Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study.

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.

Melphalan Dose in Combination with Fludarabine Affects GI Toxicity and GVHD after Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Fludarabine (Flu) and melphalan (Mel) reduced-intensity conditioning is frequently used for allogenic hematopoietic cell transplant (allo-HCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, there is limited evidence on the impact of Mel dosing on toxicities and clinical outcomes of allo-HCT. We retrospectively compared 8/8 HLA matched donor allo-HCT outcomes of 345 patients with AML or MDS receiving total Mel dose of 100 mg/m2 (Mel-100, n=62) versus 140 mg/m2 (Mel-140, n=283) in combination with Flu. Median age at allo-HCT was 66 years and median follow-up was 36.5 months. For Mel-100 versus Mel-140 groups, any grade gastrointestinal toxicity rates were 40.3% vs. 67.8% (p<0.001), day 100 grade II-IV acute graft-versus-host disease (GVHD) rates were 21.0% vs. 43.1% (p=0.001) and 2-year chronic GVHD rates were 17.4% vs. 27.1% (p=0.033). In multivariable analysis, Mel-140 resulted in higher risks of gastrointestinal toxicity (HR=1.83, p=0.013), grade II-IV acute GVHD (HR=2.35, p=0.003), and moderate/severe chronic GVHD (HR=3.13, p=0.007). Total Mel dose had no independent impact on oral mucositis, non-relapse mortality, relapse, relapse-free survival, and overall survival. While independent validation of our observation is warranted, our findings support using Mel-100 in combination with Flu to minimize allo-HCT toxicities and morbidities related to GVHD.

Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial.

BACKGROUND: The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial. METHODS: COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting). FINDINGS: Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis. INTERPRETATION: Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups. FUNDING: Celgene and Acceleron Pharma.

Influence of TP53 Gene Mutations and its Allelic Status in Myelodysplastic Syndromes with Isolated 5q Deletion.

Mutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, while the remaining patients displayed monoallelic mutations. TP53 multihit alterations were predictive of an increased risk of leukemic transformation. The impact of monoallelic alterations was dependent on the variant allele frequency (VAF); patients with TP53 monoallelic mutations and VAF <20% exhibited behavior similar to TP53 wild type, and those with TP53 monoallelic mutations and VAF ≥20% presented outcomes equivalent to TP53 multihit patients. This study underscores the importance of considering TP53 allelic state and VAF in the risk stratification and treatment decision-making process for patients with MDS-del(5q).

Outcomes of acute myeloid leukemia patients who responded to venetoclax and azacitidine and stopped treatment.

Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.

ASXL1/TET2 genotype-based risk stratification outperforms ASXL1 mutational impact and is independent of mutant variant allele fractions in chronic myelomonocytic leukemia.

Not available.

Personalized Timing for Allogeneic Stem-Cell Transplantation in Hematologic Neoplasms: A Target Trial Emulation Approach Using Multistate Modeling and Microsimulation.

PURPOSE: Decision about the optimal timing of a treatment procedure in patients with hematologic neoplasms is critical, especially for cellular therapies (most including allogeneic hematopoietic stem-cell transplantation [HSCT]). In the absence of evidence from randomized trials, real-world observational data become beneficial to study the effect of the treatment timing. In this study, a framework to estimate the expected outcome after an intervention in a time-to-event scenario is developed, with the aim of optimizing the timing in a personalized manner. METHODS: Retrospective real-world data are leveraged to emulate a target trial for treatment timing using multistate modeling and microsimulation. This case study focuses on myelodysplastic syndromes, serving as a prototype for rare cancers characterized by a heterogeneous clinical course and complex genomic background. A cohort of 7,118 patients treated according to conventional available treatments/evidence across Europe and United States is analyzed. The primary clinical objective is to determine the ideal timing for HSCT, the only curative option for these patients. RESULTS: This analysis enabled us to identify the most appropriate time frames for HSCT on the basis of each patient's unique profile, defined by a combination relevant patients' characteristics. CONCLUSION: The developed methodology offers a structured framework to address a relevant clinical issue in the field of hematology. It makes several valuable contributions: (1) novel insights into how to develop decision models to identify the most favorable HSCT timing, (2) evidence to inform clinical decisions in a real-world context, and (3) the incorporation of complex information into decision making. This framework can be applied to provide medical insights for clinical issues that cannot be adequately addressed through randomized clinical trials.

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis.

The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); patients in cohort 3A/3B had stable ruxolitinib treatment prior to and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary endpoint was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary endpoint. In cohorts 1 and 3A (NTD), 27% and 50% of patients respectively had mean hemoglobin increase ≥1.5 g/dL from baseline. Among TD patients, ~50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. NCT03194542 clinicaltrials.gov.

Toward a more patient-centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS).

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.

Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). PATIENTS AND METHODS: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. RESULTS: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001). CONCLUSION: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.

Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.

Investigation of Serum Albumin as a Dynamic Treatment-Specific Surrogate for Outcomes in Patients With Myelofibrosis Treated With Ruxolitinib.

PURPOSE: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes. METHODS: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin. RESULTS: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients. CONCLUSION: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib.

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.

BACKGROUND: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation. PATIENTS AND METHODS: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations. RESULTS: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib. CONCLUSION: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant.

BACKGROUND: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. PATIENTS AND METHODS: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. RESULTS: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. CONCLUSION: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

Long-term follow up of the combination of ofatumumab, high-dose methylprednisolone, and lenalidomide for untreated chronic lymphocytic leukemia with biomarker analysis.

BACKGROUND: Advancements in frontline therapy and chemotherapy-sparing treatments in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have altered the treatment algorithms of this disease. We present a frontline alternative for treatment- naïve (TN) CLL/SLL patients. METHODS: This was a single-center, phase 2 study of high-dose methylprednisolone (HDMP) and ofatumumab with lenalidomide and ofatumumab consolidative therapy for all comers with TN CLL/SLL. Treatment was continued until disease progression or intolerable side effects. Patients were assessed for response per iwCLL 2008 criteria after completing cycles 3 and 12. RESULTS: Forty-five patients were enrolled (median age, 62.6 years). High-risk features included del17p (18%), Del11q (22%), and unmutated IGHV gene (76%). Median treatment duration was 32·2 (2·7-75·9) months. Thirty-six patients discontinued treatment due to disease progression (22%), adverse events (40%), allogeneic hematopoietic cell transplantation (allo-HCT) (7%), consent withdrawal (4%), and secondary malignancies (7%). The best overall and complete response rates were 96& and 29% respectively. At median follow-up of 61·7 (5·6-84·9) months, 9 patients remained on treatment. Median progression-free survival was 54·4 (2·9-77·6) months. Three patients underwent allo-HCT after a median of 3 (3-4) treatment cycles. Treatment was well tolerated, with a grade 3/4 infusion reaction in one patient. The most common grade 3/4 hematological adverse event was neutropenia (69%). Four patients had grade 3/4 infections. No grade 3/4 tumor flares, tumor lysis syndrome, or thrombosis were observed. CONCLUSION: The combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options. FUNDING: The funders had no role in the study.

Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

Mutations highly specific for secondary AML are associated with poor outcomes in ELN favorable risk NPM1-mutated AML.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in ∼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.

Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS. METHODS: In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting). FINDINGS: Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported. INTERPRETATION: Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs. FUNDING: Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.