IPSS Int-2 Research Articles

Phase 3b Study Design for a Comparison of Treatment Preference between Oral Decitabine/Cedazuridine and Azacitidine in Adult Patients with IPSS-R Intermediate Myelodysplastic Syndrome, IPSS Intermediate-2 or High-Risk Myelodysplastic Syndrome, Low-Blast Acute Myeloid Leukaemia, or Chronic Myelomonocytic Leukaemia

Myelodysplastic syndromes (MDS) are heterogeneous clonal bone marrow neoplasms characterised by marrow dysplasia, low blood counts and risk of progression to acute myeloid leukaemia (AML). Hypomethylating agents (HMAs) decitabine and azacitidine (AZA) are effective treatments for hematologic cancers including MDS. AZA is indicated to treat International Prognostic Scoring System (IPPS) defined Intermediate-2 (Int-2) and high-risk (HR) MDS, low blast AML (LB-AML; 20-30% blasts) with multi-lineage dysplasia, and chronic myelomonocytic leukaemia (CMML) with 10-29% blasts without myeloproliferative disorder. Oral decitabine/cedazuridine is currently the only oral hypomethylating agent indicated to treat IPSS Int-1, Int-2 or HR MDS and CMML, in the United States, Canada and Australia. AZA administration requires daily visits to a hospital or clinic for 7 days every 28 days, for either intravenous infusions, or large-volume subcutaneous (SC) injections for a minimum of 6 cycles.This places a burden on this patient population, resulting in low treatment adherence, early discontinuation, and subsequently low treatment uptake. Oral decitabine/cedazuridine is administered as one tablet daily for the first 5 days of a 28-day cycle for a minimum of 4 cycles. This allows patients to take their medication at a location of their choice. Alongside previously reported preference for oral therapy, patients may favour oral decitabine/cedazuridine over SC AZA due to improved treatment convenience and reduced discomfort. However, this is untested in a controlled setting. This study aims to evaluate preference between oral decitabine/cedazuridine and SC AZA treatment for adult patients with Revised International Prognostic Scoring System (IPSS-R) intermediate, IPSS Int-2 or HR MDS, LB-AML or CMML. This phase 3b, open-label, multi-centre study (NCT05883956) has sites planned in Australia (4 sites) and New Zealand (5 sites), to compare preference for oral decitabine/cedazuridine (Treatment A) and SC AZA (Treatment B). The study design includes 28 days of screening, four continuous 28-day cycles of study treatment, and a follow-up period with two 28-day cycles of continued therapy. Patients will be randomised to two balanced treatment sequences: ABBA or BAAB (Figure 1). Patients will express a preference twice in the study; after completing Cycle 1 and 2, and after completing Cycle 3 and 4. This cross-over design is twice the length of a typical 2-period AB vs BA design and allows patients to act as their own controls. The study design allows estimation of the treatment effect while mitigating factors that may influence preference. These include the order of treatments, and fluctuations in the patient's physical and disease state over the course of the trial. All available preferences expressed throughout the trial will be used for primary analysis. A total of 42 patients are planned for this study. The primary objective of this study is to compare patients' treatment preference for oral decitabine/cedazuridine and SC AZA for the treatment of MDS, LB-AML or CMML. Secondary objectives include evaluation of carers' and clinicians' treatment preference between oral decitabine/cedazuridine and SC AZA for the treatment and continued treatment of adult patients with MDS, LB-AML or CMML. The primary objective will be assessed by a treatment preference in myelodysplasia questionnaire (pTPMQ), which instructs patients to indicate a preference for injection, oral/tablets or no preference. The secondary objectives will be evaluated by a carer treatment preference in myelodysplasia questionnaire (cTPMQ) and a medical clinician treatment preference in myelodysplasia questionnaire (mTPMQ). Treatment discontinuation rates, quality of life and safety of SC AZA and oral decitabine/cedazuridine will also be compared. The primary analysis will be conducted with a multilevel logistic regression model analysing all available preferences. Descriptive statistics including frequencies, proportions, mean, standard deviation, median, and interquartile range will be used to summarize the study data. When complete, this study will address an evidence gap in the comparison of patient preference for oral decitabine/cedazuridine and SC AZA, and subsequently inform the value of oral decitabine/cedazuridine for the treatment of MDS, LB-AML and CMML.

Allogeneic Stem Cell Transplantation with Myeloablative Compared with Reduced- Intensity Conditioning for AML and Mds; 20 Years Later

Background. Allogeneic stem cell transplantation (SCT) with both myeloablative (MAC) and reduced intensity conditioning (RIC) regimens is effective therapyin AML and MDS. However, the relative merits of each may differin different settings and at different time-points after SCT. We have previously reported on the role of dose intensity in a group of 112 patients with AML/MDS given SCT with different regimens between 1999 and 2004 (ASH 2004, Leukemia 2005). At that time we showed that MAC was associated with lower relapse rate, higher non-relapse mortality (NRM) and similar overall survival (OS) as RIC. MAC was associated with survival advantage in patients with active leukemia at SCT. There is paucity of data on the comparison of these 2 approaches very late after SCT (beyond 20 years). Methods. We have now updated SCT outcomes in the same cohort with a median follow up of 20 years (range, 15-22) in order to better predict long-term outcome and confirm whether late events may have changed the initial conclusions. Updated follow-up is available for all but one patient. Results. The median age at SCT was50 years (18-70). Eighty-five patients had AML and 17 had MDS (IPSS int2 or high). Fifty-eight hadactive disease at SCT (>10% marrow blasts) and 54 were inremission. The donor was HLA-matched sibling (n=58), 1-Ag mismatchedrelated (n=6) or matched-unrelated (n=48). Twenty-nine patients (26%) had poor risk cytogenetics. Forty-five patients meteligibility criteria for standard MAC and were given intravenous-busulfan (ivBu, 12.8 mg/kg) and cyclophosphamide(BuCy). Sixty-seven patients were considered non-eligible for standardMAC and were given RIC with fludarabineand ivBu (6.4 mg/kg, FB2, n=41) or reduced toxicity conditioning (RTC) with fludarabine and myeloablative dosesof ivBu (12.8 mg/kg, FB4, n=26). The medianage of RIC, RTC and MAC recipients was 57, 51 and 42 years at transplantation, respectively (p=0.001) and a larger proportion of RIC/RTC recipients had unrelateddonors (p=0.01). In all, 31 patientsare alive and 81 have died, 50 of relapse and 31 of NRM.The median age at last follow-up was 66 years (35-81). The 20-year OS rate was 29% (20-37). The rate was 40% (26-54), 19% (7-31) and 19% (7-31) after BuCy, FB4 and FB2, respectively (P=0.19). The 20-year NRM was 29% (18-45), 27% (14-51) and 27% (16-45) respectively (Figure 1, P=0.94). The 20-year relapse mortality was 31% (20-48), 54% (38-77) and 54% (40-71), respectively (Figure 2, P=0.12). Five patients with relapse in the first 5 years are very long-term survivors with no recurrent disease following additional treatments. Forty patients were alive and disease-free 5 years after SCT with a 5-year OS of 42% (33-51). Fourteen patients died beyond 5 years, 3 from late relapse (6.6 -11.8 months after SCT) and 11 due to NRM. The causes of late NRM were second malignancies (n=6), cardiovascular disease (n=3), pulmonary disease (n=1) and liver disease (n=1). The risk of late NRM was 17% (6-47), 25% (7-83) and 44% (24-81) after BuCy, FB4 and FB2, respectively (P=0.29). The risk of late NRM was 14% (4-52) and 35% (21-59) in patients younger and older than 55 years at SCT, respectively (P=0.18). Late relapse mortality was low; 6 (8-37), 13% (2-78) and 7% (1-5), respectively (P=0.81). In all, the subsequent 15-year OS in those who were alive and disease-free 5-years after SCT was 78% (59-97), 63% (29-96) and 49% (22-76), respectively. The small number of events did not allow a meaningful multivariate analysis. Conclusions. With a long-term follow-up of 20 years, RIC/RTC is an acceptable alternative to MAC in ineligible patients. NRM is lower after RIC in the early post SCT period, but late NRM negates this early advantage and at longer follow-up there is no difference between the regimens. Relapse after RIC is higher at the first 5 years after SCT. However, late relapses beyond 5 years from SCT are rare after all regimens. In all, the very long-term OS is better after MAC. However, older age at SCT for RIC may be a major cause of these observations. Longer follow up of randomized studies is needed for more definite conclusions.

PD-1 Inhibitors Can be the First-Line Therapy for Myelodysplastic Syndrome (MDS) --Study on the Bone Marrow Immune Microenvironment of MDS By Multispectral Imaging of Multiplex Immunofluorescence

Objective: Myelodysplastic Syndrome (MDS) is a special myeloid neoplasm with still limited treatment choices and poor survival. Although current therapies including HMAs have been shown to prolong survival, only 40-50% of patients respond to therapy, and responses are universally transient, with loss of response within 2 years. With the increasing understanding of the pathogenesis of MDS in recent years, MDS was found closely associated with the bone marrow microenvironment, including immune microenvironment (IME). More and more evidences show that the immune microenvironment of MDS is related with its disease characteristics and prognosis. Knowing more of the IME of MDS may facilitate the diagnose and treatment on MDS. However, till now little was known about the bone marrow immune microenvironment of MDS. Previous studies mostly applied multiparameter flow cytometry and based on the PB samples or frozen bone marrow fluid samples, less was known about the immune landscape of MDS bone marrow biopsies. Methods: We use multispectral imaging of multiplex immunofluorescence (mIF) to analyze the bone marrow biopsy slides and explore the bone marrow immune microenvironment of MDS patients. A total of 20 de novo MDS patients, 20 post-treatment MDS patients and 20 normal controls were included in this study. In HMAs treated group, 10 patients were response to HMA and another 10 patients were not response. HMAs were either decitabine with a dose at 20mg/m2 d1-5 or 5-Azacytidine with a dose at 75mg/m2 d1-7. The multiplex staining panel could differentiate the distinct cell subpopulations into CD34+CD117+ cells, CD8+ cells, PD1+ cells, CTLA4+ cells, CD8+PD1+ cells and CD8+CTLA4+ cells, CD8-PD1+ cells and CD8-CTLA4+ cells, respectively. We analyzed the proportion of these cells in MDS patients and normal controls, and analyzed the proportion of these cells in MDS patients with different IPSS risk stratifications, and we also assessed the degree of myelofibrosis in MDS patients and analyzed the relationship between myelofibrosis and immune cells. Results: We found that compared with the normal control, the proportion of CD8+ cells in de novo MDS patients increased, and CD8+PD1+ T cells increased too, but the CD8+CTLA4+ T cells decreased. Compared with the lower-risk groups, CD8+ T cells as well as CD8+PD1+ T cells increased in higher-risk groups, while CD8+CTLA4+ T cells decreased. We also found a higher CD8+ T cells as well as CD8+/PD1+ T cells in MDS-F patients, especially in MDS-F patients with higher IPSS risk levels. We also found that compared with the normal control, the proportion of CD8+ T cells per CD34+CD117+ cell reduced, and was lower in IPSS int-2 risk/high-risk group than that in low-risk/int-1 risk group. But the proportion of CD8+PD1+/CD34+CD117+ increased compared with normal control. To analyze the bone marrow immune microenvironment after HMAs treatment, CD8+PD1+ T cells decreased in patients who are effective to HMAs, but still remain high in patients who had no response to HMAs, so did the proportion of CD8+PD1+/CD8+ and CD8+PD1+/CD34+CD117+. However, such findings were not found on CD8+/CTLA4+ T cells. Conclusions: Our research findings provide a new insight on the bone marrow IME of MDS. The results confirmed that the immune checkpoint molecule PD-1 positive CD8+ T cells are abundant in MDS IME and associated with the risk. However, CTLA4 may not be a major molecule interfere with the IME of MDS. Our result also suggest that PD-1 inhibitor combines with HMAs might be used as a first-line therapy for de novo MDS patients to cover those patients who may not have response to HMAs. Also, PD-1 inhibitor may cover higher risk MDS and MDS-F, the latter is a high-risk subtype of MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS. Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS). Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 - 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34). In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%). Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934). Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day cycle in the ongoing Phase 2 study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASXL1 mutations with serum EPO levels predict poor response to darbepoetin alfa in lower-risk MDS: W-JHS MDS01 trial

Darbepoetin alfa (DA) is used to treat anemia in lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict the effectiveness of DA has not been examined. The present study aimed to determine predictive gene mutations. The primary endpoint was a correlation between the presence of highly frequent (≥ 10%) mutations and hematological improvement-erythroid according to IWG criteria 2006 by DA (240 μg/week) until week 16. The study included 79 patients (age 29–90, median 77.0 years; 52 [65.8%] male). Frequently (≥ 10%) mutated genes were SF3B1 (24 cases, 30.4%), TET2 (20, 25.3%), SRSF2 (10, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate to DA was 70.9%. Multivariable analysis including baseline erythropoietin levels and red blood cell transfusion volumes as variables revealed that erythropoietin levels and mutations of ASXL1 gene were significantly associated with worse response (odds ratio 0.146, 95% confidence interval 0.042–0.503; p = 0.0023, odds ratio 0.175, 95% confidence interval 0.033–0.928; p = 0.0406, respectively). This study indicated that anemic patients who have higher erythropoietin levels and harbor ASXL1 gene mutations may respond poorly to DA. Alternative strategies are needed for the treatment of anemia in this population. Trial registration number and date of registration: UMIN000022185 and 09/05/2016.

PB2057: REAL -WORLD OVERALL SURVIVAL OF MYELOFIBROSIS PATIENTS ON RUXOLITINIB – A 6 YEAR ANALYSIS IN ALBANIAN POPULATION

Background: The survival and the outcome of the patients with Myelofibrosis has been prolonged with the use of Janus kinase inhibitors. The long term follow -up of the patients with primary /secondary Myelofibrosis treated with ruxolitinib demonstrated through several clinical trials an improvement in overall survival and in the quality of life of those patients. The use of IPSS risk classification in Myelofibrosis has played an important role in the prognostic stratification of the patients predictioning also the survival. Aims: Our study aims to evaluate the Overall Survival (OS) of all the patients diagnosed with Myelofibrosis and treated with Ruxolitinib from 2015 until january 2022. We also aimed to evaluate the role of IPSS risk group classification in the outcome and survival of MF patients in the Albanian population. Methods: We selected retrospectively all the patients diagnosed in our University Hospital Center “Mother Teresa” in Tirana, Albania with primary and secondary Mielofibrosis who started the treatment with ruxolitinib from 2015 until January 2022. We collected the data from the registries and database of Hematology Clinic based on the first availability of ruxolitinib in Albania since 2015. The data were analysed with SPSS Statistics 25.01. Results: From 2015 until January 2022 we have treated with Ruxolitinib 103 patients diagnosed with Myelofibrosis, 87 (84.5%) were primary MF and 16 (15.5%) were secondary MF. The median age resulted of 64 (range 31 – 88) years old. According to the IPSS risk group classification 1(!%) resulted IPSS Low risk, 21 (20.4%) were IPSS Int-1 risk, 49 (47.6%) resulted IPSS Int-2 risk, and 32(31.1%) were IPSS High risk. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of IPSS, we delineated 4 risk groups with no overlapping in their survival curves and the respective median survivals were 75, 40, 33, and 24 months We classified as IPSS Low risk all the patient with IPSS low and Int-1 risk, and as High risk all the patients with IPSS Int-2 and High risk. We identified 22 (21.4%) low risk patients and 81(78.7%) high risk patients. We compared the median overall survival between the Low risk and High risk MF groups and concluded that median OS in Low risk MF resulted 47 months (95% Confidence interval (CI): 11.2-82.7) and in High risk MF resulted of 32 months (95% Confidence interval (CI): 3,9 – 39,7) with P<0.01. Image:Summary/Conclusion: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm who can develop de novo (primary MF) or secondary in patients with antecedent polycythemia vera (PV) or essential thrombocythemia (ET). The mean age at the moment of diagnosis is 65 year old. In our study me median age at the moment of the diagnosis resulted 64 years old. In our study we compared the median overall survival between the Low risk and High risk MF groups and concluded that median OS in Low risk MF resulted 47 months (95% Confidence interval (CI): 11.2-82.7) and in High risk MF resulted of 32 months (95% Confidence interval (CI): 3,9 – 39,7) with P<0.01Despite the established fact on efficacy of Ruxolitinib in MF patients, real -world data still are limited. Our objective was to analyse the overall survival of our patients with Mielofibrosis under treatment with ruxolitinib, however additional data are needed.

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Oral Decitabine/Cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: A Longer-Term Follow-up of from the Ascertain Study

▪Background/Introduction:Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study.Methods:We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety.Results:Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant.Conclusions:Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population.

Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC “MDS-ALLO-Risk”

Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC “MDS-ALLO-Risk”

MPN-388: Assessment of Prevalence and Risk Factors for Subclinical Splanchnic Thrombosis in Patients with Myelofibrosis

Context Splanchnic thrombosis (ST) is a characteristic feature of MPN-associated prothrombotic state. Objective To determine the prevalence of subclinical ST in patients with myelofibrosis and assess disease-related and hereditary factors as potential risk predictors. Design Single-center, cross-sectional. Setting Clinic of Medical Oncology, University Hospital “Sveti Georgi” EAD, Plovdiv, Bulgaria. Patients or Other Participants Patients were considered eligible if diagnosed with myelofibrosis according to WHO 2016 criteria (incl. post-PV and post-ET), >18 years, no symptoms of overt ST, and no previous history of thrombosis. 21 subjects were recruited. Interventions Patients underwent CT scan angiography to detect the presence of vascular occlusion in the splanchnic circulation. Digital droplet PCR was performed to quantitate JAK2 mutant and wild-type allele burden in copies per nanogram DNA. Hereditary thrombophilia was analyzed for a panel of four genes: f.V(R506Q), f.II(20210G>A), PAI(4G/5G), and MTHFR(677C>T) by RT-PCR. Statistical analysis was performed in R v.4.0.4. All patients provided written informed consent. Main Outcome Measures Primary outcome was presence of thrombosis (arterial and/or venous) in the splanchnic circulation. Potential predictors were Jak2mut/ng DNA, WBC, HGB, PLT, spleen size, ruxolitinib therapy, and presence of hereditary thrombophilia. Results Baseline characteristics: mean age 67 ±10.51 years, 53% (11) females, 48% (10) with IPSS int-2/high, 57% (12) on ruxolitinib. FV(R506Q) and f.II(20210G>A) were detected in two patients each (9%), PAI(4G/4G) was detected in 10 patients, only one patient was wild-type homozygous, 3 patients were MTHFR(677TT), and 9 were heterozygous. ST was detected in 7 patients (33%). Jak2mut/ng DNA, WBC, HGB, PLT, spleen size, and ruxolitinib were not found to be significant predictors by logistic regression. 6 out of 7 patients with thrombosis were homozygous mutant [either PAI(4G/4G): 5 patients or MTHFR(677TT): 1 patient] and heterozygous for at least one of the other three genes. The presence of mutant homozygosity and heterozygous carrier state were significantly predictive of ST (Bhereditary = 3.497, 95%CI: 1.22–6.76, p=0.008). Conclusions Subclinical ST has a relatively high incidence in myelofibrosis. However, hereditary rather than disease-related factors emerge as risk factors. Further investigation of PAI(4G/5G) and MTHFR(677C>T) screening utility is warranted. This study was funded by Medical University-Plovdiv [grant SDPD-18/2019].

Validation of the Myelofibrosis Secondary to PV and ET-Prognostic Model in Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: MD Anderson Cancer Center

Validation of the Myelofibrosis Secondary to PV and ET-Prognostic Model in Patients with Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: MD Anderson Cancer Center

Mutational Profile and Analysis of Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Luspatercept: Phase 2 PACE-MDS Study

Background: Management of anemia is a common therapeutic challenge in patients (pts) with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept acts as a ligand trap for GDF11 and other TGF-β family ligands to suppress Smad2/3 signaling, promote late-stage erythroid differentiation, and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014; Attie K, Am J Hematol, 2014). Luspatercept has demonstrated clinical activity in ring-sideroblast positive (RS+,≥15% in bone marrow) MDS pts and comparable responses in non-RS+ pts with EPO<500 U/L. While RS+ pts have distinct clinical and molecular features including SF3B1 splicing mutations, non-RS+ pts have a more heterogeneous population of mutations.Aims: This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in pts with lower-risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI,≥8 weeks), and duration of HI-E. New analyses focus on clinical, molecular, and bone marrow morphological features of disease and factors associated with luspatercept response.Methods: Inclusion criteria: MDS IPSS low or int-1, age ≥18 yr, Hgb<10 g/dL (if <4U RBC/8 wks), no prior HMA, no current lenalidomide or erythropoiesis-stimulating agent (ESA). The dose-escalation phase of the study is completed. An expansion cohort was added to this phase 2 study to evaluate response in pts not qualified for the phase 3 MEDALIST trial (for regularly transfused RS+ pts refractory to ESA or EPO>200 U/L). These include pts with low transfusion burden (<4U RBC/8 weeks) and either 1) RS+ with baseline EPO ≤200 U/L or 2) non-RS+ and any EPO level. Non-RS+ pts allowed up to 6U RBC/8 wks. Pts treated every 3 weeks subcutaneously for up to 5 doses (titration up to 1.75 mg/kg) in the base study (NCT01749514) and are then eligible for long-term treatment up to 5 additional years (NCT02268383).Results: Data (as of 13Apr2017) were available for 88 pts treated at therapeutic dose levels (≥0.75 mg/kg) in both the base and ext studies. 88 pts were evaluable for IWG HI-E and 60 pts were evaluable for RBC-TI (baseline transfusions of ≥2 units/8 wks). 75 pts were evaluable for mutational data analysis.Baseline characteristics are shown in Table 1. In pts with mutational data, the most common mutations were SF3B1 (57%), TET2 (39%), DNMT3A (21%), ASXL1 (17%), and SRSF2 (11%). Response by subgroup is shown in Table 2.Responses were observed in both RS+ and non-RS+ pts of various mutational backgrounds. Many pts possessed mutations in multiple genes; pts carrying SF3B1 mutations tended to have increased response rates compared to SF3B1 WT pts. Other commonly observed (>10%) mutations (TET2, DNMT2A, ASXL1, and SRSF2) demonstrated similar responses in pts when either mutated or not. Longer-term data on all pts plus additional exploratory analyses of molecular, cellular, and morphologic parameters and their relationship to response will be presented at the meeting.Luspatercept has been well tolerated, with seven possibly related grade 3 non-serious adverse events (AE): ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, platelet count increase, and pleural effusion and four possibly related SAEs as of 15June2017: ataxia, general physical health deterioration, muscle weakness, and myalgia. Related AEs in >2 pts were headache, fatigue, hypertension, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and peripheral edema.Conclusions: Lower-risk MDS pts treated long-term with luspatercept demonstrated robust and sustained increases in Hgb and decreases in transfusion burden and a high rate of RBC-TI. Encouraging responses were seen across EPO levels up to 500 U/L in both RS+ and non-RS+ patients. The presence of an SF3B1 mutation was associated with a higher response in this initial cohort of pts and responses were also observed in SF3B1 WT pts with mutations typically associated with poor prognosis (e.g., ASXL1). The data support continued study of luspatercept in MDS pts, including aPhase 3 study in regularly-transfused RS+ pts with lower-risk MDS according to IPSS-R (MEDALIST study; NCT02631070; fully enrolled) and a future Phase 3 study planned in first-line lower-risk MDS pts. [Display omitted] DisclosuresPlatzbecker:Acceleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kiewe:Acceleron: Consultancy, Honoraria, Research Funding. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Götze:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Radsak:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Gilead: Other: Travel support; Acceleron: Research Funding. Wilson:Acceleron: Employment, Equity Ownership. Zhang:Acceleron: Employment, Equity Ownership. Rovaldi:Acceleron: Employment, Equity Ownership. Laadem:Celgene: Employment, Equity Ownership. Sherman:Acceleron: Employment, Equity Ownership. Attie:Acceleron: Employment, Equity Ownership. Reynolds:Acceleron: Employment, Equity Ownership. Linde:Acceleron: Employment, Equity Ownership. Giagounidis:Celgene: Consultancy; Acceleron: Consultancy.

Efficacy and Safety of Imetelstat in RBC Transfusion-Dependent (TD) IPSS Low/Int-1 MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agents (ESA) (IMerge)

Background: There are limited treatment options for anemic patients with lower-risk MDS who are relapsed after or are refractory to ESA. Imetelstat is a novel, first-in-class telomerase inhibitor that targets cells with short telomere lengths and highly active telomerase, and has clinical activity in myeloid malignancies (Cancer Res 2014;4:362; NEJM 2015;373:920; NEJM 2015;373:908; BJC 2016;6:e405). Targeting MDS clones with imetelstat may improve outcomes including anemia in MDS patients relapsed/refractory to ESA. We explored the safety and efficacy of imetelstat in RBC TD patients with IPSS Low or Intermediate-1 (Int-1) risk MDS relapsed/refractory to ESA.Methods: IMerge is an ongoing 2-part, global, multicenter study in TD patients (planned enrollment 200) with Low or Int-1 IPSS risk MDS relapsed/refractory to ESAs and with transfusion requirement of ≥4 units over 8 weeks prior to study entry. ESA-naïve patients with sEPO >500 mU/mL are also eligible. Part 1 is an open-label, single-arm study assessing the efficacy and safety of imetelstat administered IV every 4 weeks at a dose of 7.5 mg/kg. Part 2 is a double-blind, randomized design comparing the efficacy of imetelstat to placebo. The primary endpoint is the rate of RBC transfusion-independence (TI) lasting ≥8 weeks. Key secondary endpoints include safety, rate of ≥24-week TI, time to and duration of TI, and hematologic improvement (HI) rate. Here we report findings from the 32 patients enrolled in Part 1 with a median follow up of 48 weeks.Results: 29 (91%) patients had ECOG 0-1, median age was 68.5 years. 59% of patients were IPSS Low and 41% Int-1. 13 patients (43%) had sEPO>500 mU/mL. 34% had a cytogenetic abnormality, including 22% with del(5q). Prior treatments for MDS included ESAs (88%), lenalidomide (38%), and decitabine or azacitidine (HMAs) (25%); 56% of patients were both lenalidomide and HMA naïve. Baseline median RBC transfusion burden was 6 units per 8 weeks (range: 4-14). As of May 2017, RBC-TI ≥8-week was achieved in 34% of patients. Median time from treatment initiation to onset of TI was 8 weeks with a median duration of TI of 19 weeks, while 16% of patients achieved ≥24-week TI. 63% of patients achieved erythroid HI; transient platelet improvement was reported for one patient. Of the 13 lenalidomide and HMA naïve patients without del(5q), 54% achieved ≥8-week TI, 31% had ≥ 24-week TI and 69% achieved erythroid HI. TI response was 35% (6/17) and 38% (5/13) in patients with sEPO level ≤500 mU/L and >500 mU/L, respectively. The most frequently reported adverse events were cytopenias, including grade ≥3 and 4 neutropenia in 66% and 41% of patients, respectively and grade ≥3 and 4 thrombocytopenia in 50% and 19% of patients, respectively. Dose reductions or cycle delays due to adverse events were required for 59% of patients. One patient experienced neutropenic fever and two patients had grade 3 thrombocytopenia concurrent with grade 1 bleeding events both considered related to imetelstat; all recovered without sequelae. 28 patients (88%) had reversible LFT elevations by at least one grade; 4 of these were by 2 grades. Reversible grade 3 elevations were reported in 3 patients.Conclusions: In IPSS Low/Int-1 RBC transfusion dependent MDS patients relapsed/refractory to ESA, TI was observed in 34% and erythroid HI in 63% with imetelstat therapy. TI response appeared to be independent of sEPO level. Reversible cytopenias were the most frequent adverse events, which were generally manageable with dose reduction or delays. Elevated LFTS were reversible. Patients who were naïve to lenalidomide and HMAs and who lacked del(5q) had a higher rate of durable TI (54%) than other groups, which should be further explored. DisclosuresFenaux:Novartis: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raza:Kura Oncology: Research Funding; Novartis: Speakers Bureau; Celgene Inc.: Research Funding; Genoptix: Speakers Bureau; Janssen R&D: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau; Syros Pharmaceuticals: Research Funding. Platzbecker:Novartis: Consultancy, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Santini:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Samarina:Janssen: Research Funding. Van Eygen:Janssen: Consultancy, Honoraria, Research Funding. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Rizo:Janssen: Employment, Equity Ownership. Steensma:Pfizer: Consultancy; Takeda: Consultancy; H3 Biosciences: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Equity Ownership; Onconova: Consultancy; Celgene: Consultancy.

A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

AZA + Glutaminase Inhibition with Telaglenastat (CB-839) for Advanced MDS: An Updated Interim Analysis

AZA + Glutaminase Inhibition with Telaglenastat (CB-839) for Advanced MDS: An Updated Interim Analysis

Initial Results of a Phase I/II Study of Venetoclax in Combination with Azacitidine in Treatment-Naive and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Introduction: Venetoclax (VEN) is an oral BCL2 inhibitor, that has been shown to overcome apoptotic stress in cells from patients (pts) with high-risk myelodysplastic syndrome (MDS). Pre-clinical evidence indicates that VEN plus azacytidine (Aza) combination results in synergistic effects in myeloid malignancies. The objective of this trial is to evaluate the safety, tolerability, and overall response rate (ORR) of VEN in combination with Aza in pts with treatment-naive high-risk MDS or chronic myelomonocytic leukemia (CMML) and pts that were relapsed/refractory (R/R) to prior hypomethylating agent (HMA) therapy. Methods: This is a single-arm phase I/II clinical trial for pts with treatment-naive high-risk MDS or CMML, or pts with R/R MDS or CMML post-HMA failure (NCT04160052). Pts with prior BCL2 inhibitor therapy or low-risk disease (IPSS low or Int-1) are excluded. Aza is administered at 75mg/m2 IV or SC for 5 days on days 1-5 of each treatment cycle. VEN is studied at 100 mg, 200 mg, or 400 mg daily, on days 1-7 or 1-14 of each cycle. The primary endpoint is to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of VEN in combination with Aza, as well as to evaluate ORR, defined as achieving complete remission (CR), marrow complete remission (mCR), partial response (PR), or hematologic improvement (HI) lasting ≥4 weeks. Response is assessed based on the modified International Working Group 2006 criteria (Cheson et al Blood 2006). Overall survival (OS) is calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) is calculated from the start date of treatment to the date of disease progression, or last follow-up. Duration of response is calculated from the date of response to the date of disease progression, or last follow-up. Safety profile events were recorded according to the CTCAE v5.0. Results: To date 9 pts were enrolled. Four pts received VEN at 100mg dose, 3 pts at 200mg dose, and 2 pts at 400mg dose on days 1-7. There has been no protocol defined DLTs. The median age was 66 years (range, 59-83), 89% were male, 67% with MDS, 67% with normal karyotype. Five pts (56%) were treatment-naive, and 4 (44%) with R/R disease. Of the treatment-naive cohort (N=5), 4/5 (80%) pts had normal karyotype and none had TP53 mutations. ORR rate in this treatment-naive cohort was 100%, all pts achieving mCR, of which 1 (20%) had neutrophil response. Of the R/R cohort (N=4), cytogenetics were normal in 2/4 (50%) and complex in 2/4 (50%), and 2/4 (50%) had TP53 mutations. ORR in this R/R cohort was 3/4 (75%), all achieving mCR. One pt (25%) had stable disease (Table 1 and Figure 1). With a median follow-up duration of 3.6 months (95% CI: 1.4-8.4), 3 (33%) had disease progression and 1 (11%) died. Pts received median 2 courses of therapy (range, 1-4). One pt went to transplant. Median progression-free survival (PFS) for the entire cohort was 4.6 months (95% CI: 3.4-NA) and median OS has not been reached (Figure 2). Median duration of response is 4.1 months (95% CI: 2.4-NA). Possibly/probably related grade 3/4 adverse events included neutropenia in 4/9 (44%), thrombocytopenia in 3/9 (33%), and anemia in 1/9 (11%) pts. There were no grade 5 events (Table 2). Conclusions: The administration of VEN with Aza appears safe and well tolerated in treatment-naive and R/R pts with high-risk MDS and CMML. The study continues to accrue. Disclosures Thompson: Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Alvarado:BerGenBio ASA: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding.

Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients - Interim Analysis of the European Sintra-REV Trial

Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients - Interim Analysis of the European Sintra-REV Trial

Preliminary Results from the Phase II Study of the IDH2-Inhibitor Enasidenib in Patients with High-Risk IDH2-Mutated Myelodysplastic Syndromes (MDS)

Preliminary Results from the Phase II Study of the IDH2-Inhibitor Enasidenib in Patients with High-Risk IDH2-Mutated Myelodysplastic Syndromes (MDS)

Quantitative Modeling of Azacitidine Resistance in Patients with Myelodysplastic Syndrome Identifies Distinct Phenotypes of Disease Progression: Evidence for the Presence of a Disease Versus Native Clone Effect

Introduction Myelodysplastic syndrome (MDS) patients who are treated with azacitidine (AZA) may develop drug resistance in a number of different ways. Distinguishing the mechanisms underlying disease progression to leukemia while on AZA as opposed to clonal evolution without an increasing blast count is challenging due to the difficulty of studying MDS clones and their effect on non-diseased hematopoietic stem cells (HSCs). The application of a robust mathematical model of hematopoiesis to MDS patients allows for the calculation of kinetic parameters reflective of the function of the dominant hematopoietic clones, and infers the behaviour of both HSCs and MDS clones. We demonstrate the application of such a model applied to IPSS int-2/hi risk MDS patients treated with AZA, and show how different natural histories of disease can be explained by changes in model parameters over time. We also demonstrate how interactions between modeled HSCs and MDS clones can be inferred from the model. Methods A database of 97 IPSS int-2/hi risk MDS patients treated with AZA was previously constructed containing longitudinal peripheral blood count and laboratory data during the period 2008-2016, and was used for model fitting. Of these patients, 79 patients had sufficient data for modeling. A mathematical model of hematopoiesis was developed based on a formulation by Colijn and Mackey and modified to include a bone marrow blast compartment. Hematopoietic kinetic parameters were fit to de-identified patient laboratory data using a Kalman filter. The model data input was adjusted for red blood cell and platelet transfusion frequency and weighted so that parameter fits were made insensitive to periods of acute illness as identified from chart review and ancillary laboratory values. The resulting fit parameters represented a weighted average of disease and native HSCs contributions. Model parameters were evaluated with respect to time and sensitivity analysis was done identifying optimal correlation with the development of AZA resistance. A novel analysis was developed to determine if the contributions of the native and disease HSCs to peripheral blood counts are in proportion to their clonal burdens, or if the AZA-resistant phenotype reflected an additional effect of the MDS clones on the native HSCs. Results A schematic of the improved model of hematopoiesis adapted to MDS is shown along with the distribution of data collected over time (Fig 1A-B). The model fits for three representative patients are shown with different disease courses: AZA resistance with a rapidly rising blast count (patient 90), AZA resistance with a minimal rise in the blast count (patient 86), and AZA resistance with cytogenetic evolution without an increase in the blast count (patient 74). The model was fit to the longitudinal peripheral blood counts and bone marrow blast count data (Fig 2A-D). Development of AZA resistance in patient 74 was best correlated with a reduction in the average HSC self-renewal time (τS in Fig 2E), and this reduction was related to disease burden in a linear manner (Fig 2F, leftmost panel). Similarly, the development of AZA resistance in patient 86 was best correlated with an increase in the intrinsic threshold rate at which a stem cell differentiates (k0 in Fig 2E), and this increase was related to disease burden in a non-linear manner (Fig 2F, middle panel). For patient 90, the development of AZA resistance was best correlated with a decrease in the maximum rate of HSC differentiation (f0 in Fig 2E), and this decrease was related to disease burden in a non-linear manner (Fig 2F, rightmost panel). Discussion MDS patients in our cohort developed AZA resistance in distinct ways, and this correlated with changes in either HSC self-renewal time, differentiation threshold, or maximum differentiation rate. In the former case, the linearity in modeled HSC self-renewal time with respect to disease burden suggested this parameter change is accounted for by an expanding MDS clone. In the latter two cases, the mechanism of AZA resistance is hypothesized to be associated with an increased MDS clone threshold for differentiation as well as decreased maximum rate of HSC differentiation. The non-linearity of the association between these rate changes and disease burden suggests they were driven in large part by an external influence from the MDS clone on the HSCs. Further validation of these findings in a larger cohort of MDS patients is anticipated. Disclosures No relevant conflicts of interest to declare.