Modern Risk Stratification of Acute Myeloid Leukemia in 2023: Integrating Established and Emerging Prognostic Factors.

An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML subgroups. In recent years, this rapidly evolving field has made the prognostic evaluation of AML more challenging. Traditional prognostic factors, established in cohorts of patients treated with standard intensive chemotherapy, are becoming less accurate as new effective therapies are emerging. The widespread availability of next-generation sequencing platforms has improved our knowledge of AML biology and, consequently, the recent ELN 2022 recommendations significantly expanded the role of new gene mutations. However, the impact of rare co-mutational patterns remains to be fully disclosed, and large international consortia such as the HARMONY project will hopefully be instrumental to this aim. Moreover, accumulating evidence suggests that clonal architecture plays a significant prognostic role. The integration of clinical, cytogenetic, and molecular factors is essential, but hierarchical methods are reaching their limit. Thus, innovative approaches are being extensively explored, including those based on "knowledge banks". Indeed, more robust prognostic estimations can be obtained by matching each patient's genomic and clinical data with the ones derived from very large cohorts, but further improvements are needed.

Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS).

PURPOSE: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia. METHODS: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 103/mm3) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 103/mm3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics. RESULTS: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times. CONCLUSION: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.

Thrombosis in Acute Myeloid Leukemia: Pathogenesis, Risk Factors and Therapeutic Challenges.

OPINION STATEMENT: Prophylaxis and treatment of thrombosis in leukemic patients still represent a major challenge with several clinical questions yet to be solved. Indeed, the paucity of evidence makes the management of venous thromboembolic events difficult and not uniform. Due to thrombocytopenia, patients with acute myeloid leukemia (AML) are underrepresented in trials investigating prophylaxis and treatment of thrombosis in cancer, and prospective data are lacking. Likewise, the therapeutic approach with anti-coagulants in leukemic patients is inferred from guidelines originally developed in the solid cancer setting and clear recommendations in the thrombocytopenic population are limited. Importantly, the discrimination of patients at high risk of bleeding from those with a predominant risk of thrombosis remains extremely difficult with no predictive score validated so far. Thus, the management of thrombosis often relies on clinician experience, and it is tailored to the individual patient, constantly balancing thrombotic and hemorrhagic risks. Who would benefit from primary prophylaxis and how a thrombotic event should be appropriately treated are some of the unanswered questions that the future guidelines and trials should address. Moreover, a greater effort should be made to identify robust predictive factors able to guide clinicians in the management of this potential serious complication for AML patients.

Lack of efficacy of convalescent plasma in COVID-19 patients with concomitant hematological malignancies: An Italian retrospective study.

A multicenter retrospective study was designed to assess clinical outcome of COVID-19 in patients with hematological malignancies (HM) following treatment with anti-SARS-CoV-2 convalescent plasma (CP) or standard of care therapy. To this aim, a propensity score matching was used to assess the role of non-randomized administration of CP in this high-risk cohort of patients from the Italian Hematology Alliance on COVID-19 (ITA-HEMA-COV) project, now including 2049 untreated control patients. We investigated 30- and 90-day mortality, rate of admission to intensive care unit, proportion of patients requiring mechanical ventilatory support, hospitalization time, and SARS-CoV-2 clearance in 79 CP recipients and compared results with 158 propensity score-matched controls. Results indicated a lack of efficacy of CP in the study group compared with the untreated group, thus confirming the negative results obtained from randomized studies in immunocompetent individuals with COVID-19. In conclusion, this retrospective analysis did not meet the primary and secondary end points in any category of immunocompromized patients affected by HM.

Frequency and risk factors for thrombosis in acute myeloid leukemia and high-risk myelodysplastic syndromes treated with intensive chemotherapy: a two centers observational study.

The frequency of thrombosis in AML has been evaluated only in a few studies and no validated predictive model is currently available. Recently, DIC score was shown to identify patients at higher thrombotic risk. We aimed to evaluate the frequency of thromboembolism in AML patients treated with intensive chemotherapy and to assess the ability of genetic and clinical factors to predict the thrombotic risk. We performed a retrospective observational study including 222 newly diagnosed adult AML (210) and high-risk MDS (12), treated with intensive chemotherapy between January 2013 and February 2020. With a median follow-up of 44 months, we observed 50 thrombotic events (90% were venous, VTE). The prevalence of thrombosis was 22.1% and the 6-months cumulative incidence of thrombosis was 10%. The median time to thrombosis was 84 days and 52% of the events occurred within 100 days from AML diagnosis. Khorana and DIC score failed to stratify patients according to their thrombotic risk. Only history of a thrombotic event (p = 0.043), particularly VTE (p = 0.0053), platelet count above 100 × 109/L at diagnosis (p = 0.036) and active smoking (p = 0.025) significantly and independently increased the risk of thrombosis, the latter particularly of arterial events. AML genetic profile did not affect thrombosis occurrence. Results were confirmed considering only thromboses occurring within day 100 from diagnosis. DIC score at diagnosis, but not thrombosis, was independently associated with reduced survival (p = 0.004). Previous VTE, platelet count above 100 × 109/L and active smoking were the only factors associate with increased thrombotic risk in AML patients treated intensively, but further studies are needed to validate these results.

Hematopoietic Stem Cells (HSC) and Granulocyte Macrophage Progenitors (GMP) are the Oxidative Stress Targets in Low/Intermediate-1 Risk Myelodysplastic Syndromes.

Introduction: Myelodysplastic Syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell malignancies. Previous studies showed that Reactive Oxygen Species (ROS) play a role in the pathogenesis and clinical evolution of MDS, contributing to Hematopoietic Stem and Progenitor Cells (HSPC) genetic instability. Less is known about ROS levels in the various sub-populations of MDS HSPC and how they correlate with clinical data in MDS patients. Our study aims to analyze ROS levels in MDS Hematopoietic Stem Cells (HSC), common myeloid progenitors (CMP), Granulocyte Macrophages Progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP); afterwards, we looked at the relationship between ROS levels and clinical data. Methods: thirty-eight MDS and 27 Normal Bone Marrow (NBM) samples were collected; ROS levels were analyzed via multicolor flow cytometry. Results: In both NBM and MDS, HSC showed much higher ROS levels than progenitors (3 to 4 folds, p < 0.0001); HSC ROS were significantly more elevated in MDS-no excess blasts versus MDS with excess blasts and versus NBM. GMP from MDS-no excess blasts showed higher ROS compared to NBM GMP. The 3 MDS with Ringed Sideroblasts (RS) showed more elevated ROS in HSC and GMP compared to the not RS low/intermediate-1 MDS; the 2 monosomy 7 patients displayed higher ROS levels in each subpopulation compared to the normal karyotype MDS; the only del(5q) patient did not show relevant differences in ROS levels compared to the median of the normal karyotype MDS ROS. The 9 high transfusion burden patients exhibited higher ROS in HSC and GMP compared to NBM HSC and GMP. These data were not confirmed in low transfusion burden (n:2) and non-transfused patients (n:26). In low/intermediate-1 MDS, a direct correlation between ferritin values and ROS levels in progenitors, but not in HSC, was detected. Interestingly, low/intermediate-1 risk patients that are no longer responding to recombinant human erythropoietin (rh-EPO) showed higher ROS levels in GMP and HSC. Conclusions: Our data showed that ROS can play a role in the pathogenesis and maintenance of low and intermediate-1 risk MDS clone; ROS status can be influenced by several clinical factors as ferritin levels and rh-EPO treatment. In this scenario, high ROS levels can contribute to genetic instability and influence progression to AML. Further biological studies are needed to elucidate ROS role in MDS pathogenesis and analyze the possible benefit of antioxidant drugs added to the standard MDS treatments.