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The aim of our study was to analyze the potential survival benefit associated with HSCT according to clinico-biological scores which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n=241) and one non-transplant cohorts (n=239) were used to test the hypothesis that PMF patients with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. 105 non-transplanted patients could be matched to the 239 transplanted patients. Mean age in transplanted and non-transplanted matched patients was 55.5 and 57.9 years. Blood cell count and DIPSS score distribution were similar in both groups. HSCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients have an advantage of survival with HSCT only when their MTSS were low or intermediate. Transplanted patients had an increased mortality risk the first year but a significant benefit with HSCT after the one-year landmark was observed in higher risk patients. This study confirms that similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies., (Copyright © 2024 American Society of Hematology.)

Abstract: Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

To develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Accelerated-phase myelofibrosis, currently defined by circulating blasts 10% to 19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for accelerated-phase myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had accelerated-phase myelofibrosis. In comparison with chronic-phase (<10% blasts) myelofibrosis, median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the accelerated-phase group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval [CI], 49% to 81%) vs 64% (95% CI, 59% to 69%) for the chronic-phase group (P = .91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the accelerated-phase group was 49% (95% CI, 32% to 67%) vs 55% (95% CI, 50% to 61%) for the chronic-phase group (P = .65). Estimated 5-year nonrelapse mortality was 20% (95% CI, 8% to 33%) for the accelerated-phase group vs 30% (95% CI, 24% to 35%; P = .25) for the chronic-phase group. In terms of relapse, 5-year incidence was 30% (95% CI, 14% to 46%) for the accelerated-phase group vs 15% (95% CI, 11% to 19%) for the chronic-phase group (P = .02). Results were confirmed in multivariable analysis and propensity score matching. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for accelerated-phase myelofibrosis., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We present primary results from the phase 1b GO29754 study evaluating the safety and tolerability of atezolizumab, a programmed death-ligand 1 inhibitor, alone and in combination with azacitidine, a hypomethylating agent (HMA), in patients with relapsed/refractory (R/R) or HMA-naïve myelodysplastic syndrome (MDS). Patients with R/R MDS received atezolizumab for 12 months (cohort A) or atezolizumab plus azacitidine for 6 cycles followed by atezolizumab as maintenance for 8 cycles (cohort B). Patients with HMA-naïve MDS received atezolizumab plus azacitidine until loss of clinical benefit (cohort C). Safety, activity, and exploratory end points were investigated. Forty-six patients were enrolled and received treatment (cohort A, n = 11; cohort B, n = 14; cohort C, n = 21). All patients experienced ≥1 adverse event (AE) on study, and all patients discontinued atezolizumab. In cohort A, 7 patients (63.6%) died, and no patients responded. In cohort B, 8 patients (57.1%) discontinued azacitidine, 11 (78.6%) died, and 2 (14.3%) responded. In cohort C, all 21 patients discontinued azacitidine, 13 died (61.9%), and 13 (61.9%) responded. The study was terminated by the sponsor before completion of recruitment because of the unexpected high early death rate in cohort C (6 [46.2%] of 13 deaths were due to AEs and occurred within the first 4 treatment cycles.). The high death rate and poor efficacy observed in this study do not support a favorable risk-benefit profile for atezolizumab as a single agent or in combination with azacitidine in R/R or HMA-naïve MDS. This trial was registered at www.clinicaltrials.gov as #NCT02508870., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The inclusion of mutation status improved risk stratification for newly diagnosed patients with chronic myelomonocytic leukemia (CMML). Stem cell transplantation is a potentially curative treatment option, and patient selection is critical because of relevant transplant-related morbidity and mortality. We aimed to evaluate the impact of mutation status together with clinical presentations on posttransplant outcome. Our study included 240 patients with a median follow-up of 5.5 years. A significant association with worse survival was identified for the presence of mutations in ASXL1 and/or NRAS. In multivariable analysis, ASXL1- and/or NRAS-mutated genotype (hazard ratio [HR], 1.63), marrow blasts >2% (HR, 1.70), and increasing comorbidity index (continuous HR, 1.16) were independently associated with worse survival. A prognostic score (CMML transplant score) was developed, and the following points were assigned: 4 points for an ASXL1- and/or NRAS-mutated genotype or blasts >2% and 1 point each for an increase of 1 in the comorbidity index. The CMML transplant score (range, 0-20) was predictive of survival and nonrelapse mortality (P < .001 for both). Up to 5 risk groups were identified, showing 5-year survival of 81% for a score of 0 to 1, 49% for a score of 2 to 4, 43% for a score of 5 to 7, 31% for a score of 8 to 10, and 19% for a score >10. The score retained performance after validation (concordance index, 0.68) and good accuracy after calibration. Predictions were superior compared with existing scores designed for the nontransplant setting, which resulted in significant risk reclassification. This CMML transplant score, which incorporated mutation and clinical information, was prognostic in patients specifically undergoing transplantation and may facilitate personalized counseling., (© 2021 by The American Society of Hematology.)

The decision algorithm for treatment of advanced myelodysplastic syndrome (MDS) (intermediate- to very high-risk by the revised International Prognostic Scoring System [IPSS-R]) is complex. Often, the appropriate choice is unknown and not currently addressed by available clinical evidence. Although allogeneic hematopoietic cell transplantation (alloHCT) is curative for some patients with MDS, there is a concurrent high risk of mortality and morbidity. Alternatively, although hypomethylating agents (HMAs) have low toxicity, they are not thought to be curative, with a median increase in overall survival of only 9 months. Initial attempts to improve outcomes with HMAs through addition of novel agents failed, but there is hope that newer combination strategies will improve outcomes. Challenging clinical questions include who should be considered for alloHCT, appropriate timing and preparation for alloHCT, and appropriate therapeutic choices for patients who are not candidates for alloHCT. Given the interplay between alloHCT and non-alloHCT approaches, a unified coordinated approach is optimal for patients with advanced MDS. When possible, patients with advanced MDS should be encouraged to enroll into clinical trials that include alloHCT and non-alloHCT approaches., Competing Interests: Conflict-of-interest disclosure: B.L.S. is a consultant for BMS, Celgene, Incyte, Agios, and Alexion., (© 2020 by The American Society of Hematology.)

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734., (© 2020 by The American Society of Hematology.)

There is a limited understanding of the clinical and molecular factors associated with outcomes of hematopoietic cell transplantation (HCT) in patients with BCR-ABL-negative myeloproliferative neoplasms in blast phase (MPN-BP). Using the Center for International Blood and Marrow Transplant Research database, we evaluated HCT outcomes in 177 patients with MPN-BP. Ninety-five (54%) had sufficient DNA for targeted next-generation sequencing of 49 genes clinically relevant in hematologic malignancies. At 5 years, overall survival (OS), cumulative incidence of relapse, and nonrelapse mortality of the study cohort was 18%, 61%, and 25%, respectively. In a multivariable model, poor-risk cytogenetics was associated with inferior OS (hazard ratio [HR], 1.71; 95% CI, 1.21-2.41) due to increased relapse (HR, 1.93; 95% CI, 1.32-2.82). Transplants using mobilized peripheral blood (PB) were associated with better OS (HR, 0.60; 95% CI, 0.38-0.96). No difference in outcomes was observed in patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Among the 95 patients with molecular data, mutation of TP53, present in 23%, was the only genetic alteration associated with outcomes. In a multivariate model, TP53-mutant patients had inferior OS (HR, 1.99; 95% CI, 1.14-3.49) and increased incidence of relapse (HR, 2.59; 95% CI, 1.41-4.74). There were no differences in the spectrum of gene mutations, number of mutations, or variant allele frequency between patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Genetic factors, namely cytogenetic alterations and TP53 mutation status, rather than degree of cytoreduction predict outcomes of HCT in MPN-BP. No meaningful benefit of conventional HCT was observed in patients with MPN-BP and mutated TP53., (© 2020 by The American Society of Hematology.)

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

This article has a companion Counterpoint by Soiffer., (© 2020 by The American Society of Hematology.)

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up., (© 2020 by The American Society of Hematology.)

To improve patient quality of life and reduce health care costs, many conditions formerly thought to require inpatient care are now treated in the outpatient setting. Outpatient induction chemotherapy for acute myeloid leukemia (AML) may confer similar benefits. This possibility prompted a pilot study to explore the safety and feasibility of intensive outpatient initial or salvage induction chemotherapy administration for adults with AML and high-risk myelodysplastic syndrome (MDS). Patients with no significant organ dysfunction and a treatment-related mortality (TRM) score corresponding to a day 28 mortality rate of <5% to 10% were eligible for study. Patients were treated as outpatients with daily evaluation by providers and only admitted to the hospital if mandated by complications. Twenty patients were consented, and 17 were treated. Eight patients received initial induction chemotherapy and 9 received salvage induction chemotherapy. Fourteen patients completed induction chemotherapy administration in the outpatient setting (82.4%; exact 95% confidence interval [CI], 55.8-95.3). Three patients were admitted during the course of chemotherapy administration, 2 for neutropenic fever and 1 for grade 3 mucositis. No patients died within 14 days of the initiation of induction chemotherapy (exact 95% CI, 0-22.9). Results of this pilot study suggest it is feasible to complete outpatient induction chemotherapy in select patients with AML and high-risk MDS. A team including nurses, social workers, medical providers, and pharmacists was key to the successful implementation of outpatient induction., (© 2020 by The American Society of Hematology.)

Reduced-intensity conditioning (RIC) regimens were initially introduced to provide allogeneic stem cell transplantation (HCT), a potentially curative procedure for myeloid malignancies, for patients who were not considered eligible for conventional myeloablative HCT either because of advanced age or excessive comorbidities. A variety of RIC regimens have been studied. The exact definition of RIC remains arbitrary and generally depends upon the perceived toxicity of a given regimen rather than the actual dose of chemotherapy or radiotherapy administered. In several published series, RIC regimens have demonstrated a reduction in non-relapse mortality (NRM), thereby accomplishing the initial goal of expanding the patient population eligible for this potentially curative procedure. Most retrospective studies performed to date have shown a decrease in NRM and an increase in relapse-related mortality with the use of RIC as opposed to conventional myeloablative HCT in myeloid malignancies. This appears to be particularly true for patients who are in relapse at the time of HCT. In contrast, patients who are in remission at time of HCT appear to have a reduction in NRM without a subsequent increase in relapse-related mortality. There is interest in applying RIC to younger patients and to patients with fewer comorbidities as they may have a reduction in NRM without a concomitant increase in relapse. Prospective multicenter studies are needed to define the optimal conditioning regimen, which is likely dependent upon a variety of disease-specific and patient-specific factors.