Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera

Quintás‐Cardama, Alfonso; Kantarjian, Hagop M.; Manshouri, Taghi; Luthra, Rajyalakshmi; Estrov, Zeev; Pierce, Sherry; Richie, Mary Ann; Borthakur, Gautam; Konopleva, Marina; Cortes, Jorge; Verstovšek, Srđan

doi:10.1200/jco.2009.23.6075

Cited by 375 publications

(311 citation statements)

References 35 publications

Supporting

Mentioning

290

Contrasting

Unclassified

Order By: Relevance

“…Two recent studies of pegylated INF-a ( 90 mg SC weekly) in PV and ET reported hematologic remissions of 80% accompanied by decreases in JAK2V617F allele burden (complete molecular remission rate of 5-10%) [119,120]. In one of the two studies [119], 77 cases were evaluable after a median follow up of 21 months and 76% and 70% of patients with ET or PV, respectively, achieved a complete hematologic remission, mostly in the first 3 months; side effects were recorded in 96% of the patients and 22% had discontinued treatment. Controlled studies are needed to clarify the advantage (or disadvantage) of IFN therapy in PV, compared to hydroxyurea therapy.…”

Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 99%

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

2015

View full text Add to dashboard Cite

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.

show abstract

Section: Annual Clinical Updates In Hematological Malignanciesmentioning

confidence: 99%

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

2015

View full text Add to dashboard Cite

show abstract

“…Interestingly, the malignant clone tested in PV, as quantitated by the percentage of the mutated JAK2V617F, was reduced. 53,54 However, whether this drug is more efficacious than HU in reducing the rate of thrombosis remains to be demonstrated. The evidence to indicate IFN-a as the drug of choice in any ET and PV patient younger than 60 years and in hypercellular/early PMF 55 is not yet supported by clinical trials.…”

Section: What To Do In Young Patients With Thrombosismentioning

confidence: 99%

How to manage children and young adults with myeloproliferative neoplasms

Barbui

2012

Leukemia

View full text Add to dashboard Cite

On the basis of my personal clinical and research experience and validated by the current literature, my approach to the management of pediatric (age o18 years) and young patients (age o40 years) with classic myeloproliferative neoplasms is presented by focusing on diagnosis, patient communication, risk stratification and therapy. The WHO-2008 diagnostic criteria are recommended, even though in children suspected with essential thrombocythemia (ET), a specific set of diagnostic features may be required. Patient communication includes information on natural history, genetic abnormalities and counseling in all women of child-bearing age. The main challenge in children and young adults with ET and polycythemia vera (PV) is to avoid recurrence of major thrombosis by selecting those patients who ultimately can benefit from cytotoxic and antithrombotic therapy without increasing the incidence of drug-induced side effects. In asymptomatic low-risk patients no therapy is prescribed while in high-risk low-dose aspirin, hydroxyurea and interferon-alpha are my first line drugs. My first decision when considering treatment of a young patient with primary myelofibrosis (PMF) or post-PV or post ET-myelofibrosis, is whether he/she qualifies for bone marrow allotransplantation. In the remaining young PMF patients palliative therapy or experimental drugs are considered.Leukemia ( Keywords: myeloproliferative neoplasms; treatment; young people INTRODUCTION Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are currently classified among the bcr/abl-negative, 'classic' myeloproliferative neoplasms (MPNs) and represent a stem cell-derived clonal myeloproliferation. Hematopoietic progenitors derived from patients with MPNs are hypersensitive to the stimulation of physiological growth factors such as thrombopoietin or erythropoietin (EPO). 1 Since 2005, the pathophysiology of these diseases has advanced considerably with the discovery of an acquired mutation of JAK2 V617F in a vast majority of PV patients and in almost half of those with ET and PMF. 2 The mutation, located within the negative regulatory pseudokinase, or Janus homology 2 domain, causes cytokine-independent activation of several biochemical pathways implicated in EPO receptor signaling. Subsequently, mutations in MPL were reported in B4% of patients with ET or PMF. The significance of JAK2 and MPL mutations for the evolution of the MPNs and their relative roles in determining disease phenotype as well as progression to myelofibrosis and leukemic transformation are unclear at present.In this context, it should be underscored that most of the information in terms of diagnosis, prognosis and therapy focuses on the 'average' MPN patients of whom median age ranges between 60 and 65 years. On the other hand, less consistent data are available in the groups of MPN patients who are presenting below this median age such as pediatric and young adults (20% of MPN patients). This issue is now becoming more and more important, because with the ad...

show abstract

“…Cell-based quantitative assays are also useful to monitor treatment response, including assessment of minimal residual disease after allogenic stem cell transplantation. [53][54][55][56] Recent studies in PV have suggested the association of higher mutant allele burden with a higher risk of fibrotic transformation 57 and in PMF a lower mutant allele burden with inferior survival. 58,59 However, the lack of assay standardization across different laboratories undermines the practical translation of such observations, at present.…”

Section: Jak2 and Mpl Mutation Screening In Routine Clinical Practicementioning

confidence: 99%

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

Tefferi

Noël

Hanson

2011

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. Morphology is the cornerstone of current diagnosis and classification in myeloid malignancies. 1 Cytochemical, immunophenotypic, cytogenetic, and molecular data enhance diagnostic accuracy and form the basis for the World Health Organization classification of myeloid malignancies into five main categories 2 : acute myeloid leukemia, myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and platelet-derived growth factor receptor gene or fibroblast growth factor receptor 1 gene rearranged myeloid/lymphoid neoplasms associated with eosinophilia. The World Health Organization MPN category includes eight subcategories: chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and MPN unclassifiable. 1 Among these subcategories, the first four (ie, chronic myelogenous leukemia, PV, ET, and PMF) are currently referred to as "classic" MPNs, because they were included in the original description of myeloproliferative disorders by William Dameshek. 3 In general, current evidence supports consideration of all myeloid malignancies, including MPN, as clonal stem cell diseases.JAK2 and MPL mutations occur across the spectrum of myeloid malignancies, including MPN, MDS, MDS/MPN, and acute myeloid leukemia (Table 1). 4 -7 These mutations are most prevalent in the BCR-ABL1-negative classic MPN (ie, PV, ET, and PMF), which are morphologically characterized by the absence of both cellular dysplasia

show abstract

Pegylated Interferon Alfa-2a Yields High Rates of Hematologic and Molecular Response in Patients With Advanced Essential Thrombocythemia and Polycythemia Vera

Cited by 375 publications

References 35 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

How to manage children and young adults with myeloproliferative neoplasms

Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

Contact Info

Product

Resources

About