MDS/myeloproliferative Neoplasm Research Articles

Myelodysplastic Syndromes and Myelodysplastic Syndromes/Myeloproliferative Neoplasms: A Real-World Experience From a Developing Country.

Myelodysplastic syndromes (MDS) include a heterogeneous group of clonal bone marrow disorders characterized by ineffective hematopoiesis. They manifest as dysplasia in bone marrow hemopoietic elements associated with peripheral cytopenias with variable risk of AML transformation. We analyzed retrospectively registry data collected prospectively from patients with primary MDS and patients with MDS/myeloproliferative neoplasm (MPN) in the Jordan University Hospital between January 2007 and September 2021. The registry captured epidemiologic information such as date of diagnosis, age, gender, date of AML transformation, cytogenetics, MDS subtype, risk group according to Revised International Prognostic Scoring System, and survival. The registry also captured baseline ferritin, B12, and lactate dehydrogenase levels. A total of 112 patients with MDS and MDS/MPN were included in the registry. Median age at diagnosis was 59 years. The male-to-female ratio was about 1.2. In a multivariate cox regression model, baseline serum ferritin significantly affected survival as patients with levels exceeding 1,000 μg/L had a risk of death three times higher compared with those with <1,000 μg/L levels (P < .05). To our knowledge, our study is the first comprehensive study examining the epidemiology and prognostic factors in patients with MDS and patients with MDS/MPN in Jordan. Our results show that MDS and MDS/MPN epidemiology in Jordan is different compared with Western countries. Our results also show that baseline serum ferritin levels can be used as a prognostic marker for patients with MDS.

Sole DNMT3A/TET2/ASXL1 Mutations Define a Distinct Clinical Trajectory for Patients with Clonal Hematopoiesis

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a clinically defined entity that is recognized by the 2022 International Consensus Classification and the 5 th Edition of the WHO. While the Clonal Hematopoiesis Risk Score (CHRS) incorporates 8 variables that underlie a prognostic framework for prediction of risk for progression to myeloid neoplasm (MN) (Weeks LD et al., NEJM Evidence 2023), there remains debate as to the role of mutations in epigenetic regulators, such as DNMT3A, TET2 and ASXL1 (“DTA”), with respect to clinical outcomes in the real-world setting. Although DTA mutations often occur early in myeloid pathogenesis, the persistence of these mutations as age-related clonal hematopoiesis (CH) might not significantly influence clinical course (Jongen-Lavrencic M et al., NEJM 2018). We have previously observed impaired clearance of DTA-mutant clones with hypomethylating agent or intensive chemotherapy for myelodysplastic neoplasms and acute myeloid leukemia (ASH abstract 4122; Blood (2022) 140 (Supplement 1): 9150-9151), and we now seek to understand the impact of sole DTA mutations in patients with CH. Methods: We studied a pre-selected group of patients who had an indication for undergoing bone marrow evaluation. Such indications included cytopenia(s), elevated blood cell count(s), staging/workup for lymphoma, and radiographic marrow abnormalities. Patients with CH were identified via concurrent morphologic, cytogenetic, and molecular diagnostics of bone marrow aspirates reviewed by UMass and Stanford Hematopathology from 2013 to 2023. CH was defined as presence of a somatic mutation with variant allele frequency (VAF) ≥ 2% on molecular diagnostics or non-myelodysplastic syndrome (MDS)-defining clonal cytogenetic aberration in a patient without morphologic evidence of MN. A total of 79 patients with CH were identified, then segregated based on presence or absence of sole DTA mutations. Results: We assessed the clinical trajectory of patients with CH who did not exclusively have DTA mutations (“non-sole DTA;” n = 58) (Panel A) compared to patients with CH who had DTA mutations alone without any other concurrent mutations (“sole DTA;” n = 21) (Panel B). The median age at detection of CH for sole DTA vs. non-sole DTA was 71.0 ± 2.11 years vs. 71.5 ± 1.45 years, respectively ( p = 0.454). Median number of mutations for sole DTA vs. non-sole DTA patients was 1.24 ± 1.2 vs. 2.24 ± 0.18, respectively ( p &amp;lt; 0.0001). Median follow-up for all patients was 450 days, and the median overall survival was not reached for either group. For non-sole DTA patients, 44 of 58 patients (76%) did not progress, while 14 of 58 patients (24%) progressed to frank MN at the time of analysis. Types of frank MN in the 14 progressors included MDS (50%), MDS/myeloproliferative neoplasm (MPN) overlap (28.6%), AML (14.3%), and MPN (7.1%). For sole DTA patients, 0 of 21 patients (0%) progressed. Regarding distribution of VAFs for sole DTA patients vs. non-sole DTA patients, mean VAF was 13.5% ± 1.91% vs. 31.6% ± 2.18%, respectively ( p &amp;lt; 0.001). For patients with both DTA mutations plus additional mutations, mean VAF for non-progressors vs. progressors was 30.4% ±1.47% vs. 38.6% ± 2.97%, respectively ( p = 0.206). For patients without any DTA mutations but with other somatic mutations, mean VAF for non-progressors vs. progressors was 29.7% ±1.67% vs. 35.2% ± 2.26%, respectively ( p = 0.160). Conclusion: In this study of pre-selected patients with CH, DTA mutations alone were insufficient for progression to frank MN. Progressors included patients with either (1) DTA mutations plus concurrent mutations, or (2) patients without DTA mutations but presence of mutations in other gene clusters. The clinical trajectory of patients with CH in our study differs from that of patients from large consortia possibly because our patients presented with an indication for testing, reflecting real-world data. A limitation of our analysis is the variability in time to recognition and diagnosis of CH, which reflects the high heterogeneity of these patients. Still, our data suggest the need for large-scale studies in the real-world setting to better prognosticate the relevance of DTA mutations for this patient population.

Subunit-Specific Analysis of Cohesin-Mutant Myeloid Malignancies Reveals Distinct Ontogeny and Outcomes

Introduction:Loss of function mutations in the cohesin complex ring components and modulators STAG2, RAD21, SMC1A, SMC3, and PDS5B are recurrent genetic drivers in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and MDS/myeloproliferative neoplasm (MPN) overlap syndromes. However, whether different cohesin subunit mutations share disease characteristics and prognostic impact is not well understood. Methods: We assembled a cohort of 4,439 patients with hematologic neoplasms at the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), and identified a subset of 790 cohesin-mutant patients, the largest cohesin-mutant cohort to date. We performed a retrospective analysis of the incidence, clinical presentation, genomic landscape, and clinical outcomes in a cohesin subunit-specific way. Results: STAG2 mutations were most common and present in 610 cases (diagnosed as MDS (50%), AML (36%), MDS/MPN (10%)), followed by RAD21 in 104 (20% MDS, 64% AML, 2% MDS/MPN), SMC3 in 26 (35% MDS, 42% AML, no MDS/MPN), SMC1A in 22 (27% MDS, 55% AML, 5% MDS/MPN), PDS5B in 16 (13% MDS, 38% AML and 6% MDS/MPN), and 12 cases with more than one mutated cohesin gene (50% MDS, 33% AML, 8% MDS/MPN). Within the DFCI cohort, 256 (82%) patients were diagnosed with a myeloid malignancy and 55 (18%) patients with a non-myeloid hematologic malignancy. We focused our subsequent analysis on 735 patients diagnosed with MDS, MDS/MPN or AML, and compared them to 3,649 cohesin-wildtype (WT) patients in the DFCI and MLL cohorts. We found that STAG2 mutations were acquired at the MDS stage and were associated with MDS with increased blasts (75% cases with MDS-IB1 or IB2) and secondary AML. We also noted their co-occurrence with secondary AML-type mutations, such as ASXL1 (64%, OR=5.5, FDR=5e-29), SRSF2 (45%, OR=7.4, FDR=5-e31) and RUNX1 (37%, OR=3.5, FDR=2e-13), and trisomy 8 (OR=10.6, FDR= 2.2e-50). In contrast, mutations in RAD21, SMC1A, SMC3 and PDS5B shared features with de novo AML, including co-occurrence with NPM1 (32%, OR 4.3, FDR=1e-6) and FLT3 (23%, OR= 2.8, FDR= 0.01), and association of RAD21 and SMC1A with t(8;21) AML (OR= 131;134; FDR= 3.8e-5;4.1e-19). Of note, both STAG2 and RAD21 mutations shared a mutational exclusivity with TP53 mutations (OR=0.04-0.06, FDR &amp;lt; 0.001, Figure 1A). We next assessed the impact of different cohesin mutations on clinical outcomes. We conducted independent analyses of overall survival (OS) and progression free survival (PFS) in MDS and AML. Given our observations that cohesin mutations were mutually exclusive with TP53 mutations, and the established prognostic impact of TP53 mutations, we compared the overall survival (OS) and AML-free survival (PFS) of patients with STAG2-mutant MDS (n=119) to TP53-mutant MDS (n=280) and cohesin/ TP53-WT MDS (n=1,023). With a median follow-up (FU) of 51.1 months we observed a significantly worse OS of STAG2-mutant MDS compared to cohesin and TP53-WT MDS (HR 1.44, CI= 1.10-1.89, p=0.007) and a similar risk of leukemic transformation as TP53-mutant MDS cases (median AML-PFS of 15.4 months for STAG2, and 12.1 months for TP53, p=0.3). Furthermore, STAG2-mutant AML (n=148) had significantly worse OS than AML without myelodysplasia related changes (MR) (n=1384) (HR= 0.62, 95% CI=0.5-0.76, p&amp;lt;0.001, median FU 42.8 months), and similar outcomes as AML-MR without TP53 mutations (n=567), (HR=1.25, 95% CI= 1.01-1.55, p=0.04). Importantly, this pattern was distinct from outcomes of RAD21-mutant AML (n=39), which was almost identical to AML-non-MR and significantly better than STAG2-mutant AML OS (HR= 0.56, 95% CI= 0.34-0.93, p=0.024) ( Figure 1B). The effects of STAG2 and RAD21 mutations on OS remained significant when censored for allogeneic stem cell transplantation. Our findings suggest that only STAG2 mutations confer a negative impact on MDS and AML, and this is attributed to secondary ontogeny. Conclusions: In summary, our study establishes a role for different cohesin subunit mutations in distinct subtypes of MDS and AML, which has significant prognostic implications and expands our current understanding of this important group of driver genes. The findings from our subunit-specific analysis demonstrate that while STAG2 mutations are characterized by secondary AML ontogeny arising from MDS and associated with a worse prognosis, RAD21 mutations are associated with de novo AML and better survival.

Unraveling the Impact of 2022 Classifications on Secondary Acute Myeloid Leukemia: Assessing the True Qualification Power of Diagnostic Qualifiers

Background: In 2022, two new acute myeloid leukemia (AML) classifications (World Health Organization, WHO and International Consensus Classification, ICC) and a new edition of the European LeukemiaNet (ELN) prognostic system have been released. These advances have been driven by the need to incorporate molecular characterization into the diagnosis and management of AML. Although important similarities in the diagnostic classifications have been recently recognized by diverse validation studies, the different approach to define AML ontogenesis (primary vs secondary) remains a central issue of the classification discrepancy. While for the WHO 2022 a prior diagnosis of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) is sufficient to define AML myelodysplasia-related (MR), the ICC no longer recognizes the AML arising from MDS (sAML) as a disease entity, and instead introduces a list of “diagnostic qualifiers”, also including therapy-related AML (tAML). Nevertheless, whether these “diagnostic qualifiers” represent a mere “descriptive” information or impact on prognosis and outcome is not well defined. Methods: We studied a cohort of 936 AML patients collected through a multicenter international collaboration across 5 academic centers. An integration of clinical and cytogenetic/molecular data was used to apply the WHO 2016, WHO 2022 and ICC diagnostic classifications and the 2017 and 2022 edition of ELN prognostic risk stratification criteria. Results: Overall,220 cases were classified as secondary AML (155 sAML and 65 tAML). As per the2016 and 2022 WHO editions, the majority of sAML cases, accounting for 98.1% and 95.5% respectively, fell into the myelodysplasia-related changes (MRC) AML and AML-MR categories due to the “disease defining” presence of an antecedent MDS or MDS/MPN. According to the ICC, 81.9% of sAML cases were defined by the presence of a MDS-related genetic profile, belonging to AML with mutated TP53 (AML- TP53) and AML with MDS-related gene mutations (AML-MDSgene) and cytogenetic abnormalities (AML-MDSk) subcategories. The tAML group showed a greater diagnostic heterogeneity, with a higher frequency of KMT2A-related categories (10.8% and 7.7% according to WHO 2022 and ICC, respectively) and AML- TP53 for the ICC (21.5%, Fig. 1A). In terms of outcomes, according to the ELN 2022 risk classification the sAML and tAML groups were classified into favorable risk 5.8% and 13.9%, intermediate 12.3% and 36.9%, and adverse 81.9% and 49.2%, respectively. Notably, while the ELN 2022 edition was effective in stratifying the group of tAML patients receiving conventional treatment (p=0.002), no statistically significant differences were noticed when sAML patients were stratified based on the same ELN 2022 risk categories ( Fig. 1B). We then compared our sAML cohort to AML cases with ICC MDS-related profile not fulfilling the anamnestic criterion of a prior MDS diagnosis (233 cases, 32.54% - AML- TP53/MDSgene/MDSk subcategories), in terms of molecular characteristics and outcome. Remarkably, both groups showed a similar prevalence of MDS genes, except for RUNX1, which was more frequent in the AML cases with the ICC MDS-related profile (14%) than in sAML (6.3%, p =0.034). Finally, both groups showed similar outcomes. Conclusions: Here, we demonstrated the overarching importance of the biological ontogenetic profile in AML (&amp;gt;80% of sAML presented an MDS-related profile) and of the risk stratification according to the new classifications (&amp;gt;80% of sAML belonged to adverse ELN 2022 risk). As to outcomes, 2022 ELN edition confirmed its stratification capability for tAML, while sAML were not adequately stratified. This evidence supports the idea that therapy-related AML should be acknowledged and classified as “second” neoplasms, rather than being categorized as secondary AML. Considering the overlap in AML of MDS-related profile regardless of the presence of an antecedent diagnosis of MDS as “diagnostic qualifier”, these cases could potentially benefit from treatments specifically tailored for MDS-related conditions or those typically reserved for secondary AML, such as CPX-351.

Bromodomain and Extra-Terminal Inhibitor INCB057643 (LIMBER-103) in Patients with Relapsed or Refractory Myelofibrosis and Other Advanced Myeloid Neoplasms: A Phase 1 Study

Introduction: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of myelofibrosis (MF) and other hematologic malignancies including B-lymphoma-2, nuclear factor kappa, and c-Myc. In a previous phase 1/2 clinical trial, the small-molecule oral BET inhibitor INCB057643, evaluated as monotherapy and in combination with ruxolitinib, was associated with favorable tolerability and encouraging clinical activity in patients with advanced malignancies. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) is evaluating the safety and tolerability of INCB057643 (4 mg once daily [qd] with escalation up to 12 mg qd) in patients aged ≥18 years as (1) monotherapy (part 1) in relapsed or refractory (R/R) MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to ruxolitinib (part 2) in patients with MF and suboptimal response to ruxolitinib. The primary endpoints are safety and tolerability, including identification of dose-limiting toxicities (DLTs). Secondary endpoints in patients with MF include spleen volume response (≥35% reduction from baseline at Week 24 per magnetic resonance imaging/computed tomography scan) and symptom response (≥50% reduction from baseline at Week 24 in MPN-Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]). Results: As of data cutoff on June 1, 2023, 14 patients were treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=2; 12 mg, n=2), and 6 were treated in part 2 (4 mg, n=3, 6 mg, n=3). In part 1, patients had a median (range) age of 69.5 (50.0-79.0) years and a median (range) study treatment duration of 177 (9-375) days; 8 were men. In part 2, patients had a median (range) age of 71 (64-76) years; median (range) study treatment duration of 92.5 (46-274) days; 3 were men. 16 patients had MF; 4 had MDS/MPN, including 1 with chronic myelomonocytic leukemia. A total of 10 patients discontinued treatment, 4 for lack of efficacy or disease progression and 4 due to adverse events (AEs; 3 in the monotherapy group, 1 in the combination group). Thrombocytopenia (n=3) and anemia/thrombocytopenia (n=1) were the only treatment-emergent AEs (TEAEs) leading to discontinuation, and thrombocytopenia was the most common TEAE (n=11). Grade ≥3 TEAEs occurring in ≥1 patient were thrombocytopenia (n=5), anemia (n=4), and hypokalemia (n=2). 12 serious AEs occurred across 5 patients (only COVID-19 occurred in &amp;gt;1 patient [n=2]); all but one serious AE (pneumonia) was considered unrelated to study treatment. There were 2 DLTs: thrombocytopenia in 1 patient with MDS/MPN in the 12 mg cohort and hyperbilirubinemia in 1 patient with MF in the 12 mg cohort. 2 deaths occurred on study, both in the 4 mg monotherapy cohort due to disease progression (MF, n=1; MDS/MPN, n=1). Overall, 5 patients on monotherapy and 2 on combination therapy demonstrated a reduction in spleen volume at Week 12 (≥35% reduction in 2 patients and 1 patient, respectively); at Week 24, 3 patients on monotherapy and 2 on combination therapy had a reduction in spleen volume (≥35%: 1 patient and 1 patient, respectively; Figure 1). Percentage change from baseline in MPN-SAF TSS in individual patients is reported in Figure 2; at Week 12, ≥50% improvement from baseline occurred in 3 patients on monotherapy and 1 on combination therapy (≥50% improvement at Week 24: 2 patients and 1 patient). Conclusions: INCB057643 monotherapy (4 and 8 mg qd) and combined (4 and 6 mg qd) with ruxolitinib was generally well tolerated, whereas the 12 mg qd monotherapy dose caused 2 DLTs. There were no treatment-related fatal events. Improvements in spleen size and symptom burden were observed in patients receiving ≥8 mg in the monotherapy group and 4 mg in the combination therapy group. Dose finding (part 1) is ongoing with 10 mg qd, after which the recommended dose(s) for expansion will be declared. Dose escalation is also ongoing in the combination therapy group.

A Clinical-Molecular Prognostic Scoring System for Myelodysplastic Syndrome in Asia - a Multicenter Study of the Asian Myeloid Working Group (AMWG)

Background: In Asia, treatment decisions in myelodysplastic neoplasms (MDS) are conventionally based on the Revised International Prognostic Scoring system (IPSS-R). A unique clinical-molecular prognostic model, the IPSS-molecular (IPSS-M), has been developed based on 2957 patients with de-novo MDS, therapy-related MDS, and MDS/myeloproliferative neoplasm (MPN) overlap syndrome. The IPSS-M comprises haematological parameters, karyotypic abnormalities and somatic mutations in a 31-gene panel. Validation of the IPSS-M in large multicentre studies in Asian has however not been performed. Hence, prognostic models taking into account the unique clinical-molecular characteristics of Asian MDS patients remain undefined. Aims: The objectives of this multicenter cohort study were: 1. to define the haematological, cytogenetic and molecular characteristics of Asian MDS patients; and 2. to develop a prognostic model based on these characteristics. Methods: Consecutive MDS patients in Hong Kong, Singapore and Taiwan diagnosed between 2004 to 2021 were studied. Data were censored on 17 September 2022. Patients with MDS/MPN overlap syndrome were excluded. A panel of 54 myeloid-related genes was sequenced in the diagnostic bone marrow by next-generation sequencing. Hematological, pathological, cytogenetic and molecular variables were evaluated for their association with overall survival (OS), leukemia-free survival (LFS), and time to progression to secondary acute myeloid leukemia (TTP-sAML). Variable selection was performed to determine the confounding variable and independent prognostic variables. The relative weights of the selected variables were estimated using a Cox multivariable model adjusted for confounders. According to the weights of each prognostic variable, individual patient-specific prognostic scores were calculated. Based on the scores of the entire cohort, six prognostic subgroups were defined. The statistical predictive power of this prognostic model was assessed by the concordance index (C-index). The prognostic model was validated with publicly available data from the IPSS-M cohort. Results: Seven hundred and seventy-eight men (63.5%) and 447 women (36.5%) at a median age of 68.4 (interquartile range, IQR: 57-77) years were studied. After a median follow-up of 2.85 (IQR: 0.97-7.06) years, there were 693 deaths (56.6%) and 284 transformations to sAML (23.2%). Three-hundred and ninety-four patients (32.2%) received hypomethylating agents (azaciticine, N=367; decitabine, N=27), and 158 patients (12.9%) underwent allogeneic haematopoietic stem cell transplantation. All patients showed at least one genetic alteration in the 54-gene panel (Figure 1A). Prognostic scoring systems (each with 6 prognostic subgroups) were established for OS (C-index: 0.72) (Figure 1A), LFS (C-index:0.71) (Figure 1B) and TTP-sAML (C-index: 0.74) (Figure 1C). Genomic factors significantly associated with inferior outcomes were monosomy 7, del(5q), and mutations in GNAS and TP53 for OS; trisomy 19, del(5q), monosomy 7, and mutations in GNAS, PTPN11 and TP53 for LFS, and i(17q), del(5q), and mutations in NPM1, NRAS, GNAS, IDH2, SF3B1, and RUNX1 for TTP-sAML. Using the IPSS-M publically available dataset as the validation cohort, our prognostic model gave C-indices of 0.70, 0.71 and 0.74 for OS, LFS and TTP-sAML respectively. Finally, this prognostic model had superior prognostic power as compared with the IPSS-R and IPSS-M for the current Asian cohort (Figure 1D). Conclusion: Combining genomic with hematological and cytogenetic parameters, the Asian clinical-molecular prognostic model improved the risk stratification of patients with MDS in Asia, potentially improving clinical decision-making.

Discordant pathologic diagnoses of myelodysplastic neoplasms and their implications for registries and therapies

AbstractMyelodysplastic neoplasms (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Accurate pathologic diagnoses present challenges because of interobserver variability in interpreting morphology and quantifying dysplasia. We compared local clinical site diagnoses with central, adjudicated review from 918 participants enrolled in the ongoing National Heart, Lung, and Blood Institute National MDS Natural History Study, a prospective observational cohort study of participants with suspected MDS or MDS/myeloproliferative neoplasms (MPNs). Locally, 264 (29%) were diagnosed as having MDS, 15 (2%) MDS/MPN overlap, 62 (7%) idiopathic cytopenia of undetermined significance (ICUS), 0 (0%) acute myeloid leukemia (AML) with <30% blasts, and 577 (63%) as other. Approximately one-third of cases were reclassified after central review, with 266 (29%) diagnosed as MDS, 45 (5%) MDS/MPN overlap, 49 (5%) ICUS, 15 (2%) AML with <30%, and 543 (59%) as other. Site miscoding errors accounted for more than half (53%) of the local misdiagnoses, leaving a true misdiagnosis rate of 15% overall, 21% for MDS. Therapies were reported in 37% of patients, including 43% of patients with MDS, 49% of patients with MDS/MPN, and 86% of patients with AML with <30% blasts. Treatment rates were lower (25%) in cases with true discordance in diagnosis compared with those for whom local and central diagnoses agreed (40%), and receipt of inappropriate therapy occurred in 7% of misdiagnosed cases. Discordant diagnoses were frequent, which has implications for the accuracy of study-related and national registries and can lead to inappropriate therapy. This trial was registered at www.clinicaltrials.gov as #NCT05074550.

Bromodomain and extra-terminal (BET) inhibitor INCB057643 (LIMBER-103) in patients (pts) with relapsed or refractory myelofibrosis (R/R MF) and other advanced myeloid neoplasms: A phase 1 study.

7069 Background: BET proteins are epigenetic readers that regulate expression of critical oncoproteins involved in the pathophysiology of hematologic malignancies, including MF. INCB057643 is a small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Methods: This ongoing phase 1, 3+3 dose-escalation/expansion study (NCT04279847) evaluates safety and tolerability of INCB057643 (4 mg once daily [qd]; escalation up to 12 mg qd) in pts aged ≥18 years as (1) monotherapy (part 1) in R/R MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes (MDS/MPN) or (2) added to RUX (part 2) in pts with MF and suboptimal response to RUX. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs). Results: 13 pts have been treated in part 1 (4 mg, n=6; 8 mg, n=4; 10 mg, n=1; 12 mg, n=2), and 3 pts received 4 mg + RUX in part 2 (overall age range, 50–79 years; men, n=9; study treatment duration range, 15–314 days). 12 pts had MF, and 4 had MDS/MPN. All 6 pts in the 4-mg cohort discontinued treatment (3 for progressive disease [PD]; MF, n=2; MDS/MPN, n=1); 1 pt with MF in the 12-mg cohort discontinued for thrombocytopenia. The other 9 pts remain on treatment. Thrombocytopenia was the most common treatment-emergent adverse event (TEAE; n=9; Table) and the only TEAE leading to discontinuation (n=3). Grade ≥3 TEAEs occurring in ≥1 pt were thrombocytopenia (n=4), anemia (n=3), and hypokalemia (n=2). There were 8 serious AEs across 4 pts, with only COVID-19 occurring in &gt;1 pt (n=2); all but one (pneumonia) were considered unrelated to study treatment. There were 2 DLTs (thrombocytopenia [MDS/MPN pt] and hyperbilirubinemia [MF pt]; both 12-mg cohort) and 2 deaths (both 4-mg cohort due to PD [MF, n=1; MDS/MPN, n=1]). Conclusions: Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events. Dose finding in part 1 is ongoing with 10 mg qd, after which a recommended phase 2 dose will be declared. Combination dose escalation is also ongoing. Preliminary efficacy including spleen size and symptoms will be available for presentation. Clinical trial information: NCT04279847 . [Table: see text]

INCB057643 Monotherapy in Patients with Relapsed or Refractory Myelofibrosis: A Phase 1 Study

Background: Bromodomain and extra-terminal (BET) proteins are a class of epigenetic readers that regulate expression of regulatory proteins, such as B-cell lymphoma-2, c-Myc, and nuclear factor kappa B, that are implicated in oncogenesis of hematologic malignancies, including myelofibrosis (MF). INCB057643 is a small-molecule inhibitor of BET that was evaluated as monotherapy and in combination with ruxolitinib in patients with advanced malignancies in 2 previous phase 1/2 clinical trials. Aim: This ongoing, phase 1, dose-confirmation/expansion study (NCT04279847) is evaluating the safety and tolerability of INCB057643 as monotherapy in patients with relapsed/refractory MF, myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MPN) overlap syndromes and in combination with ruxolitinib in patients with advanced MF and suboptimal response to ruxolitinib. Methods: The study includes a 3+3 design dose-escalation phase (part 1) followed by dose-expansion (part 2). Eligible patients in part 1 are aged ≥18 years with histologically confirmed MF and palpable spleen ≥5 cm below the left subcostal margin, MDS or MDS/MPN, Eastern Cooperative Oncology Group performance status of 0-2, and ≥1 line of prior therapy with no available subsequent therapy known to provide clinical benefit. Exclusion criteria include prior BET inhibitor treatment within 5 half-lives, platelet counts <50 × 109/L, absolute neutrophil count <0.75 × 109/L, and allogeneic transplant ≤6 months before enrollment. The initial part 1 dose is INCB057643 4 mg once daily (qd; escalation up to 12 mg qd), administered continuously in 28-day cycles. Doses deemed safe and tolerable in part 1 will be further evaluated in part 2 as monotherapy or in combination with ruxolitinib in patients with MF. The primary endpoint is safety and tolerability, including identification of dose-limiting toxicities (DLTs); pharmacokinetics (PK) are evaluated as a secondary endpoint. Additional secondary endpoints include overall response rate, symptom response, anemia response, red blood cell transfusion requirement, and change in spleen volume and length. PK data were analyzed using noncompartmental analysis. Results: Six patients have been evaluated in part 1 (age range, 59-77 years; men, n=4; study treatment duration range, 29-169 days); 4 had a diagnosis of MF, and 1 each had MDS/MPN unclassifiable and chronic myelomonocytic leukemia (CMML). All patients received INCB057643 4 mg qd. Four patients remain on treatment; treatment was discontinued in the remaining 2 patients for progressive disease. The most common treatment-emergent adverse events (TEAEs) occurring in >1 patient were thrombocytopenia (n=3), anemia (n=2), and hyperuricemia (n=2). Grade ≥3 TEAEs occurred in 1 patient each: acute myeloid leukemia (AML), anemia, chronic obstructive pulmonary disease, hypokalemia, leukocytosis, pancytopenia, and thrombocytopenia. There were 3 serious AEs (SAEs) across 2 patients (chronic obstructive pulmonary disease in 1 patient [dose was not changed; patient recovered with sequelae], pancytopenia and AML transformation from CMML in a second patient [study drug was interrupted; patient death followed related to disease progression]); none were considered related to study treatment. No DLTs were observed. The mean steady-state maximum plasma concentration (Cmax) and area under the curve (AUC) for a 4-mg qd dose were 92.4 nM and 1260 h·nM, respectively, indicating a dose proportionality from 4 mg to 12 mg. Conclusions: Treatment with a 4-mg qd dose of INCB057643 monotherapy in this patient population was generally well tolerated, with no treatment-related SAEs, no DLTs, and no TEAEs leading to treatment discontinuation. INCB057643 will be further evaluated at higher doses in dose-escalation and dose-expansion phases as monotherapy and in combination with ruxolitinib in patients with MF (preliminary combination data to be available for presentation).

AML-387 Clinical Characteristics of Secondary Myeloid Neoplasms (MNs) in Patients With Inflammatory Bowel Disease (IBD)

Patients with ulcerative colitis (UC) and Crohn's disease (CD) are at increased cancer risk. Very little data is available regarding the risk of secondary MN in patients with IBD. To describe the clinical characteristics of secondary MNs in patients with IBD. Retrospective study of patients with MNs previously treated for IBD. Between 2012 and 2020, 43 patients were identified as having developed secondary MN during or after IBD treatment; 63% were women, and 81% were of white ethnicity. In 70% (30/43) of cases, secondary MNs arose after CD therapy, whereas 30% (13/43) arose after UC therapy. The median age at the time of MN diagnosis was 59 years (23-83 years), and latency from IBD diagnosis was 16 years (0-56 years). At the time of MN diagnosis, 25 patients were on active treatment for IBD (9 biological agent, 11 mesalamine, and 2 azathioprine), whereas 18 were in remission. Additionally, 8 patients (19%) had secondary cancer before the MN diagnosis (2 lymphoma, 2 skin cancer, ovarian cancer, uterine cancer, schwannoma, and adrenal tumor), and 3 patients received therapy. Acute myeloid leukemia (AML) was diagnosed in 74% of MN cases, 9 (21%) were myelodysplastic syndrome (MDS), and one each was MDS/myeloproliferative neoplasm (MPN) and chronic myelomonocytic leukemia (CMML). Cytogenetic abnormalities were detected in 70%: 13 patients (30%) with complex karyotype and 6 patients (14%) with core-binding factor (CBF) abnormalities (5 inv16 and 1 t [8;21]). Most common mutations were TP53 (23%), FLT3 (16%), RAS (19%), TET2 (16%), and DNMT3A (14%). Interestingly, all patients with CBF-AML had prior history of CD, including two treated with anti-TNF-α. The median overall survival (OS) was 2.17 yrs for the whole cohort, with no difference in OS between MNs arising from CD and UC (2.35 and 2.08 yrs for CD and UC, respectively). Seventeen patients underwent allogeneic stem cell transplantation (ASCT), which resulted in IBD remission in 13 patients (76%). Secondary MNs after IBD therapy included higher than expected prevalence of CBF-AML and were strongly associated with prior history of CD. ASCT led to remission of both MNs and IBD.

COVID-19 Outcomes Among Participants in the NHLBI Myelodysplastic Syndromes (MDS) Natural History Study

COVID-19 Outcomes Among Participants in the NHLBI Myelodysplastic Syndromes (MDS) Natural History Study

Post-Transplantation Cyclophosphamide for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Higher-Risk Myelodysplastic Syndrome

Introduction: Allogeneic hematopoietic cell transplantation is an only potentially curative option for patients with higher-risk myelodysplastic syndrome (MDS). Owing to the advances in treatment strategies including reduced intensity conditioning, graft-versus-host disease (GVHD) prevention and supportive care, more elderly patients or those with comorbidities can proceed to allogeneic HCT. However, the long-term survival rate following allogeneic HCT is reported to be less than 50%, and non-relapse mortality (NRM) rate is still high reaching upto 30%. In this study, we aimed to evaluate the feasibility of using post-transplantation cyclophosphamide (PTCy) as a GVHD prophylaxis in allogeneic HCT for higher-risk MDS patients. We also compared the post-transplantation outcomes of PTCy group and those of historical control who received HCT using anti-thymocyte globulin (ATG).Methods: Patients with higher-risk MDS or MDS/myeloproliferative neoplasm (MPN) with bone marrow blast ≥ 5% were included in this study. Higher-risk MDS was defined by MDS with International Prognostic Scoring System >1.0 or bone marrow blast ≥ 5% at any time points before HCT. Conditioning regimen consists of busulfan (4-days for patients aged <55 years, 2-days for 55 years), fludarabine. For GVHD prophylaxis, PTCy (50 mg/kg on days 3 and 4), cyclosporine, and mycophenolate mofetil were administered. In historical group, patients received 2- or 4-days of busulfan, fludarabine, and ATG with short course of methotrexate and cyclosporine.Results: Ninety-two and 144 patients received allogeneic HCT using PTCy and ATG, respectively. The median overall survival were 47.9 and 44.0 months, respectively (P=.383). Cumulative incidence of total and grade II-IV acute GVHD in PTCy and ATG group were 19.6% vs. 37.5% (P=.002), and 2.6% vs. 21.7% (P<.001), respectively. Incidence of total and extensive chronic GVHD (50.0% vs. 49.1%, P=.567; 32.5% vs. 33.4%, P=.581), 1-year NRM (20.8% vs. 22.9%, P=.702), and 2-year relapse (16.0% vs. 18.1%, P=.605) were not different between two groups. Neutrophil and platelet engraftment was significantly faster with ATG than PTCy (median 12 vs. 15 for neutrophil; median 15 vs. 24 days for platelet).Conclusion: Allogeneic HCT using PTCy as GVHD prophylaxis in higher-risk MDS seems feasible in terms of low rate of acute GVHD and relapse incidence. DisclosuresChoi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board.

Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active

AbstractAdding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity and thereby reduce the risk of posttransplant relapse. This phase 1 study investigated the recommended phase 2 dose (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day −8 for 6-7 doses) in combination with fludarabine 30 mg/m2 per day for 4 doses and busulfan 0.8 mg/kg twice daily for 8 doses on day −5 to day −2 (FluBu2). Transplant related–toxicity was evaluated from the first venetoclax dose on day −8 to day 28. Twenty-two patients were treated. At study entry, 5 patients with MDS and MDS/MPN had 5% to 10% marrow blasts, and 18 (82%) of 22 had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea, and liver transaminitis (n = 3 each). Neutrophil/platelet recovery and acute/chronic graft-versus-host-disease rates were similar to those of standard FluBu2. No dose-limiting toxicities were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (range, 8.6-24.8 months), median overall survival was not reached, and progression-free survival was 12.2 months (95% confidence interval, 6.0-not estimable). In patients with high-risk AML, MDS, and MDS/MPN, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is ongoing. This study was registered at clinicaltrials.gov as #NCT03613532.

Novel Therapeutic Targets for DNMT3A Mutant Myeloid Neoplasms

The DNMT3A mutations (DNMT3AMT) that occur in acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS) are either hypomorphic or inactivating, consistent with bone fide tumor suppression function of DNMT3A . The most recurrent mutation involves the canonical R882, resulting in a hypomorphic protein most likely also acting in a dominant-negative manner by affecting the methyltransferase activity of the remaining wild type DNMT3A allele (DNMT3AWT).To assess the clinical context of DNMT3A alterations, 1059 samples from patients with myeloid neoplasia (422 MDS, 240 MDS/myeloproliferative neoplasms (MPN), 163 secondary (s) AML, 234 primary (p) AML were examined. DNMT3AMT were found in 21% of patients, of which 71% were missense mutations [52% R882; 48% non-canonical mutation (NCM)] and 29% were truncating mutations or frameshift mutations. DNMT3AR882 was significantly overrepresented in pAML (P=.04) and underrepresented in MDS (P=.03). In contrast, truncating mutations were more common in MDS and sAML vs. pAML (55% vs. 29%; P<.01). DNMT3AMT were associated with ASXL1 (P=.05) and SF3B1 (P<.01) mutations in MDS but not in pAML. In contrast, DNMT3AMT associated with NPM1 (P<.01), FLT3ITD/TKD (P=.04) and IDH1 mutations in pAML but not sAML. Clonal architecture analyses showed that 49% of R882 were ancestral events with TET2, FLT3ITD/TKD and NPM1 as the most common secondary hits. In contrast, only 33% of non-R882 variants (39% truncating; 33% NCM) were an ancestral event (P=.04). Gene expression analyses of AML [n=167 (26% DNMT3AMT)] and MDS [n=175 (8% DNMT3AMT)] showed a decrease in DNMT3A mRNA levels in DNMT3AMTvs. DNMT3AWT AML (mean ± SD= 1079 ± 582 vs. 1376 ± 556), though not in MDS, probably due to the high percentage of truncating mutations and resulting nonsense mediated decay of mRNA.Exclusively heterozygous DNMT3AMT configurations imply that biallelic DNMT3A loss may be lethal and thus that mutant cells may be amenable to synthetic lethal therapeutic approaches. DNMT3A inhibitors may however, also phenocopy DNMT3A loss in normal DNMT3AWT cells. Although such concerns are not huge, as they would likely be reversed by withdrawing the inhibitor, there is also rationale to instead overcome haploinsufficiency by increasing the throughput of the remaining DNMT3AWT allele, i.e. to revert malignant cells toward normalcy rather than attempt to kill them. We achieve this by supplementation of the universal methyl donor S-adenosyl- L -methionine (SAM), i.e. by increasing DNMT3A substrate availability.To test this principle we quantified the differential sensitivity of DNMT3AMTvs. DNMT3AWT and primary cells to SAM (disulfate tosylate) supplementation. As in vitro models, we selected a myeloid derived cell line, OCI-AML3, which harbors R882 and shows a 9% decrease in global DNA-methylation. As controls we used a panel of myeloid cell lines with DNMT3AWT (K562, THP1, U937, MOLM13). We observed that OCI-AML3R882 exhibited higher sensitivity to 24h SAM supplementation than DNMT3AWT cell lines using an MTT assay (IC50 of ~2mM). This dose did not affect healthy human bone marrow cells as shown by no change in growth upon SAM treatment.We then assessed DNMT3A enzymatic activity using an ELISA-like colorimetric assay and found that 2mM SAM exposures increased DNMT3A activity by 20% vs. baseline (P=.04) in OCI-AML3R882 cells, suggesting that SAM supplementation was able to increase DNMT3AWT throughput. DNMT3AWT cells did not show increases in DNMT3A activity with SAM supplementation.We also generated a cellular model of DNMT3A insufficiency using lentiviral shRNA in K562 (55% reduction by qPCR) (K562-shRNA DNMT3A). SAM treatment (500µM, 1mM, 2mM, 3mM) induced a decrease in cell growth in K562-shRNA DNMT3A vs. not (30% vs. 60%; P<.01).In sum, we present the first novel DNMT3AMT therapeutic strategy based on the principle of overcoming the functional deficiency of a monoallelic mutants through up-modulation of DNMT3AWT activity. SAM showed a promising increase in DNMT3AWT activity in mutant cells at safe/feasible doses, opening the possibility of combinational strategies with existing/ approved agents. SAM could be beneficial in healthy older adults with clonal hematopoiesis of indeterminate potential and DNMT3AMT. We are in the process of determining if SAM treatment will enhance DNMT3AWT in murine models of DNMT3A (Dnmt3aMT, Flt3ITD, Npm1C) resulting in a fully penetrant leukemic phenotype. DisclosuresSekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Modeling ASXL1 Mutation Revealed Myelodysplasia Caused By Derepression of p16Ink4a through Aberrant PRC1-Mediated Histone Modification

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant condition in patients with blood cells that possess somatic mutations of genes known to be recurrently mutated in hematologic malignancies. Among them is additional sex combs like 1 (ASXL1), whose mutation is frequent in various myeloid malignancies and associated with poor prognosis, and ASXL1 is known to act as an epigenetic modulator. Despite the clinical impact of ASXL1 mutations in myeloid malignancies, lack of animal models expressing mutated Asxl1 at endogenous levels mimicking human ASXL1-mutated diseases hinders from dissecting precise molecular mechanisms of mutated Asxl1. Here in this study, with newly generated knock-in mice carrying a frameshift mutation at the exon 13 of the Asxl1 gene (Asxl1G643WfsX12), which is identical to the most frequent human ASXL1 G646WfsX12 mutation, we extensively investigated the biological effects of the mutant.Asxl1G643fs/+ mice showed decreased body size and weight, resembling hypomorphic features in patients with Bohring-Opitz syndrome carrying de novo constitutive ASXL1 mutation.Asxl1G643fs/+ mice developed slowly progressive peripheral leukopenia, and Wright-Giemsa stain of bone marrow (BM) cells from Asxl1G643fs/+ mice showed dysplastic myeloid cells represented by hypersegmented neutrophils, apoptotic neutrophils and hyposegmented neutrophils with fine nuclear bridging consistent with pseudo-Pelger-Huët anomaly. Flow cytometric analyses of Asxl1G643fs/+ BM cells confirmed aberrant myeloid differentiation with significant increase of granulocytic and monocytic cell fraction, significant decrease of hematopoietic stem cell (HSC) pool (c-kit+ Sca-1+ Lin- (LSK) cells and CD34- CD135- LSK cells), increased apoptosis in hematopoietic stem/progenitor cells (HSPC) and significant accumulation of G1-phase HSC in the cell cycle analysis, all of which were reminiscent of human myelodysplastic syndromes (MDS). Interestingly, Asxl1G643fs/+ mice became moribund about 600 days after birth when compared to Asxl1+/+ littermates with anemia, leukocytosis, neutrophilia/monocytosis and hepatosplenomegaly, suggesting the development of MDS/myeloproliferative neoplasm (MPN)-like disease, most relevant to human cases with chronic myelomonocytic leukemia.RNA sequencing and gene set enrichment analysis in Asxl1G643fs/+ mice identified derepression of sets of genes that are normally repressed by BMI1, a critical regulator of histone modification in polycomb repressive comprex 1 (PRC1). Among these genes were p16Ink4a, p21, and p15Ink4b all of which were significantly upregulated in Asxl1G643fs/+ LSK cells. We performed chromatin immunoprecipitation (ChIP) assay with an anti-H2AK119ub1 antibody using LSK cells from Asxl1G643fs/+ mice and found that H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in Asxl1G643fs/+ LSK cells, suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutated Asxl1. Co-immunoprecipitation assay and in vitro pull-down assay revealed that the mutant form of ASXL1 had no ability to interact with BMI1 as opposed to wild type ASXL1 protein. In addition, we performed ChIP assay with an anti-BMI1 and anti-FLAG antibody using a cell line stably expressed FLAG-tagged wild-type (WT) ASXL1 or mutant form (MT), and found that BMI1 level around the promoter region of p16Ink4a was significantly decreased in the ASXL1 MT-expressed cell line, whereas no significant change in the FLAG level between WT and MT. Furthermore, we intercrossed Asxl1G643fs/+ mice with p16Ink4a heterozygous knock out mice to elucidate the effect of p16Ink4a up-regulation in Asxl1G643fs/+ mice, and found restoration of HSC pool and amelioration of increased apoptosis in HSPC obtained from Asxl1G643fs/+p16Ink4a+/- mice. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in MDS-like phenotypes represented by decreased HSC pool and aberrant myeloid differentiation in Asxl1G643fs/+ mice.Taken together, our Asxl1 G643fs mutation knock-in mouse line is useful as a model of CHIP or early stage MDS, and our detailed analysis highlights the functional role of ASXL1 mutation on MDS and MDS /MPN development. DisclosuresMasamoto:Astellas Pharma Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Other: Scholarship donations for the laboratory; Pfizer Inc.: Research Funding. Arai:Bristol-Myers Squibb: Research Funding. Kurokawa:Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Celgene Corporation: Speakers Bureau; Pfizer Inc.: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Astellas Pharma Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Other: Scholarship donations for the laboratory, Speakers Bureau.

British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.

British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.

Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes.

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.

Patient-Reported Outcomes and Frailty Among Participants in the NHLBI MDS Natural History Study

Introduction: Patient-reported outcomes (PROs) such as quality of life (QOL) are variably affected in patients with myelodysplastic syndromes (MDS), but the heterogeneous composition of disease states grouped together as "MDS" increases the difficulty of assessing and understanding these outcomes. Moreover, little is known about the potential relationship between QOL and frailty in this population. Methods: The NHLBI MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated participants undergo bone marrow assessment with centralized histopathology review at enrollment for assignment into subcategories for longitudinal follow-up: MDS, MDS/MPN, ICUS, AML (&amp;lt;30% blasts), and "At-Risk" (cases with sub-threshold dysplasia or select karyotypic or genetic mutations). PRO and frailty data are collected at enrollment and every six months thereafter. PRO instruments include MDS-specific (QUALMS) and general (FACT-G, PROMIS Fatigue Short Form 7a, EQ-5D-5L) instruments, and a measure of frailty (VES-13). While no frailty instrument alone has been shown to be a substitute for comprehensive geriatric assessment, VES-13 has been successfully used in cancer-related studies for basic screening, where a score of 3 or more is considered frail (vulnerable). An analysis of variance (ANOVA) was used for the overall comparisons of mean baseline scores between diagnostic categories. Pairwise comparisons of scores between diagnostic categories and vulnerability subgroups were performed via two-sample t-tests. Results : Of 835 participants assessed for eligibility, 369 (44%) were classified as MDS, MDS/MPN, AML, ICUS or At-Risk, and further evaluated. Mean age was 72 years (standard deviation (SD)=10.7) and 68% were male. Mean baseline scores on the PRO measures are compared between diagnostic categories in the Table; scores did not differ significantly across categories. In particular, no significant differences were found between MDS and the other diagnostic categories. ICUS had similar QOL scores to MDS and MDS/MPN (e.g., means (SD) on EQ-5D-5L of 74.1 (17.8) in ICUS and 70.8 (19.4) in MDS, p=0.348) but had significantly higher scores than those for AML on EQ-5D-5L (60.7 (28.4), p=0.031). For the 216 participants with diagnostically-confirmed MDS, QOL impairment was similar to that routinely seen in other cancers; for example, the mean total FACT-G was 81.8 (SD=15.9), similar to localized breast cancer (82.4, SD=16.2), localized colorectal cancer (79.6, SD=16.1), and lung cancer with no current evidence of disease (82.6, SD=15.5; comparison means from Pearlman, Cancer, 2014). For frail/vulnerable participants with MDS or MDS/MPN (N=87), the most common reasons for vulnerability were age ≥75 years (68%), overall rating of health as poor or fair (62%), and difficulty with prolonged physical activity (90%) such as walking a quarter mile (75%) or doing heavy housework (70%). A minority also were vulnerable due to requiring help with instrumental activities of daily living (iADLS) such as shopping (28%) or managing money (16%). Mean QOL scores were compared between vulnerability subgroups (Figure). Vulnerable participants pooled over all diagnostic categories had significantly worse PROs than non-vulnerable participants for all measures (p&amp;lt;0.001). In particular, vulnerable MDS participants scored significantly worse on the QUALMS (mean 64.4, SD=13.4) vs. non-vulnerable MDS participants (mean 72.7, SD=13.3), p&amp;lt;0.001. Conclusions: Participants in our cohort with histologically-confirmed MDS-even low-grade MDS-had similar impairments in PROs as those with other cancers. Among those with histologically-confirmed MDS, vulnerable participants had significantly worse QOL on many measures compared to non-vulnerable participants, suggesting that this domain of function be specifically assessed in clinic. Moreover, while a "gestalt" of frailty may be inferred by observing how patients present and move in the office, these data suggest that other contributing domains, such as difficulty with prolonged physical activity and iADLs, should be evaluated explicitly. Disclosures Foran: H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Agios: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Revolution Medicine: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Padron:Incyte: Research Funding; Kura: Research Funding; Novartis: Honoraria; BMS: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A sequential two-stage dose escalation study of eltrombopag in patients with myelodysplastic syndrome and thrombocytopenia after hypomethylating agent failure

Thrombocytopenia occurs frequently in patients with myelodysplastic syndromes (MDS), and the survival of patients after failure of hypomethylating agents (HMAs) is poor. We conducted a trial of eltrombopag in patients with MDS, MDS/myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML) with 20–30% myeloblasts after HMA failure and mean baseline platelet count ≤ 50 × 109/L. Eltrombopag was escalated from 50 mg daily up to 200 mg daily. The primary objective was to determine the maximally tolerated dose (MTD). 37 patients were enrolled, and MTD was not reached. Responses were observed in 9 patients (24%), 2 achieving marrow CR with hematologic improvement (HI), 1 marrow CR without HI, and 6 HI. Median overall survival was 7.5 months. Eltrombopag was well-tolerated and yielded modest responses in heavily treated, predominantly higher-risk MDS patients after HMA failure. Future studies should focus on determining characteristics that predict response.

Geno-Clinical Model for the Diagnosis of Bone Marrow Myeloid Neoplasms

Geno-Clinical Model for the Diagnosis of Bone Marrow Myeloid Neoplasms