Citations

7059 Background: TP53-mutated ( TP53mut) myeloid neoplasms (MN) are aggressive leukemia with poor survival. A subset of TP53mut MN is preceded by TP53mut CCUS that is conventionally considered to be high-risk premalignant condition, though evidence supporting the notion is lacking. We studied outcomes of TP53mut CCUS compared to TP53 wild-type ( TP53wt) CCUS. Methods: Mayo Clinic Molecular Hematology Database (N=7593) was queried to identify patients (pts) harboring pathogenic variant(s) in exons 4-11 of the TP53 gene with ≥2% variance allele frequency (VAF). CCUS was defined using the 5th edition of the WHO Classification for MN. Results: Of 457 pts with TP53mut, 29 (5.9%) had TP53mut CCUS. The median age at diagnosis was 67 years, 17 (59%) were female, and 20 (69%) had received cytotoxic therapies. One and ≥2 TP53mut were seen in 26 (89.6%) and 3 (10.3%) pts, respectively. Median TP53mut VAF was 9% (range 3-42), 3 had TP53mut VAF ≥20%, and 4 (14%) had non-MDS defining cytogenetic anomalies. Of 16 pts with available follow up evaluation (median interval 22 months, Table), 3 (10.3%) progressed to TP53mut MN at 5, 13, and 14 months from diagnosis. We next compared outcomes of TP53mut CCUS to TP53wt CCUS (n=138). The proportion of pts developing MN was not different between TP53wt and TP53mut CCUS (18.1 vs 10.3%, P= .42). Progression free survival of TP53mut CCUS was comparable to TP53wt CCUS at 1- (77 vs 83%), 2- (67 vs 67%), and 5-years (67 vs 59%, P=.9). Similarly, overall survival of TP53mut vs TP53wt CCUS at 1- (81 vs 89%), 2- (76 vs 76%), and 5-years (76 vs 67%) was comparable ( P= .94). Conclusions: In contrast to the prevalent notion, TP53mut was not associated with a higher risk of MN progression or mortality compared to TP53wt CCUS. Majority of TP53mut clones showed remarkable stability over years. [Table: see text]

Abstract Disease Overview JAK2 unmutated or non‐polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities. Diagnosis Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12–15) mutation screening. Initial assessment should also include gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list. Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity Hgb variants, 2,3‐bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% Hgb saturation (P50). The latter include germline oxygen sensing pathway ( HIF2A–PHD2–VHL ) and other rare mutations. Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high‐altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo‐producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis stimulating agents, sodium‐glucose cotransporter‐2 inhibitors). Idiopathic erythrocytosis is an ill‐defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation. Management Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non‐clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low dose aspirin is often advised. Future Directions Advances in molecular hematology might result in better characterization of “idiopathic erythrocytosis” and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.

Abstract Disease Overview Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied by JAK2 , CALR , or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival. Diagnosis Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2 , CALR or MPL mutation is expected but not required. New Classification System The International Consensus Classification distinguishes “prefibrotic” from “overtly fibrotic” PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post‐ET/PV MF. Mutations SRSF2 , ASXL1 , and U2AF1 ‐Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival. Karyotype Very high‐risk abnormalities include −7, inv (3), i(17q), +21, +19, 12p‐ and 11q‐. Favorable risk abnormalities include normal karyotype or isolated +9, 13q‐, 20q‐, 1q abnormalities and loss of Y chromosome. Risk Stratification Contemporary prognostic systems include GIPSS (genetically‐inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSS v2 ; mutation‐and karyotype‐enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSS v2 includes, in addition, clinical risk factors. Risk‐Adapted Therapy Observation alone is advised for MIPSS v2 “low” and “very low” risk disease (estimated 10‐year survival 56%–92% ); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for “very high” and “high” risk disease ( estimated 10‐year survival 0–13% ), as well as in carefully selected patients with intermediate‐risk disease ( estimated 10‐year survival 30% ). Drug therapy in MF is currently palliative and targets anemia, splenomegaly, and constitutional symptoms. JAK2 Inhibitors Ruxolitinib, fedratinib, and pacritinib are FDA approved and respectfully utilized in patients failing treatment with hydroxyurea, ruxolitinib, or with platelet count <50 × 10 (9)/L. Momelotinib is another JAK2 inhibitor that is poised for approval sometime in 2023 and has shown erythropoietic benefits, in addition to affecting spleen and symptom responses. Other Treatment Modalities Splenectomy is considered for drug‐refractory splenomegaly and involved field radiotherapy for non‐hepatosplenic EMH and extremity bone pain. New Directions New agents, alone or in combination with ruxolitinib, are currently under clinical trial investigation ( ClinicalTrials.gov ) and preliminary results were presented at the 2022 ASH annual meeting and highlighted in the current review.