Risk Myelodysplastic Syndromes Research Articles

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.

A phase 2/3 trial of oral azacitidine (Oral-AZA) in patients (pts) with low- or intermediate-risk myelodysplastic syndromes (MDS).

TPS7083 Background: MDS, a heterogeneous group of clonal myeloid malignancies, are characterized by ineffective hematopoiesis and peripheral blood cytopenias, which can often lead to red blood cell (RBC) transfusion dependence and a risk of progression to acute myeloid leukemia (AML). In early clinical trials, 14- and 21-day (d) dosing regimens of the hypomethylating agent Oral-AZA were well tolerated and induced hematologic improvement (HI) in pts with lower-risk (LR) MDS. In a phase 3 trial, Oral-AZA 300 mg QD for 21d per 28d cycle significantly improved the rate of RBC transfusion independence (TI) and induced durable HI versus placebo (PBO) in patients (pts) with LR-MDS with RBC-transfusion-dependent anemia and thrombocytopenia (Garcia-Manero, et al. J Clin Oncol 2021). Grade 3/4 cytopenias were common in the Oral-AZA arm. Given the substantial clinical benefit of Oral-AZA observed in this setting, a new phase 2/3 trial is ongoing to further evaluate the 14d Oral-AZA regimen in pts with International Prognostic Scoring System Revised (IPSS-R)-defined low or intermediate (int)-risk MDS. Methods: This ongoing, multicenter, randomized, phase 2/3 trial (CA055-026; NCT05469737) will evaluate the safety and efficacy of Oral-AZA in pts with IPSS-R low- or int-risk MDS. Key eligibility criteria include ≥ 18 years, ECOG performance status score ≤ 2, and ≥ 1 cytopenia (anemia, thrombocytopenia, or neutropenia). Pts with an absolute neutrophil count &lt; 0.5 × 109/L within a week of randomization will be excluded. Informed consent will be obtained from all participants. The phase 2 portion will enroll and randomize ~42 pts 1:1 to receive open-label Oral-AZA 200 or 300 mg QD for 14d per 28d cycle, plus best supportive care (BSC), to determine the recommended phase 3 dose (RP3D). The primary endpoints are safety and rate of complete remission (CR) within 6 Tx cycles. The secondary endpoints are overall response rate (ORR), and packed (p) RBC-TI and platelet-TI sustained for 84d in ≤ 6 Tx cycles. ORR includes CR, partial remission (PR), marrow CR, and any HI, per IWG 2006 response criteria. In the phase 3 portion, ~188 additional pts will be enrolled and randomized 1:1 to Oral-AZA at the RP3D or PBO for 14d per 28d cycle, plus BSC. Pts in the PBO arm with stable disease at Tx cycle 6 disease assessment or with documented disease progression after ≥ 3 Tx cycles will have the option to cross over into the Oral-AZA arm. The primary endpoint is CR in ≤ 6 Tx cycles. The key secondary endpoint is 84d pRBC-TI. Other secondary endpoints include those described in the phase 2 portion plus overall survival, event-free survival, time to AML progression, iron parameters, health-related quality of life, healthcare resource utilization, and safety parameters. Pts who benefit from Oral-AZA in phase 2 or 3 may continue to receive Tx in an extension phase. Trial recruitment began in December 2022 and is ongoing. Clinical trial information: NCT05469737 .

Methylation-based prediction of myelodysplastic syndrome survival outcomes.

7058 Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies associated with a myriad of deleterious outcomes and a 5-year relative survival of 37%. MDS risk stratification is key for optimal treatment decisions. DNA methylation is associated with MDS biology due to frequent somatic mutations in genes (i.e. TET2, DNMT3A, IDH1, IDH2, and WT1) that affect DNA methylation. We hypothesized that methylation-based markers may help stratify risk and improve IPSS-R (the Revised International Prognostic Scoring System). Here, we evaluated the potential of both Bone Marrow (BM) Whole-genome Bisulfite Sequencing (WGBS) and Serum-based Targeted Methylation (TM) Sequencing to predict survival of MDS patients. Methods: We conducted paired BM WGBS and Serum-based TM sequencing on a cohort of 127 patients with MDS (N = 104) and secondary AML (N = 23) treated at the Columbia University Medical Center. We categorized patients based on an overall survival of &gt; 3 (“long”, N = 50) or &lt; 3 years (“short”, N = 77). We then identified differentially methylated regions (DMRs) differing between long and short survivor groups, and analyzed the biological pathways and functions enriched in these regions. To assess survival association, we trained a random forest classifier on principal components (“methylation classifier”) on the methylation fractions from a subset of 96 Serum and 98 BM MDS patient samples to predict long vs. short survival, and compared this against a logistic regression IPSS-R model. We optimized the hyperparameters and assessed classifier performance using six-fold nested cross-validation. Finally, we conducted a multivariable cox regression with predicted scores from the methylation classifier, IPSS-R scores (recalculated at sample collection), age, and gender. Results: We identified a total of 7,742 DMRs in the BM WGBS and 14,093 DMRs in the Serum TM as significantly different between long and short survivor groups. Signaling pathways for calcium, cAMP, MAPK, Rap1, and PI3K-Akt were significantly enriched in DMRs. We also identified a previously-reported CpG island hypermethylation signature associated with AML progression in BM and Serum. The methylation classifier achieved a comparable AUROC compared to IPSS-R logistic regression for both BM WGBS (0.80 vs 0.78) and Serum TM (0.77 vs 0.73) samples. Multivariable Cox regression demonstrated that both predicted scores from the methylation classifier (Serum p =0.002; BM p =0.016) and IPSS-R scores (Serum p =0.003; BM p =0.004) are significant predictors of survival. Conclusions: We demonstrated methylation-based sequencing represents a promising new tool for MDS patient risk stratification. As IPSS-R relies on bone marrow aspirates, the Serum-based TM assay offers a less-invasive method for MDS risk stratification.

CPX-351 for higher risk myelodysplastic syndrome: cytarabine and daunorubicin in disguise?

Higher-risk myelodysplastic syndrome is a heterogenous disease with a poor prognosis that occurs in older people. 1 Greenberg PL Myelodysplastic syndromes, thy name is heterogeneity. Br J Haematol. 2023; 201: 381-382 Crossref PubMed Scopus (0) Google Scholar Current treatment regimens usually result in a transient and often less than complete response. Only allogeneic haematopoietic stem-cell transplantation (HSCT) can potentially cure a select group of relatively young and fit patients. These patients usually receive remission induction therapy before allogeneic HSCT, but in the absence of well designed, prospective randomised clinical trials, its value remains uncertain. 2 de Witte T Bowen D Robin M et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017; 129: 1753-1762 Crossref PubMed Scopus (213) Google Scholar CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 studyCPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients. Full-Text PDF

CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: a multicentre, single-arm, phase 2 study

CPX-351, an encapsulated form of cytarabine and daunorubicin, has shown greater efficacy than the classic 3 + 7 treatment administration in secondary acute myeloid leukaemia. Given that higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia share similarities with secondary acute myeloid leukaemia, we aimed to investigate the safety and efficacy of CPX-351 in this context. This investigator-initiated two-cohort phase 2 trial was conducted by the Groupe Francophone des Myélodysplasies, with 12 participating centres in France. It comprised cohort A (reported here and completed), which included patients in first-line treatment, and cohort B, which was stopped for lack of inclusion (ie, not enough patients met the inclusion criteria), for patients with hypomethylating agent failure that is not reported here. Cohort A enrolled patients with newly diagnosed higher-risk myelodysplastic syndrome or chronic myelomonocytic leukaemia (aged 18-70 years old) with an Eastern Cooperative Oncology Group performance status of 0-1. Intravenous CPX-351 (100 mg/m2 cytarabine and 44 mg/m2 daunorubicin) was given on days 1, 3, and 5, with a second induction cycle given (same daily dose on days 1 and 3) if at least a partial response was not reached. Patients who responded could receive up to four monthly consolidation cycles (same daily dose on day 1) or allogeneic haematopoietic stem-cell transplantation (HSCT). Overall response rate after one or two induction courses according to European LeukemiaNet 2017 acute myeloid leukaemia was the primary endpoint after CPX-351 induction, whether patients received one or two induction cycles. Safety was assessed in all patients enrolled (in cohort A). This trial is registered with ClinicalTrials.gov, NCT04273802. Between April 29, 2020, and Feb 10, 2021, 21 (68%) male and ten (32%) female patients were enrolled. 27 (87%) of 31 patients responded (95% CI 70-96). 16 (52%) of the 31 patients received at least one consolidation cycle. 30 (97%) of the 31 patients included were initially considered eligible for allogeneic HSCT and 29 (94%) of the 31 patients had the procedure. Median follow-up was 16·1 months (IQR 8·3-18·1). The most common grade 3-4 adverse events were pulmonary (eight [26%] of 31 patients) and cardiovascular (six [19%] of 31 patients). There were 14 serious adverse events (mainly hospitalisation for infection [n=5] and only one was treatment-related) and no treatment-related death. CPX-351 appears to be active and safe in patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukaemia, allowing bridging to allogenic HSCT in most patients. Jazz Pharmaceuticals.

Improving the diagnosis of myelodysplastic syndrome by red blood cell parameters.

To investigate the value of red blood cell parameters in Myelodysplastic syndrome (MDS) diagnosis and their relations to MDS subtypes and risk groups. The red blood cell parameter [mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width (RDW)] levels [203 MDS, 99 aplastic anemia (AA), 145 megaloblastic anemia (MA)] were collected from a single-center retrospective cohort. The cut-off values, area under the receiver operating characteristic curve (ROC) curve (AUC), sensitivity and specificity of the four parameters were calculated from the ROC. Furthermore, Kruskal-Wallis test and Dunn's Test were performed to determine erythrocyte parameters in different subtypes and prognostic risks MDS. There are significant statistic differences in RDW (P < 0.001), MCH (P = 0.036) and MCHC (P < 0.001) (MDS vs AA); RDW (P = 0.009), MCV (P < 0.001), MCH (P < 0.001) and MCHC (P = 0.001) (MDS vs MA); MCV (P = 0.011) and MCH (P = 0.008) (higher-risk MDS vs lower-risk MDS). Between MDS and MA, the area under the receiver operating characteristic curve (ROC) curve (AUC) values of MCV, MCH, MCHC, RDW were 0.846, 0.855, 0.617, and 0.593. Between MDS and AA, the AUC values of MCH, MCHC, RDW were 0.609, 0.671, and 0.662, respectively. The red blood cell parameters contribute to the differential diagnosis of MDS, AA and MA and are related to MDS subtypes and risk groups.

Current Therapeutic Landscape in Lower Risk Myelodysplastic Syndromes.

Lower risk myelodysplastic syndromes are typically characterized by an indolent disease course with a relatively low risk of transformation into acute myeloid leukemia. These patients are classically identified using the revised International Prognostic Scoring System and most likely its molecular version in the near future which may change the paradigm of treatment. The overall goals of care are symptomatic control to reduce transfusion requirements and improve quality of life. Symptomatic anemia is the most common indication to initiate disease-specific therapies after the optimization of supportive measures. Currently, erythropoiesis-stimulating agents remain the standard upfront therapy for anemia, and patients with del(5q) cytogenetic changes can benefit from lenalidomide monotherapy. Other therapeutic options after failure of upfront treatment include luspatercept, hypomethylating agents, and immunosuppressive therapies after taking into account of individualized disease features. Allogeneic hematopoietic stem cell transplant is the only potentially curative option and is usually reserved for medically fit patients with severe symptomatic cytopenias who failed all standard options and/or the disease is progressing toward higher risk categories. Fortunately, novel investigational therapies are rapidly emerging by targeting different biological processes contributing to MDS pathogenesis, and eligible patients should be managed in clinical trials if available.

SOHO State of the Art Updates and Next Questions: Treatment of Lower Risk Myelodysplastic Syndromes.

MDS is a clonal stem cell neoplasm with a spectrum from lower risk disease to short term life threatening higher risk disease. The disease risk is dictated by clinical and molecular features. Majority of MDS patients including lower risk disease unfortunately succumb from disease related complications namely cytopenia. While cytopenias may be mild early upon diagnosis and can be surveilled, ultimately treatment is required. Anemia is the hall mark of disease and most common indication to treat in lower risk MDS. Erythroid stimulating agents are used in the first line setting. Treatment can be a personalized approach as in select patient such as patients with del(5q) and those with ringed sideroblasts, lenalidomide, and luspatercept can be extremely effective respectively at improving cytopenias. Younger patients and hypoplastic MDS have also shown and improved response to immunosuppressive therapy. Hypomethylating agents can be option for patients with higher risk features or thrombocytopenia/neutropenia. Refractory cytopenias still poses frustration as options are limited and there is need to add more treatments to our armamentarium.

Solute Carrier Family 29A1 Mediates In Vitro Resistance to Azacitidine in Acute Myeloid Leukemia Cell Lines.

Azacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (14C-AZA), gene expression, transporter pump activity with or without inhibitors, and cytotoxicity in naïve and resistant cell lines provided insight into the mechanism of AZA resistance. AML cell lines were exposed to increasing concentrations of AZA to create resistant clones. 14C-AZA IUR was significantly lower in MOLM-13- (1.65 ± 0.08 ng vs. 5.79 ± 0.18 ng; p < 0.0001) and SKM-1- (1.10 ± 0.08 vs. 5.08 ± 0.26 ng; p < 0.0001) resistant cells compared to respective parental cells. Importantly, 14C-AZA IUR progressively reduced with downregulation of SLC29A1 expression in MOLM-13- and SKM-1-resistant cells. Furthermore, nitrobenzyl mercaptopurine riboside, an SLC29A inhibitor, reduced 14C-AZA IUR in MOLM-13 (5.79 ± 0.18 vs. 2.07 ± 0.23, p < 0.0001) and SKM-1-naive cells (5.08 ± 2.59 vs. 1.39 ± 0.19, p = 0.0002) and reduced efficacy of AZA. As the expression of cellular efflux pumps such as ABCB1 and ABCG2 did not change in AZA-resistant cells, they are unlikely contribute to AZA resistance. Therefore, the current study provides a causal link between in vitro AZA resistance and downregulation of cellular influx transporter SLC29A1.

Clinical Experience of Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients Aged 60 Years and Older in South Korea.

The purpose of this study is to share our outcomes and experiences on allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients aged 60 years and older with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in South Korea, and to compare them with other studies. We analyzed the clinical outcomes of 116 patients with AML or MDS aged 60 years and older who underwent allogeneic HSCT. We also analyzed which pretreatment factors affect the overall survival (OS) after allogeneic HSCT. Neutrophil and platelet engraftment were achieved at median day +11 [interquartile range (IQR) 10-15] and +14 (IQR 11-19), respectively. A complete donor chimerism was confirmed in 65 (56.0%) patients at 3 weeks and in 63 (54.3%) patients at 3 months after HSCT. The estimated incidence of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 13.7%. The estimated incidence of chronic GVHD at 2 years was 38.8%. Within a median follow-up of 14 months after HSCT, OS was 64% at 1 year and 55% at 2 years, and non-relapse mortality (NRM) was 20% at 1 year and 28% at 2 years. Multivariate analysis revealed that male sex and Hematopoietic Cell Transplantation-Specific Comorbidity Index ≥3 were associated with poor OS. This study showed that allogeneic HSCT in elderly adults aged 60 and older can be performed with successful engraftment and acceptable NRM and OS are expected given the generally known survival of patients with higher risk MDS and poor risk AML.

Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy.

Prognostic implications of mono-hit and multi-hit TP53 alterations in patients with acute myeloid leukemia and higher risk myelodysplastic syndromes treated with azacitidine-based therapy.

Effects of Autoimmune Disease on Non-High Risk MDS Outcomes: A Population Analysis

Introduction: Myelodysplastic syndromes (MDS) frequently occur in patients (pts) with autoimmune diseases (AD). Concomitant inflammatory or AD are found in 10-30% of MDS cases. Studies exploring the impact of AD on MDS outcomes show discordant results and small samples in these studies hinder definitive conclusions. We conducted a large epidemiological analysis aimed at defining the impact of concomitant AD on outcomes of non-high-risk MDS pts. Methods: Pts ≥66 years with MDS were identified from 2007 - 2017 in the Surveillance, Epidemiology, and End Results (SEER) - Medicare database. Cases were excluded if they lacked continuous Medicare A and B, were enrolled in HMOs, had MDS diagnosed solely from death certificate or autopsy, or had MDS with excess blasts. Using claims from 12 months before MDS diagnosis, pre-existing AD was identified. MDS cohorts with and without concomitant AD were compared. Covariates included age, sex, race, and MDS risk, classified into low and intermediate using the International Classification of Diseases for Oncology (ICD-O-3) codes, rurality (using Rural-Urban Continuum Codes), and Charlson Comorbidity Index (CCI). Outcomes included transformation to acute myeloid leukemia (AML) during follow-up and overall survival, calculated from MDS diagnosis to date of death or end of follow-up. Logistic regression tested the association between AD and AML transformation. Cox proportional hazards regression estimated the association of AD with survival. Risk estimates are reported as odds ratio (OR) and hazard ratios (HR), with a corresponding 95% confidence interval (CI). Results: A total of 13,344 pts diagnosed with MDS between 2007 - 2017 were analyzed, including 1,978 (14.8%) with baseline AD. Pts with concomitant AD were younger, proportion >80 years accounted for 60% vs. 65.2% in MDS cases without AD (p<0.001). They were also predominantly female (55.4% vs. 45.3%, p<0.001), non-Hispanic whites (NHW) (88.8% vs. 86.2%, p=0.045), and had a higher comorbidity burden, with CCI ≥2 accounting for 68.5% in the AD cohort compared to 51.2% (p<0.001). MDS risk distribution based on ICD-O-3 histology codes is similar between groups. In a multivariate logistic regression model adjusting for age, sex, race, MDS risk/histology, rurality, and CCI, baseline AD at MDS diagnosis was associated with 18% increased odds of AML transformation; OR = 1.18 (95% CI 1.01-1.39). Table 1 shows other covariates significantly associated with AML transformation. Increasing age, female sex, and higher CCI score were factors associated with decreased odds for AML transformation. As expected, MDS risk had the largest effect, the intermediate risk was associated with 2.3-fold increased odds of AML transformation (95% CI 1.8-2.8) compared to low risk. In a multivariate Cox-proportional hazard model adjusting for age, sex, race, MDS risk/histology, rurality, and CCI, baseline AD at MDS diagnosis was associated with a 6% decreased risk of overall death (HR 0.94, 95% CI 0.89 - 0.99). Table 2 shows other covariates significantly associated with overall survival. Non-Hispanic Black race and female sex were factors associated with decreased risk of death while rising age, rurality, and higher CCI were associated with increased hazard for death. MDS risk had the largest effect on overall survival, with the intermediate risk associated with a 52% increased risk of death (95% CI, 1.44-1.60) compared to low risk. Conclusions: In a large population-based analysis, pts with AD and non-high risk MDS were predominantly female, and Non-Hispanic Whites had a higher comorbidity burden. Concomitant AD at MDS diagnosis was associated with increased risk of AML transformation but decreased risk of mortality. These seemingly contradicting results suggest that the pathophysiologic mechanisms linking systemic inflammation with MDS and their clinical consequences remain to be fully elucidated. Inflammatory bone marrow microenvironment in AD may promote clonal evolution while neoplastic clones driven by auto-inflammation could have a less aggressive phenotype. Future studies should assess molecular mutations and clonal dynamics involved in autoimmunity and MDS to build on these epidemiologic findings. Despite the limitations of a claim-based analysis, AD prevalence among MDS pts and factors associated with MDS outcomes in our cohort were consistent with previous reports. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax-Based Non-Intensive Combinations Successfully Salvage Molecular Relapse of Acute Myeloid Leukemia and Are an Important Bridge to Cellular Therapy in Relapsed/Refractory Disease - Real-World Data from a UK-Wide Programme

Background Optimal treatment for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML), particularly after molecular relapse or disease recurrence following allogeneic hematopoietic stem cell transplantation (HSCT), is undefined. Intensive salvage chemotherapy is frequently offered but is often ineffective and carries significant risk of toxicity, especially post-HSCT. Such toxicity is particularly undesirable in those patients with low burden disease, such as molecular relapse. While venetoclax (VEN, BCL-2 inhibitor) combined with FLAG-Ida was effective in a phase Ib/2 study of R/R AML (DiNardo, 2021), molecular relapse was not included, and only 14/68 subjects were treated at post-HSCT relapse. Concerns regarding toxicity of that regimen persist. Alternatively, VEN combined with hypomethylating agents or low dose cytarabine (HMA, LDAC) has shown clinical activity with good tolerability in relapsed AML, but only in small studies with little focus on outcomes following molecular or post-transplant relapse. Herein, we report outcomes after non-intensive VEN salvage combinations in a large population of patients with R/R AML treated in the UK. Methods The outcomes of adults with R/R AML receiving non-intensive VEN combinations as salvage therapy in UK hospitals were studied. Patients included had a diagnosis of AML/high risk myelodysplastic syndrome (MDS, ≥10% bone marrow blasts); refractory disease/relapse following ≥1 line of chemotherapy and at least 3 months follow up from initiation of VEN combined with non-intensive chemotherapy regimens. Response was defined by European Leukemia Net (ELN) criteria. Results 126 evaluable patients (117 AML, 9 high risk MDS) were treated during 2017-2022 (Table 1). The median age was 58 years (range 17-83 years). By ELN 2017 criteria, 32 AML patients were adverse risk, 39 intermediate and 42 favourable (4 unknown). Diagnostic analyses, where available, demonstrated mutations of NPM1 in 34 AML patients, IDH1/2 (n=17), tumour suppressor genes (n=12) and signalling pathway genes (n=37), predominantly FLT3 (n=21). 30 patients had primary refractory disease whilst 96 had relapsed (45 pre-HSCT, 51 post-HSCT). 19 patients had molecular measurable residual disease (MRD; 18 molecular relapse, 1 molecular persistence) whilst 103 had morphologic, flow cytometric or extramedullary disease (4 unknown). VEN was combined with HMA (n=75), LDAC (n=44) or used with other low intensity agents/as monotherapy (n=7). For the whole cohort, with a median follow up of 16.6 months, the median overall survival (OS) was 8.5 months (95% confidence interval [CI] 4.8-12.2 months), including when censored at subsequent transplant. 56 (44%) patients achieved CR/CRi; best response occurred after a median of 1 cycle (range 1-6). Those patients with ELN 2017 favourable risk disease experienced the best outcomes (median OS not reached vs 6.5 months [95% CI 4-9-8.2 months] for the remaining cohort; p <0.001). Median OS was inferior for both intermediate and adverse risk groups at 7.1 months (95% CI 4.5-9.7 months) and 5.8 months (95% CI 3.6-8.1 months), respectively. Notably, 16/19 (84%) patients treated for molecular MRD achieved molecular CR/CRi. This group experienced superior median OS compared with the 103 patients with morphologic/flow positive/extramedullary disease (18.4 months vs 7.1 months, 95% CI 4.9-9.3 months; p = 0.004), Figure 1. In total, 34 patients (27%) were successfully bridged to transplant after VEN salvage. Median OS from transplant not reached, despite follow up of 11.8 months, with similar outcomes regardless of whether disease was R/R when treated with VEN combinations (Figure 1). Of 51 patients treated for post-HSCT relapse, 21 (41%) achieved CR/CRi, 16 (31%) received donor lymphocyte infusions and 13 (25%) proceeded to second HSCT. Toxicity of non-intensive VEN combinations was consistent with previous reports: tumour lysis syndrome was reported in 6 (5%) patients and infection requiring antibiotics in 76 (60%). Conclusion These real-world data demonstrate that VEN-based non-intensive combinations are well tolerated and active in R/R AML, particularly in patients with molecular relapse, and represent an important route to potentially curative cellular therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1b Study to Evaluate Safety and Efficacy of IBI188 in Combination with Azacitidine (AZA) As a First-Line Treatment in Subjects with Newly Diagnosed Higher Risk Myelodysplastic Syndrome

Background: IBI188 is a recombinant fully human IgG4 monoclonal antibody targeting CD47, an antiphagocytic ('don't eat me') signal present on cancer cells. Blockage of this innate immune checkpoint, IBI188 enhances tumor cell phagocytosis. The study reported updated results from a phase 1b study (NCT04485065) that evaluated safety and efficacy of IBI188 in combination with AZA as a first-line treatment in subjects with newly diagnosed higher-risk myelodysplastic syndrome (MDS). Methods: IBI188 plus AZA was given to untreated intermediate to very high risk (IPSS-R > 3.5) MDS patients. An IBI188 priming/intrapatient dose escalation regimen (0.1-30 mg/kg QW) was used. AZA was dosed 75mg/m2 days 1-7 Q4W. Patients received IBI188 until disease progression, unacceptable toxicity, or withdraw ICF. The primary endpoint was to evaluate the safety and tolerability of IBI188 in combination with AZA. Efficacy was assessed by IWG 2006 (MDS). Results: Ninety-three patients (pts) were enrolled (median age: 59.0 years, 58 [62.4%] males). 72% pts were high to very high risk by IPSS-R. With a median follow-up of 9.2 mos (range: 0.1-21.0 mos), the most common IBI188-related AEs (≥30%) were platelet count decreased (49.5%), anaemia (44.1%), blood bilirubin increased (36.6%), neutrophil count decreased (36.6%), white blood cell count decreased (36.6%), and haemolysis (34.4%). Nine pts (9.7%) discontinued treatment due to IBI188-related AE. For 45 evaluable pts with ≥ 6 mos follow-up, 37/45 (82.2%) pts had an objective response with 14 pts (31.1%) achieving a complete response (CR), 16 (35.6%) with marrow CR (9/16 also had hematologic improvement (HI)), and 7 (15.6%) with HI alone. The median duration of response was 12.0 months (95%CI, 6.5-NC). A randomized phase 3 MDS trial is planned. Additional patients/analyses will be updated. Conclusions: IBI188 in combination with azacitidine demonstrated promising efficacy, and a manageable safety profile as a first-line treatment in subjects with newly diagnosed higher risk myelodysplastic syndrome. Keywords: Myelodysplastic syndrome, Immune therapy, CD47, IBI188 Clinical trial information: NCT04485065

Uncovering Gaps in the Evaluation and Integration of New Evidence into the Treatment and Management of Myelodysplastic Syndromes: Results from a Nationwide Survey

Background Myelodysplastic syndromes (MDS) are underreported and underdiagnosed, due to their rare occurrence and ambiguous presentation. Appropriate treatment selection, in light of an expanding therapeutic landscape, is highly dependent on an accurate diagnosis and risk stratification. To identify educational gaps limiting MDS risk stratification and individualized treatment selection, we surveyed hematology/oncology providers regarding clinical evidence on new and emerging therapies and challenges in care related to MDS treatment. Methods During March 2022, a nationwide survey was conducted among 117 hematology/oncology healthcare providers (HCPs) caring for patients with MDS (Table 1). Survey questions were designed to identify knowledge and competence barriers in performing MDS risk assessment and treatment-decision making, as well as to provide a platform for HCPs to ask 'top-of-mind' questions in MDS care. Of the survey respondents, 47% were hematologists or oncologists, and providers reported an average monthly MDS caseload of 112 patients. Results HCPs identified selecting optimal therapies for individual patients (35%) and obtaining an accurate diagnosis (22%) as the most challenging issue encountered in managing patients in MDS. In addition to clinical guidelines, HCPs considered treatment effectiveness (50%) and quality of life (50%) as the top two factors in treatment-decision making. When addressing barriers to adopting new therapies, HCPs reported being uncertain about who the "right" patients for new therapies are (35%) and having difficulty differentiating the roles of new therapies in the treatment armamentarium (20%). When asking HCPs to self-report their confidence levels in various aspects of MDS treatment, HCPs reported high confidence in their ability to identify and interpret genetic or molecular tests that should be ordered for MDS patients (53%), evaluate clinical data on the safety and efficacy of novel therapies for MDS (56%), and recognize and manage adverse events related to newer targeted therapies (54%) (Figure 1). 45% of HCPs reported moderate to low confidence in their ability to distinguish patient- and disease-related factors that affect risk stratification, and of this provider population, 40% stated that interpreting the correlation between cytogenetic abnormality and prognostic value is the biggest challenge impeding high confidence. Furthermore, of the 50% of HCPs that reported moderate to low confidence in selecting appropriate therapies for individualized MDS treatment, 47% stated their reported confidence was due to the challenge of keeping up with the clinical safety and efficacy therapy for new and emerging therapies. HCPs postulated key questions to MDS experts, including insight on the value of molecular tests in selecting novel therapies, how to individualize patient treatment plans, understanding the burden of transfusion-dependent anemia, timing for stem cell transplantation, and how to balance cost management and quality of life. Conclusions HCPs disclosed key educational barriers that limit their ability to accurately diagnosis, risk stratify, develop individualized treatment plans, and manage treatment care for patients with MDS. Of note, HCPs revealed having difficulty differentiating the roles of the rapidly evolving therapies for MDS and identifying the patients that would benefit from them, which is exacerbated by limited confidence in incorporating cytogenetic findings into MDS patient risk assessment. To optimize MDS care, educational programming to inform HCPs on how to diagnose and risk stratify patients, as well as to report data on new and emerging therapies, is critical. These findings can inform future educational initiatives to close persistent gaps in quality MDS care. Study Sponsor Statement The study reported in this abstract was funded by an independent educational grant from Gilead Sciences, Inc. The grantor had no role in the study design, execution, analysis, or reporting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Understanding What Matters to Myelodysplastic Syndrome Patients - a Study of Preferences for Treatments with Hypomethylating Agents

Introduction/Background: Hypomethylating agents (HMAs) are the standard of care for the treatment of myelodysplastic syndrome (MDS). Understanding how patients with MDS perceive and value different HMA characteristics provides critical treatment selection insight for healthcare providers. Objectives: To understand HMA preferences for United States (US) and Canadian patients with MDS. Given HMAs’ treatments’ similar efficacy and safety profiles, we also investigated how HMA administration burden can play a role in patients’ preferences when all other factors are equal. Materials and Methods: We used the discrete-choice experiment (DCE) method to conduct a preference study in collaboration with patient organizations in the US and Canada (i.e., MDS Foundation, the Aplastic Anemia and MDS International Foundation, and the Aplastic Anemia and Myelodysplasia Association of Canada). The study was comprised of two Phases: (1) a qualitative Phase (i.e., DCE survey design) and (2) a quantitative Phase (i.e., DCE survey implementation). In Phase 1, literature review, interviews with clinician, patient and caregiver, and input from the patient organizations informed the DCE survey design. Qualitative interviews were analyzed through content analysis. In Phase 2, survey participants answered a series of DCE choice tasks to indicate their preference between different hypothetical HMA profiles that varied in characteristics (i.e., attributes). Respondents were also asked to indicate their preferences by choosing between HMA profiles mirroring real-life options, all associated with the same risk of AML transformation and level of fatigue but differing in mode of and frequency administration: IV HMAs requiring 5 days or 7 days of treatment session each month, SC HMA with 5 sessions each month, oral HMA and no treatment. Survey results were analyzed using random parameter logit models. The relative importance of attributes (RAI) was calculated, which is the contribution (expressed in percentages) of each attributes relative to all attributes in patient preferences. A larger RAI percentage score shows that the attribute has a larger effect on how the respondents make their decisions. All patient respondents were recruited through the patient organizations’ networks. Results: 16 Phase 1 respondents completed the interview and 184 Phase 2 respondents (including 158 patients and 26 caregivers serving as patient proxies) completed the DCE survey. Interview respondents in Phase 1 valued efficacy attributes (i.e., risk of AML transformation and fatigue) and expressed the treatment burdens associated with injectable treatments (such as injection site reaction, stressful experience of damaged veins, burden of travelling to clinic, etc.). The Phase 2 survey participants had a mean age of 67.2 years old and 88% were from the US. About one-third of the survey participants did not know their MDS risk, 35% were low risk and 31% were high risk. Most (56%) participants were currently receiving treatment, while 24% had received treatment but discontinued and the remaining 20% had not received treatment. The attributes’ importance rankings (via RAI) were risk of AML transformation (40%), fatigue level (33%), number of visits (12%), mode of administration (6%), visit duration (5%), and administration frequency (4%). When HMA treatments were assumed to be associated with the same risk of AML and level of fatigue but to differ in terms of mode and frequency administration, 77% of respondents were predicted to switch to an oral pill if available to them. When considering real-life profiles, 77% and 88% of participants considered the oral option to be the best choice and no treatment to be the worst one, respectively. Conclusion: MDS patients demonstrated strong preferences for HMA with lesser treatment burden (i.e., oral pill) when such agents are with similar treatment efficacy and safety profiles. Understanding patients’ treatment preferences can facilitate shared decision making towards optimal management of MDS.

Micrornas Analysis in Patients with Myelodysplastic Syndrome. Possible Implications in Risk Stratification

Background. MicroRNAs (miRNAs) are significant regulators of human hematopoietic stem cells (HSC), and their deregulation contributes to hematological malignancies. Systematic analysis of miRNA expression and function during hematopoiesis has revealed regulatory loops where miRNAs contribute to hematopoietic differentiation and function. Among the identified miRNAs, miR-155 can regulate myelopoiesis and erythropoiesis and its overexpression along with the overexpression of miR-125 and miR-181 has been suggested to have functional effects in the regulation of HSC homeostasis. Myelodysplastic syndromes (MDS) are characterized by dysfunctional HSC, ineffective blood cell production, progressive marrow failure, and exhibit a significant risk of progression to acute myeloid leukemia (AML). Although the pathogenesis of MDS has not been fully understood, various alterations of microRNAs (miRNAs) have been reported in MDS. There is recent evidence that the miRNAs mediated post-transcriptional control of gene expression is key component in the pathogenesis of MDS and AML. Several studies have reported that differentially expressed microRNAs are associated with the transformation of MDS to AML and clinical outcomes. Aim. In this study we examined the potential prognostic impact of six previously described miRNAS (miR-181a-2-3p, miR-124-3p, miR-550a-3p, miR-155-5p, miR-151a-3p, and miR-125b-5p) on the pathogenesis of MDS. Methods. Total RNA was extracted from diagnostic bone marrow samples of 41 MDS patients. Patients were stratified per the revised International Prognostic Scoring System (IPSS-R). After polyadenylation of 1 μg total RNA by poly(A) polymerase and subsequent reverse transcription with an oligo-dT adapter primer, miRNAs transcript levels were determined using a reverse transcription quantitative real-time PCR method, based on SYBR Green chemistry. U6 was used as reference gene. Relative microRNA transcript levels were calculated by the 2-ΔΔct method. The IBM SPSS statistics, version 26 (IBM Corporation, North Castle, NY, USA) was used for the statistical analysis of the results. Results. The basic characteristics of the patients are shown in Table 1. Of the microRNAs analyzed in this study, miR-125b-5p, miR-155-5p, miR-181a-2-3p transcript levels were significantly elevated in higher (intermediate, high, and very high) risk MDS than in lower (very low and low) risk MDS (p=0.012, p=0.010, and p=0.024 respectively). MiR-125b-5p, miR-151a-3p, miR-155-5p, miR-181a-2-3p, and miR-550a-3p presented a positive correlation with the percentage of bone marrow blasts [p(0.001-0.05)], while a negative correlation was observed between the expression levels of mir-151-a-3p, miR181a-2-3p, miR-550a-3p, and the neutrophil count (p=0.05, 0.013, 0.010, and 0.007 respectively). None of the remaining factors that were tested (MDS type per the 2016 WHO classification, gender, age at diagnosis, hemoglobin levels, platelet count, and cytopenias) were correlated with the miRNAs levels. Discussion. In this study we demonstrated the notable difference in the pattern of miRNA expression between lower and higher risk MDS patients. It has been shown that deregulation of miR-155-5p and miR-181a-2-3p may promote aberrant hematopoietic stem cell proliferation, differentiation, and progression to AML. Moreover, mice transplanted with miR-155-5p transfected stem cells developed a myeloproliferative disorder with abnormal granulocyte morphology analogous to MDS, suggesting a role in the higher risk MDS phenotype. Finally, it has been reported that miR-181a-3p was strongly expressed in the cytoplasm of high risk MDS cells, in contrast to low risk samples which displayed reduced levels. The identification of miRNAs that distinguish lower risk from higher risk MDS indicates that microRNA expression profile may be exploited to assist with making treatment decisions. Given that certain miRNAs can discriminate MDS subtypes and risk groups, it is not unlikely to think that an miRNA signature could be a useful tool for MDS risk stratification. Based on our current findings and other previously reported results, we continue the study in a larger cohort of patients. Targeting miRNAs may provide new treatment options for MDS Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Favorable Outcomes of DDX41-Mutated MDS and Low Blast Count AML Treated with Azacitidine with or without Lenalidomide (ALLG MDS4 Trial)

Introduction. The Australasian Leukaemia and Lymphoma Group (ALLG) MDS4 phase II trial randomized 160 patients (pts) with higher risk (by IPSS) myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast acute myeloid leukemia (AML) to either azacitidine (AZA) or combination AZA with lenalidomide (LEN, from cycle 3 onwards) (Kenealy, Haematologica 2019; ANZCTR12610000271000). Whilst the combination of LEN and AZA was tolerable, there was no improvement in clinical benefit, response rates or overall survival in patients compared to treatment with AZA alone. We performed a post-hoc genomic analysis of pts on this trial to further understand the molecular changes in this cohort and any correlation with outcomes. Methods. A unique molecular index (UMI) based QIAseq targeted DNA panel (QIAGEN) was performed as previously described (Blombery, Blood 2020). Sensitivity for variant calling was 0.5% variant allele frequency (VAF). HumanCytoSNP-12 BeadChip array (SNP-A) was previously performed and reported (Kenealy, Haematologica 2019). Primary endpoint of the study was ongoing clinical benefit at 12 months, defined as being alive and progression-free. Logistic regression and Cox proportional hazards regression were used respectively to assess the differences in response rates and overall survival between two treatment groups according to the molecular subgroups. Results. A total of 66 pts, representative of the 160 enrolled, had baseline gDNA available for targeted panel testing; 36 and 30 pts on AZA alone and AZA+LEN therapy, respectively. Median age was 71.6 years. IPSS-R risk groups were very low or low (n=20), intermediate (n=18), high or very high (n=25), and not available (n=3 due to missing karyotype). Disease subtypes were MDS (n=52), CMML (n=9), and AML (n=5). 47% of pts had an abnormal SNP-A, including 18% with complex (≥3) copy number changes. The most common gene mutations observed were ASXL1 (48.5%), TET2 (47%) and RUNX1 (30%) (Figure 1). Overall clinical benefit at 12 months was achieved in 39 pts (59%). TET2 was the only gene mutation associated with significantly improved benefit when treated with AZA alone (OR 10 [95% CI, 2 to 81]). Median follow up among survivors was 49 months and the median overall survival was 33.2 months (95% CI, 21.7 - NE). Mutations in TP53, U2AF1, EZH2 and SRSF2 were associated with inferior overall survival. Molecular subgroup analyses did not identify any significant difference between the two treatment arms. Given the recent discovery of DDX41 mutations in MDS/AML and early data supporting a favorable response to AZA/LEN, we focused on 6/66 (9%) patients with detectable DDX41 mutations. All 6 pts had a second mutation detectable in DDX41 as well as no detectable abnormalities on SNP-A. The most commonly co-mutated gene in this group was ASXL1 (in 4/6). One patient with DDX41 mutation died before receiving any therapy. Best responses achieved in DDX41 mutated patients were complete remission (CR, n=1), marrow CR (n=1), hematologic improvement (HI, n=1), and stable disease (SD, n=2). Remarkably, of the 5 patients that received treatment (4 AZA, 1 AZA+LEN), the overall survival at 52 months (range 47-58) follow up was 100% (Figure 2), despite having intermediate (n=3) and high (n=2) R-IPSS. Mutations were also serially assessed on therapy in 45 pts: ≤2 cycles in 38 pts, and ≥4 cycles in 7 pts (2 AZA+LEN). Of 166 mutations observed at baseline, majority (67%) were stable with <10% change in VAF (median +2%). Overall, 27 (60%) pts had clearance or >10% VAF reduction in ≥1 variant, including clearance in 20 (12%) variants (most commonly TET2 [n=4] and RUNX1 [n=3]), and reduction in 33 (20%) variants (ASXL1 [n=6], SF3B1, SRSF2 and TET2 [n=5 each], but no pt had complete molecular clearance. In contrast, new mutations (n=18 variants) or >10% VAF increase (n=2 variants) were observed in 14 (31%) pts, most commonly TET2 (n=6), RUNX1 (n=4), and DNMT3A and BRAF (n=3 each). Conclusions. In summary, our correlative molecular analysis of the ALLG MDS4 trial of AZA vs AZA+LEN in MDS/AML has identified, in addition to established molecular risk factors for inferior outcomes, that pts with DDX41 mutations are associated with highly favorable outcomes with either AZA or AZA+LEN. This observation and subgroup of patients warrants further study in randomized trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequential Use of Flamsa, FLAG, CLAG or TEC-Based Conditioning Regimen Followed By Allogeneic Hematopoietic Transplantation Results in Favorable Outcome for High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myeloproliferative Neoplasia Patients: 15 Year Follow-up of the Multicenter Study in Singapore

Introduction: Allogeneic hematopoietic cell transplant (allo-HCT) is an effective consolidative treatment for patients with certain hematological malignancies and gives the best outcome when done in remission. However, patients with refractory acute myeloid leukemia (AML) or some myeloproliferative neoplasia (MPN) and myelodysplastic syndrome (MDS) deemed unable to achieve remission with standard induction are often excluded from allo-HCT with conventional conditioning regimen as pre-transplant remission could not be achieved. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/Cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results. Methods: We studied 72 patients (median age 51 years, range 17-68) with HR AML (n=57), as defined by refractory, relapsed disease, secondary leukemia, complete remission with adverse-risk cytogenetics according to ELN criteria, or high/very risk refined Disease Risk Index (DRI), MPN (n=3) and HR MDS (n=12) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 transplant centers in Singapore between January 2009 and July 2022. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=21), FLAG [Fludarabine/Cytarabine/Granulocyte Colony Stimulating Factor (GCSF)] +/- Idarubicin (n=30), CLAG (Clofarabine +/- Cytarabine +/- GCSF) (n=18), or TEC (Thiotepa, Etoposide, Cyclophosphamide) (n=3) followed by reduced intensity (RIC) (n=61) or myeloablative (MAC) (n=11) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (MRD) (n=36), mismatched related donors (MMRD) (n=7), matched unrelated donors (MUD) (n=21), or mismatched unrelated donors (MMURD) (n=8). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil (MMF) in all patients. Thymoglobulin and post-transplant cyclophosphamide were added for GVHD prophylaxis for MUD/MMURD and MMRD transplant, respectively. One MMRD had selective ex vivo T-cell depleted transplant followed by MMF as GVHD prophylaxis. Results: The median time to neutrophil > 1000/μL was 11 days (range, 8-25). With a median follow-up duration of 51 months (range, 1-148), the Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 5 years were 42% (95% CI, 30-54) and 32% (95% CI 20-44), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) at 2 years were 47% (95% CI, 35-59) and 16% (95% CI, 9-26), respectively. Patients receiving FLAG, CLAG or TEC-based sequential regimen showed a trend towards lower NRM and relapse compared to FLAMSA-based regimen, although the difference was not statistically significant. This translated into a more favorable 5-year LFS (40% vs 13%, p=0.04), but no statistically significant difference in 5-year OS (42% vs 40%, p=0.56). Patients with refractory disease (n=49) were at higher risk of relapse compared to patients whom had achieved at least a partial remission prior to sequential allo-HCT (n=17) (2-year cumulative incidence of relapse: 59.0% vs 34.0%, p=0.02). This resulted in an inferior 5-year OS (31% vs 66%; p=0.02) and LFS (20% vs 75%, p<0.01). On multivariable analysis, only refined DRI showed significant impact on OS (p=0.01) and LFS (p=0.02) but had no significant impact on NRM and relapse. The 5-year OS for patients with intermediate/high risk and very high risk DRI were 51% and 21% (p<0.01), and the corresponding 5-year LFS were 42% and 10% (p<0.01), respectively (Figure 1 and Figure 2). Conclusions: Sequential transplant conditioning with FLAMSA, FLAG, CLAG or TEC-based cytoreductive regimen followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of HR AML, MDS and MPN, including patients with high risk DRI, and enabling favorable long-term disease-free survival. More studies on effective strategies such as optimising the conditioning regimen intensity or post-transplant maintenance therapy with prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal