Tefferi, Ayalew

Abstract “Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

Abstract Allogeneic hematopoietic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MNs) harboring TP53 mutations (TP53mut). The aim of this international study across 7 transplant centers in the United States and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype; 94% of TP53 variants were localized to the DNA-binding domain (DBD). Most common comutations were ASXL1 (7%), TET2 (7%), and DNMT3A (6%). Median post-HCT survival was 1.03 years, and overall survival (OS) at 1 year, 2 years, and 3 years was 51.4%, 35.1%, and 25.1%, respectively. A total of 103 cases (76.9%) met the International Consensus Classification (ICC) criteria for MN with mutated TP53 (referred to as ICC-defined TP53mut MN hereafter). The 3-year OS of ICC-defined TP53mut was significantly shorter compared with that of other TP53mut MNs (3-year OS, 16.9% vs 54.9%; P = .002). ICC-defined TP53mut MNs was independently associated with inferior OS (hazard ratio [HR], 2.62; P = .019). The presence of non-DBD TP53mut only (HR, 3.40; P = .005), DNMT3A comutation (HR, 2.64; P = .016), and pre-alloHCT bone marrow blasts ≥5% (HR, 2.76; P = .006) was independently associated with inferior relapse-free survival (RFS), whereas melphalan-based conditioning was associated with superior RFS (HR, 0.52; P = .005). Combining these variables, we constructed a hierarchical model that stratified patients into low-, intermediate-, and high-risk categories with 1-year RFS of 81.3%, 31.3%, and 6.7%, respectively (P < .001). In conclusion, a subset of MN harboring TP53mut who have low blasts pre-alloHCT and received melphalan-based conditioning derived long-term benefit from alloHCT.

Abstract This retrospective analysis aimed to provide evidence-based risk stratification of TP53-mutated (TP53mut) myeloid neoplasms (MNs). Of 580 MNs harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.4%), 92 (15.9%), and 75 (12.9%) were classified as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) with low blasts (MDS-LB), MDS with excess blasts (MDS-EB)-2, and -EB1 according to the revised fourth edition of the World Health Organization (WHO) classification, respectively. Hierarchical analysis identified the following 4 risk groups with distinct survival: (1) MDS-LB, (2) MDS-EB1/EB2/AML VAF <10%, (3) MDS-EB1/EB2 VAF ≥10%, and (4) AML VAF ≥10%. We next evaluated the impact of allelic status, VAF, and complex karyotype (CK). In our cohort, the significance of biallelic status was limited to MDS with <5% blasts and not for blasts 5% to 9%, as proposed by the International Consensus Classification (ICC), or 5% to 19%, as proposed by the fifth edition of the WHO (WHO-5). MDS-EB1 and -EB2 with VAF ≥10% had comparable survival (9.6 vs 7.2 months; P = .12), regardless of allelic status. Contrary to the ICC proposal, MDS-EB1/EB2 with VAF <10% and CK had poor survival compared with those without CK, comparable to MDS-EB1/EB2 with VAF ≥10% (5.6 vs 26.2 vs 6.3 months; P = .003). Survival of TP53mut AML was poor (median 3.9 months) regardless of allelic/CK status. Thus, using ICC or WHO-5 may underestimate prognosis of MDS with blasts 5% to 19% and 5% to 9%, respectively. Collectively, the hierarchical model acknowledges poor survival of 91.9% TP53mut MDS and AML compared with 36.5% and 80.7% by WHO-5 and ICC, respectively.

ABSTRACTA total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (mTP53 MUT) were accessed from the Mayo Clinic database and included (i) chronic phase MPN (MPN‐CP; N = 19), (ii) accelerated phase MPN (MPN‐AP; N = 14), (iii) blast phase MPN (MPN‐BP; N = 28), and (iv) AML (N = 81). Concurrent ASXL1 MUT, EZH2 MUT, IDH1,MUT and IDH2 MUT were more common in MPN‐MUTBP‐mTP53 compared to AML‐mTP53 MUT. At median of 11.6 months follow‐up, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from the time of mTP53 MUT detection, was similar between MPN‐BP‐mTP53 MUT (median 4.6 months) and MPN‐AP‐mTP53 MUT (5.6 months; p = 0.5) but both were inferior to MPN‐CP‐mTP53 MUT (11.6 months, p < 0.01). OS in MPN‐CP‐mTP53 MUT was similar to that of AML‐mTP53 MUT (median 7.4 months, p = 0.07). In multivariable analysis, OS was favorably affected by ASCT (HR 0.4, p = 0.03) and disease stage (i.e., chronic phase disease) or achieving response to pre‐transplant chemotherapy (HR 0.2, p < 0.01) and unfavorably by the presence of concurrent TET2 MUT or DNMT3A MUT (HR 2.7, p < 0.01). Based on these risk factors, a 3‐tiered risk model was constructed: low (no risk factors; N = 18; median OS 23.8 months); intermediate (one risk factor; N = 44; 11.1 months); and high (two or more risk factors; N = 80; 4 months; p < 0.01). The current study highlights the equally detrimental impact of mTP53 MUT on long‐term survival in MPN and AML and identifies predictors of short‐term survival.

ABSTRACT Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin‐induced iron‐restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF‐β)‐bone morphogenic protein/sons of mothers against decapentaplegic (BMP‐SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF‐β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor‐like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti‐hemojuvelin antibody‐based therapies (DISC‐0974). Luspatercept and momelotinib are approved for anemia related to lower‐risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower‐risk MDS. A promising strategy to overcome the limitations of existing anemia‐directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC‐0974 + momelotinib), and harnessing the erythropoietic potential of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender‐specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia‐directed therapies.

ABSTRACT The clinical relevance of TP53 mutations ( TP53 MUT ) in myeloproliferative neoplasms (MPN) and their prognostic interaction with MPN subtype designation has not been systematically studied. In the current study, 114 patients with MPN harboring TP53 MUT (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of TP53 MUT detection: chronic phase myelofibrosis (MF‐CP; N = 61); blast‐phase (MPN‐BP; N = 31) or accelerated‐phase (MPN‐AP; N = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; N = 6). Sixty‐five (57%) patients harbored International Consensus Classification (ICC)‐defined multihit TP53 MUT and 56 (49%) monosomal/complex karyotype (MK/CK). Majority of MPN‐BP (90%) and MPN‐AP (81%) while 39% of MF‐CP and none of PV/ET patients harbored multihit TP53 MUT . OS in MPN‐BP and MPN‐AP was equally dismal (median 6 vs. 4.5 months, respectively; p = 1.0), regardless of multihit configuration ( p = 0.44), while OS in TP53 MUT MPN‐BP/AP ( N = 47; median 4 months) was inferior to that of a separate cohort ( N = 49) with TP53 wild‐type MPN‐BP/AP (median 11 months; p < 0.01). OS in MF‐CP was significantly shorter with multihit versus non‐multihit TP53 MUT (median 10 vs. 35 months; HR 2.9; p < 0.01), independent of other MF‐relevant genetic risk factors, including ASXL1/SRSF2/U2AF1 mutations. Multihit TP53 MUT was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus “not reached” in patients with ( N = 9) versus without ( N = 8) multihit TP53 MUT ( p < 0.01). The presence of multihit or non‐multihit TP53 MUT in MPN‐BP/AP or multihit TP53 MUT in MF‐CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of “myeloid neoplasms with mutated TP53 .” By contrast, detection of non‐multihit TP53 MUT , by itself, might not endanger short‐term survival in MF‐CP, PV, or ET.

Importance Essential thrombocythemia, a clonal myeloproliferative neoplasm with excessive platelet production, is associated with an increased risk of thrombosis and bleeding. The annual incidence rate of essential thrombocythemia in the US is 1.5/100 000 persons. Observations Patients with essential thrombocythemia have a persistent platelet count of 450 × 10 9 /L or greater. The differential diagnosis includes myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia); inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus; infections; splenectomy; iron deficiency anemia; and solid tumors such as lung cancer. Approximately 90% of individuals with essential thrombocythemia have genetic variants that upregulate the JAK-STAT (signal transducer and activator of transcription 5) signaling pathway, including Janus kinase 2 (JAK2, 64%), calreticulin (CALR , 23%), and myeloproliferative leukemia virus oncogene (MPL , 4%). The median age at diagnosis of essential thrombocythemia is 59 years. The median overall survival exceeds 35 years in those diagnosed at 40 years or younger. Patients with essential thrombocythemia are at increased risk of arterial thrombosis (11%), venous thrombosis (7%), and hemorrhagic complications (8%). Thrombosis risk is increased among those with a history of thrombosis, age older than 60 years, a JAK2 gene variant, and cardiovascular risk factors (eg, hypertension, diabetes mellitus, hyperlipidemias, tobacco use). Use of aspirin (81-100 mg/d) is suggested for most patients with essential thrombocythemia to lower thrombosis risk. In a retrospective study of 300 affected patients with a low thrombosis risk (younger than 60 years with no prior thrombosis), those not taking aspirin (100 mg/d) had a risk of arterial thrombosis of 9.4/1000 patient-years and a venous thrombosis risk of 8.2/1000 patient years; cardiovascular risk factors were associated with a higher risk of arterial thrombi (incidence rate ratio, 2.5 [95% CI, 1.02-6.1]), and a JAK2 gene variant was associated with increased risk of venous thrombosis (incidence rate ratio, 4.0 [95% CI, 1.2-12.9]). In a randomized trial of 114 patients at higher risk for thrombosis (age older than 60 years or a prior thrombotic event), cytoreduction with hydroxyurea significantly lowered the risk of arterial or venous thrombotic events compared with no cytoreductive therapy (3.6% vs 24%; P &amp;lt; .01). At a median of 8.5 years from diagnosis, approximately 10% of patients with essential thrombocythemia develop myelofibrosis and about 3% develop acute myeloid leukemia. Conclusions Essential thrombocythemia is a rare clonal myeloproliferative neoplasm associated with an increased risk of venous and arterial thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. Based on individual risk factors for thrombosis, persons with essential thrombocythemia may be treated with low-dose aspirin, either alone or in combination with a cytoreductive drug such as hydroxyurea.