Myelodysplastic Syndrome/myeloproliferative Neoplasm Research Articles

Five-Year Follow up Results of Phase II Clinical Trial Evaluating Ruxolitinib (RUX) and Azacitidine (AZA) Combination Therapy in Patients (pts) with Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

Introduction: MDS/MPN represent a distinct category of Philadelphia chromosome negative myeloid neoplasms that share pathological and morphological characteristics with both MDS and MPN. Very few prospective studies have been conducted in pts with MDS/MPN, with currently available data showing a median overall survival (OS) of less than two years in this challenging subset. We conducted a phase 2 clinical trial evaluating the combination of JAK-inhibitor RUX with demethylating agent AZA in pts with MDS/MPN. The interim analyses (Assi et al, AJH 2018) showed objective responses in 57% pts and a median duration of response (DOR) of 8 months (mos). Herein we report the long-term follow up of a larger cohort of pts treated on this prospective ongoing clinical trial. Methods: We conducted an open label single-arm phase 2 clinical trial (NCT01787487) at the MD Anderson Cancer Center, Houston, evaluating the use of RUX-AZA in newly diagnosed or previously treated MDS/ MPN. Adults aged ≥ 18 years with MDS/MPN categorized as Intermediate 1-2 or High-risk by Dynamic International Prognosis Scoring System (DIPSS) (Passamonti et al, Blood 2010) were included. Pts previously exposed to RUX and/or AZA were excluded. RUX 5-20mg twice daily (per RUX label depending upon platelet counts at initiation) was given in 28-day cycles, and AZA 25mg/m2 (SQ or IV) Days 1- 5 was added starting cycle 4. Cycles were repeated every 4-6 weeks depending on count recovery. Response assessment was carried out using the 2015 International Consortium Proposal of response MDS/MPN criteria (Savona M et al, Blood 2015) and best objective response was tabulated. Progression free survival (PFS) included treatment change because of disease progression or inadequate response, transformation to acute myeloid leukemia (AML) or death and calculated from the time of therapy initiation. Results: From May 2013 to August 2022, 52 pts with a median age of 68 years (range, 39-82 years) were treated on trial. The data cutoff was July 15, 2023 ( Table 1). 32 pts (61%) were males, and 9 (75%) pts were white. 50 pts (96%) had ECOG PS<2. Baseline median bone marrow (BM) blasts were 4.5% (range 0-19%), with 19 (37%) carrying JAK2 mutations, and 16 (31%) with an abnormal karyotype. Intermideate-2 DIPSS was the most prevalent risk category, seen in 23 (44%) pts. At least one cytopenia was present in 32 (61%) pts, and three (6%) pts had bicytopenia. 24 of 49 (49%) had palpable splenomegaly, and 3 pts had undergone prior splenectomy. After a median follow up of 60 months (mos) (95% CI: 50.0-71.3) from therapy initiation, 18 (35%) pts are alive, and 1 pt is on active trial therapy. Objective responses per the MDS/MPN international consensus response criteria were observed in 28 (54%) pts and included clinical improvement in 14 (50%) pts, partial marrow response in 12 (43%) pts, optimal marrow response and cytogenetic complete remission in 1 (4%) pt each. The DOR in the 28 pts with objective response to therapy (censored for death in pts who died without evidence of progression) was 35 mos (95% CI: NE-73.5). The median OS in this group of responders was 36.4 mos (95% CI: NE-77.2). Five of these pts died without confirmed disease progression at the time of death. For the full cohort the median PFS was 13.4 mos (95% CI: 7.9-18.8) and median OS was 31.8 mos (95% CI: 18.5-44.9 ) (Figure 1). Transformation to AML occurred in 12 (23%) pts, with the median time to transformation being 13.2 mos (range 2.9-71.3) and all of them have died at the time of last follow-up. 8 (15%) pts underwent allogenic stem cell transplant (ASCT) as subsequent therapy following treatment with AZA-RUX amongst whom 6 (75%) had shown objective responses prior to transplant. For the pts who underwent ASCT, median PFS from the initiation of AZA-RUX was 40.8 months and median OS was not reached. Conclusion: Long term follow up from this phase II prospective clinical trial demonstrates durable disease responses with the RUX-AZA combination in MDS/MPN, with the responses translating into improved survival outcomes.

Outcomes of Haplo-Cord and Dual-Cord Transplants: A Single-Center Retrospective Analysis

Background: Despite the concurrent use of tandem haploidentical-umbilical cord (haplo-cord) and dual-umbilical cord (dual-cord) allogeneic hematopoietic stem cell transplant (HSCT) approaches for over a decade, there have been few comparisons of their outcomes (van Besien et al. Hematologica, 2016). No previous studies have evaluated differences following identical conditioning regimens. We report a retrospective analysis comparing patients treated with haplo-cord or dual-cord HSCTs at our institution following the same conditioning regimen. Methods: Between 10/2012-10/2022, 70 haplo-cord and 133 dual-cord transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m 2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. Cyclosporine and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. Patient selection, infectious disease prophylaxis, and donor selection were per institutional standards. Patient characteristics between groups were compared using Fisher's exact test. Kaplan-Meier estimates were used to evaluate OS and RFS. Cumulative incidence estimates were used to compare relapse, aGVHD, cGVHD, and neutrophil and platelet engraftment. Two-tailed t-test was used to compare average in-hospital stays for transplant admissions. Results: There were no significant differences between median age at transplant (51.6 vs 50.3), female representation (41.4% vs 45.1%), or disease types (47.1% vs 51.1% acute myeloid leukemia (AML), 25.75% vs 17.3% acute lymphoblastic leukemia (ALL), 17.2% vs 15.1% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% vs 16.5% other; p=0.373). With a median follow-up of over 2 years, there was no difference in or OS (p=0.96) or RFS (Figure 1, p=1) for all patients, or for the MDS/MPN and AML subset (OS p=0.47, RFS p=0.43). There was a significant increase in grade 3-4 acute GVHD (aGVHD) in haplo-cord recipients (Figure 2, p=0.007), but no difference in grade 2-4 aGVHD (p=0.11), all chronic GVHD (p=0.8), and moderate-severe cGVHD (p=0.3). Time to neutrophil recovery was faster in haplo-cord recipients (p=0.021), but there was no difference in platelet recovery to 20,000/uL (p=0.12). Average days admitted for haplo-cord HSCTs was 20.61 days compared to 27.56 days for dual-cord HSCTs (p<0.0001). Conclusion: In our experience, there were no differences in survival, relapse, or cGVHD between haplo-cord and dual cord HSCT. Haplo-cord HSCTs were associated with faster neutrophil engraftment and shorter hospital stays compared to dual-cord HSCTs; however, haplo-cord SCTs had significantly higher grade 3-4 aGVHD. When both are options, the choice of haplo-cord versus dual-cord HSCTs should consider these opposing factors. Reference: 1. Koen van Besien, Parameswaran Hari, Mei-Jie Zhang, Hong-Tao Liu, Wendy Stock, Lucy Godley, Olatoyosi Odenike, Richard Larson, Michael Bishop, Amittha Wickrema, Usama Gergis, Sebastian Mayer, Tsiporah Shore, Stephanie Tsai, Joanna Rhodes, Melissa M. Cushing, Sandra Korman, Andrew Artz. Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival. Haematologica 2016;101(5):634-643; https://doi.org/10.3324/haematol.2015.138594.

The Human Leukemia Immunopeptidome Is Driven By Pathogenic Molecular Variant Biotypes

Background Historically, acute myelogenous leukemia (AML) has been characterized as having a low somatic mutational burden and is predicted to have low neoantigen levels compared to solid tumors. However, recent data has shown that AML is an immunogenic malignancy and oncogenic driver mutations promote immune escape through immunoediting. Downregulation of human leukocyte antigen (HLA) class II HLA-DRB1, HLA-DQB1, HLA-DPA1 and HLA-DPB1 gene expression on leukemia cells has previously been associated with immune escape in AML following allogeneic hematopoietic stem cell transplantation (allo-HCT). While allo-HCT and cellular therapies are well-known potentially curative treatment options in AML, the human leukemia immunopeptidome has still not been well characterized. Here, we sought to uncover the human leukemia immunopeptidome by detecting differential major histocompatibility complex (MHC) class I neopeptide expression using molecular biotype subgroups. Methods We conducted retrospective analysis on 31 patients with hematopoietic malignancies including AML, chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), MDS, chronic myelogenous leukemia (CML) and other hematopoietic malignancies (i.e. NK cell leukemia) at MedStar Georgetown University Hospital. Mutations were identified using next generation sequencing and separated into the following annotated molecular biotypes based on the mechanism of pathogenesis: Group 0 (G0) DNA repair, G1 splicing, G2 transcription factor, G3 kinase activation, G4 epigenetic modification, G5 chromatin remodeling, G6 cohesin, G7 tumor suppressor (i.e. p53), G8 telomere maintenance, G9 histone modification, G10 nucleotransport (i.e. NPM1) and G11 cell cycle regulation. FASTA nucleotide sequences were obtained by subjecting mutations to transcript expression and cDNA alignment in the National Center for Biotechnology Information (NCBI) gene database. MHC class I binding neopeptides were identified by mapping patient FASTA nucleotide sequences and HLA class I alleles in the Net MHC pan 4.1 database. Neopeptides were grouped by % Rank and categorized as weak binding (WB) if > 0.5 and strong binding (SB) if ≤0.5. Descriptive and inferential statistics were performed using SAS. Results Thirty-one patients were evaluated including 17 AML (54.8%), 5 MDS (16.1%), 3 CMML (9.7%), 2 MDS/MPN (6.5%), 1 CML (3.2%) and 3 hematopoietic malignancies (9.7%). The median age was 65 years (range 28 -89); 43.8% were female and 43.3% were African American (AA). 144mutations were identified; thus far, 82 mutations have been subjected to FASTA NP_ protein extraction. The G3 biotype had the highest frequency of neopeptide bindings (n=59) followed by G2 (n=50) and G4 biotypes (n=42) ( Fig.1). Among patients with MDS, smokers were more likely to exhibit neopeptide binding compared to non-smokers (p=0.032). Patients with neopeptide binding had a longer median overall survival (mOS) compared to patients without neopeptide binding (mOS = 566 vs 114 days, p=0.0174) (Fig 2). Data exploration allowed isolation of a 54-year-old Asian male with Li-Fraumeni syndrome and p53 mutated AML who demonstrated high affinity neopeptide binding to HLA-B*39:01 with %Rank 0.08. Additionally, a 34 -year-old AA female with FLT3 mutated AML showed very high affinity neopeptide binding to HLA-A*29:02 with %Rank 0.007 as well as evidence of somatic HLA-A*03:01 deletion. Conclusions Pathogenic molecular variant biotypes constitute a novel immune signature, the human leukemia immunopeptidome. Smoking increased the likelihood of MHC class I neopeptide binding among patients with MDS. The presence of neopeptide binding predicted improved mOS in patients with myeloid malignancies. Further investigation of the human leukemia immunopeptidome may provide additional prognostic significance above that of standard molecular and cytogenetic risk stratification.

CSF3R-mutant chronic myelomonocytic leukemia is a distinct clinically subset with abysmal prognosis: a case report and systematic review of the literature

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) chacaterized by persistent peripheral blood monocytosis, hypercellular bone marrow and dysplasia at least in one myeloid lineage. CMML shares much of its molecular landscape with other myeloid neoplasms, while differs from others such as chronic neutrophilic leukemia (CNL), given the high frequency of CSF3R mutations in the latter. In this article, we report a case of CSF3R-mutated CMML and dissect this rare entity by reviewing the medical literature, with the intent to understand how this rare mutation shapes CMML's clinical and morphological phenotype. CSF3R-mutated CMML emerges as a rare entity meeting the ICC/WHO diagnostic criteria for CMML and simultaneously showing clinical-pathological and molecular traits of CNL and atypical chronic myeloid leukemia, rising an important and difficult diagnostic and therapeutical issue.

Myelodysplastic Syndromes/Myeloproliferative Overlap Neoplasms and Differential Diagnosis in the WHO and ICC 2022 Era: A Focused Review.

The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and pathologic overlapping features of both myelodysplastic and myeloproliferative neoplasms. For these reasons, these tumors are challenging in terms of diagnosis. The recent World Health Organization (WHO) 2022 classification and the International Consensus Classification (ICC) made changes in the classification of MDS/MPN compared to the previous 2016 WHO classification and improved the diagnostic criteria of these entities. The aim of this review is to describe the main entities reported in the more recent classifications, focusing on chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (or atypical CML [aCML]), and MDS/MPN with SF3B1 mutation and thrombocytosis/MDS/MPN with ring sideroblasts and thrombocytosis. A particular emphasis is given to the differential diagnosis and analysis of subtle divergences and semantic differences between the WHO classification and the ICC for these entities.

Haplodeficiency of the 9p21 tumor suppressor locus causes myeloid disorders driven by the bone marrow microenvironment

AbstractThe chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A, and CDKN2B, and its homo- or heterozygous deletion is associated with reduced survival in multiple cancer types. We report that mice with germ line monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-like disease associated with aberrant trabecular bone formation and/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in vitro. It also showed reduced expression of factors maintaining hematopoietic stem/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the profibrotic chemokine Cxcl13 and the osteogenesis- and fibrosis-related multifunctional glycoprotein osteopontin/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN–like disease.

Characterization and prognostic factors of secondary to MDS/MPN and therapy-related AML: a single-center study

Introduction: Secondary acute myeloid leukemia (sAML) accounts for 15–30% of overall AML cases and is associated with shorter survival compared to de novo AML. The pathogenetic spectrum of sAML is heterogeneous, i.e. therapy-related AML (tAML) arises from prior cytotoxic, radiation, or immunosuppressive therapy, while myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-AML develops from a previous clonal disorder of hematopoiesis. Material and methods: We performed a single-center retrospective analysis of MDS/MPN-AML and tAML patients diagnosed between 2013 and 2018 in the Hematology Department of the Medical University in Lodz, Poland. Simultaneously, demographic data, clinical factors, and laboratory findings were collected. For statistical analysis, we used Cox proportional hazard models and log-rank tests. Results: The study included 110 patients with either MDS/MPN-AML (n = 78) or tAML (n = 32), with a median age of 66 years (range 31–86). The median follow-up was 3.2 months [95% confidence interval (CI): 2.5–5.3]. The median overall survival (OS) for MDS/MPN-AML patients was 4.1 months (95% CI: 2.5–7.0) and for tAML it was 2.8 months (95% CI: 1.6-5.6). In multivariate Cox regression model for OS, factors such as age at diagnosis [hazard ratio (HR) 1.03, 95% CI: 1.00–1.06], higher Eastern Cooperative Oncology Group score (HR 1.85, 95% CI: 1.08–3.15), hypoalbuminemia (HR 3.20, 95% CI: 1.95–5.24) and percentage of bone marrow blasts infiltration (HR 1.01, 95% CI: 1.00–1.03) were independent predictors of poor survival for the whole cohort. On the other hand, the intensive treatment approach was related to longer survival (HR 0.42, 95% CI: 0.21–0.82). There were no differences in OS between MDS/MPN-AML and tAML ( p = 0.81). Conclusion: The poor treatment outcomes for sAML consist of a combination of low response rate and high early mortality. The positive influence of intensive chemotherapy should be highlighted, but nevertheless, optimizing treatment for thishigh-risk subpopulation remains crucial.

Chinese expert consensus on the comprehensive management of thromboembolism in polycythemia vera

Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms (MPN), with the highest incidence. Thromboembolism is the most common complication of PV, which has significant effects on the quality of life and survival of patients. To standardize the diagnosis, treatment and prevention strategies of thromboembolism associated with PV, the Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPN) Association affiliated to Chinese Medicine Education Association has reached the following consensus based on available proofs from evidence-based medicine after repeated considerations. The consensus covers risk stratification, diagnosis and treatment of PV, multidisciplinary management of PV thromboembolism, and patient follow-up, thereby providing the reference for the standardized diagnosis, treatment and management of thromboembolism for Chinese PV patients.

What’s new in the MDS/MPN overlap syndromes

The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterised by the co-occurrence of clinical and pathologic features of both myelodysplastic and myeloproliferative neoplasms. The recently published International Consensus Classification of myeloid neoplasms revised the list of entities in this category and the criteria for their diagnosis (Arber DA, Orazi A, Hasserjian RP, et al. Blood 2022; 140: 1200–1228). In addition to the presence of increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective haematopoiesis is now an explicit requirement to diagnose these diseases.

Advances in myelodysplastic/myeloproliferative neoplasms.

The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterized by the co-occurrence of clinical and pathologic features of both myelodysplastic and myeloproliferative neoplasms. The recently published International Consensus Classification of myeloid neoplasms revised the entities included in the MDS/MPN category as well as criteria for their diagnosis. In addition to the presence of one or more increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective hematopoiesis is now an explicit requirement to diagnose the diseases included in this category. The increasing availability of modern gene sequencing has allowed better understanding of the biologic characteristics of these myeloid neoplasms. The presence of specific mutations in the appropriate clinicopathologic context is now included in the diagnostic criteria for some of MDS/MPN entities. In this review, we highlight what has changed in the diagnostic criteria of MDS/MPN from the WHO 2016 classification while providing practical guidance in diagnosing these diseases.

Allogeneic Hematopoietic Stem Cell Transplantation for Mixed or Overlap Myelodysplastic/Myeloproliferative Disorders.

Chronic myelomonocytic leukemia (CMML) and the remaining, less frequent hybrid, mixed, or overlap myelodysplastic syndromes/myeloproliferative neoplasms (MDSs/MPNs) are difficult to treat neoplastic hematological disorders, exhibiting substantial clinical and prognostic heterogeneity, for which clear therapeutic guidelines or effective treatment options are still missing. CMML has an overall survival ranging from a few months to several years. Although patients with proliferative or dysplastic features may benefit from hydroxyurea and hypomethylating agent treatment, respectively, none of these treatments can establish long-term remission and prevent the inevitable transformation to acute leukemia. Novel targeted treatment approaches are emerging but are still under investigation. Therefore, currently, allogeneic stem cell transplantation (allo-SCT) remains the only treatment modality with a curative potential, but its widespread application is limited, due to significant morbidity and mortality associated with the procedure, especially in the elderly and in patients with comorbidities. Recognition of patient eligibility for allo-SCT is crucial, and the procedure should be addressed to patients with a good performance status without severe comorbidities and mainly to those in intermediate- to high-risk category, with a suitable stem cell donor available. The issues of best timing for performing transplantation, patient and donor eligibility, the type of conditioning regimen, and the outcomes after various allo-SCT procedures are the topics of this review.

Genetic mutations associated with blood count abnormalities in myeloid neoplasms

ABSTRACT Introduction Myelodysplastic syndromes (MDS) predominantly present with varying degrees of cytopenia, while myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) exhibit proliferative features. Genetic defects underlying different complete blood count (CBC) alterations remain to be defined. Objective We aimed to evaluate mutations and impacts on abnormal blood counts in MDS and MDS/MPN. Method MDS and MDS/MPN patients were recruited and sequenced by targeted next-generation sequencing. Clinical parameters, especially CBC, were evaluated for the association with genetic abnormalities and clinical outcomes. Results A total of 168 patients with myeloid neoplasms were recruited (92 cases of low-risk MDS, 57 cases of high-risk MDS and 19 cases of MDS/MPN). Compared to low-risk MDS and MDS/MPN, patients with high-risk MDS were presented with more severe neutropenia with 17.5% showing absolute neutrophil counts (ANC) lower than 0.5 × 109/L. Patients with MDS/MPN more commonly harboured mutations and had a higher number of mutations per case than low-risk MDS (94.7% vs. 56.5%; p < 0.001 and 3 vs. 1; p < 0.001, respectively). Patients with SF3B1 mutations showed lower haemoglobin levels than wild-type (7.9 vs. 8.4 g/dL, p = 0.02), but were associated with normal platelet counts (286 vs. 93 × 109/L; p < 0.001). Patients with U2AF1 mutations were associated with more severe leukopenia than wild-type (3 vs. 4.18 × 109/L; p = 0.02). KRAS mutations were associated with monocytosis (p < 0.001). Multivariate analysis revealed high-risk MDS, MDS/MPN, severe neutropenia (ANC < 0.5 × 109/L), and mutations in ASXL1 and SETBP1 were associated with inferior survival outcomes. Conclusion Certain mutations were related to more severe anaemia, lower white blood cell count or monocytosis in Asian MDS and MDS/MPN patients.

Phase II trial of luspatercept with or without hydroxyurea for the treatment of patients with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts.

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with &gt; 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level &gt; 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

Clinical and molecular characteristics of acute myeloid leukemia with MPL mutation

ABSTRACT Objectives The current study aimed to explore the incidence of MPL mutations and the clinical and molecular characteristics of AML with MPL mutation. Methods In total, 1509 patients with newly diagnosed AML were retrospectively analyzed between January 2017 and December 2020. MPL mutations were detected via next-generation sequencing. During the same period, we also enrolled 30 patients with other myeloid neoplasms (MNs) with MPL mutation, which included myelodysplastic syndrome (n = 15), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (n = 6), and MPN (n = 9). The clinical characteristics of MPL-mutated AML and other types of MNs or MPL-wide type (MPL-wt) AML were compared, and the spectrum of co-mutations and MPL mutation profiles in MPL-mutated AML were analyzed. Results MPL mutations were identified in 19 (1.26%) of 1509 patients with AML. The waterfall diagram showed that the co-mutations were mainly epigenetic modifications (TET2, IDH1, and EZH2), spliceosomes (SRSF2), and transcription factors (RUNX1). The platelet count of the AML group was significantly lower than that of the MPN group (p = 0.001). MPL mutations were commonly observed in the intracellular region in AML but the transmembrane region in MPN (p = 0.013). The MPL-mutated AML group had a lower white blood cell count and a lower rate of complete remission than the MPL wild-type AML group (p = 0.037). Conclusion MPL mutations are clinically relevant in patients with AML, and they may be a novel subtype characterized by lower white blood cell counts and poor complete remission rates. However, further studies must be conducted to identify its correlated mechanism.

EP056: Myelodysplastic syndrome/myeloproliferative neoplasm with highly complex intrachromosomal rearrangements resulting from multiple 5q15q32 deletions, 5’PDGFRβ deletion, pericentric inversion and TP53 inactivation

Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of clonal disorders defined by overlapping elements of peripheral cytopenias and/or elevated cell counts and generally show morphologic dysplasia in the bone marrow and carry an increased risk of transformation to acute myeloid leukemia. Chromosome 5q deletions are common in MDS occurring either as isolated deletions or associated with additional chromosomal changes. PDGFRβ rearrangements in MDS/MPN are rare but delineate a distinct type of myeloid neoplasm with characteristic clinicopathologic features for most defined rearrangements.

Chronic Myelomonocytic Leukemia (CMML): A systematic Review of Literature and Update

Chronic Myelomonocytic Leukemia (CMML) is a hematologic malignancy classified as an overlapping Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) that can transform into Acute Myelogenous Leukemia (AML) with poor outcomes. CMML has distinctive biologic characteristics that may warrant new therapeutic approaches separate from MDS/MPN. There are limited effective therapies for this disease to prevent progression or transformation into AML, and outcomes are often dismal without allogeneic transplantation, especially in patients with high risk disease. As the genomic landscape of CMML continues to unravel and our prognostic scoring systems improve, individualized treatment approaches considering the entirety of this information will follow. We reviewed the literature on the current diagnostic criteria, subtypes of disease, common cytogenetic/molecular aberrations, scoring systems, current treatment and future directions of therapeutic intervention.

The genetic analysis of Chinese patients with clonal cytopenias using targeted next-generation sequencing

BackgroundClonal hematopoiesis (CH) can be found in various myeloid neoplasms (MN), such as myelodysplastic syndromes (MDS), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), also in pre-MDS conditions.MethodsCytogenetics is an independent prognostic factor in MDS, and fluorescence in-situ hybridization (FISH) can be used as an adjunct to karyotype analysis. In the past 5 years, only 35 of 100 newly diagnosed MDS and MDS/MPN patients were identified abnormalities, who underwent the FISH panel. In addition, we examined a cohort of 51 cytopenic patients suspected MDS or MDS/MPN with a 20-gene next generation sequencing (NGS), including 35 newly diagnosed MN patients and 16 clonal cytopenias of undetermined significance (CCUS) patients.ResultsCompared with the CCUS group, the MN group had higher male ratio (22/13 vs 10/6), cytogenetics abnormalities rate (41.4% vs 21.4%) and frequency of a series of mutations, such as ASXL1 (28.6% vs 25%), U2AF1 (25.7% vs 25%), RUNX1 (20% vs 0.0%); also, higher adverse mutations proportion (75% vs 85.2%), and double or multiple mutations (54.3% vs 43.75%). There were 7 MN patients and 4 CCUS patients who experienced cardio-cerebrovascular embolism events demonstrated a significant difference between the two groups (25% vs 20%). Ten of the 11 patients had somatic mutations, half had DNA methylation, while the other half had RNA splicing. Additionally, six patients had disease transformation, and four patients had mutated U2AF1, including two CCUS cases and two MDS-EB cases. Following up to January 2021, there was no significant difference in over survival between the CCUS and MN groups.ConclusionNGS facilitates the diagnosis of unexplained cytopenias. The monitoring and management of CCUS is necessary, also cardio-cerebrovascular embolism events in patients with CH need attention in the clinical practice.

ASXL1 Mutation Is a Novel Risk Factor for Bleeding in Patients with Philadelphia-Negative Myeloproliferative Neoplasms (MPN)

▪Background:Bleeding and thrombosis are prevalent across all myeloproliferative neoplasm (MPN) subtypes and have significant impact on morbidity and mortality. Although risk factors for thrombosis are well established, bleeding risk factors in these patients are poorly characterized. Identifying MPN patients at higher risk for bleeding could guide the duration of anticoagulation for patients with MPN associated thrombosis (balancing the risk between bleeding and thrombosis), select individuals at higher risk for bleeding during prophylactic anticoagulation, and predict for bleeding complications with surgical procedures.Methods:We performed a retrospective analysis of bleeding risk factors among consecutive adult MPN patients treated at Roswell Park Comprehensive Cancer Center. Bleeding events were classified as minor or major events as defined by the International Society of Thrombosis and Hemostasis (ISTH). The primary outcome of interest was time to initial bleeding after MPN diagnosis. Patient characteristics were summarized as range and medians (for continuous variables) and counts with percentages (for categorical variables) (Table 1). Cox regression was used to examine the associations between candidate risk factors with identified bleeding events in univariate and multivariable analyses. Variables with p<0.1 in univariate analyses were selected for multi-variate analysis. A time-dependent variable of thrombosis status was included in the model. A stepwise feature selection based on Akaike Information Criterion was used for model selection. Continuous variables were dichotomized at median for the regression analyses.Results:A total of 170-consecutive adult MPN patients were identified between 2005 and 2021. Median follow-up was 43.5 months (range 0.66-485.72). The rate of bleeding (major and minor) was 4.9/100 patient-years and rate of thrombosis was 5.4/100 patient-years (5.4/100 patient-years for arterial thrombosis and 2.9/100 patient-years for venous thrombosis).In univariable analysis, predictors of bleeding included age > 60 years (HR 2.8; 95% CI 1.47-5.34; p=0.001), diagnoses of primary myelofibrosis (PMF) (HR 2.98; 95% CI 1.29-6.9; p=0.01) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS-MPN) overlap syndrome (HR 4.56, 95% CI1.91-10.88; p=0.0004), prior history of thrombosis (HR 3.3, 95% CI 1.27-8.8; p=0.01) and presence of ASXL1 (HR 4.13, 95% CI 2.13-8.04; p=0.0001), JAK2 V617F (HR 0.58; 95% CI 0.31-1.08; p=0.08) and TET2 mutations (HR 3.46; 95% CI 1.5-7.9; p=0.003). In multivariate analysis, the presence of JAK2 V617F (HR 4.8; 95% CI 1-21.5; p=0.03) and ASXL1 (HR 12.7, 95% CI 1.7-93; p=0.01) mutations were associated with increased risk of bleeding (Figure 2). Patients with polycythemia vera were at lower risk of bleeding (HR -3.5, 95% CI 0-0.8; p=0.03).Since ASXL1 mutation was associated with a higher risk of bleeding, we studied the association between ASXL1 mutation and other clinical variables. Patients with ASXL1 mutations were more likely to have a diagnosis of PMF and MDS-MPN overlap syndrome (p=0.0001), age > 60 years (p=0.0001), risk for thrombosis (p=0.04), lower hematocrit (p=0.009) and platelets (p=0.0003) but higher white blood cell count (WBC) (p= 0.04) (Figure 3). We then studied the correlation between ASXL1 mutation and factor VIII/Von Willebrand complex and factor V, the two most described abnormal coagulation factors in MPN. ASXL1 mutation was not associated with a statistically significant lower VWF Ag (p=0.07) or factor V (p=0.1) that could potentially explain the higher risk of bleeding seen with this mutation (figure 4).Conclusion:ASXL1 mutations are associated with a significantly higher risk of bleeding in adult MPN patients. The risk of bleeding with ASXL1 mutations was independent of prior thrombosis and was not associated with abnormalities in VWF profile or factor V. Confirmation of these findings in additional patients and studies of underlying platelet function to identify the possible mechanism of ASXL1 associated bleeding in these patients are ongoing. [Display omitted] DisclosuresElshoury: Bristol Meyers Squibb: Other: advisory board. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Griffiths: Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Novartis: Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Genentech: Research Funding. Wang: Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.

CG '806, a First-in-Class Pan-FLT3/BTK Inhibitor, Exhibits Potent Growth Inhibition As a Single Agent and in Combination with a BET Bromodomain Inhibitor or a Bcl2 Inhibitor on Primary AML and CLL Patient Samples

CG '806, a First-in-Class Pan-FLT3/BTK Inhibitor, Exhibits Potent Growth Inhibition As a Single Agent and in Combination with a BET Bromodomain Inhibitor or a Bcl2 Inhibitor on Primary AML and CLL Patient Samples