Dezern, Amy Elizabeth

Abstract Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation’s effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.

Abstract Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.

Abstract Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.

Abstract Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.

Introduction The International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) were developed using datasets from patients (pts) with untreated MDS. The cytogenetic risk groups used in IPSS-R were expanded to 5 groups from the 3 used in IPSS. Among the new groups introduced in IPSS-R is the “very complex” karyotype (VCK) where ≥4 karyotypic abnormalities are seen compared to “complex karyotype (CK)” with only 3 abnormalities. However, the prognostic impact of VCK vs CK, as well as individual cytogenetic abnormalities and TP53 mutation (TP53mut) status within the CK and VCK subgroups in pts with MDS treated with hypomethylating agents (HMAs) has not been well studied. Hence, we analyzed these questions in a large cohort of HMA-treated MDS pts in the icMDS VALIDATE database. Methods The icMDS VALIDATE database contains MDS pts treated with frontline HMA monotherapy or HMA-based combinations from 22 specialized international centers. Pts with unknown HMA type, date of HMA initiation, missing age, missing sex, missing cytogenetic data, bone marrow or peripheral blood blasts ≥20%, or missing survival status were excluded. We performed time-to-event analyses using the Kaplan-Meier method and compared groups by the log-rank test. We measured overall survival (OS) from time of HMA initiation. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from Abbvie. Results A total of 1940 pts were included. Median age was 70 (range: 18-99) years and 66% were men. According to IPSS-R cytogenetic risk groups, 1.9% (37) were very good, 43.4% (841) good, 15.5% (301) intermediate, 11.6% (226) poor, and 27.6% (535) very poor. By HMA type, 71% of pts were treated with azacitidine, 14% with decitabine, 6% with HMA and venetoclax, and 9% with another HMA combination. Approximately 28% of pts underwent allogeneic hematopoietic stem cell transplant (alloHSCT). The IPSS-R cytogenetic risk groups had different OS (p<0.001)with median OS (mOS; months [mo], 95% CI) as follows: very good (43.4, 34.7-72.5), good (41.7, 36.4-46.8), intermediate (24.5, 23.1-32.4), poor (24.2, 19.2-28.5), and very poor (13.6, 12.5-14.5). The difference remained significant (p=0.001) after censoring at time of alloHSCT with mOS as follows: very good (40.4, 23.2-64.3), good (24.3, 22.2-26.3), intermediate (19.3, 15.1-22.2), poor (12.2, 10.3-14.8), and very poor (9.1, 8.2-19.7). Interestingly, the difference between mOS for intermediate and poor risk cytogenetics became more apparent after censoring at time of alloHSCT. Next, we compared the outcomes of pts with CK and VCK to non-complex karyotype (NCK) MDS. The mOS for pts with VCK MDS (13.6 mo, 12.5-14.5) was worse compared to pts with CK (19.9 mo, 19.9-16.8; p=0.004) and NCK (36.1 mo, 32.7-37.8; p<0.001) MDS. Among the 1458 pts with available molecular data, more pts with VCK (75%, 330) MDS had a concurrent TP53mut compared to pts with CK (40%, 21; p<0.001) and NCK (7%, 64 p<0.001) MDS. Considering only patients with TP53mut MDS, mOS for pts with VCK (12.2, 11.1-13.9) was worse compared with NCK (24.2, 16-1-53.1; p<0.001) but not with CK (19.9, 9.5-NR; p=0.9); the difference between CK and NCK was not significant (p=0.16). Among pts with TP53 wildtype (TP53WT) MDS, VCK (15.0, 13.2-18.2) had a similar mOS to TP53WT CK (18.8, 12.6-41.1; p=0.19) while both groups had worse mOS compared to TP53WT NCK (33.4, 30.1-37.0) (p=0.01). In a survival analysis of 616 pts with MDS with ≥3 cytogenetic abnormalities, -17/del(17p) (12.8 mo; p=0.009), inv(3)/t(3q)/del(3q) (10.9 mo; p=0.006), and del(7q) (12.1mo; p=0.024), though not -7 (12.6mo; p=0.23), were associated with lower mOS compared to the pts with MDS without these abnormalities (14.3mo). Conclusions Using one of the largest databases of HMA-treated MDS pts, we show that IPSS-R cytogenetic risk categories associate with significantly different survivals among HMA-treated MDS pts, even after censoring at time of alloHSCT. Importantly, VCK MDS was associated with worse mOS compared to CK and NCK MDS but not in pts with a concurrent TP53mut. Among pts with MDS with ≥3 chromosomal abnormalities, having -17/del(17p), inv(3)/t(3q)/del(3q), or del(7q) was associated with worse survival.

Introduction: Response assessment is used to evaluate effectiveness of hypomethylating agent (HMA)-based therapy in myelodysplastic syndromes/neoplasms (MDS) in clinical practice and trials. Recently, the clinical response criteria (IWG 2023) and the clinical-molecular risk assessment (IPSS-M) in MDS were published. However, it remains unknown whether the IWG 2023 response criteria have an independent impact on overall survival (OS) when adjusting for baseline IPSS-M risk. Additionally, the association of IWG 2023 response criteria with OS in patients (pts) undergoing allogeneic stem cell transplantation (allo-HCT) versus those who do not is unknown. Lastly, it is unclear if optimal time-to-transplant impacts OS in MDS pts who achieve a IWG 2023 defined remission with HMA therapy. We examined these questions in a large population of MDS pts within the multi-institutional international consortium for MDS (icMDS) VALIDATE database. Methods: High-risk MDS pts with IPSS ≥1.5 or IPSS-R >3.5 treated with HMA-based therapy were included in the study. Baseline IPSS-M risk was stratified into very low/low/moderate low (VL+L+ML), moderate-high/high (MH+H), and very high (VH). Response to treatment was evaluated using the IWG 2023 criteria and grouped into: composite complete response (cCR) and no cCR. cCR included: complete response (CR), CR equivalent (CRequ), CR bilineage (CRbi), CR unilineage (CRuni), and CR with partial hematologic recovery (CRh). We analyzed the differential impact of achieving cCR on HMA-based therapy prior to transplant on OS in pts who either did or did not undergo allo-HCT, while adjusting for their baseline IPSS-M risk in Cox regression analysis. Optimal time-to-transplant was determined based on age and IPSS-M category as described by Tentori et al. (JCO 2024). Pts proceeding to allo-HCT were stratified on whether they underwent transplant within the optimal time-to-transplant timeframe after MDS diagnosis or not. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from AbbVie. Results: We analyzed 762 MDS pts. The median age at MDS diagnosis was 68 years (range: 19-95 years) and 64% of pts were male. Distribution of the baseline IPSS-M risk was: VL+L+ML in 110 (14%) pts, MH+H in 347 (46%) pts, VH in 305 (40%) pts. Pts received azacitidine monotherapy, decitabine monotherapy, and HMA-based combination therapy (e.g. HMA + venetoclax) in 52%, 21%, and 28% of cases, respectively. A total of 282/762 (37%) pts achieved cCR as their best response to HMA-based therapy. The median OS for all pts was 18.7 months (95% CI: 16.6-21.3 months). Pts who did not undergo allo-HCT (n=436, 57%) had an improved median OS if they achieved cCR when compared to pts in the no cCR group in all IPSS-M risk groups (VL+L+ML: 23.5 months vs. 10.7 months; MH+H: 20.8 months vs. 11.6 months; VH: 13.8 months vs. 7.5 months). Cox analysis demonstrated an independent effect of cCR on OS in these pts when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 0.60, 95% CI 0.48-0.76, p<0.001). In contrast, in pts who subsequently received an allo-HCT (n=326, 43%), achieving cCR with HMA prior to allo-HCT did not provide an additional OS benefit, when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 1.00, 95% CI 0.73-1.38, p=0.986). The median time-to-transplant was 6.7 months and 34% of transplanted MDS pts received their allo-HCT during the optimal timeframe. Among pts who achieved cCR with HMA-based therapy prior to allo-HCT, optimal time-to-transplant was associated with significantly improved OS (optimal vs. non-optimal timing: HR 0.55; p=0.033). Conclusion: Baseline IPSS-M risk and allo-HCT had an independent impact on OS, while IWG 2023 defined cCR had an independent effect on OS only in non-transplanted MDS pts. While this retrospective analysis occurred at large academic centers with specific expertise in the management of MDS, our data may have an impact on clinical practice: (i) failure to achieve cCR on HMA therapy prior to transplant should not impact the decision to proceed to allo-HCT, (ii) upfront allo-HCT without prior HMA therapy might also be an option if the clinical situation and availability of donors allow, and (iii) allo-HCT should ideally be performed during the timeframe that is considered optimal as defined by pt age and baseline IPSS-M.

Background: Immunosuppressive therapy (IST) is considered the standard front-line treatment for acquired severe aplastic anemia (SAA) for pts >40 years. For pts aged <40 years who have a suitable human leukocyte antigen (HLA)-matched sibling donor (MSD), hematopoietic stem cell transplantation (HSCT) is recommended. This recommendation is based on the toxicity associated with alternative donors; haploidentical (HAPLO) and unrelated donor (URD) HSCT for patients who lack a MSD. However, the hematopoietic response after IST is ~ 70-80%, even after augmentation with eltrombopag in the front-line setting, and failure-free survival (FFS, defined as patients alive and in remission without clonal disease more than 10 years after IST) remains < 40%. HSCT is often employed as a second line salvage therapy for those who do not respond to IST or have disease recurrence. However, outcomes after HSCT are often compromised because of IST-related complications such as clonal evolution, development of donor specific antibodies, infectious adverse events and organ dysfunction. In contrast, a successful allogeneic HSCT leads to relatively prompt hematopoietic and immune reconstitution and mitigates the risk of secondary clonal disease. Innovations in recent decades, such as improved graft versus host disease (GVHD) prophylaxis and supportive care, have steadily reduced the morbidity and mortality of adults undergoing HSCT from unrelated or mismatched donors and expanded the donor pool such that almost all pts with SAA have a potential donor available. The use of post-transplant cyclophosphamide (PTCy) is now a well-established approach to facilitate engraftment and mitigate the risk of GVHD. It was successfully used in relapsed/refractory SAA pts using HAPLO donors in the multi-center BMT CTN #1502 trial (NCT02918292). Similar PTCy based approaches have been effective in the upfront setting with HAPLO and URD in small single center studies. Opened in July 2024, the CureAA trial (NCT06517641), seeks to increase donor options for SAA pts who have not yet received IST by using PTCy based GVHD prophylaxis for HSCT using HAPLO or URD. Study Design and Methods: This BMT CTN study (#2207) is a prospective multi-center phase II trial to assess efficacy of HSCT using HAPLO or URD bone marrow with a reduced intensity, thymoglobulin (ATG)-containing preparative regimen and PTCy GVHD prophylaxis in previously untreated SAA pts. This trial has two parallel cohorts for each donor type, HAPLO and URD, with an accrual goal of 30 participants in each cohort. All will receive ATG (0.5mg/kg on day -9 and 2mg/kg on days -8 and -7), cyclophosphamide (14.5mg/kg on days -6 and -5), fludarabine (30mg/m2 on days -6 to -2), 400 cGy total body irradiation (day -1 in a single fraction), a marrow graft (goal >2.5 x 108 nucleated cells per kg of recipient) on day 0 and PTCy (50mg/kg on days +3 and +4). Additionally, participants receive tacrolimus (until day +180) and mycophenolate mofetil days +5-35. The primary objective of the trial is to estimate the GVHD-free failure-free survival (GFFS) rate at 1 year after initiation of conditioning. GFFS is a composite endpoint of survival without grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, or primary or secondary graft failure requiring second definitive therapy within 1 year after initiation of conditioning. Secondary objectives will evaluate patient survival, engraftment, transfusion dependence, cumulative incidence of GVHD and hematologic response. Health related quality of life, healthcare utilization and financial toxicity data will also be collected. These endpoints will allow clinical comparison with current results achieved with upfront IST in other studies. We hypothesize that this HSCT approach will improve survival without significant transplant-associated morbidity by using a low toxicity regimen that reduces rates of GVHD and provides rapid hematologic recovery without graft failure, thereby making HAPLO and URD HSCT a viable option for initial upfront treatment of SAA. The ability to use mismatched donors will also ensure that a HSCT option is more widely available to all racial/ethnic groups. This collaborative study was funded by grants U10HL069294, U24HL138660 to the BMT CTN from the NHLBI/ NCI, along with funding from Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Introduction Knowledge of epidemiologic risk factors, clonal changes associated with MDS development from precursor states, and evolution from one MDS state to another (lower- (LR) or higher-risk (HR) disease or leukemia (AML)) are largely limited to retrospective studies, which may not reflect the true MDS spectrum. The MDS NHS is an established prospective cohort of patients (pts) with suspected MDS enrolled at diverse US sites. Extensive clinical data and biospecimens are collected at baseline and throughout follow-up (F/U), in real time, as pts are followed for life. Here, we assess rates and potential predictors of progression providing a foundation for precise stratification across the MDS spectrum, which may ultimately guide intervention. Methods At baseline, all MDS NHS pts have central pathology review and those assigned to MDS, MDS/MPN overlap, AML<30% blasts, or at-risk of MDS (AR-MDS: CCUS and other at-risk) are followed prospectively. We compared AR-MDS with LR-MDS (MDS and MDS/MPN overlap with IPSS-R ≤ 3.5) and HR-MDS (MDS and MDS/MPN overlap with IPSS-R > 3.5). We defined disease progression as any F/U diagnosis of worsening disease or documented disease-related death. Rates of disease progression were compared between groups using survival analysis methods for cumulative incidence incorporating non-disease death as a competing risk. Associations between progression and predictor variables were explored using univariate tests of association and multivariable survival (Cox regression) models for time-to-progression and logistic models for probability of progression (yes/no). Results The MDS NHS enrolled 2051 pts during June 2016-February 2024, with 54% (1111, above categories) followed prospectively. Median F/U is 1.7 yrs (IQR: 0.8-3.1 yrs, max: 7.9 yrs). For the current analysis, 582 MDS and 505 AR-MDS pts were included. Compared to AR-MDS, MDS patients were more often male (70% v 61%, p<0.01), older (median age: 75 v 72 years, p<0.01), and had lower baseline hemoglobin (median: 10.1 v 11.9 g/dL, p<0.001), platelets (median: 124 x109 v 146 x109 cells/L, p<0.001), and absolute neutrophil counts (median: 1.9 x109 vs 2.8 x109 cells/L, p<0.001). F/U time was similar among AR-MDS and MDS (median: 1.9 vs 1.6 yrs), with both groups having a 75th percentile of 3 yrs and maximum of 7 yrs. A total of 331 deaths were observed (30%), with 145 (44%) of these due to causes related to MDS (myeloid disease and/or cardiovascular disease). Overall, 18.5% had disease progression, with annual rates of 8% (MDS) and 2% (AR-MDS) (p<0.01). Among HR-MDS, progression rates were greatest in the 1st year following diagnosis (33%) and declined thereafter, whereas progression rates remained between 5-8% for LR-MDS and 1-3% for AR-MDS over 5 yrs of F/U. AR-MDS had similar rates of progression within the first 3 yrs from diagnosis as MDS with the lowest IPSS-R category. Among AR-MDS, low hemoglobin (hazard ratio, HR [95% CI]=3.2 [1.4-7.3], p<0.01) was significantly associated with progression. Among MDS, low hemoglobin (HR=4.0 [2.2-7.0], p<0.001), low platelet count (HR=3.1 [1.7-5.6], p<0.001) and higher numbers of mutations (HR=1.13 [1.0-1.2], p<0.01) were significantly associated with progression. Due to the low rate of progression in AR-MDS, meaningful comparisons of mutations could not be completed. In MDS, univariate analyses showed that somatic mutation prevalence in gene pathways for transcription, cell cycle and RAS signaling, and in genes TP53, BCOR, SF3B1, DDX41, PTPN11, SETBP1, and JAK2 were significantly associated with the probability of progression (p<0.05 in all). In multivariable models, adjusting for patient age, sex, and MDS risk level, the probability of progression (PP) was significantly higher among those with vs without somatic mutations in BCOR (PP=63% vs 29%, p=0.004), PTPN11 (PP=67% vs 29%, p=0.009), SETBP1 (PP=61% vs 30%, p=0.02), JAK2 (PP=59% vs 30%, p=0.02), DDX41 (PP=56% vs 30%, p=0.03) and TP53 (PP=43% vs 29%, p=0.04). Conclusions In this large prospective cohort of MDS and pts at risk for MDS, the annual rate of any disease progression was 8% among MDS and 2% among AR-MDS, lower than some retrospective series. Specific cytopenias and genetic factors associated with progression were identified. The MDS NHS provides an incomparable opportunity to address the critical clinical challenges of management and prevention of MDS progression across its spectrum.