Efficacy of ruxolitinib in myeloid neoplasms with PCM1-JAK2 fusion gene

Rumi, Elisa; Milosevic, Jelena D.; Selleslag, Dominik; Casetti, Ilaria Carola; Lierman, Els; Pietra, Daniela; Cavalloni, Chiara; Bellini, Marta; Milanesi, Chiara; Dambruoso, Irene; Astori, Cesare; Královics, Róbert; Vandenberghe, Peter; Cazzola, Mario

doi:10.1007/s00277-015-2451-7

Cited by 54 publications

(36 citation statements)

References 3 publications

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“…Two reports highlighted complete hematologic remissions and cytogenetic responses (1 compete and 1 major) in 2 patients with chronic eosinophilic leukemia with the PCM1‐JAK2 fusion [t(8;9)(p22;p24)] treated with the JAK1/JAK2 inhibitor ruxolitinib . Hematologic and cytogenetic remissions, however, can be variable in JAK2 ‐rearranged patients, with some lasting only 1‐2 years, and HSCT should be therefore considered for suitable candidates . Similarly, in FLT3 ‐rearranged cases, hematologic and cytogenetic responses have been observed with FLT3/multikinase inhibitors such as sorafenib or sunitinib, but durability can be brief, necessitating consideration of HSCT …”

Section: Risk‐adapted Therapymentioning

confidence: 99%

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

2019

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Disease overview: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage.Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 10 9 /L, and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ-hybridization, flow immunophenotyping, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2", and the MPN subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.Risk-adapted therapy: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (eg, <1.5 × 10 9 /L) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), as well as other targets on eosinophils remains an active area of investigation.

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Section: Risk‐adapted Therapymentioning

confidence: 99%

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

2019

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“…For example, two reports highlighted complete hematologic remissions and cytogenetic responses (1 compete and 1 major) in 2 patients with chronic eosinophilic leukemia with the PCM1‐JAK2 fusion [t(8;9)(p22;p24)] treated with the JAK1/JAK2 inhibitor ruxolitinib . Hematologic and cytognetic remissions, however, can be variable JAK2 ‐rearranged patients, with some lasting only 1–2 years, and HSCT should be therefore considered for suitable candidates . Similarly, in FLT3 ‐rearranged cases, hematologic and cytogenetic responses are observed with FLT3/multikinase inhibitors such as sorafenib or sunitinib, but durability can be brief, necessitating consideration of HSCT …”

Section: Risk‐adapted Therapymentioning

confidence: 99%

World Health Organization‐defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management

2017

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Disease overview: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm 3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder.Risk stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semimolecular classification scheme of disease subtypes which includes the major category "myeloid/ lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2," and the "MPN subtype, chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. Risk-adapted therapy:The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., < 1500/mm 3 ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these dis-

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“…78 Two patients with CEL exhibited complete hematologic and cytogenetic remissions, as well as marked reduction of PCM1-JAK2 transcripts, at 33 and 46 months after the start of ruxolitinib therapy at the time of publication. 79,80 Schwaab et al treated 2 male patients with chronic myeloid neoplasms and a PCM1-JAK2 or a BCR-JAK2 fusion gene, respectively, with ruxolitinib. 81 After 12 months of treatment, both patients achieved a complete clinical, hematologic, and cytogenetic response.…”

Section: Sptbn1mentioning

confidence: 99%

Myeloid neoplasms with eosinophilia

Reiter

Gotlib

2017

Blood

222

274

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Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, “Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.” In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed-phenotype leukemias or lymphomas. Eosinophilia is a common, but not invariable, feature of these diseases. The natural history of PDGFRA- and PDGFRB-rearranged neoplasms has been dramatically altered by imatinib. In contrast, patients with FGFR1 and JAK2 fusion TK genes exhibit a more aggressive course and variable sensitivity to current TK inhibitors, and in most cases, long-term disease-free survival may only be achievable with allogeneic hematopoietic stem cell transplantation. Similar poor prognosis outcomes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ETV6), and further investigation is needed to validate their inclusion in the current WHO-defined group of eosinophilia-associated TK fusion-driven neoplasms. The diagnosis chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is assigned to patients with MPN with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance, reclassifying some of these cases as eosinophilia-associated neoplasms. Looking forward, one of the many challenges will be how to use the results of molecular profiling to guide prognosis and selection of actionable therapeutic targets.

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Efficacy of ruxolitinib in myeloid neoplasms with PCM1-JAK2 fusion gene

Cited by 54 publications

References 3 publications

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

World Health Organization‐defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management

Myeloid neoplasms with eosinophilia

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