Isabel; Xicoy, Blanca; Martínez‐Trillos, Alejandra; Gómez-Casares, M. Teresa; Durán, Ma del Carmen; Marcote, Bárbara; Ancochea, Águeda; Senín, Alicia; Angona, Anna; Gómez, Montse; Vicente, Vicente; Cervantes, Francisco; Bellosillo, Beatríz; Besses, Carles

doi:10.1007/s00277-014-2152-7

Cited by 66 publications

(50 citation statements)

References 23 publications

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“…In a more recent study of over 1,500 patients with PV, use of busulfan was not correlated with leukemic transformation [50]. Most recently, the use of busulfan in hydroxyurea-resistant PV produced over 80% complete hematologic response and molecular remission in about a third of the patients [117].…”

Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 97%

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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Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 97%

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

2015

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“…There is adequate long-term safety information on these drugs, which have both been shown to significantly reduce JAK2 or CALR mutant allele burden, although the effect of such biologic activity on risk of thrombosis or survival is unknown [116][117][118][119][120]. The JAK inhibitor ruxolitinib was recently approved for use in hydroxyurea-intolerant/resistant PV, based on its ability to alleviate constitutional symptoms and reduce spleen size [121].…”

Section: Polycythemia Vera and Essential Thrombocythemiamentioning

confidence: 99%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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“…We currently use busulfan to this purpose: before prescribing this drug, we inform the patient that alkylating agents and the sequential use of different cytoreductive treatments might increase the risk of leukemic transformation. 36,51,62 Microvascular symptoms such as erythromelalgia and acroparesthesia generally resolve with low-dose aspirin. We consider an ad hoc cytoreductive treatment only in the few patients whose symptoms severely affect quality of life and do not respond to low-dose aspirin.…”

Section: How We Treat Patients With Et According To Their Individual mentioning

confidence: 99%

How I treat essential thrombocythemia

Rumi

Cazzola

2016

Blood

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Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm that may be complicated by vascular events, including both thrombosis and bleeding. This disorder may also transform into more aggressive myeloid neoplasms, in particular into myelofibrosis. The identification of somatic mutations of JAK2, CALR, or MPL, found in about 90% of patients, has considerably improved the diagnostic approach to this disorder. Genomic profiling also holds the potential to improve prognostication and, more generally, clinical decision-making because the different driver mutations are associated with distinct clinical features. Prevention of vascular events has been so far the main objective of therapy, and continues to be extremely important in the management of patients with ET. Low-dose aspirin and cytoreductive drugs can be administered to this purpose, with cytoreductive treatment being primarily given to patients at high risk of vascular complications. Currently used cytoreductive drugs include hydroxyurea, mainly used in older patients, and interferon α, primarily given to younger patients. There is a need for disease-modifying drugs that can eradicate clonal hematopoiesis and/or prevent progression to more aggressive myeloid neoplasms, especially in younger patients. In this article, we use a case-based discussion format to illustrate our approach to diagnosis and treatment of ET.

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Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea

Cited by 66 publications

References 23 publications

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

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

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

How I treat essential thrombocythemia

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