TY - JOUR
T1 - Accelerated Phase of Myeloproliferative Neoplasms
AU - Shahin, Omar A.
AU - Chifotides, Helen T.
AU - Bose, Prithviraj
AU - Masarova, Lucia
AU - Verstovsek, Srdan
N1 - Funding Information:
This work was supported, in part, by the MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).
Funding Information:
P.B. has received research support from Incyte Corporation, Celgene (BMS), CTI Biopharma, Kartos Therapeutics, Blueprint Medicines, Constellation Pharmaceuticals, NS Pharma, Prome-dior, Astellas, and Pfizer. P.B. has received honoraria from Incyte Corporation, Celgene, CTI Biopharma, Kartos Therapeutics, and Blueprint Medicines. S.V. has received research support from In-cyte Corporation, Roche, Celgene (BMS), Gilead, Promedior, CTI Biopharma Corporation, Genetech, Blueprint Medicines Corporation, NS Pharma, Novartis, Sierra Oncology, Pharma Essentia, Astra Zeneca, Italfarmaco, Kartos Therapeutics, Prelude Therapeutics, Protagonist Therapeutics, AbbVie, Constellation Pharmaceuticals, and Telios Pharmaceuticals. S.V. has received consultancy fees from Constellation Pharmaceuticals, Sierra Oncology, Incyte Corporation, Novartis, and Celgene. The remaining authors have no conflicts of interest to disclose.
Publisher Copyright:
© 2021 S. Karger AG, Basel. Copyright: All rights reserved.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Background: Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of the cases. MPN-AP and MPN-BP are characterized by 10-19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival. Summary: MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3-5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.
AB - Background: Myeloproliferative neoplasms (MPNs) can transform into blast phase MPN (leukemic transformation; MPN-BP), typically via accelerated phase MPN (MPN-AP), in ∼20-25% of the cases. MPN-AP and MPN-BP are characterized by 10-19% and ≥20% blasts, respectively. MPN-AP/BP portend a dismal prognosis with no established conventional treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole modality associated with long-term survival. Summary: MPN-AP/BP has a markedly different mutational profile from de novo acute myeloid leukemia (AML). In MPN-AP/BP, TP53 and IDH1/2 are more frequent, whereas FLT3 and DNMT3A are rare. Higher incidence of leukemic transformation has been associated with the most aggressive MPN subtype, myelofibrosis (MF); other risk factors for leukemic transformation include rising blast counts above 3-5%, advanced age, severe anemia, thrombocytopenia, leukocytosis, increasing bone marrow fibrosis, type 1 CALR-unmutated status, lack of driver mutations (negative for JAK2, CALR, or MPL genes), adverse cytogenetics, and acquisition of ≥2 high-molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1Q157). The aforementioned factors have been incorporated in several novel prognostic scoring systems for MF. Currently, elderly/unfit patients with MPN-AP/BP are treated with hypomethylating agents with/without ruxolitinib; these regimens appear to confer comparable benefit to intensive chemotherapy but with lower toxicity. Retrospective studies in patients who acquired actionable mutations during MPN-AP/BP showed positive outcomes with targeted AML treatments, such as IDH1/2 inhibitors, and require further evaluation in clinical trials. Key Messages: Therapy for MPN-AP patients represents an unmet medical need. MF patients, in particular, should be appropriately stratified regarding their prognosis and the risk for transformation. Higher-risk patients should be monitored regularly and treated prior to progression to MPN-BP. MPN-AP patients may be treated with hypomethylating agents alone or in combination with ruxolitinib; also, patients can be provided with the option to enroll in rationally designed clinical trials exploring combination regimens, including novel targeted drugs, with an ultimate goal to transition to transplant.
KW - Accelerated phase myeloproliferative neoplasms
KW - Blast phase myeloproliferative neoplasms
KW - Myelofibrosis
KW - Myeloproliferative neoplasms
KW - Post-myeloproliferative neoplasm acute myeloid leukemia
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U2 - 10.1159/000512929
DO - 10.1159/000512929
M3 - Review article
C2 - 33882481
AN - SCOPUS:85104891890
SN - 0001-5792
VL - 144
SP - 484
EP - 499
JO - Acta haematologica
JF - Acta haematologica
IS - 5
ER -