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Philadelphia-chromosome negative (Ph-neg) myeloproliferative neoplasms (MPNs) are hematopoietic stem disorders with a risk of progression to the accelerated-phase (AP) or blastphase (BP) that is influenced by clinical, pathologic, cytogenetic, and molecular variables. Overall survival is limited in MPN-AP/BP with current treatment approaches, particularly in those patients that cannot receive an allogeneic hematopoietic stem cell transplant (allo-HCT). In addition, long-term survival with allo-HCT is predominantly seen in chronic-phase MPNs which suggests that the ideal time for intervention may be before MPNs evolve to AP/BP. Over the course of this review we will focus on the risk factors for progression to MPN-AP/BP, identification of high-risk chronic-phase MPNs, potential early-intervention strategies, and considerations around the timing of allo-HCT. We will also summarize current survival outcomes in MPN-AP/BP, discuss the uncertainty around how to best gauge response to therapy, and outline clinical trial considerations for this patient population. Lastly, we will highlight future directions in the management of high-risk MPNs.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patients' management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs of samples. In contrast to solid tumors, in hematologic malignancies conventional sources of normal control material (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell-free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control material, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we found that nail cfDNA is a robust germline control for paired genomic studies. In a subset of patients, nail DNA may be contaminated by tumor DNA, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1,482) than among those with lymphoid diseases (5.4%; 61/1,128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. Donor DNA was identified in 22% (11/50) of nails collected after allogeneic stem-cell transplantation. In this cohort, an association with a recent history of graft-versus-host disease was identified. These findings should be considered as a potential limitation to the use of nails as a source of normal control DNA but could also provide important diagnostic information regarding the disease process.

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ("much" or "very much" improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.

Wilms tumor 1 (WT1) has long been implicated in acute myeloid leukemia. It has been described to be both overexpressed and mutated in different forms of acute myeloid leukemia, and overexpression has been reported to play a prognostic role in this disease. However, the precise mechanism through which WT1 may play a role in leukemogenesis has remained elusive. In recent years, new evidence has emerged that points towards a novel role of WT1 mutations in the deregulation of epigenetic programs in leukemic cells through its interaction with TET proteins. Herein we review the current status of the field and its therapeutic and prognostic implications in acute myeloid leukemia., (Copyright© Ferrata Storti Foundation.)