Myelodysplastic Research Articles

Imetelstat (Rytelo) for Myelodysplastic Syndromes

The FDA has approved imetelstat (Rytelo – Geron), a first-in-class telomerase inhibitor, for treatment of low- to intermediate-1 risk myelodysplastic syndromes (MDS) in adults with transfusion-dependent anemia requiring 4 or more red blood cell (RBC) units over 8 weeks who have not responded to, are no longer responding to, or are ineligible for erythropoiesis-stimulating agents (ESAs).

Proton Density Fat Fraction Quantification (PD-FFQ): Capability for hematopoietic ability assessment and aplastic anemaia diagnosis of adults

PurposeThe purpose of this study was to determine the capability of proton density with fat fraction (PD-FFQ) imaging to help assess hematopoietic ability and diagnose aplastic anemia in adults. MethodsBetween January 2021 and March 2023, patients diagnosed with aplastic anemia (AA: n = 14) or myelodysplastic syndrome (MDS: n = 14) were examined by whole-body PD-FFQ imaging, and 14 of 126 age and gender matched patients who had undergone the same PD-FFQ imaging were selected as control group. All proton density fat fraction (PDFF) index evaluations were then performed by using regions of interest (ROIs). Pearson's correlation was used to determine the relationship between blood test results and each quantitative index, and ROC-based positive test and discrimination analyses to compare capability to differentiate the AA from the non-AA group. Finally, sensitivity, specificity and accuracy of all quantitative indexes were compared by means of McNemar's test. ResultsMean PDFF, standard deviation (SD) and percentage of coefficient of variation (%CV) for vertebrae showed significant correlation with blood test results (−0.52 ≤ r ≤ −0.34, p < 0.05). Specificity (SP) and accuracy (AC) of %CV of PDFF in vertebrae were significantly higher than those of mean PDFF in vertebrae and the posterior superior iliac spine (SP: p = 0.0002, AC: p = 0.0001) and SD of PDFF in vertebrae (SP: p = 0.008, AC: p = 0.008). Moreover, AC of SD of PDFF in vertebrae was significantly higher than that of mean PDFF in vertebrae and the posterior superior iliac spine (p = 0.03). ConclusionWhole-body PD-FFQ imaging is useful for hematopoietic ability assessment and diagnosis of aplastic anemia in adults.

Higher prevalence of poor prognostic markers at a younger age in adult patients with myelodysplastic syndrome – evaluation of a large cohort in India

BackgroundThe karyotype is a major determinant of prognosis in myelodysplastic syndrome (MDS). Details of the cytogenetic profile of MDS in South Asia are limited because cytogenetic services are not widely available.MethodsWe performed a retrospective analysis of the cytogenetic and clinicopathologic profile of adult primary MDS seen consecutively at a tertiary-care centre in South India between 2003 and 2017. Patients were re-categorised according to the 2022 World Health Organisation (WHO) and the International Consensus classifications (ICC).ResultsThere were 936 patients aged 18–86 years (median age 53, 65% males), with MDS with del 5q, low blasts and increased blasts in 7.5%, 58.4% and 34.1% respectively. Clonal abnormalities were seen in 55% of patients, with solitary abnormalities in 29.8% and complex karyotypes (CK, ≥ 3 abnormalities) in 15%. The most frequent abnormalities were monosomy 7/deletion 7q (16.1%), deletion 5q (14.5%), trisomy 8 (11.5%), and deletion 20q (5.1%). Cytogenetic prognosis groups were distributed as follows: very good, 2%; good, 55.6%; intermediate, 16.2%; poor, 15%; very poor, 11.2%. Clinical (IPSS-R) risk stratification (842 patients) showed: very low-risk, 3.9%; low-risk, 30.9%; intermediate-risk, 24.2%; high-risk, 21%; very high-risk, 20%. Age-adjustment (IPSS-RA) raised the very low-risk group to 12.4%; the other groups decreased by 1–3% each.ConclusionThe most significant finding of this cytogenetic analysis of MDS in India is that abnormal karyotypes with poor prognosis markers including monosomy 7 and CK were more frequent than in most other reports, among patients who were overall younger. Trisomy 8, deletion 20q, the IPSS-R intermediate-risk and both high-risk groups were more common than in the West. Trisomy 8 was less common than in South-East Asia while CK and deletion 20q were comparable. Evaluation of such large cohorts highlights the unique features of MDS in different parts of the world. These findings suggest that there could be differences in predisposing factors, environmental or genetic, and emphasise the need for further exploration to better understand the varied nature of MDS.

Deferasirox, an iron chelator, impacts myeloid differentiation by modulating NF-kB activity via mitochondrial ROS.

The iron chelator deferasirox (DFX) is effective in the treatment of iron overload. In certain patients with myelodysplastic syndrome, DFX can also provide a dramatic therapeutic benefit, improving red blood cell production and decreasing transfusion requirements. Nuclear Factor-kappa B (NF-kB) signalling has been implicated as a potential mechanism behind this phenomenon, with studies focusing on the effect of DFX on haematopoietic progenitors. Here, we examine the phenotypic and transcriptional effects of DFX throughout myeloid cell maturation in both murine and human model systems. The effect of DFX depends on the stage of differentiation, with effects on mitochondrial reactive oxygen species (ROS) production and NF-kB pathway regulation that vary between progenitors and neutrophils. DFX triggers a greater increase in mitochondrial ROS production in neutrophils and this phenomenon is mitigated when cells are cultured in hypoxic conditions. Single-cell transcriptomic profiling revealed that DFX decreases the expression of NF-kB and MYC (c-Myc) targets in progenitors and decreases the expression of PU.1 (SPI1) gene targets in neutrophils. Together, these data suggest a role of DFX in impairing terminal maturation of band neutrophils.

Impact of platelet transfusion refractoriness in the first 30 days post-hematopoietic stem cell transplantation on outcomes of patients with myelodysplastic syndrome.

Currently, no study has determined whether platelet transfusion refractoriness (PTR) post-hematopoietic stem cell transplantation (HSCT) before engraftment in patients with myelodysplastic syndrome (MDS) would impacts clinical outcomes. We performed a MDS-specific retrospective analysis to determine whether PTR in one-month post-HSCT in patients with MDS could influence outcomes. Among the 315 patients enrolled, 110 (34.9 %) had PTR from stem cell infusion to one-month post-HSCT. Baseline characteristics of the PTR and non-PTR groups were similar. We found that patients with PTR had a slower and lower rate of platelet engraftment by day 28, as well as a slower recovery of neutrophils. The median days of neutrophil and platelet engraftment were 14 days (9-23) and 17 days (8-28) in the PTR groups versus 13 days (9-23) and 15 days (7-28) in the non-PTR group (P<0.001). By day 28, 84 of 110 patients (76.4%) with PTR achieved platelet engraftment compared with 181 of 205 patients (88.3%) without PTR achieving platelet engraftment (P=0.007). In addition, patients in the PTR group received significantly more red blood cell (median, 17 units vs. 10 units, P<0.001) and platelet transfusions (median, 13 units vs. 7 units, P<0.001). However, the overall survival was similar between the two groups. PTR in one-month post-HSCT, haploidentical donor, and ferritin level>1041ng/ml (median level) were independent adverse factors of platelet engraftment.

Iron overload impact on peripheral blood cells, lymphocytes and karyotypes in newly diagnosed myelodysplastic syndromes (MDS) patients: a single-center retrospective analysis

We conducted a retrospective analysis of 68 newly diagnosed myelodysplastic syndrome (MDS) patients who were treated in the Department of Hematology at Yuncheng Central Hospital affiliated to Shanxi Medical University from October 2017 to March 2022. Based on the serum ferritin (SF) level, the newly diagnosed MDS patients were divided into two groups: iron overload (IOL) group (SF > 1000 ng/mL) and non-iron overload (NIOL) group(SF ≤ 1000 ng/mL). General clinical data, peripheral blood cells, lymphocyte subsets and marrow karyotypes were compared. We found that MDS patients with IOL had lower hemoglobin (Hb), lower reticulocyte (RET) counts, and lower absolute natural killer (NK) cell counts compared with NIOL group (p < 0.05). The correlation analysis also showed a negative correlation between the NK cell counts and SF level (r = −0.270, P = 0.026). Furthermore, we found IOL group had higher incidence of complex and poor karyotypes. In conclusion, we found that IOL is correlated with anemia in MDS patients, which may lead to a decrease in T lymphocyte cells, especially in NK cells, that play a role in the immune pathogenesis of MDS, thereby suppressing immune surveillance function. Additionally, IOL may contribute to the pathogenesis of MDS by affecting karyotypes.

Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response.

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

Ferroptosis: a new mechanism of traditional Chinese medicine for treating hematologic malignancies.

Ferroptosis is a recently identified form of cell death characterized by lipid peroxidation and elevated iron levels. It is closely associated with hematologic malignancies, including leukemia, multiple myeloma (MM), and myelodysplastic syndromes (MDS). Research indicates that ferroptosis could represent a novel therapeutic target for these hematologic malignancies. Furthermore, traditional Chinese medicine (TCM) has been shown to modulate hematologic malignancies through the ferroptosis pathway. This paper aims to elucidate the mechanisms underlying ferroptosis and summarize the current research advancements regarding ferroptosis in hematologic malignancies, as well as the role of traditional Chinese medicine in the prevention and treatment of ferroptosis, with the goal of enhancing treatment efficacy.

Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study.

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

Cellular and immunotherapies for myelodysplastic syndromes

In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis. Unfortunately, these approaches have been largely unsuccessful. There is significant potential for T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells, but there are also several limitations to these approaches that are unique to MDS. However, many of these limitations may be overcome by the next generation of cellular therapies, including those with engineered T-cell receptors or natural killer (NK)-cell based platforms. Regardless of the approach, all these immune cells are subject to the complex bone marrow microenvironment in MDS, which harbours a variable and heterogeneous mix of pro-inflammatory cytokines and immunosuppressive elements. Understanding this interaction will be paramount to ensuring the success of immune and cellular therapies in MDS.

Therapy-related myelodysplastic syndromes and acute myeloid leukemia

Progress always comes at a price: the field of oncology has seen unprecedented progress in treatment options recently for many solid and hematologic cancers. Unfortunately, these long-term survivors of prior cancer and cytotoxic therapy exposure are at higher risk of therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML.) T-MDS/AML is a myeloid malignancy which occur after exposure to chemotherapy or radiation therapy for unrelated malignancy. T-MDS/AML is associated with adverse cytogenomic features and poor prognosis. While advances in the field of clonal hematopoiesis and germline variants has unraveled the molecular underpinnings of t-MDS/AML, we have miles to go in terms of t-MDS/AML directed therapy and improvement in outcomes. In this review, we discuss the epidemiology of t-MDS/AML, clinical and biological insights, evolution of t-MDS/AML and available treatment options.

Distinct mutation features and its clinical significance in myelodysplastic syndromes with normal karyotype.

Myelodysplastic syndromes (MDS) is a highly heterogeneous myeloid neoplastic disease, which needs personalized evaluation and therapy. To analyze the features and significance of gene mutations for MDS patients with normal karyotype (NK) at diagnosis, targeted sequencing was conducted on 616 MDS patients with NK, alongside 457 MDS cases with abnormal karyotype (AK). The results showed that the incidence of somatic mutation reached 70.3% and 83.8% in the NK and AK group, respectively. Initial mutation including ASXL1, DNMT3A and TET2 were common in NK group, which is the same as AK group. Some karyotype-associated gene mutations, such as TP53 and U2AF1, were relatively rare in NK group. Moreover, 34 out of 91 samples who progressed to acute myeloid leukemia (AML) underwent repeat sequencing during follow-up. 25 cases were checked out with newly emerged mutations. The AML-associated genetic alterations mainly involved with active signaling and transcription factors. In patients with NK, serial targeted sequencing was employed for minimal residual disease (MRD) monitoring, indicating the efficacy and relapse of the patients. In summary, MDS with NK showed distinct mutation features from those with AK. High-frequency gene mutations together with the mutational evolution suggested the diagnostic and monitoring significance of next generation sequencing for NK-MDS.

Diagnostic Value of Serum Biomarkers for Invasive Aspergillosis in Haematologic Patients.

Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in patients with haematological malignancies. Accurate diagnosis of IA is challenging due to non-specific symptoms and the impact of antifungal prophylaxis on biomarker sensitivity. This retrospective study evaluated the diagnostic performance of three serum biomarkers: Aspergillus Galactomannan Ag VirClia Monotest® (VirClia), Wako β-D-Glucan Test® (Wako BDG), and MycoGENIE Real-Time PCR® (MycoGENIE PCR). True positives were defined as patients with proven or probable IA (n = 14), with a positive Platelia Aspergillus Antigen® (Platelia) serving as a mycological criterion. True negatives were identified as patients with a positive Platelia assay but classified as non-probable IA (n = 10) and outpatients who consistently tested negative with the Platelia test throughout the study period (n = 20). Most patients diagnosed with proven or probable IA were acute myeloid leukaemia or myelodysplastic syndrome patients receiving mould-active antifungal prophylaxis or treatment (71%). VirClia demonstrated high sensitivity (100%) for detecting IA, with a specificity of 83%. Wako BDG and MycoGENIE PCR showed lower sensitivities for IA (57% and 64%, respectively). MycoGENIE PCR detected Aspergillus spp. and Mucorales in two patients. Accurate diagnosis of IA remains challenging, especially in patients who have received mould-active antifungal treatment. VirClia showed comparable performance to Platelia, suggesting its potential for routine use. However, Wako BDG and MycoGENIE PCR results were less favourable in our study cohort. Nevertheless, MycoGENIE PCR detected two probable co-infections with Aspergillus spp. and Mucorales.

Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.

Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS). To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings. The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.

Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 .

Real-World Study of the Burden of Myelodysplastic Syndromes in Patients and Their Caregivers in Europe and the United States

Real-World Study of the Burden of Myelodysplastic Syndromes in Patients and Their Caregivers in Europe and the United States

Standardized bone marrow assessment, risk variables, and survival in dogs with myelodysplastic syndrome and acute myeloid leukemia.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous neoplasms of hematopoietic stem cells that are challenging to diagnose, differentiate, and prognosticate. Cytogenetic and mutational analyses are useful in humans but unavailable for dogs, where diagnosis and classification still rely largely on hematologic and morphologic assessment. The objectives of this study were to apply a classification scheme to myeloid neoplasms and to assess outcome in relation to predictor variables. Keyword search of a laboratory database, application of sequential exclusion criteria, and consensus from 3 reviewers yielded 70 cases of myeloid neoplasia with hematology results, and cytologic (11), histologic (14), or both (45) types of marrow specimens. Based on blast percentage and morphology, 42 cases were classified as MDS and 28 as AML. Dogs with MDS had significantly lower body weights, hemoglobin concentrations and blood blasts, and higher red blood cell size variability and platelet numbers than dogs with AML. Estimates of median survival using Kaplan-Meier curves for dogs with MDS and AML were 384 and 6 days, respectively (P < .001). The instantaneous risk of death for dogs with MDS was approximately 5× lower than that of dogs with AML. Significant predictor variables of survival were body weight, white blood cell count, platelet count, and percent blood blasts (P < .05). Hazard ratios (HRs) derived from best-fitting Cox regression models were 1.043, 0.998, and 1.061 for increased neutrophils, decreased platelets, and increased blood blasts, respectively. Findings from this study suggest that hematologic and morphologic variables are useful to predict outcomes in myeloid neoplasia.

Use of Hematopoietic Cell Transplant for Hematologic Cancers by Race, Ethnicity, and Age.

Utilization of hematopoietic cell transplantation (HCT) for hematologic cancers previously demonstrated race, ethnicity, and age-based disparities. To evaluate utilization over time by race, ethnicity, and age to determine if disparities persist in light of recent significant increases in HCT volume. This US population-based retrospective cohort study includes patients who received transplants from January 2009 to December 2018. Data collection and cleaning occurred from February 2019 to November 2021, and data analysis occurred from January 2022 to October 2023. Method 1 restricted the analysis to Surveillance, Epidemiology and End Results (SEER) reporting areas for cases and transplants. Method 2 applied SEER age-, race-, and ethnicity-specific incidence rates to corresponding US census population and included all transplants reported to the Center for International Blood and Marrow Transplant Research. Race and ethnicity groups were hierarchically defined as Hispanic (any race), non-Hispanic White, non-Hispanic Black, and non-Hispanic Other (Asian and American Indian). Receipt of HCT. Utilization rate of autologous or allogeneic HCT for patients with hematologic cancers by age, race, and ethnicity. From 2009 to 2018, 136 280 HCTs were analyzed for 6 hematologic cancers comprising 16.7% pediatric/adolescent/young adults (0-39 years), 83.3% adults (40-84 years), 58% male, 10.3% Hispanic, 11.4% non-Hispanic Black, 3.8% non-Hispanic Other, and 74.5% non-Hispanic White patients, with 49 385 allogeneic and 86 895 autologous HCTs performed. HCT utilization increased over time for all disease, age, race, and ethnic groups. From 2017 to 2018, adult (40-84 years) allogeneic transplant utilization for acute myeloid leukemia and myelodysplastic syndrome (MDS) was similar for Hispanic and non-Hispanic White or Other patients but was lower for non-Hispanic Black patients (acute myeloid leukemia: 19% vs 13%; MDS: 9%-10% vs 5%). Similarly, autologous transplant utilization for lymphoma was similar for all race and ethnicity groups; however, autologous transplant for multiple myeloma was highest for non-Hispanic White patients and lower for all other groups (31% vs 26%-27%). In patients aged 0 to 39 years, utilization of allogeneic transplant for acute lymphoblastic leukemia was highest in Hispanic patients, followed by non-Hispanic White, Black, and Other races (acute lymphoblastic leukemia: 19%, 18%, 17%, and 16%, respectively). In this cohort study of autologous and allogeneic transplant utilization for hematologic cancers, disparities persisted for non-Hispanic Black patients. Hispanic, non-Hispanic Other, and younger age groups had increased utilization over time that was on par with non-Hispanic White patients in the most recent cohort.

Myelodysplastic syndrome/ Myeloproliferative disorder, Nos.

Background: Population-based research is limited for myelodysplastic syndrome/ myeloproliferative neoplasm, not otherwise specified (MDS/MPN-NOS) which comprises a heterogenous group of patients that do not fit into the other established MDS/MPN subgroups. Methods: We identified patients from the Surveillance, Epidemiology, and End Results (SEER) database with a diagnosis of MDS/MPN-U logged from 2010-2020. Age-standardized incidence rates (ASIR) and incidence rate ratios (IRR) were calculated using eight age subgroups. Subgroup analyses were performed for race and gender. Join point regression analyses were performed to model trends in ASIRs, and annual percent change (APC) was calculated. Results: A total of 2447 patients over age 50 were included in analysis. Incidence of MDS/MPN-U increased gradually between 2010-2016 (APC 12.90) then decreased between 2016-2020 (APC -19.56). ASIR was significantly higher in males compared to females in several age groups (age 65-69, 80-84, 85+). Conclusion: The underlying molecular complexity of these diseases remains a significant challenge. It is critical to identify MDS/MPN- specific therapeutic response criteria and suitable end points correlated with survival and AML risk for transformation to acute myeloid leukemia (AML) uniform assessment of treatment benefit.

Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial.

Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood. To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor. This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months. National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers. Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available. Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (∼25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective. Cumulative incidence of transplantation by Search Prognosis arm. Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113). A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor. Trial Registration: NCT#03904134.