Acute Myeloid Leukemia Transformation Research Articles

PTPN11 Mutations Are Associated with Poor Outcomes across Myeloid Malignancies

PTPN11 Mutations Are Associated with Poor Outcomes across Myeloid Malignancies

IL-6 Deficiency Reverses Leukemic Transformation in an MDS Mouse Model

Myelodysplastic syndromes (MDS) are a group of age-related myeloid malignancies that are characterized by ineffective hematopoiesis and increased incidence of developing acute myeloid leukemia (AML). The mechanisms of MDS to AML transformation are poorly understood, which is partially due to the scarcity of leukemia transformation mouse models. Recently, we established a mDia1/miR146a double knockout (DKO) mouse model mimicking human del(5q) MDS. DKO mice present with pancytopenia with aging due to myeloid suppressive cell (MDSC) expansion and over-secretion of pro-inflammatory cytokines including TNF-a and interlukine-6 (IL-6). In the current study, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. The bone marrow of these mice was largely replaced by c-Kit+ blasts in a background of fibrosis. Flow cytometry analysis and in vitro colony formation assay demonstrated that hematopoietic stem progenitor cells (HSPCs) in DKO bone marrow were dramatically declined. The leukemic DKO mice had elevated white blood cell counts and circulating blasts, which contributes to the myeloid cell infiltration in non-hematopoietic organs including liver and lung. Moreover, the splenocytes from DKO old mice efficiently reconstitute the hematopoiesis, but led to a 100% disease occurrence with rapid lethality in gramma irradiated recipient mice, suggesting the leukemic stem cells enriched in DKO spleen were transplantable. Given the significant roles of the inflammatory cytokines in the pathogenesis of the DKO mice, we crossed DKO mice with IL-6 knockout mice and generated mDia1/miR-146a/IL-6 triple knockout (TKO) mice. Strikingly, the TKO mice showed dramatic rescue of the leukemic transformation of the DKO mice in that all the aforementioned leukemic phenotypes were abolished. In addition, IL-6 deficiency normalized the cell comparts and prevented leukemic transplantation ability in TKO spleen. Single cell RNA sequencing analyses indicated that DKO leukemic mice had increased monocytic blast population with upregulation of Fn1, Csf1r, and Lgals1, that was completely diminished with IL-6 knockout. Through a multiplex ELISA, we found IL-6 deficiency attenuated the levels of multiple inflammatory cytokines in TKO serum. In summary, we report a mouse model with MDS leukemic transformation during aging, which could be reverted with the depletion of IL-6. Our data indicate that IL-6 could be a potential target in high risk MDS. Disclosures No relevant conflicts of interest to declare.

MDS-112: A SEER-Medicare Analysis of Treatment Patterns and Outcomes in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agent

Context: The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) are standard-of-care in patients with higher-risk MDS. However, real-world outcomes of patients with MDS treated with HMAs have not been comprehensively assessed. Objective: To describe real-world treatment patterns and outcomes among patients with MDS treated with HMAs. Design: Adult patients with a confirmed MDS diagnosis between 01/2009-12/2015 treated with HMAs were identified in the SEER-Medicare database (01/2006-12/2016). The index date was the date of HMA initiation. Patients were required to have Medicare Parts A and B coverage for ≥12 months pre-index and ≥1 month post-index. Patients with evidence of stem cell transplant or acute myeloid leukemia (AML) pre-index, or enrollment in a clinical trial at any time were excluded. Results: A total of 3,046 patients with MDS treated with HMAs were included. Average age was 77.4 years and 36.8% were female. Most patients (70.9%) were classified in the higher-risk MDS group; 8.0% and 21.1% were classified in the intermediate-1-risk and unknown-risk MDS groups. Median OS was 11.6, 18.4, and 19.1 months in the higher-risk, intermediate-1-risk, and unknown risk MDS groups, respectively; median time to AML transformation was 19.3 months, 50.4 months, and not reached, respectively. Patients received an average of 5.1 HMA cycles (median, 4.0 cycles); most were complete cycles (90.9%; per label or, for AZA, also including the commonly used alternative regimens of 5-day 5-0-0 or 7-day with a weekend break 5-2-2). Mean duration of HMA cycles was 32.6 days (median, 28.0 days). Overall, 45.3% of patients received Conclusions: In this US real-world observational study, >70% of patients with MDS treated with HMAs were at higher-risk of AML transformation or death. Patients in the higher-risk MDS group had poor prognosis, with a median OS

SET Domain Containing 2 Deficiency in Myelodysplastic Syndrome

Recent studies have shown that myelodysplastic syndrome’s (MDS) progression to acute myeloid leukemia (AML) is associated with gene mutations. SET domain containing 2 (SETD2) variants were reported as a risk factor of poor prognosis in patients with AML. However, little is known about the potential contribution of the SETD2 gene in MDS. In this study, we investigated the roles of SETD2 gene mutations/variants on clinical features and prognosis in patients with MDS. A 43-gene panel was used for next-generation sequencing in 203 patients with primary MDS, and then the effects of SETD2 mutation on Wnt/β-catenin signaling was investigated during the different stages of MDS. At a median follow up of 33 months, 65 (32.0%) deaths and 94 (46.3%) leukemic transformations were recorded. The most frequent mutations/variants included TET2, DNMT3A, and ASXL1 mutations/variants. 37 patients had SETD2 gene mutations/variants, and these patients exhibited a significantly increased frequency of TP53 mutations. Multivariate survival analyses indicated that SETD2 mutations/variants were closely associated with overall survival (OS), and they were identified as risk factors for progression-free survival (PFS), especially with low expression of SETD2 gene. Further, we found that SETD2 loss could promote MDS progression via upregulation DVL3 mRNA level in BM cells and it could also cause genomic instability. Secondary mutations, such as TP53 and FLT3 mutations, were acquired at the time of progression to AML. In conclusion, we showed that SETD2 deficiency was associated with poor outcomes in patients with MDS. Moreover, SETD2 deficiency may upregulate DVL3 expression and modulate genomic stability that caused AML transformation.

Prognostic Value of CD200 Expression and Soluble CTLA-4 Concentrations in Intermediate and High-Risk Myelodysplastic Syndrome Patients.

Objective:This study was designed in order to identify the prognostic relevance of CD200 expression and soluble Cytotoxic T-lymphocyte antigen-4 (CTLA-4) levels in myelodysplastic syndrome (MDS) patients. Methods:The study included 57 MDS (37 intermediate and 20 high risk) patients and 10 controls. For all of included patients; CD200 expression was identified by flowcytometry on CD33 positive cells and soluble CTLA-4 (CD152) concentration was determined by ELISA. Results: CD200 positive expression was detected in 32/57 (56.1%) of MDS cases, the mean serum CTLA-4 concentrations were significantly higher in MDS patients as compared to controls (P<0.01). Significant association between high CD200 positive expression; high CTLA-4 concentration levels and MDS risk stages being higher in high risk MDS group as compared to intermediate risk one (P < 0.01). After 36-month follow-up; the subgroup of MDS patients with high expression of CD200; and high serum CTLA-4 concentrations showed high death rate and high frequency of acute myeloid leukemia transformation. Conclusions: CD200 positive expression could be considered as a new prognostic marker for risk stratification of MDS patients. CD200 expression may exert its effect through upregulation of CTLA-4.

Transcriptomic Profiles of MV4-11 and Kasumi 1 Acute Myeloid Leukemia Cell Lines Modulated by Epigenetic Modifiers Trichostatin A and 5-Azacytidine

Background: Acute myeloid leukemia (AML) is the most common form of acute leukemias in adults which is clinically and molecularly heterogeneous. Several risk and genetic factors have been widely investigated to characterize AML. However, the concomitant epigenetic factors in controlling the gene expression lead to AML transformation was not fully understood. This study was aimed to identify epigenetically regulated genes in AML cell lines induced by epigenetic modulating agents, Trichostatin A (TSA) and 5-Azacytidine (5-Aza). Materials and Methods: MV4-11 and Kasumi 1 were treated with TSA and/or 5-Aza at IC50 concentration. Gene expression profiling by microarray was utilized using SurePrint G3 Human Gene Expression v3. Gene ontology and KEGG pathway annotations were analyzed by DAVID bioinformatics software using EASE enrichment score. mRNA expression of the differentially expressed genes were verified by quantitative real time PCR. Results: Gene expression analysis revealed a significant changes in the expression of 24,822, 15,720, 15,654 genes in MV4-11 and 12,598, 8828, 18,026 genes in Kasumi 1, in response to TSA, 5-Aza and combination treatments, respectively, compared to non-treated (p<0.05). 7 genes (SOCS3, TUBA1C, CCNA1, MAP3K6, PTPRC, STAT6 and RUNX1) and 4 genes (ANGPTL4, TUBB2A, ADAM12 and PTPN6) shown to be predominantly expressed in MV4-11 and Kasumi 1, respectively (EASE<0.1). The analysis also revealed phagosome pathway commonly activated in both cell lines. Conclusion: Our data showed a distinct optimal biological characteristic and pathway in different types of leukemic cell lines. These finding may help in the identification of cell-specific epigenetic biomarker in the pathogenesis of AML.

Inhibition of the deubiquitinase USP10 induces degradation of SYK

BackgroundThere is growing evidence that spleen tyrosine kinase (SYK) is critical for acute myeloid leukaemia (AML) transformation and maintenance of the leukemic clone in AML patients. It has also been found to be over-expressed in AML patients, with activating mutations in foetal liver tyrosine kinase 3 (FLT3), particularly those with internal tandem duplications (FLT3-ITD), where it transactivates FLT3-ITD and confers resistance to treatment with FLT3 tyrosine kinase inhibitors (TKIs).MethodsWe have previously described a pharmacological approach to treating FLT3-ITD-positive AML that relies on proteasome-mediated FLT3 degradation via inhibition of USP10, the deubiquitinating enzyme (DUB) responsible for cleaving ubiquitin from FLT3.ResultsHere, we show that USP10 is also a major DUB required for stabilisation of SYK. We further demonstrate that degradation of SYK can be induced by USP10-targeting inhibitors. USP10 inhibition leads to death of cells driven by active SYK or oncogenic FLT3 and potentiates the anti-leukemic effects of FLT3 inhibition in these cells.ConclusionsWe suggest that USP10 inhibition is a novel approach to inhibiting SYK and impeding its role in the pathology of AML, including oncogenic FLT3-positive AML. Also, given the significant transforming role SYK in other tumours, targeting USP10 may have broader applications in cancer.

Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia.

Recently, several targeted agents have been developed for specific subsets of patients with acute myeloid leukaemia (AML), including midostaurin, the first FDA‐approved FLT3 inhibitor for newly diagnosed patients with FLT3 mutations. However, in the initial Phase I/II clinical trials, some patients without FLT3 mutations had transient responses to midostaurin, suggesting that this multi‐targeted kinase inhibitor might benefit AML patients more broadly. Here, we demonstrate submicromolar efficacy of midostaurin in vitro and efficacy in vivo against wild‐type (wt) FLT3‐expressing AML cell lines and primary cells, and we compare its effectiveness with that of other FLT3 inhibitors currently in clinical trials. Midostaurin was found to synergize with standard chemotherapeutic drugs and some targeted agents against AML cells without mutations in FLT3. The mechanism may involve, in part, the unique kinase profile of midostaurin that includes proteins implicated in AML transformation, such as SYK or KIT, or inhibition of ERK pathway or proviability signalling. Our findings support further investigation of midostaurin as a chemosensitizing agent in AML patients without FLT3 mutations.

Myelodysplastic Syndromes: How to Recognize Risk and Avoid Acute Myeloid Leukemia Transformation.

To understand how myelodysplastic syndromes (MDS) transform to AML and to describe how transformation can be predicted and prevented. Recent genomic analyses have shown that MDS progression to AML is associated with clonal expansion and clonal evolution. Mutation profiles of MDS change during progression and new mutations in signaling genes and transcription factors emerge. AML transformation can be predicted by several parameters including International Prognostic Scoring System IPSS risk category and transfusion requirements. The prognostic relevance of the acquisition of some gene mutations (i.e., IDH1 and 2, CBL, FT3, RAS, NPM1, TP53, and ASXL1) has to be prospectively validated. The most effective preventive therapy for AML transformation is allogeneic stem cell transplantation. Hypomethylating agents have been associated with prolonged time to AML transformation even in patients who did not achieve an objective response. The recent progress in the understanding of the molecular events leading to transformation and the event of new effective therapies open new avenues for a better prediction and prevention of AML transformation in patients with MDS.

Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes

AbstractMyelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed “antioxidogram,” for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM blasts [GLRX family]); (2) increased expression of enzymes detoxifying H2O2 (MDS with 5% to 19% BM blasts [PRDX and GPX families]); and finally (3) decreased expression of these enzymes in sAML. The antioxidant score (AO-Score) defined by logistic regression from the expression levels of transcripts made it possible to stage disease progression and, interestingly, this AO-Score was independent of the revised International Scoring System. Altogether, this study demonstrates that MDS and sAML present an important disturbance of redox metabolism, especially in BM stem and progenitor cells and that the specific molecular antioxidant response parameters (antioxidogram, AO-Score) could be considered as useful biomarkers for disease diagnosis and follow-up.

Prognostic value of U2AF1 mutant in patients with de novo myelodysplastic syndromes: a meta-analysis.

U2 small nuclear RNA auxiliary factor 1 (U2AF1) mutant is the most common molecular biological abnormality in patients with myelodysplastic syndromes. Some studies have reported the prognostic impact of U2AF1 mutant in patients with de novo MDS, with discrepant results, so we do a meta-analysis about the relevant literatures to further investigate their prognostic impact on patients with de novo MDS. We conducted a literature search on databases such as PubMed, Embase, and the Cochrane Library to obtain studies on the prognosis of U2AF1 mutant in patients with de novo MDS published up to August 9, 2018. The primary endpoint was overall survival (OS), and the secondary endpoint was acute myeloid leukemia (AML) transformation. We extracted the hazard ratios (HRs) of OS and AML transformation and their 95% confidence intervals (CIs). Meta-analysis was performed by selecting a fixed-effect model or a random-effects model based on the heterogeneity between studies. A total of 14 cohort studies were included in the final meta-analysis, including 3322 patients with de no MDS, in which 390 patients were associated with U2AF1 mutant. The results showed that U2AF1 mutant had an adverse prognostic impact on OS (HR = 1.84, 95% CI: 1.45-2.33, P < 0.00001) and AML transformation (HR = 2.47, 95% CI: 1.50-4.06, P = 0.0004). U2AF1 mutant was associated with shorter OS in subgroup analyses of low- or intermediate-1-IPSS, U2AF1S34 and U2AF1Q157/R156. Out meta-analysis indicates that U2AF1 mutants are independent, detrimental prognostic factors for OS and AML transformation in patients with de novo MDS, as well as associating with shorter OS in subgroups of low- or intermediate-1-IPSS, U2AF1S34 and U2AF1Q157/R156. Further prospective studies are needed in the future, and subgroup analysis of U2AF1 subgroups is needed to obtain a more reliable basis for the impact of U2AF1 mutant on the prognosis of de novo MDS.

Crosstalk between Oxidative Stress, Chronic Inflammation and Disease Progression in Essential Thrombocythemia

Essential thrombocythemia (ET) is a Philadelphia-negative chronic myeloproliferative neoplasm characterized by acquired somatic mutations: JAK2, CALR or MPL. It is associated with low-grade chronic inflammation, oxidative stress, overproduction of reactive oxygen species (ROS) and antioxidant deficiency. In ET, chronic inflammation and oxidative stress contribute to the genomic instability, the clonal evolution to myelofibrosis and the leukemic transformation. We evaluated ROS levels and the total antioxidant capacity (TAC) in 62 ET patients and investigated the relationship between ROS, TAC, chronic inflammation, leukocytosis, JAK2V617F mutation, and disease progression to myelofibrosis or leukemic transformation. We observed increased levels of ROS and inflammation markers and a decreased TAC in ET patients vs. controls. The acute myeloid leukaemia transformation associated increased levels of oxidative stress and inflammation markers and increased leukocyte counts, while myelofibrosis progression associated an increase in ROS and serum ferritin.

Crosstalk between Oxidative Stress, Chronic Inflammation and Disease Progression in Essential Thrombocythemia

Essential thrombocythemia (ET) is a Philadelphia-negative chronic myeloproliferative neoplasm characterized by acquired somatic mutations: JAK2, CALR or MPL. It is associated with low-grade chronic inflammation, oxidative stress, overproduction of reactive oxygen species (ROS) and antioxidant deficiency. In ET, chronic inflammation and oxidative stress contribute to the genomic instability, the clonal evolution to myelofibrosis and the leukemic transformation. We evaluated ROS levels and the total antioxidant capacity (TAC) in 62 ET patients and investigated the relationship between ROS, TAC, chronic inflammation, leukocytosis, JAK2V617F mutation, and disease progression to myelofibrosis or leukemic transformation. We observed increased levels of ROS and inflammation markers and a decreased TAC in ET patients vs. controls. The acute myeloid leukaemia transformation associated increased levels of oxidative stress and inflammation markers and increased leukocyte counts, while myelofibrosis progression associated an increase in ROS and serum ferritin. Keywords: essential thrombocythemia, reactive oxygen species, inflammation, JAK2V617F

TP53 State Dictates Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes

TP53 State Dictates Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes

WHO-Defined Chronic Myelomonocytic Leukemia-2 (CMML-2) Patients Rapidly Progress to AML Suggesting This Entity Represents a Transitory Clinical State

WHO-Defined Chronic Myelomonocytic Leukemia-2 (CMML-2) Patients Rapidly Progress to AML Suggesting This Entity Represents a Transitory Clinical State

Iadademstat Shows Efficacy in Elderly AML Patients in Combination with Azacitidine. Alice Trial

Introduction: Acute Myeloid Leukemia (AML) is an elderly disease with a rising incidence in the past decades. Probability to achieve complete remission and survival rates decrease with age with standard chemotherapy options leading to very poor outcomes with less than 20% 5-year overall survival rates. It has been shown that Lysine-specific demethylase 1 (LSD1) is a partner in some gene transformation in AML and helps sustain the oncogenic process. Iadademstat is a potent and selective LSD1 inhibitor that has shown to be effective in preclinical models, both alone and in combination with other compounds, including azacitidine (Aza). A Phase I FiM study in acute leukemia showed that iadademstat exhibits a good safety profile and preliminary anti-leukemic activity as monotherapy. Iadademstat in combination with Aza may thus offer an alternative option for such a population with limited therapeutic options. Methods: ALICE is a Phase IIa clinical trial to assess the safety, tolerability and dose finding of iadademstat in combination with Aza and also to measure the clinical activity of the combination as overall response rate (ORR), time to response (TTR) and duration of response (DOR). Other assessments include hematological improvement and overall survival, along with PK/PD measures (including a set of 6 blood biomarkers). The dose finding stage (Part 1) planned to dose a maximum 18 patients with a starting dose of iadademstat of 90 μg/m2/d in combination with Aza. Iadademstat may be escalated or de-escalated depending on the observed dose limiting toxicities. Once the Recommended Dose (RD) is identified, an expansion cohort of 18 patients will be enrolled and treated with iadademstat combined with Aza (Part 2). ALICE includes subjects ≥ 60 years of age with AML according to World Health Organization (WHO) classification, who are considered by the investigator to be ineligible for intensive chemotherapy at that time or have refused standard chemotherapy and who have not received prior treatment for AML other than hydroxyurea. Results: According to the Safety Monitoring Committee of the study, the selected RD of iadademstat was 90μg/m2/d. This decision was made based on first dose finding cohort including 6 subjects with the observation of 1 DLT due to a differentiation syndrome (the sole SAE reported due to treatment) and based on the fact that the selected dose: i) was able to saturate LSD1 target engagement in PBMCs after 5 days of treatment; ii) was well tolerated (11 treatment cycles were completed at the moment of decision) and iii) demonstrated the first signs of efficacy. A short median time to first response was observed (around 1.5 months). Analysis of the first patients yielded an ORR in 4 of 5 evaluable patients (80%): in all of them the best observed response was CRi as per July 2019. A lower maintenance regime has been established for those patients that had attained CRi. The first patient that has followed this strategy has become transfusion independent. To date, no grade 3-4 non-hematological adverse events have been reported. The patient assessments of the still-ongoing subjects from Part 1 and all new enrolled study subjects in the expansion cohort will be presented following a November 2019 cut-off, with particular emphasis on available preliminary efficacy outcomes. Conclusions: To date, data from this Phase II study supports that iadademstat in combination with azacitidine in elderly previously untreated AML patients has a manageable toxicity and is a meaningful candidate for specific combinations in this and future leukemia studies. These encouraging results will be enriched with the inclusion of up to 18 additional patients in the expansion cohort and with longer clinical observation periods to better assess the frequency, deepness and duration of the responses. Disclosures Buesa: Oryzon Genomics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Mendelion SL: Membership on an entity's Board of Directors or advisory committees. Somervaille:Novartis: Consultancy. Arevalo:Oryzon Genomics: Employment. Xaus:Oryzon Genomics: Employment. Gutierrez:Oryzon Genomics: Employment. Bullock:Oryzon Genomics: Consultancy.

Therapy-Related Myeloid Neoplasms Following Treatment for Multiple Myeloma : A Single-Center Analysis

Therapy-Related Myeloid Neoplasms Following Treatment for Multiple Myeloma : A Single-Center Analysis

Bone Marrow Mastocytosis Is Independently Associated with Inferior Survival in Chronic Myelomonocytic Leukemia

Introduction: Systemic mastocytosis with associated hematologic neoplasm (SM-AHN) is defined by the presence of a concomitant hematologic malignancy with chronic myelomonocytic leukemia (CMML) being a particularly common partner. The overall survival of patients with SM-AHN is inferior to those with SM alone, even when matched for relevant prognostic covariates. However, the prognostic impact of mastocytosis in patients with CMML is unknown. Methods: CMML patients with concomitant mastocytosis were identified from the Moffitt Cancer Center CMML database. We assessed baseline demographic, clinical, and molecular findings and used Kaplan-Meier method to estimate overall survival (OS). The log-rank test was used to compare Kaplan-Meier curves, We then compared the SM-CMML cohort to a well-established institutional database of CMML patients. Baseline demographic and clinical variables were analyzed using GraphPad Prism and SPSS was used for Cox Regression Analysis. Results: Between 5/2004 and 5/2019 22 of 645 CMML patients (3.4%) were identified to have concomitant mastocytosis. The median follow-up for the 22 patients with SM-CMML was 51 months. Nine (41%) patients were diagnosed with de novo CMML prior to SM. In these cases, secondary SM-CMML occurred at a median time of 7 months after CMML diagnosis. Ten patients (45%) were diagnosed with CMML and SM concurrently and 3 (14%) were diagnosed with SM prior to CMML. Among 17 patients tested for KIT mutations, 12 were found to harbor a mutation. The remaining five patients did not undergo high-sensitivity KIT testing on a bone marrow aspirate. Eleven patients had extended gene sequencing performed with the most common additional mutations involving TET2 (45%), SRSF2 (55%), ASXL1 (27%), RAS (27%), DNMT3A (27%), and RUNX1 (27%). The median overall survival (OS) was estimated to be 38.6 months. Next, we compared this cohort of SM-CMML patients to a large, established database of CMML patients (excluding those with concomitant SM). Age at diagnosis, baseline white blood cell count, hemoglobin, and platelet count were well matched between the two groups. Applying the Mayo CMML Prognostic Model to the cohort of SM-CMML patients demonstrated that 32%, 41%, and 27% were low, intermediate and high risk, respectively. In the CMML cohort, 13%, 35%, and 51% were low, intermediate and high, risk respectively, suggesting the SM-CMML was more common in the lower-risk group (p=0.025). The median OS was similar between the two cohorts (median OS 31.3 vs 38.6 months, p = 0.43). However, multivariate analysis including Mayo Prognostic Scoring System, age &gt; 65, and SM component revealed all three variables to be independently associated with survival (HR 1.8, p &lt; 0.001; HR 1.7, p = 0.047; and HR 1.5, p 0.003, respectively). Assessing the impact of mastocytosis in low, intermediate, and high-risk groups separately, the inferior prognostic impact of mastocytosis was most prominent in high-risk patients (OS 19.6 mo vs. 5.4 mo; p = 0.049). Survival outcomes between SM-CMML and CMML were not statistically different in intermediate and low-risk groups (p = 0.47 and p = 0.19, respectively). Among 16 deaths in the SM-CMML cohort, cause of death was able to be assessed in 13 patients. Four (31%) patients died after transformation to acute myeloid leukemia (AML). These patients were either intermediate- or high-risk by Mayo Prognostic Model. Nine patients (69%) died due to multisystem organ failure due to progressive systemic mastocytosis without development of acute leukemia. Among these, 4 (44%) were low-risk, 3 (33%) were intermediate-risk, and 2 (22%) were high-risk. Conclusions: SM-CMML typically presented with lower-risk disease when graded by the Mayo CMML Prognostic Model. Compared head-to-head, OS was similar between SM-CMML and CMML; however multivariate analysis revealed the SM component to be a significant adverse prognostic factor. The presence of bone marrow mastocytosis is associated with inferior survival in high-risk CMML cases. Cause of death among SM-CMML patients was attributable to both progressive mastocytosis and transformation to AML. AML transformation was limited to intermediate- and high-risk group while progressive mastocytosis was seen across the risk spectrum. Future studies are warranted to determine if SM therapy can mitigate this outcome. Figure 1 Disclosures Kuykendall: Abbvie: Honoraria; Celgene: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy. Talati:Celgene: Honoraria; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria. Komrokji:DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; JAZZ: Speakers Bureau; Novartis: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy.

Treatment Patterns and Outcomes in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents: A SEER-Medicare Analysis

Treatment Patterns and Outcomes in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents: A SEER-Medicare Analysis

Early Intervention with Hypomethylating Agents in Transfusion-Independent Patients with Myelodysplastic Syndrome

Early Intervention with Hypomethylating Agents in Transfusion-Independent Patients with Myelodysplastic Syndrome