Advanced Myelodysplastic Syndrome Research Articles

Efficacy and safety of azacitidine in pediatric patients with newly diagnosed advanced myelodysplastic syndromes before hematopoietic stem cell transplantation in the AZA-JMML-001 trial.

Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.

Decitabine in combination with idarubicin within a modified busulfan/cyclophosphamide conditioning regimen for patients with advanced myelodysplastic syndrome: A prospective multicenter clinical cohort study.

Decitabine in combination with idarubicin within a modified busulfan/cyclophosphamide conditioning regimen for patients with advanced myelodysplastic syndrome: A prospective multicenter clinical cohort study.

The role of genetic factors in pediatric myelodysplastic syndromes with different outcomes

BackgroundPediatric myelodysplastic syndromes (MDS) are rare disorders with an unrevealed pathogenesis. Our aim is to explore the role of genetic factors in the pathogenesis of MDS in children with different outcomes and to discover the correlation between genetic features and clinical outcomes as well as disease characteristics.MethodsWe conducted an analysis of archived genetic data from 26 patients diagnosed with pediatric MDS at our institution between 2015 and 2021, examining the association between different genetic characteristics and clinical manifestations as well as prognosis. Additionally, We presented three cases with distinct genetic background and outcomes as examples to elaborate the role of genetic factors in pediatric MDS with different prognoses.ResultsGenetic variations were detected in 13 out of the 26 patients, including 8 patients with co-occurrence of somatic and germline mutations (CSGMs) and 5 patients with somatic mutations alone. Our analysis revealed that advanced MDS (4/8, 50% vs. 1/5, 20% and 4/11, 36.4%), PD (3/8, 37.5% vs. 1/5, 20% and 1/11 9.1%), and TD (6/8, 75% vs. 2/5, 40% and 2/11, 18.2%) were more common in patients with CSGMs than those with somatic mutations alone or without any mutations. We also found out in our study that 8 patients with CSGMs had evidently different clinical outcomes, and we presented 3 of them as examples for elaboration. Case 1 with germline and somatic mutations of unknown significance had a relatively slow disease course and a good prognosis. Case 2 with compound heterozygous germline SBDS variants and somatic mutations like del20q had a stable disease course and a reversed outcome. Case 3 with a germline GATA2 variant and somatic mutations including − 7 had a rapidly progressive disease course and a worst prognosis.ConclusionOur findings indicate that genetic background of pediatric MDS is closely linked with disease characteristics as well as outcomes and that CSGMs may lead to disease progression. It should be emphasized that the interaction between certain germline variants and somatic mutations, such as SBDS and del20q, may result in hematopoietic stem cell adaptation (improved hematopoiesis) and reversed clinical outcomes, which can facilitate the development of targeted therapy.

The Efficacy and Prognosis of Advanced Myelodysplastic Syndrome in Children

Pediatric myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell neoplasm with an annual incidence of 1-4 cases/million. The low incidence of advanced MDS in children and poor prognosis attract our attention. However, there are limited reports on the scheme and efficacy of pediatric advanced MDS. In this study, we retrospectively analyzed the efficacy of chemotherapy in pediatric advanced MDS and assessed the prognosis of patients. According to 2016 World Health Organization (WHO) classification of haematolymphoid tumours, 30 newly diagnosed pediatric advanced MDS patients during Dec 2007 to Apr 2022 from our single center were selected as the research object. The clinical data and prognosis were analyzed. The median age of patients is 8 years (range: 1-15years). The median bone marrow blast is 15.75% (range: 5-29.5%), while the median peripheral blood blast is 4% (range: 0-29%). Cytogenetic analysis was available for 29 patients, 69% (20/29) cases had abnormal karyotype. Monosomy 7 (37.9%) was the most common cytogenetic abnormality. Out of the total, 7 patients were treated with CAG/HAG regimen (C: aclarubicin 6mg d1-14, H: homoharringtonine 1mg/m 2d1-14, A: cytarabine 10mg/m 2 q12h d1-14, and G: Granulocyte Colony-stimulating Factor 200mg/m 2 d1-14 ), 8 patients with decitabine (20mg/m 2 d1-5), 11 patients with decitabine and CAG/HAG, 4 patients with AML-like chemotherapy (Daunorubicin+cytarabine+etoposide ) or other. The evaluation of response of therapy was available in 25 patients, 5 cases (20%) in partial remission (PR), 11 cases (44%) in complete remission (CR), 9 cases in(36%)non-remission (NR). The total response rate of chemotherapy is 60%, with CAG/HAG therapy 33%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 78%, AML-like chemotherapy 100%. The total complete remission rate of chemotherapy is 44%, with CAG/HAG therapy 17%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 56%, AML-like chemotherapy 67%. Patients receiving CAG/HAG in combination with decitabine had higher response rates compared to CAG/HAG or decitabine alone (OR=17.5, 95% CI 1.2-250.3, P=0.035). With a median follow-up of 20 months (range: 1-158months), 23 patients received HSCT after chemotherapy, and they had a higher 2-year overall survival rate compared to those who did not undergo transplantation (86% vs 0%, p<0.001). Decitabine combined with CAG/HAG improve the response rate of advanced pediatric MDS. Chemotherapy bridged hematopoietic stem cell transplantation significantly improves the prognosis of advanced pediatric MDS.

Decitabine in Combination with Aclacinomycin, Cytarabine and Granulocyte Colony-Simulating Factor (CAG) Had a High Response Rate in Children with Advanced Myelodysplastic Syndrome and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Advanced myelodysplastic syndrome (MDS) is a rare disease in children with poor prognosis. Allogeneic transplantation is the only curative option. However, there has been no established treatment prior to transplant. We conducted a retrospective study exploring the response rates and safety of decitabine combined with aclacinomycin, cytarabine and granulocyte colony-stimulating factor (CAG) for induction treatment of advanced MDS and acute myeloid leukemia with myelodysplasia-related changes (MDR-AML) in children. Patients from 1 to 14 years administrated in Pediatric Blood Disease Center of CAMS Blood Disease Hospital between January 1the 2019 and December 31th 2022 were screening. All diagnosed with MDS-EB or MDR-AML according to WHO 2016 criteria and treated with decitabine combined with CAG were identified. The efficacy of one-cycle treatment of MDS-ED was evaluated based on The International Working Group Response Criteria 2006. The response for MDR-AML was evaluated according to the criteria for AML published by ELN. The response of MDR-AML was defined as complete remission (CR) or CR with incomplete count recovery (CRi). The response of MDS-EB was defined as CR or bone marrow CR with hematological improvement (HI). A total of 13 patients, including MDS-EB (n=7) and MDR-AML (n=6), were enrolled for analysis. 5-day decitabine was administrated, combined with modified CAG regimen for 7 days. Eventually 12 patients of those were available for evaluation. For patients with MDS-EB, four achieved CR and three reached marrow CR with HI. Four patients with MDR-AML, three achieved CR and two reached CRi. The overall response rate was 100%(12/12). The most frequent adverse events were myelosuppression and suppression-induced infections, but no infection-related mortality was recorded. There had been no cardiotoxic event happened, either. Only one patient experienced fatal bleeding in early stage after treatment. The median follow-up time was 16 months (range 1-48). At last follow-up, 10 patients who had underwent allo-HCT were alive without disease. The remaining 2 patients died of disease progression. The 2-year estimated overall survival was 62.9%. Decitabine combined with modified CAG had a high response rate for children with advanced MDS and MDR-AMl, and it can bridge patients to curative allogeneic transplantation.

Real-World Data Suggest Effectiveness of Allogeneic Mesenchymal Stromal (MSC-FFM) Cells in Ruxolitinib-Refractory Acute Graft-Versus-Host Disease

Introduction: Acute graft-versus-host disease (aGvHD) remains the leading cause of treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Current first-line treatment of aGvHD is with high-dose corticosteroids, the standard for steroid-refractory aGvHD (SR-aGvHD) is the Janus kinase (JAK) inhibitor ruxolitinib. Outcomes for patients with ruxolitinib-refractory or -intolerant aGvHD (RR-aGvHD) are poor. Thus in a recent real-world study of adult patients with RR-aGvHD (Abedin BJH 2021) median survival was 28 days (21 days for ruxolitinib refractoriness, 50 days for ruxolitinib intolerance), the probability of overall survival (OS) at 6, 12, and 24 months were about 20%, 16%, and 10%, respectively. We assessed real-world outcomes of patients with RR-aGvHD treated with the random-donor allogeneic MSC preparation “MSC-FFM,” available via Hospital Exemption in Germany. Patients: Between December 2017 and February 2023, 156 patients, including 33 children and adolescents (<18 years of age), received MSC-FFM for RR-aGvHD. Thirty-two German sites contributed 139 patients, while the remaining 17 patients came from seven transplant centers in France, Hungary, Norway, Sweden, and Switzerland. The adult cohort (n=123) consisted of 41% females, with an age range of 19 to 79 years (median 55 years). Except for one patient, all had been diagnosed with malignant diseases (missing information, n=3). Among the adult patients with malignant diseases, 88% (n=105) received HSCT for acute myeloid leukemia (AML), advanced myelodysplastic syndrome, myeloproliferative neoplasm or lymphoma, and 12% (n=15) for acute lymphoblastic leukemia (ALL). In the pediatric cohort (n=33), 48% of patients were females, with an age range of 0 to 17 years (median 9 years). Overall, 58% of pediatric patients (n=19) had malignant diseases as the indication for allogeneic HSCT, 42% (n=8) having ALL and 32% (n=6) with AML. The remaining 42% of pediatric patients (n=14) had non-malignant diseases as the indication for HSCT. Of the adult patients, 6 (4.9%) had grade II, 52 (42.3%) had grade III, and 63 (51.2%) had grade IV aGvHD, with no specification reported for 2 patients (1.6%). In children, 2 (6.1%) had grade II, 10 (30.3%) had grade III, and 21 (63.6%) had grade IV Treatment: MSC-FFM is manufactured from pooled bone marrow mononuclear cells from eight HLA-disparate healthy donors. MSCs are selected by plastic adherence, expanded until the end of passage 3, then frozen in saline-albumin with DMSO. The recommended dosing for MSC-FFM is 1-2 million cells/kg body weight (BW), for four weekly doses. The median dose administered was 1.18 million cells/kg BW, with a median number of four doses and a median inter-dose interval of 7 days. Results: Safety: Tolerability of MSC-FFM was good, with only five adverse drug reactions reported in three adult patients (chills, BK virus cystitis, increase in C-reactive protein [reported twice in one patient], nausea) and did not result in cessation of MSC treatment or dose reductions. Response: The overall response rate at day +28 was 49% (95%-CI: 41-58%), with 45% (36-55%) in adults and 64% (45-80%) in children. Most responses were durable, resulting in an overall response rate of 49% (41-57%) for both adults and children at 2 months, and 40% (31-48%) at 6 months. Survival: Overall survival at 6, 12, and 24 months was 47% (38-56%), 35% (27-44%), and 29% (21-38%) for adults, and 59% (40-74%), 42% (24-58%), and 37% (19-54%) for children, respectively (Table 1). Median overall survival was 5.8 months. These outcomes compare favourably to published overall survival estimates for adult RR-aGvHD patients not treated with MSC-FFM (Abedin BJH, see above). Summary: The unique MSC-preparation MSC-FFM appears to be effective against RR-aGvHD.

A Phase 1 Study of Avapritinib in Combination with Decitabine in Patients with Systemic Mastocytosis with an Associated Hematologic Neoplasm

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Prevalence and Outcome of Vexas Syndrome in Unrelated Hematopoietic Stem Cell Transplantation

Introduction Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a newly identified monogenic disorder defined by somatic UBA1 mutations in hematopoietic progenitor cells, resulting in bone marrow failure (BMF) and systemic inflammation. This syndrome is frequently associated with myelodysplastic syndrome (MDS) or plasma cell dyscrasia. Although high-dose corticosteroids alleviate symptoms and cytopenia, allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potentially curative treatment. This study evaluated the safety and efficacy of unrelated HSCT for treating VEXAS syndrome and its prevalence in patients with hematologic diseases. Methods We conducted retrospective screening for UBA1 mutations in patients with BMF or plasma cell neoplasms who underwent their first HSCT from unrelated donors in Japan between 1995 and 2020. Pre-HSCT blood DNA samples and clinical data were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Multiplex real-time PCR was used to detect the most common pathogenic UBA1 mutations, including p.M41L (c.121A>C), p.M41V (c.121A>G), and p.M41T (c.122T>C), with detection limits of 0.13%, 0.5%, and 1%, respectively. The presence of these mutations was confirmed using Sanger sequencing and droplet digital PCR. In addition, we examined UBA1 mutations in 2 patients previously diagnosed with MDS but suspected of having VEXAS syndrome based on specific clinical features. Results Among 4340 patients with either BMF or plasma cell neoplasms who underwent unrelated HSCT, 1771 had available pre-HSCT blood DNA samples. The diagnoses of the 1771 patients included MDS (n = 1264), acquired aplastic anemia (n = 375), inherited BMF syndromes (n = 89), plasma cell neoplasms (n = 23), and other acquired BMF syndromes (n = 20). The median patient age at HSCT was 46 (range, 0-75; interquartile range, 20-59) years old, and the male-to-female ratio was 1.6:1. Pathogenic UBA1 mutations were detected in 2 of the 1771 patients (0.11%), both of whom were male MDS patients older than the median age (cases 1 and 2); thus, the prevalence of VEXAS syndrome within this patient subgroup was 0.36%. Both patients received chemotherapy before unrelated donor bone marrow transplantation (BMT), including induction chemotherapy and azacitidine, and achieved complete and partial responses, respectively. In addition, UBA1 mutations were detected in the 2 MDS patients at Kanazawa University Hospital (cases 3 and 4). Case 3 also underwent unrelated BMT after experiencing cytopenia relapse and inflammatory symptoms during corticosteroid reduction. The clinical characteristics and outcomes of the 4 patients with VEXAS syndrome are summarized in Table 1. Variant allele frequencies (VAFs) of UBA1 mutations ranged from 2% to 71%. The 3 patients who underwent unrelated BMT received fludarabine and busulfan-based conditioning regimens and graft-versus-graft disease (GVHD) prophylaxis with tacrolimus + methotrexate or cyclosporine + methotrexate. All 3 patients achieved neutrophil and platelet engraftment. One patient required systemic corticosteroids for acute skin GVHD. One patient died of idiopathic interstitial pneumonia 5 months after BMT. The other 2 patients were alive without relapse, chronic GVHD, or other complications at 18 and 28 months after BMT. Discussion Our results support the curative potential of allogeneic HSCT for VEXAS syndrome without excessive toxicity. The occurrence of transplant-related mortality due to idiopathic interstitial pneumonia may be related to the reported poor outcome of the p.M41V mutation following non-transplant therapy. The low prevalence of VEXAS syndrome in the current cohort may be due to the late age of onset and the rare progression to advanced MDS. The low VAFs of UBA1 mutations in the 2 patients who responded to chemotherapy before HSCT may indicate the efficacy of chemotherapy in selectively eradicating UBA1 mutant clones. Our rapid, sensitive, and cost-effective screening method for VEXAS syndrome can help optimize treatment strategies for this rare disease in future studies.

Soluble PD-L1 Predicts Poor Outcome and Disease Progression in Patients with De Novo Myelodysplastic Syndromes

Background: Myelodysplastic syndromes (MDS) consist of a spectrum of myeloid malignancies typified by regular genetic abnormalities, clonal hematopoiesis, dysfunctional myelopoiesis, inefficient blood cell production, peripheral-blood cytopenia, and an elevated risk for progressing to acute myeloid leukemia (AML). Mounting evidence suggests that the dysregulation of immune checkpoints (ICs) plays critical roles in immune evasion of MDS, which thus led to a series of trials using HMAs in combination with immune checkpoints inhibitors (ICIs). Of these, programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway has been studied most extensively. Recently, forms of cell-free soluble PD-1/PD-L1 (sPD-1/sPD-L1) detection in plasm of patients with solid tumors has open a new paradigm for PD-1/PD-L1 investigations. However, within the context of MDS, the potential dysregulation and prognostic impact of sPD-1/sPD-L1 remains uncertain. This study was aimed to assess roles of sPD-1/sPD-L1 in newly diagnosed MDS patients. Method: Between July 2020 and March 2023, 130 MDS/sAML patients matched the inclusion criteria and 55 healthy individuals with no familial or personal history of autoimmune or cancer disorders were included. The criteria for patient inclusion included: (1) a diagnosis of MDS confirmed pathologically according to 2016/2022 World Health Organization (WHO) classification, or sAML patients with a verified prior MDS history; (2) absence of other conditions like autoimmune diseases or different types of tumors; (3) availability of complete clinical information and survival data. MDS patients were categorized by IPSS-R as: lower-risk (very low risk/ low risk; higher-risk (intermediate risk/high risk/very high risk. Follow-up was conducted until June 16th, 2023. The median follow-up was 14.32 months (range 3.2-34.63 months). Profile of sICs (sPD-L1, sPD-1, sCTLA-4, sGITR, sTIM-3, sOX40, sLAG-3, s4-1BB, sICOS) were tested by ELISA, cytokines (IFN-γ, IFN-α2, IL-2, IL-2α, IL-6, IL-7, IL-10, IL-15, IL-17, TNF-α) were detected using Luminex analysis, and the expression levels of PD-1 on T cells (CD3 +, CD4 +, CD8 +, DPT, DNT）were measured using flow cytometry (FCM). Result: In the plasma of 98 newly diagnosed MDS patients, sPD-L1 levels (median 66.80 pg/ml, range 25.00-219.5 pg/ml) were significantly elevated compared to 55 healthy blood donors (median 49.22 pg/ml, range 12.5-218.1 pg/ml). sPD-L1 level was higher in higher-risk IPSS-R groups ( P=0.0380). In addition, higher sPD-L1 levels also showed a correlation with lower hemoglobin concentration, implying a potential link between higher sPD-L1 levels and a more advanced MDS disease state. The AUC for sPD-1 was found to be 0.6333 [95% CI 0.5331-0.7334, P=0.0100] and for sPD-L1, it was 0.6785 [95% CI 0.5836-0.7733, P=0.0002]. The optimal cut-off values were established at 187.5 pg/mL for sPD-1 and 55.08 pg/mL for sPD-L1. Based on these cut-off values, patients with increased sPD-L1 experienced shorter OS ( P=0.0305). By using multivariate Cox model, high expression of sPD-L1 ( P=0.019, HR = 4.172, 95% CI: 1.265-13.755) and high IPSS-R scores ( P=0.030, HR = 2.898, 95% CI: 1.111-7.565) were found to be independent risk factors for newly diagnosed MDS patients. In addition, compared to healthy controls, the PD-1 + T cell subpopulations in MDS patients were significantly reduced, sPD-1 levels were positively correlated with proportion of CD4 + PD-1 + T cells, absolute count of CD4 + PD-1 + T cells and PD-1 + DPT cells, suggesting that CD4 + T cells and DPT cells may be potential sources of sPD-1 in plasma. Subsequently, we analysed the potential roles of cytokines and HMAs in sPD-1/sPD-L1 regulation. It was found that sPD-1 levels had a positive correlation with sPD-L1, IL-2Rα, IP-10, MIG, TNFα, GROα, and TRAIL. sPD-L1 was positively correlated with IL-2Rα, IP-10, MCP-1, MIG, MIP1α, and SCF (Figure 1 A). Notably. We found a reduced sPD-L1 levels in MDS patients who achieved remission after HMA treatment compared to treatment-naïve patients. ( P=0.0302) (Figure 1 B). Conclusions: In conclusion, we found sPD-L1 is an independent risk factors for overall survival in newly diagnosed MDS patients. The elevation of plasma sPD-L1 levels is associated with disease progression in MDS, and may be a potential target for MDS immunotherapy.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n=331) or single-unit unrelated cord blood (UCB) (n=668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P=0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P=0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P=0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P=0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P<0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P<0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P<0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P<0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

DNA and RNA Profiles in Machine Learning Algorithm to Predict Which Patients with AML/MDS Will Respond to Venetoclax-Based Therapy

Introduction Venetoclax in combination with hypomethylation agents is currently used as an alternative to standard induction therapy in patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS). This is particularly relevant when patients are not eligible for standard induction therapy due to age or comorbidity. However, little is known about which patients will benefit from such therapy and which patients will not respond. Selecting the right patient for such therapy is very important considering the clinical fragility of these patients. Genomic profiling using DNA and RNA is becoming a standard of care in clinical testing and there is a need to expand on the clinical utility of the generated data for this profiling. We explored the potential of using these genomic DNA and RNA profiles in a machine learning algorithm to predict which patients with AML/MDS will respond to venetoclax-based therapy. Methods: DNA and RNA from bone marrow samples from 46 patients with AML or advanced high-grade MDS treated with venetoclax (plus either azacitidine or decitabine) were extracted. Using next generation sequencing (NGS), the DNA was sequenced using a 177-gene panel and the RNA was sequenced using a 1408-gene panel. Sequencing was performed using the Illumina NextSeq 550 platform. Ten million reads per sample in a single run were required. Read length was 2 × 150 bp. Expression profiles were generated using Cufflinks. We developed a machine learning algorithm that first selected the relative genes based on performance of each gene with cross-validation and based on stability measures using statistical significance tests. The selected genes were then used to predict response or survival with a k-fold cross-validation procedure (k=12). A naïve Bayesian classifier was constructed on the training of k-1 subsets and tested on the other testing subset. We applied geometric mean naïve Bayesian (GMNB) as the classifier for prediction. Results: Of the 46 patients included in the study, 18 (39%) were females. The median age was 70.5 years (range 33-84). The most common mutations detected in these patients were: ASXL1 (41%), RUNX1 (26%), DNMT3A (24%), FLT3 (21%), NPM1 (20%), NRAS (20%), IDH1/2 (20%), TET2 (17%), TP53 (15%), and SRSF2 (11%). Of these 46 patients, 17 (37%) achieved complete response (CR). Using machine learning we were able to predict those who achieved CR with AUC of 0.972 (95% CI: 0.914-1.00) (Figure), sensitivity of 94.1% and specificity of 93.1%. To achieve this prediction only 10 genes were necessary. There was no significant difference between responders and non-responders in expression level of BCL2 (P=0.11), BAX (P=0.18), or MCL1 (P=0.54). BCL2L1 (BCL-XL) was significantly higher in non-responders (P=0.006) as compared with responders. TP53 was mutated in seven patients, six of whom were non-responders, but no other statistically significant association between specific mutation and response occurred. With a median follow-up of 13 months, 28 (61%) patients were alive and 18 (39%) were dead. Using a machine learning algorithm, we were able to predict overall survival with AUC of 0.970 (95% CI: 0.923-1.00 ) (Figure), sensitivity of 100% and specificity of 94.4%. The algorithm selected 90 genes for this prediction. Conclusion: This data shows that bone marrow expression profiling when used in machine learning can provide a valuable and practical approach for predicting response and overall survival to venetoclax-based therapy in patients with AML/MDS. This prediction requires complex data from a large number of genes (10 to 90 genes) that must be incorporated in a machine learning algorithm. While further studies are needed for confirmation, genomic profiling along with machine learning algorithms can be a practical test for selecting a specific therapeutic approach for specific patients with AML/MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS: Assessment of Leukemia Stem Cell Eradication By High-Resolution MRD Assay

Background: For the past five decades the standard of care for fit patients with acute myeloid leukemia (AML) has been induction with the "7+3" regimen, using a combination of cytarabine (AraC) and anthracycline (daunorubicin, idarubicin) followed by consolidation high-dose AraC (HiDAC). With this approach, approximately 70% of younger (≤60 years of age) and 60% of older (>60 yrs) fit patients achieve a complete remission, with 30-50% of those patients attaining measurable residual disease (MRD) negative state by multiparameter flow cytometry (MFC). However, even patients with MRD-negative remissions relapse due to remaining chemotherapy-resistant pre-leukemic and leukemic stem cells (LSCs). Eradication of residual disease at the LSC level is therefore the ultimate goal to achieve durable remissions and cure. The combination of Venetoclax (Ven) with chemotherapy can have a synergistic effect; by reducing the apoptotic threshold, Ven can facilitate increased apoptosis induced by genotoxic agents, while at the same time chemotherapy can downregulate MCL-1 that drives Ven resistance. Ven in combination with hypomethylating agents has shown to not only eradicate AML blasts but also target and eliminate LSCs. Early phase trials combining Ven with intensive chemotherapy (IC) have shown encouraging safety and efficacy signals. However, the optimal dose and schedule of Ven that can best synergize with IC to eradicate LSCs remain unknown. Here we present a phase 1b study evaluating the safety and tolerability of Ven in combination with daunorubicin (dauno)/AraC) induction followed by HiDAC consolidation in patients with newly diagnosed AML or high-risk myelodysplastic syndrome (MDS). Objective: The primary objectives of this study are to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) of the combination of Ven plus dauno & AraC, as well as HiDAC IC. Secondary objectives are response per 2017 ELN and revised IWG criteria, survival, event-free survival and duration of response. A key exploratory objective is to comprehensively analyze LSC and assess rates of LSC eradication by means of MFC and single cell sequencing ("high-resolution MRD assay"). Design: This is a Phase 1b, open-label, dose-escalation study, evaluating Ven in combination with IC in previously untreated, adult patients with AML and high-risk MDS (NCT05342584). In Part 1, we are utilizing a 3+3 design to evaluate the safety and tolerability of different Ven doses in combination with IC. In Part 2, we will evaluate the safety and clinical activity in additional 12 patients at the dose determined in Part 1. To evaluate for LSC MRD, bone marrow aspirates obtained at the time of each disease evaluation will be analyzed by high-resolution MRD assays. Specifically, we will perform multicolor flow cytometry assays optimized for primary samples and able to distinguish, quantify, and sort pre-LSCs and LSCs. Furthermore, we will combine this assay with ultra-deep sequencing (1Million x) to detect very low levels of mutant cells, importantly within the LSC compartment. Eligible patients must have a new diagnosis of AML or high-risk MDS (blasts>10% AND R-IPSS>3.5%), be 18-75 yrs of age and deemed fit for intensive chemotherapy. During induction, escalating Ven doses (400 mg x8 -> 11 -> 14 days) will be combined with AraC 100mg/m2 and 2 doses of dauno (60 and 90mg/m2) in patients aged 60yrs or younger, whereas dauno 60 will be used for all patients older than 60yrs. During consolidation, the Ven dose will be escalated (200 -> 400mg) in a similar 3+3 design at a fixed 7-day duration in combination with age-adjusted high dose AraC regimen (1.5g/m2 in ≤60yrs and 1g/m2 in >60yrs, every 12hrs on days 1,3,5). Conclusion: This study will evaluate the optimal dosing of Venetoclax and daunorubicin as part of the Ven plus "7+3" induction regimen. It will also evaluate the optimal dose of Venetoclax in combination with HiDAC consolidation chemotherapy. This trial will utilize a novel highly-sensitive LSC MRD assay to test the efficacy of Venetoclax in eliminating LSCs when combined with conventional chemotherapy.

Predictors of Disease Progression and Survival in Patients with Myelodysplastic Syndrome Secondary to Inherited Bone Marrow Failure Syndromes

Introduction Inherited bone marrow failure syndromes (IBMFSs) are rare genetic disorders characterized by abnormal hematopoiesis resulting in cytopenias, risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Once patients develop MDS, the only cure is hematopoietic stem cell transplant (HSCT). Proceeding to HSCT before transformation to advanced MDS or AML leads to better outcomes (Smith et al., PBC 2013). The rate of disease progression from early MDS to advanced MDS or AML is variable and risk factors for progression in IBMFS patients are unknown. We hypothesized that certain variables could predict the likelihood of progression, and that the type of disease progression may impact overall survival (OS). Methods Data were collected from patients prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR), a Canadian collaboration including >95% of pediatric IBMFS patients. Patients were diagnosed with a specific syndrome or unclassified IBMFS (ucIBMFS) based on published criteria. Diagnostic criteria for pediatric MDS defined by Cada et al. (Haematologica 2015) were used, patients with refractory cytopenia (RC) with or without dysplasia or ringed sideroblasts were included. Patients with refractory cytopenia with excess blasts (RCEB) were excluded. MDS progression was defined as 1 or more of: a new cytogenetic abnormality, more advanced cytopathology, worse cytopenias requiring HSCT. Variables evaluated included: involvement of specific organ systems, hematologic parameters within 3 months of cytogenetic clones/MDS diagnosis, type of mutation (as per Waespe et al., Genomic Medicine 2017). Univariate Cox Proportional Hazard modelling was used to estimate association with specific variables and disease progression, Kaplan-Meier analysis was used for survival evaluation. Results Between January 1, 2001 and November 30, 2018, 601 patients were enrolled in the CIMFR, and during this time 59 (9.8%) developed cytogenetic clones/MDS. Four did not meet the pre-defined criteria for IBMFS, 9 had RCEB at diagnosis with MDS and 1 did not have data available; these were excluded from our cohort of 45 patients. Twelve (26%) patients with clones/MDS had Fanconi Anemia (FA), 13 (28.3%) had Shwachman-Diamond Syndrome (SDS), 5 (10.8%) had ucIBMFS, 15 (33.3%) had other IBMFSs. The most common cytogenetic finding at diagnosis was -7/-7q (n=10, 22%). Patients who developed clones/MDS had significantly worse OS compared to those without clones/MDS (HR 3, 95% CI 2-6, p<0.0001). Among patients who developed clones/MDS, 22 (48.9%) underwent HSCT. Twenty one clones/MDS patients (46.7%) had disease progression, with a median time to progression of 7.9 months (1.2-131.4). The majority (68.4%) developed progression within one year of clones/MDS diagnosis. Nine (42.8%) developed more advanced cytopathology, 9 (42.8%) a new cytogenetic abnormality and 5 (23.8%) worsening cytopenias. Most patients with FA (67%) had disease progression, compared to 38.5% of patients with SDS. Mutation types (classified as more vs less deleterious) were similar between the groups with and without progression. The evaluated hematologic parameters (MCV, hemoglobin, platelets and neutrophils within 3 months of diagnosis) were not predictive of disease progression. Patients with disease progression, when compared to those without, were more likely to have congenital malformations of the skin (14.3% vs 0%), cardiovascular system (28.6% vs 4.2%) and kidneys (14.3% vs 4.2%). No specific system involvement predicted disease progression, although congenital malformations of the cardiovascular system had a HR of 2.63 (95% CI 0.93-7.42). Conclusion Development of MDS has a significant adverse impact on the OS of IBMFS patients, with disease progression typically occurring within the first year after MDS diagnosis. Patients with FA have a high risk of disease progression. Hematologic parameters were not predictive of the risk of disease progression, however, the presence of congenital cardiovascular anomalies is suggestive of increased risk of disease progression and warrants further investigation. Our study is limited by the rare nature of IBMFSs and MDS and the collection of additional data will help to guide treatment decisions for this high-risk patient population. Acknowledgment The authors thank Mr. Bryan Maguire for his statistical analysis of data related to this work.

ATM DNA METHYLATION ASSOCIATED WITH POOR PROGNOSIS AND LEUKEMIA TRANSFORMATION IN MYELODYSPLASTIC SYNDROME PATIENTS

Myelodysplastic syndrome (MDS) is a clonal disease of hematopoietic progenitors with a risk of progressing to acute myeloid leukemia. MDS etiology is mainly related to age, but one of the risk factors is exposure to pesticides that causes aberrant reprogramming of the genome by DNA methylation. The aim of this work was evaluating the methylation profile of genes acting in the single-strand DNA (ssDNA) repair (CSA, CSB, XPA, XPC and XPG) and double-strand DNA (dsDNA) repair (ATM, BRCA1, BRCA2, LIG4 and RAD51), and its relationship with gene expression. The analysis was performed using bone marrow samples from 56 MDS patients, 69 farmers exposed to pesticides and 10 controls without exposition or MDS. The methylation profile and gene expression were evaluated using pyro-sequencing technique and quantitative real-time PCR. Regarding ssDNA repair genes, in cases with MDS, patients under 60 years old showed a higher methylation for the XPA and CSB genes than patients over 60 years old (p = 0.008; p = 0.017). Furthermore, XPA showed increased methylation levels in initial forms of MDS (p = 0.019). The MDS group presented a higher percentage of XPA methylation than exposed farmers (p = 0.000) and the control group (p = 0.011). In the prognostic classification, lower risk presented higher methylation than high-risk (p = 0.027). Among the dsDNA repair genes methylation in MDS patients, only ATM gene showed significant results with increase of methylation levels in (1) males (p = 0.037); (2) patients aged up to 60 years (p = 0.002) and (3) those who progressed to AML (p = 0.016). Regarding the methylation between the groups of exposed farmers, MDS advanced forms and controls, we also detected significant differences with levels always increased in the control group: ATM (control group vs. farmers p = 0.000), BRCA1 exposed vs. control group, p = 0.001; MDS vs. control, p = 0.001;), BRCA2 (farmers vs. control, p = 0.027; MDS vs. control, p = 0.004), LIG4 (farmers vs. control, p = 0.001; MDS vs. control, p = 0.012) and RAD51 (farmers vs. controls, p = 0.047). The correlation analysis between methylation and expression showed a positive and strong correlation for LIG4 gene in the advanced forms MDS group (r = 0.798) and a positive and weak correlation for BRCA1 gene in the exposed farmers group (r = 0.340). Surprisingly, in the ssDNA repair genes, the expression and methylation of both farmers and MDS patients were not correlated, suggesting that the change in the expression of these genes is not motivated by the DNA methylation mechanism. Furthermore, the analysis of dsDNA repair genes in this study corroborates the phenomenon of relative hypermethylation in some DNA repair genes in MDS.

Hematopoietic stem progenitor cells with malignancy-related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4.

The phenotypic changes in hematopoietic stem progenitor cells (HSPCs) with somatic mutations of malignancy‐related genes in patients with acquired aplastic anemia (AA) are poorly understood. As our initial study showed increased CXCR4 expression on HLA allele‐lacking (HLA[−]) HSPCs that solely support hematopoiesis in comparison to redundant HLA(+) HSPCs in AA patients, we screened the HSPCs of patients with various types of bone marrow (BM) failure to investigate their CXCR4 expression. In comparison to healthy individuals (n = 15, 12.3%–49.9%, median 43.2%), the median CXCR4+ cell percentages in the HSPCs of patients without somatic mutations were low: 29.3% (14.3%–37.3%) in the eight patients without HLA(−) granulocytes, 8.8% (4.1%–9.8%) in the five patients with HLA(−) cells accounting for >90% of granulocytes, and 7.8 (2.1%–8.7%) in the six patients with paroxysmal nocturnal hemoglobinuria. In contrast, the median percentage was much higher (78% [61.4%–88.7%]) in the five AA patients without HLA(−) granulocytes possessing somatic mutations (c‐kit, t[8;21], monosomy 7 [one for each], ASXL1 [n = 2]), findings that were comparable to those (66.5%, 63.1%–88.9%) in the four patients with advanced myelodysplastic syndromes. The increased expression of CXCR4 may therefore reflect intrinsic abnormalities of HSPCs caused by somatic mutations that allow them to evade restriction by BM stromal cells.

Health-Related Quality of Life in a Biologic Assignment Trial of Reduced Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome

Health-Related Quality of Life in a Biologic Assignment Trial of Reduced Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome

Serum Level of IFN-a2 and Regulatory T-Cell Subsets Correlates with Disease Progression in De Novo Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a group of diseases with clonal proliferation of dysplastic bone marrow hematopoietic cells. Recent studies have established that the ‘immune signature’ is substantially different in low and high-risk MDS. Nevertheless, the exact mechanism by which the immune response of the disease progresses from an early stage to advanced MDS and acute myeloid leukemia (AML) remain poorly defined.In order to explore the key immune-related factors in the progression of MDS, a total of 56 patients with newly diagnosed MDS were enrolled in this prospective study, where patients were classified as 25 cases of low-risk group (the IPSS-R score, very good risk, good risk and intermediate risk) and 31 cases of high-risk group (the IPSS-R score, very poor risk, poor risk). Levels of 48 cytokines in patients' serum were determined using Luminex assays, and flow cytometry were used to measure the percentages and absolute counts of T regulatory cell (Treg) and its subsets: induced regulatory Treg (iTreg: CD45RO +CD3 +CD4 +CD25 +CD127low +) and naturally regulated Treg (nTreg: CD45RA +CD3 +CD4 +CD25 +CD127low +).Our results showed that there were significant differences in the expression of 19 cytokines between the high-risk group versus low-risk group (Figure 1A). MDS patients in high-risk group had lower serum levels of some interleukins with promoting or amplifying inflammation signals in directly or indirectly way, including IL-1a, IL-2, IL-4, IL-9, IL-12, IL-15 and IL-17ANGF; three growth factors, influencing the immune microenvironment by regulating the growth and differentiation of corresponding cells, including GM-CSF, PDGF-bb and b-NGF; three chemokines including GRO-a, IP-10 and MIP-1b,which regulates the migration of cells to their respective locations to play a pro-inflammatory role; two immunomodulatory cytokines including TNF-b and IFN-a2; leukemia inhibitory factor (LIF) as well as TNF-related apoptosis-inducing ligand (TRAIL) compared to the MDS patients in low-risk group(p<0.05). The higher serum levels of Eotaxin (p= 0.0493), facilitating proliferation and metastasis of tumor cells expressing the it's receptor, was identified in the higher-risk MDS patients. Although there is no significant difference of Treg cells in PB between the two groups, both the percentages and absolute counts of nTreg/iTreg was decreased in high-risk group of MDS patients (Figure 1B, p<0.05). After adjusting the Cox model according to the Revised International Prognostic Scoring System (IPSS-R), age and transfusion dependency, it was found that higher IFN-a2 level was correlated with longer progression-free survival (PFS) (Figure 1C, p=0.038, HR=0.89,95%CI: 0.797~0.994).These results suggested that the pro-inflammatory cytokines during the progression of MDS, the immune disorder of microenvironment and the transformation of nTreg to iTreg may be the key immunological mechanisms for the emergence of immune tolerance and transformation to AML. The serum level of IFN-a2, contributing to inhibit cancer cell proliferation and activate immune system, is an independent protective factor for disease progression or death in patients with MDS, which may be an effective indicator to predict the progression of MDS into higher risk category or transforming into AML. At the same time, it shows that some cytokines in serum are related to the progression and prognosis of MDS, which may provide a basis for early clinical intervention to improve the prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Single Nucleotide Polymorphisms Do Not Impact Outcomes After Unrelated Donor Transplant: A Center For International Blood and Marrow Transplant Research Analysis

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is a critical T cell molecule that inhibits T cell activation and plays an essential role in T cell homeostasis and immune responses. Genetic variations in the CTLA4 gene have been hypothesized to be possible biologic markers that are predictive of transplant outcomes. Previous investigators have studied single nucleotide polymorphisms (SNPs) of the CTLA4 gene and its impact on hematopoietic cell transplantation (HCT) outcomes with discordant results. AA and AG genotypes in the donor CTLA4 regulatory region involving SNP rs4553808 in patients after unrelated donor (URD) HCT have recently been shown to be an independent predictor of improved relapse free survival (RFS) and overall survival (OS) compared to the GG genotype. To validate these preliminary findings, a Center for International Blood and Marrow Research (CIBMTR) study was performed in a larger, more homogenous cohort of patients.Adult patients with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS) undergoing a first 8/8 or 7/8 HLA matched URD HCT after myeloablative, non-myeloablative, or reduced intensity conditioning from 2002 to 2007 in first or second complete remission with available donor research samples from the National Marrow Donor Program research repository were included. The primary goal was to evaluate the impact of SNP rs4553808 on RFS, OS, and NRM and the cumulative incidence of acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Any GVHD prophylaxis could be used except in vitro T-cell depletion or use of in vivo/in vitro alemtuzumab. Patients receiving T cell depletion with anti-thymocyte globulin (ATG) were oversampled to allow analysis of any effects on outcomes. An exploratory analysis of 9 other tagSNPs that encompass the entire CTLA4 gene (rs231775, rs231779, rs11571315, rs231777, rs3087243, rs16840252, rs231725, rs10197010, rs11571316) was performed to evaluate for any additional potential associations with clinical outcomes.Each SNP was analyzed in multivariable models adjusting for clinically significant variables using the Cox proportional hazards model. Due to multiple testing, p-values <0.005 were considered significant. The interaction with CTLA4 SNPs and use of ATG was also specifically analyzed. The final analysis included 780 patients with a median followup of 63 months. Median age of recipients and donors was 50 and 34, respectively. 90% of recipients were identified to be of Caucasian descent (N=709). 80% of patients had AML (N=624) and 20% MDS (N=156). Conditioning was 61% ablative, 28% reduced intensity and 11% non-myeloablative, with 74% receiving peripheral blood grafts. 75% were HLA-matched and 25% single locus mismatched. Tacrolimus with methotrexate or mycophenolate mofetil GVHD prophylaxis was given to 62%, cyclosporine-based prophylaxis to 15% while 23% received other regimens. By design, 50% of patients received ATG. Genotyping showed that 552 (71%) were AA, 208 (27%) were AG and 19 (2%) were GG (AG, and particularly GG, were associated with worse outcomes in the prior study). Multivariable analysis adjusting for significant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS (p=0.07), RFS (p=0.41), NRM (p=0.25), and incidence of acute and chronic GVHD (Figure 1). Multivariable analysis of the other 9 tagSNPs also showed no association with transplant outcomes (p>0.005). No interaction was found between the CTLA4 SNPs and use of ATG on outcomes. These results indicate that CTLA4 SNPS do not have impact on outcomes. Other genomic or cellular biomarkers need to be studied to risk stratify patients at high risk of negative clinical events, especially as therapies targeting CTLA4 and PD-1 evolves. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Abstract CT138: Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes

Abstract Background: NCI ALMANAC, a systematic in vitro combination drug screen study, identified greater-than-additive activity for the combination of the proteasome inhibitor bortezomib and the nucleoside analog clofarabine. The combination also yielded strong, greater-than-single-agent activity in human tumor xenograft models. Our preclinical findings postulate that the activity of this drug pair may be due to modulation of DNA damage and the intrinsic apoptotic cascade. In an ongoing phase I trial, we evaluate the safety and activity of bortezomib and clofarabine in refractory solid tumors, lymphomas, and myelodysplastic syndromes (MDS). Methods: This is an open-label trial with a 3+3 design, enrolling at least one solid tumor/lymphoma and one MDS patient (pt) at each dose level. Starting doses were clofarabine 1 mg/m2 intravenously (IV) on days (D) 1-5 and bortezomib 0.8 mg/m2 subcutaneously (SC) on D1 and D4 of 21-day cycles. Response was determined per RECIST 1.1, Lugano criteria, and IWG, respectively. Exploratory endpoints include markers of DNA damage and epithelial-to-mesenchymal phenotype transition in blood. Once MTD is declared, a biopsy expansion cohort will enroll to evaluate the mechanism of action for the combination using validated apoptosis multiplex and next-generation sequencing assays. Results: As of October 2020, 22 pts were enrolled with advanced solid tumors (n=18), lymphoma (1), and MDS (3). Median pt age is 62 (range 41-80). Median lines of prior therapy is 3 (range 1-8). Three pts had DLTs in the solid tumor/lymphoma cohort: grade 3 anemia at dose level (DL) 3 (clofarabine 1.5 mg/m2, bortezomib 1 mg/m2); grade 4 neutropenia and grade 4 thrombocytopenia at DL 5 (clofarabine 2 mg/m2, bortezomib 1.3 mg/m2); and grade 4 neutropenia at DL 5. In the solid tumor/lymphoma cohort, grade 3 toxicities possibly attributed to study drugs were anemia (3), lymphopenia (3), thrombocytopenia (1), and frequent premature ventricular contractions (1); grade 4 toxicities were lymphopenia (5), neutropenia without infection (2), and thrombocytopenia (1). The only toxicity possibly attributed to study drugs in the MDS cohort was grade 3 febrile neutropenia in one pt. In the solid tumor/lymphoma cohort, 6 pts achieved a best response of stable disease (SD); 3 patients experienced prolonged SD of ≥ 6 months (1 pt each with colorectal adenocarcinoma, pancreatic adenocarcinoma, and cholangiocarcinoma). In the MDS cohort, 2 pts had SD as a best response (8 months in 1 pt following hypomethylating agent failure). Pharmacodynamic analyses in circulating tumor cells are ongoing. Conclusions: Treatment with bortezomib and clofarabine demonstrated prolonged SD in one pt each with colon adenocarcinoma, pancreatic adenocarcinoma, cholangiocarcinoma, and MDS. Hematological DLTs were seen in 2 pts on DL 5. Currently, patients are enrolling on DL 4 for the solid tumor/lymphoma cohort. Funded by NCI Contract No. HHSN261200800001E. Citation Format: James Q. Nguyen, Geraldine O'Sullivan Coyne, Larry Rubinstein, Shivaani Kummar, Lamin Juwara, Jennifer Zlott, Abdul Rafeh Naqash, Murielle Hogu, Jerry Collins, Apurva Srivastava, Brandon Miller, Ralph E. Parchment, Robert Meehan, Christopher S. Hourigan, Steven Pavletic, James H. Doroshow, Alice P. Chen, Naoko Takebe. Phase I trial of the combination of bortezomib and clofarabine in adults with refractory solid tumors, lymphomas, or myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT138.

2021 BSH guidelines for the management of adult myelodysplastic syndromes: a practical approach to a challenging disease.

Myelodysplastic syndromes (MDS) are a group of haematological malignancies with extremely variable biologic, genetic and clinical characteristics.1 The outcome of MDS patients is very heterogeneous, some having a near-normal life expectancy while others die within a few months of their diagnosis. The median age of patients at diagnosis is advanced, ranging between 70 and 75 years, thus further complicating the management of these complex syndromes, since non-haematological comorbidities frequently coexist in the elderly and tolerability of treatments is limited.2 Given the heterogeneity of the disease pathobiology and the highly variable disease course, prognostic risk stratification is of crucial importance in clinical decision-making.3 To drive appropriate counselling and individualisation of treatment decisions, several prognostic scoring systems based on clinical and haematological parameters have been developed. Principal scoring systems currently used in Europe are the International Prognostic Scoring System (IPSS), and the revised IPSS (R-IPSS), which are based on the evaluation of peripheral blood cytopenias, bone marrow blast count and cytogenetic features.4 In daily practice, reliability of these scores is limited by the variability of morphological evaluation and, less frequently, by non-informative cytogenetic findings in a proportion of patients. Moreover, other factors including the clonal mutational status have been reported to influence the prognosis of MDS patients, and to affect the clinical outcome.5, 6 In any case, diagnostic procedures and evaluation of prognosis are not covered by these guidelines as they will be published in a separate British Society for Haematology (BSH) document. Unlike the previous edition, the 2021 BSH guidelines also do not include recommendations for CMML, for which dedicated guidelines will follow. The 2021 updated BSH guidelines for the Management of Adult Myelodysplastic Syndromes provide clear, simple and practical recommendations to approach patients with such a challenging diagnosis.7 Given the heterogeneity of the disease, the importance of establishing an individual risk-adapted treatment strategy is crucial; nonetheless, transfusion requirements and infectious complications are common to almost all patients, sooner or later. The guidelines first exhaustively describe the supportive measures that should be adopted with most patients; in particular, recommendations are reported the for prevention of fungal infection, a common complication in neutropenic patients, and for transfusion thresholds and policies to be adopted to improve patient quality of life (QoL) on the one hand, saving blood products on the other. Then, individual planning of therapeutic options is described extensively, also by means of simplified algorithms. Although standard care for MDS is constantly changing, recommendations for the initial treatment choice are still based on IPSS and R-IPSS risk evaluation, and, importantly, on patient’s preference. Therapeutic measures for most lower risk patients aim to decrease the transfusion burden and improve QoL, whereas recommendations for higher risk patients aim to prolong their life. This distinction is clearly represented in these guidelines; for each group updated treatment strategies are reported, some reflecting the 2014 BSH document. Still relevant is the recommendation that the initial MDS diagnosis should be discussed by a multidisciplinary team, including a transplantation expert, as allogeneic transplantation remains the only potentially curative option. Worthy of note, in this setting recommendations for cytoreduction in advanced MDS with hypomethylating agents (HMA) or chemotherapy before transplant are still debated, although inferior survival outcomes for patients with excess BM blasts (> 5%) at the time of transplant have been reported. Moreover, it is important that clinicians review MDS cases regularly in multidisciplinary meetings to determine if a patient can become a possible transplant candidate and/or can possibly take part in a clinical trial. Patients’ details should also be made available to national and international dedicated registries, ‘to maximize information about the patient’s history and treatment of MDS in order to benefit future patients’. In general, the guidelines are proposed to improve the quality of care of patients as well as to help physicians in their daily practice. The BSH guidelines for the management of MDS represent a timely update and make a valid contribution for the diagnosis and treatment of this heterogeneous group of blood disorders.