Vannucchi, Alessandro M.

Abstract We examined the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), and monocyte (AMC) counts, on overall (OS), leukemia‐free (LFS), and myelofibrosis‐free (MFFS) survival in essential thrombocythemia (ET). Informative cases ( N = 598; median age 59 years; females 62%) were retrospectively accrued from a Mayo Clinic database: JAK2 59%, CALR 27%, triple‐negative 11%, and MPL 3%; international prognostic scoring system for ET (IPSET) risk high 21%, intermediate 42%, and low 37%; 7% (37/515) had abnormal karyotype and 10% (21/205) adverse mutations ( SF3B1/SRSF2/U2AF1/TP53 ). At median 8.4 years, 163 (27%) deaths, 71 (12%) fibrotic, and 20 (3%) leukemic transformations were recorded. Multivariable analysis resulted in HR (95% CI) of 16.5 (9.9–27.4) for age > 70 years, 3.7 (2.3–6.0) for age 50–70 years, 2.4 (1.7–3.3) for ANC ≥8 × 10 9 /L, and 1.9 (1.4–2.6) for ALC <1.7 × 10 9 /L. The corresponding HR‐based scores were 4, 2, 1, and 1, resulting in an new 4‐tiered AgeAncAlc (AAA; triple A) risk model: high (5–6 points; median survival 8 years; HR 30.1, 95% CI 17.6–54), intermediate‐2 (4 points; median 13.5 years; HR 12.7, 95% CI 7.1–23.0), intermediate‐1 (2–3 points; median 20.7 years; HR 3.8, 95% CI 2.3–6.4) and low (0–1 points; median 47 years). The AAA model (Akaike Information Criterion [AIC] 621) performed better than IPSET (AIC 647) and was subsequently validated by an external University of Florence ET cohort ( N = 485). None of the AAA variables predicted LFS while ALC <1.7 × 10 9 /L was associated with inferior MFFS ( p = .01). Adverse mutations ( p < .01) and karyotype ( p < .01) displayed additional prognostic value without disqualifying the prognostic integrity of the AAA model. This study proposes a simple and globally applicable survival model for ET, which can be used as a platform for further molecular refinement. This study also suggests a potential role for immune‐related biomarkers, as a prognostic tool in myeloproliferative neoplasms.

Abstract Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. Patients and Methods: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. Results: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells. Conclusions: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.

7016 Background: Many patients (pts) with myelofibrosis (MF) experience anemia resulting from disease or JAK inhibitor therapy. The open-label, phase 2 ACE-536-MF-001 study (NCT03194542) evaluated the safety and efficacy of luspatercept (LUSPA) for the treatment of MF-related anemia. Methods: Eligible pts comprised 4 cohorts based on transfusion dependence (TD, defined as receiving 4–12 red blood cell [RBC] units/84 days [d] immediately up to cycle 1 d 1) and stable ruxolitinib (RUX) treatment; cohort 1: no TD, no RUX; cohort 2: TD, no RUX; cohort 3A: no TD, RUX; cohort 3B: TD, RUX. Pts received subcutaneous LUSPA 1.0 mg/kg (1.33 mg/kg for pts in cohort 3B expansion) with titration up to 1.75 mg/kg in 21-d cycles. Disease response was assessed at d 169 and treatment extended for pts showing clinical benefit; pts were followed for ≥ 3 years (y) post last dose. The primary endpoint was anemia response (defined as 84 consecutive d: ≥ 1.5 g/dL hemoglobin [Hgb] from baseline without transfusion [cohorts 1 and 3A] or RBC transfusion-free [cohorts 2 and 3B]); secondary endpoints included duration of response (DOR), transfusion frequency, change in Hgb level, and symptom response. Results: Of 95 pts in the ITT group, the most common reason for treatment discontinuation was lack of clinical benefit at d 169 (n = 28). Median (range) age was 71.0 (50–89) y. Most (54.7%) pts had primary MF, intermediate-risk 2 disease (75.8%), and > 2 y since initial diagnosis (74.7%). Median prior RUX therapy was 18.1 months (cohorts 3A/3B) and 84.7% of pts had baseline transfusion burden 6–12 units/84 d (cohorts 2/3B). Mean treatment duration was 42.8 weeks. Cohort 3B had the highest anemia response rate with 26.3% (95% CI, 13.4–43.1) of pts transfusion independent during the primary treatment period and 31.6% (95% CI, 17.5–48.7) transfusion independent during the entire treatment period; median (range) DOR was 448 d (85–1582). In cohort 3B: 19 (50.0%) pts had reduced transfusion burden by ≥ 50% during the primary treatment period; 8 (21.1%) pts achieved mean Hgb increase ≥ 1.5 g/dL from baseline throughout the entire treatment period and 6 (15.8%) achieved a mean ≥ 50% reduction in symptom score from baseline. Overall, 47.4% of pts had ≥ 1 treatment-related adverse event (TRAE), most frequently hypertension (17.9%, 5.3% grade ≥ 3); 3.2% of pts had a serious TRAE. One TRAE led to LUSPA discontinuation. Two (2.1%) pts had transformation to acute myeloid leukemia. Nine pts died on treatment from: post-procedural hemorrhage, pneumonia, intracranial hemorrhage, septic shock, ischemic stroke, multiple organ dysfunction syndrome, renal failure, pneumonitis, and myelofibrosis (n = 1 each); no deaths were considered related to the study drug. Conclusions: In pts with MF, the safety profile of LUSPA was consistent with previous studies and efficacy results showed promising improvements in anemia and transfusion burden in all cohorts. Clinical trial information: NCT03194542 .

AbstractA group of international experts, including hematopathologists, oncologists, and geneticists were recently summoned (September 2021, Chicago, IL, USA) to update the 2016/17 World Health Organization classification system for hematopoietic tumors. After careful deliberation, the group introduced the new International Consensus Classification (ICC) for Myeloid Neoplasms and Acute Leukemias. This current in‐depth review focuses on the ICC‐2022 category of JAK2 mutation‐prevalent myeloproliferative neoplasms (MPNs): essential thrombocythemia, polycythemia vera, primary myelofibrosis, and MPN, unclassifiable. The ICC MPN subcommittee chose to preserve the primary role of bone marrow morphology in disease classification and diagnostics, while also acknowledging the complementary role of genetic markers for establishing clonality, facilitating MPN subtype designation, and disease prognostication.

Abstract Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.