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.
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.
Authors: Terra L Lasho; Mythri Mudireddy; Christy M Finke; Curtis A Hanson; Rhett P Ketterling; Natasha Szuber; Kebede H Begna; Mrinal M Patnaik; Naseema Gangat; Animesh Pardanani; Ayalew Tefferi Journal: Blood Adv Date: 2018-02-27
Authors: F Passamonti; T Giorgino; B Mora; P Guglielmelli; E Rumi; M Maffioli; A Rambaldi; M Caramella; R Komrokji; J Gotlib; J J Kiladjian; F Cervantes; T Devos; F Palandri; V De Stefano; M Ruggeri; R T Silver; G Benevolo; F Albano; D Caramazza; M Merli; D Pietra; R Casalone; G Rotunno; T Barbui; M Cazzola; A M Vannucchi Journal: Leukemia Date: 2017-05-31 Impact factor: 11.528
Authors: Neha Bhagwat; Priya Koppikar; Matthew Keller; Sachie Marubayashi; Kaitlyn Shank; Raajit Rampal; Jun Qi; Maria Kleppe; Hardik J Patel; Smit K Shah; Tony Taldone; James E Bradner; Gabriela Chiosis; Ross L Levine Journal: Blood Date: 2014-01-27 Impact factor: 22.113
Authors: Peter Müller; Conny K Baldauf; Tobias R Haage; Emmanouil Charakopoulos; Martin Böttcher; Vikas Bhuria; Dimitrios Mougiakakos; Burkhart Schraven; Thomas Fischer Journal: Hemasphere Date: 2022-04-15
Authors: Nico Gagelmann; Christine Wolschke; Rachel B Salit; Thomas Schroeder; Markus Ditschkowski; Victoria Panagiota; Bruno Cassinat; Felicitas Thol; Anita Badbaran; Marie Robin; Hans Christian Reinhardt; Francis Ayuk; Michael Heuser; Bart L Scott; Nicolaus Kröger Journal: Blood Adv Date: 2022-02-22