Chronic Myelomonocytic Leukemia Pts Research Articles

Results of a Phase II Study of Cladribine, Low Dose Cytarabine and Venetoclax, Alternating with Azacitidine and Venetoclax in Patients with Higher Risk Chronic Myelomonocytic Leukemia or Myelodysplastic Syndromes

INTRODUCTION: Clinical responses to hypomethylating agents (HMAs) in patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and myeloproliferative chronic myelomonocytic leukemia (CMML) remain short-lived, with high risk of transformation to acute myeloid leukemia (AML). Prior data suggests use of the purine analogue cladribine can induce monocyte apoptosis and is active in AML, particularly in combination with low dose cytarabine (LDAC) and venetoclax. We aimed to evaluate the safety and activity of cladribine, LDAC and venetoclax in HR-MDS and CMML. METHODS: We designed a phase II basket clinical trial of cladribine combined with LDAC and venetoclax alternating with azacitidine and venetoclax for pts with HR-MDS or CMML. Pts were divided into 4 cohorts: cohort A: MDS with int-1 to high risk by IPSS and >5% blasts with prior HMA-failure (HMA-F); cohort B: CMML-1/CMML-2 with prior HMA-F; cohort C: previously untreated MDS with Int-2 or High risk by IPSS and >10% bone marrow (BM) blasts; cohort D: previously untreated CMML-2 or CMML-1 with at least one high-risk feature (extramedullary disease, splenomegaly of >5cm below costal margin, platelets <100x10 9/L, Hgb level <10g/dL, WBC >13x10 9/L, clonal cytogenetic abnormality [other than monosomy Y]). HMA-F was defined as no response after 6 cycles of therapy with HMA or relapse/progression after any number of cycles. Induction consisted of cladribine 5mg/m 2 daily IV on days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg daily days 1-5. Re-induction was allowed in pts not achieving response after induction. Consolidations consisted of azacitidine 75mg/m 2 daily days 1-7 with venetoclax 400mg daily days 1-7 alternating with cladribine 5mg/m 2 days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg days 1-5 every two 28-day cycles. The primary end point was to evaluate safety, efficacy, and tolerability of the combination. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between October 2022 and June 2023, 20 pts have been treated: 10, 5, 3 and 2 in cohorts A, B, C and D, respectively. Thirteen pts had MDS, and 7 had CMML. Median age was 74 years (range 52-83). Among MDS pts, 8 (62%) had int-2 and 5 (38%) had high risk by IPSS. By the Molecular IPSS, 10 (79%) had very high, 1 (8%) had high, 1 (8%) had moderate high and 1 (8%) had low risk. Among CMML pts, 4 (57%) had high, 2 (29%) had intermediate-2 and 1 (14%) had intermediate-1 risk by the CPSS Molecular score. Among HMA-F cohorts, median number of prior therapies was 1 (range 1-4), median cycles of prior HMA was 6 (range 2-63) and 4 (27%) pts had failure to prior venetoclax therapy. Most common adverse events (AEs) were hypoalbuminemia (40%), nausea (40%), sinus bradycardia (40%), alanine aminotransferase increase (35%), constipation (35%), lower extremity edema (35%), fatigue (35%) and hypocalcemia (35%) Most common grade 3-4 AEs were leukopenia (20%) and febrile neutropenia (15%). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of cycles was 2 (range 1-6). Median cycles to best response was 1 (range 1-3). Among HMA naïve pts (cohorts C and D), the ORR was 80% (n=4): CR in 2 (40%), mCR in 2 (40%). Based on 2023 IWG response criteria, responses in cohort C (n=3) included: CR in 2 (67%) and CR bilineage (CRbi) in 1 (33%). Based on 2015 IWG MDS/MPN criteria, responses in cohort D (n=2) included optimal marrow response and clinical benefit in 1 (50%) and 1 (50%) pts, respectively. Among HMA-F pts (cohorts A and B) the ORR was 20%: 1 CR (10%) and 1 (10%) mCR with HI. Median follow up is 5.3 months (95% CI 2.4-81). Median EFS is 2.1 months in cohorts A and B and not reached in C and D (Fig 1A). Median OS has not been reached for all cohorts (Fig 1B). At the time of data cut-off, all pts in cohorts C and D discontinued study to proceed with hematopoietic stem-cell transplantation (HSCT). Among cohorts A and B, 2 pts (13%) discontinued study to proceed with HSCT, 5 (33%) due to transformation to AML, 2 (13%) due to no response, 2 (13%) due to physician choice, 1 (7%) due to patient choice and 2 (13%) pts remain on study. CONCLUSIONS: Preliminary data suggests the use of cladribine, LDAC and venetoclax can be safely administered in pts with very high risk MDS and CMML with early promising results in pts with de novo disease.

A Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML

Background Leukemic stem cells have high expression of CD123 compared to normal hematopoietic stem cells and is therefore a therapeutic target in multiple leukemias including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has shown clinical activity in relapsed/refractory AML, particularly in low-blast disease. We therefore sought to evaluate vibecotamab in other low-blast states, including MDS or CMML after hypomethylating agent failure and MRD-positive AML. Methods In this two-arm, open-label, phase II study, adults with either MDS (IPSS-R intermediate or higher risk) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents or AML in first or second morphologic remission with detectable MRD at a level of ≥0.1% by flow cytometry were eligible. CD123 expression ≥20% on aberrant myeloid blasts was required for enrollment. Vibecotamab was given IV in a ramp-up dose schedule on days 1 (0.43µg/kg), 3 (0.75µg/kg), 5 (1.1µg/kg), and 8 (1.7µg/kg) in cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7µg/kg. Patients (pts) received up to 4 cycles of vibecotamab in 28-day cycles. The primary endpoint of the MDS/CMML cohort was response rate (CR + mCR + PR + HI + clinical benefit) within 4 cycles. The primary endpoint of the AML MRD cohort was the MRD negativity rate within 4 cycles. Results Between May 2022 and July 2023, 23 pts were treated (11 MDS/CMML, 12 AML MRD). Baseline characteristics are shown in Table 1. In the MDS/CMML cohort, 7 pts (63%) had received two or more prior lines of therapy, 8 pts (73%) had prior venetoclax exposure, and 2 pts (18%) had prior hematopoietic stem cell transplant (HSCT). Six MDS pts (66%) were IPSS-R high or very high risk. In the AML cohort, 6 pts (50%) had received two or more lines of prior therapy, 11 pts (92%) had prior venetoclax exposure, and 5 pts (42%) had prior HSCT. Ten pts (83%) were ELN 2022 adverse risk. The baseline CD123 expression was 72% (range, 43%-99%) in the MDS/CMML cohort and 89% (range, 55%-99%) in the AML MRD cohort. The baseline MRD by flow cytometry in the AML MRD cohort was 1.1% (range, 0.1%-3.9%). Responses are shown in Table 2. In the MDS/CMML cohort, 7 pts responded (64%), with 6 pts (56%) achieving marrow complete remission (mCR) and 1 pt (9%) achieving hematologic improvement (HI) per International Working Group (IWG) 2006 criteria. Among the 9 MDS pts, 4 (44%) achieved mCR + HI (2 HI-N, 1 HI-P, and 1 HI-P + HI-N), and 1 (11%) achieved HI (HI-N + HI-P). Per revised IWG 2023 MDS response criteria, 5 of the 9 MDS pts (56%) achieved complete remission with limited count recovery (CR L). Two of 4 MDS pts (50%) with TP53 mutations achieved CR L. Both CMML pts achieved mCR, with one pt also achieving HI-N. Among 9 pts with baseline bone marrow blasts =>5% at trial enrollment, 6 (67%) achieved a mCR, with or without HI. Best response occurred after the first cycle in all pts. CD123 expression was not associated with likelihood of response. Of the 7 responders, 5 are in ongoing response (range 0.3-6.9 months), one died in CR L from non-hematologic complications (heart failure), and one relapsed 5 months after achieving CR L. Of the 12 pts in the AML MRD cohort, 3 (25%) achieved MRD negativity, all of which occurred after 1 cycle of vibecotamab. Among the 3 responders, all were ELN adverse risk and had prior venetoclax exposure, 2 had prior HSCT, and 1 had inv(3). The median MRD and CD123 expression in responders was 0.2% (range 0.1%-0.2%) and 98% (range 95%-99%) vs 1.8% (range 0.5%-3.9%) and 87% (range 66%-96%) in non-responders, respectively. At last follow-up, all 3 responders are still in MRD-negative remission (range 3.2-12.8 months). Vibecotamab was well-tolerated with no pts requiring dose reductions or being taken off study due to adverse events. Ten pts (44%) experienced grade 2 infusion reactions and 1 pt (4%) experienced a grade 3 infusion reaction. Myelosuppression was minimal, consistent with previous studies of vibecotamab. Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML.

Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes: A National Analysis of Overall Survival and Demographic Features

Introduction Myelodysplastic/myeloproliferative (MDS/MPN) overlap syndromes (MDS/MPN) are rare disorders characterized by concomitant myeloid hyperplasia and dysplasia. Only recognized as distinct disorders since 2001, this heterogeneous group includes chronic myelomonocytic leukemia (CMML), MDS/MPN with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) and MDS/MPN-unclassifiable (MDS/MPN-U). Timely and accurate diagnosis can be difficult outside academic medical centers, and epidemiological data are lacking. This study aims to evaluate national survival outcomes, population and disease characteristics, and socioeconomic and demographic features associated with disparate survival in these rare and complex disorders. Methods Utilizing the National Cancer Database from 2004-2019, MDS/MPN was identified by histology codes for aCML (9876), CMML (9945), MDS/MPN-U (9975), and MDS/MPN-RS-T (9982). Only adult (age >18) patients (pts) were included, excluding JMML. Demographic, socioeconomic, and first line treatment characteristics were identified for all MDS/MPN and by histology. Kaplan-Meier survival analysis was used to compare overall survival (OS), with multivariable Cox regression, adjusted for age, sex, race, ethnicity, Charlson-Deyo comorbidity score, treatment facility type, and insurance to evaluate features associated with disparate survival outcomes. Results Of the 34,245 MDS/MPN pts identified, 42% (N=14,338) had CMML, 24% (N=8,055) had MDS/MPN-RS-T, 2% (N=634) had aCML, and 33% (N=11,318) were diagnosed with MDS/MPN-U. The median age at diagnosis was 75 years (yrs) (interquartile range 66-82). MDS/MPN-RS-T and aCML pts presented at the oldest and youngest ages (median 76 yrs vs 71 yrs). The majority of pts were male (58%), and White (88%; 8% Black and 2% Asian). Notably, aCML and MDS/MPN-U pts were more likely to be a race other than White (both 15% non-White), compared to CMML (11%) and MDS/MPN-RS-T (9%), p<0.001. While molecular data is limited in the NCDB, of the 10,583 cases with JAK2 testing reported, 49% had a JAK2 mutation. This was greatest in the MDS/MPN-U group, at 65% of pts, followed by 39% of MDS/MPN-RS-T pts, and15% for both aCML and CMML pts. Approximately half of MDS/MPN pts (51%) received disease directed therapy at diagnosis, with 22% managed with active surveillance, and 27% not receiving treatment, for reasons including early death, contraindication, or hospice care. aCML pts were the most likely to be placed on disease directed therapy (78%), followed by CMML (56%), MDS/MPN-U (55%), and MDS/MPN-RS-T (28%). The median OS for all MDS/MPN was 31.4 months (mos) (95% confidence interval [CI] 30.7-32.1), with a 1-, 5-, and 10-year OS of 71%, 33%, and 16%, respectively. MDS/MPN-RS-T pts had a median OS of 52.5 mos (95% CI 50.6-54.3), similar to MDS/MPN-U with a median OS of 48.2 mos (95% CI 46.1-50.4). CMML and aCML had significantly worse survival with a median OS of 16.8 mos (95% CI 16.3-17.4) and 14.5 mos (95% CI 12.5-16.5), respectively, p<0.001. On multivariable Cox regression, MDS/MPN-RS-T and MDS/MPN-U retained a significant survival advantage over CMML (Hazard ratio [HR] 0.45 [95% CI 0.43-0.46], p<0.001 and HR 0.51 [95% CI 0.49-0.53], p<0.001, respectively). However, aCML had a significantly worse survival, with HR 1.27 (95% CI 1.15-1.40, p<0.001). Age, increasing comorbidity burden, and Black race were associated with reduced survival outcomes, while female sex, private insurance, and treatment at academic centers was associated with significantly improved OS. Conclusion We present the largest study to date on the real-world survival and demographic characteristics of MDS/MPN. Compared to prior data, which was generally limited in size, we found a lower median OS than previously reported, though MDS/MPN-U had a greater OS than prior estimates. We further identified a higher portion of MDS/MPN pts identified as MDS/MPN-U than previously estimated, and significantly higher rates of JAK2 mutations than previously reported. This study also adds clarity to ages of diagnosis, sex ratios, and racial and ethnic characteristics. We also note survival disparities in Black pts, and those who are underinsured or treated at non-academic centers, indicating that access to treatment remains a significant barrier to survival in these pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P775: CLINICAL OUTCOMES AND SOCIOECONOMIC FACTORS IN CHRONIC MYELOMONOCYTIC LEUKEMIA IN THE UNITED STATES USING THE NATIONAL CANCER DATABASE: 2004-2017

Background: Chronic myelomonocytic leukemia (CMML) is a rare myeloid malignancy characterized by proliferation of dysplastic monocytic cells and carries a risk for leukemic transformation. Previously, we described the incidence and outcomes of CMML at the population level (2004-2015) using the Surveillance, Epidemiology, and End Results Program (SEER) and National Cancer Database (NCDB) (Ruan et al., ASH 2020). We studied population-based outcomes in CMML using the NCDB from 2004-2017. Aims: Our aim was to understand the impact of social determinants of health on outcomes in CMML. Secondly, we studied if the outcomes of CMML have improved. Methods: The NCDB is a nationwide oncology outcomes database for >1500 cancer programs in the US and Puerto Rico, capturing 70% of all newly diagnosed cases of cancer. We queried the NCDB using the ICD-O-3 diagnosis code 9945/3 from 2004-2017. Only patients (pts) with diagnostic confirmation via histopathologic examination were included. Percent without high school degree (HSD) reflects the education level within the pt’s zip code, which was stratified into 4 quartiles. Median household income was estimated by matching the pt’s zip code at time of diagnosis against US Census 2000 data, which was stratified into 4 quartiles. Hazard ratios (HR) with confidence intervals (CI) were calculated using a Cox proportional hazards model. Overall survival (OS) was estimated using the Kaplan-Meier method. Variables significant in univariable analysis were included in a multivariable analysis. Results: We identified 7143 CMML pts in the NCDB. The median age at diagnosis was 72 years (interquartile range [IQR] 65-81) and 4386 (61%) were males. With a median follow up of 6.1 years (IQR 3.6-9.4), the median OS was 1.4 years (IQR 0.4-3.8). 1600 (23%) had private insurance, 4862 (70%) had Medicare, 298 (4%) had Medicaid, and 129 (2%) were uninsured. In univariate analysis, private insurance had an improved OS compared to patients with Medicaid (HR 1.2, 95% CI 1.06-1.4; p value 0.007), Medicare (HR 1.5, 95% CI 1.4-1.6; p value < 0.001), and other government insurance (HR 1.5, 95% CI 1.1-2.0; p value 0.004). Pts living in a zip code with percent of adults without an HSD of < 14% had an improved OS compared to zip codes with > 29% (HR 1.2, 95% CI 1.1-1.3; p value < 0.001). Median household income by zip code of ≥ $46,000 had an improved OS compared to < $30,000 (HR 1.2, 95% CI 1.1-1.4; p value < 0.001). Receiving treatment at an academic program had an improved OS compared to community cancer programs (HR 1.2, 95% CI 1.1-1.3; p value < 0.001), comprehensive community cancer programs (HR 1.3, 95% CI 1.3-1.4; p value < 0.001), and integrated network cancer programs (HR 1.3, 95% CI 1.2-1.4; p value < 0.001). Finally, pts diagnosed in 2012-2017 had an improved OS compared to pts diagnosed in 2004-2011 (HR 0.8, 95% CI 0.8-0.9; p value < 0.001). Variables significant in univariate analysis were included in multivariate analysis (Table 1). When education level and median household income per zip code were included in multivariate analysis, education level remained statistically significant and income did not. Image:Summary/Conclusion: CMML continues to have a poor prognosis, but OS has improved in recent years. Socioeconomic factors including insurance status, level of education and median household income per zip code, and facility type appear to be associated with outcomes. On multivariable analysis, age < 65, private insurance (vs government insurance), living in a zip code with increased percent HSD, and treatment at an academic program had improved outcomes.

Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia

Outcome with Hypomethylating Agent and Venetoclax Combination in Patients with Chronic Myelomonocytic Leukemia

Clonal Compositions Involving Epigenetic Regulator Gene Mutations in Clonal Hematopoiesis, Clonal Cytopenias of Undetermined Significance and Chronic Myelomonocytic Leukemia

Clonal Compositions Involving Epigenetic Regulator Gene Mutations in Clonal Hematopoiesis, Clonal Cytopenias of Undetermined Significance and Chronic Myelomonocytic Leukemia

A Phase II Trial of Eltrombopag in Chronic Myelomonocytic Leukemia (CMML) with Thrombocytopenia

Context: Thrombocytopenia is a frequent complication in CMML associated with worse prognosis (Itzykson JCO 2013, Patnaik Leukemia 2013). Thrombopoietin (TPO) protects HSCs from DNA damage (de Laval Cell Stem Cell 2013). The TPO analog eltrombopag (ELT) has shown efficacy in MDS (Oliva Lancet Hematol 2017). The limited data on ELT in CMML is restricted to a small cohort (n=7) with high risk features, where 4 pts had disease progression during ELT (Ramadan Clin Lymphoma Myeloma Leuk 2016). We report interim results of a multicenter phase 2 trial investigating the efficacy, toxicity and biomarkers of ELT in 25 CMML with platelets (PLT) < 50 x109/L (NCT02323178).Methods: Key inclusion criteria were: WHO 2008 defined HMA-naive CMML, PLT < 50 x109/L, marrow blasts ≤ 5%, IPSS low/int-1 in MD-CMML, and in MP-CMML no or 1 severity criteria (Hb < 10 g/dL, ANC > 16 x109/L, abnormal karyotype, extramedullary disease) ,spleen size < 16 cm. ELT was started at 100 mg/d with escalating doses to 300 mg/d. Platelet Response (HI-P) was evaluated at 12 weeks, according to IWG 2006 criteria, and responders could continue treatment. Gene mutations were analyzed by NGS at inclusion. DNA repair was explored by counting gH2AX foci in CD34+ cells obtained at inclusion, evaluation and study exit.Results: We report on the first 19 evaluable pts (median age 79y, M/F 15/4), all CMML-1 by WHO 2008, including 14 MD-CMML and 5 MP-CMML, with a low/int-1/int-2 CPSS (Such Blood 2013) in 61%, 33% and 6% of pts respectively (resp). Median PLT count was 29 x109/L (IQR 19 - 43.5) and 10 (53%) pts had PLT transfusion dependency (PLT-TD). TET2, RUNX1, ASXL1, SRSF2, PHF6, and RAS pathway mutations were present in 17, 10, 6, 7, 4 and 7 of 18 pts sequenced, resp.The median maximal dose of ELT received was 200 mg/d (IQR: 150 - 300 mg/d). Clinical grade ≥3 toxicities, all cardiovascular or pulmonary, were noted in 5 pts in the first 12 weeks, and biological grade ≥3 toxicities in 6 pts, without grade ≥3 ALT/AST elevation. Six (32%) pts went off study before week 12 because of lack of efficacy (n=2), presence of in circulating blasts (n=1), progression to CMML-2 (n=1), pancreatic cancer (n=1) and patient decision (n=1). All were considered non-responders. At 12 weeks, 12 (63%, 95%CI: 38 - 84) pts had achieved HI-P, including 3/5 MP-CMML and 9/14 MD-CMML (p=1). Responses were obtained in 7/10 pts with baseline PLT-TD and 5/9 pts without PLT-TD (p=0.65). The mutational profile of responders was comparable to that of non-responders except that none of the 4 PHF6mut pts responded (p=0.01). Responders at 12 weeks were receiving a median of 125 mg/d of ELT, compared to 225 mg/d in non-responders.Responders received ELT for a median of 21 weeks (IQR 15 - 38). With a median follow-up of 18 months (95%CI: 16.8 - NR), 11 of the responders discontinued ELT because of loss of efficacy (n=2), patient decision (n=1), death from unrelated causes (n=2), liver toxicity (n=2), renal failure (n=1) and disease progression (n=3). Median response duration was 8 months (95%CI: 5 - NR), with one pt still on treatment with a response lasting more than 14 months. The 12-month cumulative incidence of AML was 19% (95%CI: 4 - 41%) and 12-month progression-free and overall survival (OS) were 41% (95%CI: 23 - 73) and 65% (95%CI: 45-92%). By comparison, in the 21 CMML pts with PLT < 50 x109/L and ≤5% BM blasts from our previous CMML cohort (Itzykson JCO 2013), none of whom received ELT, the 12-month estimates for cumulative incidence of AML and OS were 10% (95%CI 0 - 23%) and 71% (95%CI 47 - 86%), resp. An updated analysis including all 25 pts will be presented.At protocol screening, a higher number of gH2AX foci were seen in CMML bone marrow CD34+ cells (n=14) compared to age-matched controls (n=5, p<0.01), reflecting higher levels of baseline DNA damage. However, in the 5 pts for whom serial bone marrow samples were obtained during ELT, gH2AX foci were reduced in CD34+ cells from all 5 pts, suggesting that in vivo exposure to ELT protected CMML stem/progenitor cells from DNA damage.Conclusion: Our interim results suggest that ELT is manageable in CMML pts with no excess of marrow blasts and thrombocytopenia and results in a high response rate, with no obvious increase in disease progression, though prolonged responses seem infrequent. ELT could potentially protect CMML stem/progenitor cells from DNA damage. Larger pt numbers and longer follow-up are however required to determine precisely the role of ELT in thrombocytopenic CMML pts. DisclosuresItzykson:Janssen: Research Funding; Novartis: Research Funding. Fenaux:Astex: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Prognostic Role of Gene Mutations in Chronic Myelomonocytic Leukemia (CMML) Patients Treated with Hypomethylating Agents. a Report on 183 Patients

Context: Somatic gene mutations contribute to the heterogeneous prognosis of CMML. The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) are active in CMML. The specific prognostic value of recurrent gene mutations in CMML treated with HMA has never been reported. Methods: We analyzed a multi-institution retrospective cohort of 183 CMML patients (pts) treated with either AZA or DAC with information on recurrent gene mutations. Results: CMML pts with a median age of 72 years (WHO 2016: CMML-0/1/2 in 37%, 27% and 36% respectively [resp]) were treated with AZA (n=76) or DAC (n=107) for a median of 7 cycles (InterQuartile Range [IQR]: 4 - 15). Median WBC was 15.1 x109/L, cytogenetic risk according to CPSS (Such et al, Haematologica 2011) was low, int and high in 71%, 12% and 17% of pts, resp. CPSS risk (Such et al, Blood 2013) was low, int-1, int-2 and high in 14%, 23%, 49% and 14%, resp. GFM risk (Itzykson et al, JCO 2013) was low, int and high in 33%, 35% and 32%, resp. The Overall Response Rate (ORR) to HMA was 54%, including 17% of complete responses (CR), without significant differences between AZA and DAC. With a median follow-up of 36.7 months, median overall (OS) and AML-free (AMLFS) survival were 24.4 and 19.2 months, resp. Nineteen (10%) pts were transplanted after HMA and censoring at transplant did not affect our results. Compared to AZA pts, DAC pts had higher WBC (p=0.01) and non-significant trends towards lower platelet count (p=0.07) and poorer cytogenetic risk (p=0.08), with a non-significant trend to a poorer OS (p=0.11). Propensity matching on previous treatment with chemotherapy, WBC, platelets count, peripheral blasts count, cytogenetic risk and ASXL1 status at HMA onset confirmed the lack of OS benefit with AZA in the 144 patients (79%) that could be successfully matched (Hazard Ratio [HR]=1.31, p=0.4). All further analyses were nevertheless stratified on HMA. Molecular data was obtained from Sanger sequencing (n=74) or NGS (n=109). The molecular spectrum of our cohort was comparable to previous CMML reports and dominated by frequent mutations in SRSF2 (46%), ASXL1 (45%) and TET2 (39%). Our analysis focused on genes analyzed in ≥90% of patients and found mutated in ≥10% (SRSF2, ASXL1, TET2, NRAS, RUNX1 and CBL). Mutation frequencies in these genes did not differ between AZA and DAC pts, nor between Sanger and NGS. In univariate analysis, a lower ORR was only seen in patients with ASXL1 mutations (ASXL1mut 44% vs ASXL1wt 62%, p=0.02) while only TET2 mutations predicted a higher CR rate (TET2mut 22% vs TET2wt 11%, p=0.02). Multivariate linear regressions confirmed that these differences were independent from clinical parameters. In univariate analysis, mutations in RUNX1 (13% of pts, HR=2.05, p=0.006) and to a lesser extent ASXL1 (45% of pts, HR=1.40, p=0.07) and CBL (12% of pts, HR=1.63, p=0.08) were associated with shorter OS. Similar results were found for AMLFS. There was no significant interaction between TET2 and ASXL1 or SRSF2 status in terms of ORR or OS. Clinical variables associated with poorer OS included splenomegaly (p=0.045), WBC > 13 x 109/L (p=0.003), platelets 2% (p=0.02), peripheral blasts > 1% (p=0.02) and high-risk karyotype (p=0.047). A multivariate Cox model retained RUNX1 mutations (p=0.007), splenomegaly (p=0.049), WBC > 13 x 109/L (p=0.005), platelets Conclusion: Contrary to previous results with smaller patient numbers (Braun et al Blood 2011), treatment with HMA seems to abrogate only partially the poor prognosis of ASXL1 mutations in CMML. RUNX1 mutations confer a poor prognosis in CMML treated with HMA and can be integrated with clinical and hematological parameters to improve prognostication of CMML pts treated with HMA, when compared with classical CMML risk scores. Disclosures Sallman: Celgene: Research Funding. Coombs: Pharmacyclics: Honoraria; H3 Biomedicine: Honoraria. Renneville: CELGENE: Research Funding. Platzbecker: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding. Padron: Incyte: Honoraria, Research Funding. Santini: Celgene: Honoraria, Research Funding; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Amgen: Membership on an entity9s Board of Directors or advisory committees; Otsuka: Consultancy; Novartis: Honoraria. Fenaux: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Itzykson: Janssen: Research Funding; Novartis: Research Funding.

Model Heterogeneity in Predicting Outcomes in Patients with Chronic Myelomonocytic Leukemia (CMML): An Overestimation of Survival in Lower-Risk Group

Model Heterogeneity in Predicting Outcomes in Patients with Chronic Myelomonocytic Leukemia (CMML): An Overestimation of Survival in Lower-Risk Group

Eltrombopag in Chronic Myelomonocytic Leukemia (CMML) with Severe Thrombocytopenia: Final Results of a Multicenter Phase II Study

Eltrombopag in Chronic Myelomonocytic Leukemia (CMML) with Severe Thrombocytopenia: Final Results of a Multicenter Phase II Study

The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group

Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group

A MAFB Associated Regulatory Network Distinguishes CMML from Other MDS/MPN Overlap Entities

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a unique group of hematologic malignancies characterized by overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. The category includes atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), MDS/MPN, unclassifiable (MDS/MPN, U), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). The recent adaptation of next generation sequencing in genetic testing increased the knowledge of the molecular pattern of MDS/MPN. However, no specific gene signatures have been identified and underlying transcriptional mechanisms are still poorly understood. Therefore, we analyzed the transcriptome of a cohort of 49 aCML, 102 CMML, 50 MDS/MPN-U, and 72 MDS/MPN-RS-T patients, morphologically defined according to the WHO classification.Total RNA was used for 150bp paired-end RNA sequencing with a median read depth of 50 million. The edgeR package was used to perform a combined normalization and differential expression (DE) analysis of the obtained estimated gene counts by integration of trimmed mean of M-values normalization factors into the statistical model used to test for DE. Genes with an FDR < 0.05 and an absolute logFC > 1.5 were considered DE. 273 unique genes were identified differentially expressed between the entities. We found that the transcriptional profile of CMML patients was dominated by an upregulation of MAFB compared to all other entities (p < 0.001). MAFB encodes a transcription factor which is specifically expressed in myeloid cells and a master regulator of human monocytopoiesis.In order to unravel the potential effects of MAFB regulation we performed Spearman's correlation analysis to identify co-expressed genes. 51 genes showed a similar expression (correlation coefficient > 0.7) as MAFB, establishing a CMML gene expression signature (GES) (Figure 1a). The GES included the cell cycle inhibitor CDKN1A, the transcription factors IRF8, EGR2, and MYCL, and the cell surface receptor LRP1. LRP1 represents a therapeutic target and has recently been identified as a key factor in a network for multi-cancer clinical outcome prediction. MAFB was also co-expressed with KYNU, which is synthesized by indoleamine 2,3-dioxygenase, an enzyme expressed by leukemia blasts, and which has been linked with unfavorable outcome in hematologic malignancies. MAFB and KYNU were also co-expressed with multiple CD markers, which are often used as targets of immunotherapy approaches in cancer. High expressions of KYNU can block the anti-tumor effects of chimeric antigen receptor T-cell therapy, indicating complex interactions between the co-expressed genes.To better understand these underlying molecular interactions on a more global scale and to expose potential targets for intervention, a transcriptional network of the 51 MAFB co-expressed genes was reverse engineered. We used STRING, a publicly available database of protein-protein interactions, to build the scaffold of the network and subsequently pruned the network based on our gene expression data. The reconstructed, MAFB associated regulatory network (Figure 1b) identified c-FOS as an additional regulatory link. c-FOS is a known oncogene that heterodimerizes with c-JUN, ATF3, and JDP2 to form the structure of the AP-1 complex. The AP-1 complex is a key regulator of multiple biological processes such as cell proliferation and apoptosis. We observed a considerably higher expression of c-FOS compared to c-JUN, ATF3, and JDP2 in CMMLs. The MafB/cFos heterodimer is known to explicitly repress apoptosis.The co-expression network was significantly enriched for transcriptional activation of p53 responsive genes (p < 0.001). Interestingly, we also found that the p53-regulated long intergenic non-coding RNA lncPRESS1 was down-regulated in our cohort of CMML patients (p < 0.001).Conclusions: 1) MAFB represents a promising gene expression marker to distinguish CMML pts from other MDS/MPN overlap entities. 2) The identified core regulatory signature in CMML pts showed complex interactions to modulate diverse biological processes and might serve as therapeutic targets. [Display omitted] DisclosuresWalter:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment.

Genomic Characterization Provides Diagnostic Clarity in Cases with Overlapping Bone Marrow Fibrosis and Monocytosis

Introduction: Chronic myelomonocytic leukemia (CMML) and primary myelofibrosis (MF) are distinct myeloid malignancies with clinical and pathologic features that often overlap. The presence of significant bone marrow fibrosis with concomitant monocytosis can be diagnostically challenging. Distinguishing between these two clinical entities has important prognostic and therapeutic implications. In this study, we aimed to genomically characterize cases with overlapping features of both fibrosis and monocytosis and describe their clinical outcomes. Then, using well-established CMML and MF databases, we aimed to identify disease-specific genomic abnormalities to allow for improved diagnostic characterization.Methods: Including molecularly annotated patients (pts) from our CMML and MF databases, we created 3 cohorts. Cohort 1 was comprised of MF pts without significant monocytosis. Cohort 2 included CMML pts with absent/minimal bone marrow fibrosis. Cohort 3 included CMML pts with fibrosis and MF pts with monocytosis. Significant fibrosis defined as grade 2-3 by European consensus recommendations. Monocytosis defined as an absolute (>800/µL, the upper limit of normal in our laboratory) and relative (>10%) peripheral monocyte count. Cohorts 1 and 2 were compared to establish disease-specific somatic gene mutation patterns. Enriched variables were those that occurred significantly more often with p < 0.05. Specificity threshold of > 95% was used. Blinded pathological review of overlap bone marrow cases revealed concordance with original diagnosis in > 95% of cases.Results: Cohorts 1, 2 and 3 were comprised of 181, 168 and 61 pts, respectively. Among 61 pts in cohort 3, 26 had a prior CMML diagnosis and 35 had prior MF diagnosis. Median OS (mOS) in cohort 1 was 161 months (mo) compared to 35 mo in cohort 2 (p < 0.001) and 42 mo in cohort 3 (p < 0.001). mLFS for cohorts 1, 2, and 3 were not reached, 61 mo and 42 mo, respectively (p < 0.001).We compared molecular and cytogenetic abnormalities between cohort 1 and 2, assessing individual and commonly co-occurring abnormalities. Genomic abnormalities more common in CMML were mutations in TET2 (p < 0.001), RAS (p < 0.001), RUNX1 (p < 0.001), SRSF2 (p < 0.001), CBL (p = 0.05), ASXL1 (p = 0.04), TET2/SRSF2 (p < 0.001), TET2/ASXL1 (p < 0.001), TET2/RUNX1 (p = 0.03), SRSF2/ASXL1 (p = 0.004), and normal karyotype (p = 0.002). Genomic abnormalities more common in MF included driver mutations (i.e. JAK2, MPL, or CALR) (p < 0.001), del 20q (p = 0.03), del 13q (p < 0.001), and trisomy 9 (p = 0.004). Disease-specific abnormalities were those that were enriched in either CMML or MF with a specificity of >95%. CMML-specific abnormalities included RAS mutations and co-mutations in TET2/RUNX1, TET2/SRSF2, and SRSF2/ASXL1. MF-specific genomic abnormalities included del20q, del13q, and trisomy 9.We applied these disease-specific genomic abnormalities to cohort 3 to see if these findings could stratify pts toward a CMML-like genotype or MF-like genotype. Of 61 patients, 29 displayed only CMML-like genomic features (genomic CMML), 7 only MF-like features (genomic MF), 4 had both CMML and MF-specific features (genomic overlap) and 21 genomically undefined. Among those in cohort 3 with clinical MF diagnosis, 16 (46%) were reclassified as genomic CMML, 6 (17%) as genomic MF, 3 (9%) as genomic overlap, and 10 (31%) as genomically undefined. Among those with an original clinical diagnosis of CMML, 1 was redefined as genomic MF. OS for genomic CMML did not differ from genomic MF (p = 0.70). There was a trend for inferior LFS in genomic CMML compared to genomic MF (40 mo vs 59 mo, p = 0.19). Multivariate analysis identified the strongest prognostic features in cohort 3 as age > 70 (OR 9.4, p = 0.05), platelet count < 100,000/µL (OR 4.6, p = 0.02) and degree of bone marrow fibrosis (OR 5.1, p = 0.009).Conclusions: Specific genomic features distinguish CMML from MF. Application of these findings to pts with overlapping clinicopathologic features provides clarity in >50% of cases, primarily reclassifying patients as CMML. Clinically, outcomes in this overlap group with bone marrow fibrosis and monocytosis mirror those of CMML, regardless of genomic assignment; however, the presence of thrombocytopenia and magnitude of bone marrow fibrosis provide further prognostic discrimination. Future studies testing CMML-like therapeutic strategies should be considered in MF with monocytosis. [Display omitted] DisclosuresKuykendall:Celgene: Honoraria; Janssen: Consultancy. Sweet:BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Jazz: Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Crosstalk between the IGF1 and CXCL12 Pathways Defines Objective Responses to the Farnesyl Transferase Inhibitor Tipifarnib in AML and PTCL Patients

BackgroundCXCL12 is a chemokine that is essential for the maturation of myeloid and lymphoid cells. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Treatment with this agent may translate to durable responses in subsets of patients (pts) with acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and peripheral T-cell lymphoma (PTCL) but its mechanism of action in these indications is poorly understood. We have previously reported that tipifarnib interferes with the CXCL12 pathway. Here we show that an interplay between the CXCL12 and IGF1 pathways may define those pts who may experience objective responses with tipifarnib monotherapy.MethodsGene expression profile (GEP) data generated using RNA-Seq and the Affymetrix U133A gene-chips of tumor samples from 129 pts enrolled into tipifarnib trials (CTEP-20, KO-TIP-002,KO-TIP-004, INT-17) were analyzed with respect to study outcomes and complemented with analyses of mRNA expression in data sets from the cBioportal for Cancer Genomics. Gene expression was further validated using RT-PCR assays. RNA-Seq and Whole Exome Sequencing were conducted using standard methodologies. Clinical trial information: NCT00027872, NCT02464228. NCT02807272, NCT00354146.ResultsIn order to improve our understanding of the molecular pathology of tumor CXCL12 overexpression, we investigated GEPs from 8,401 cancer pts in 25 studies available at cBioportal (TCGA, Provisional). Notably, we found a highly significant correlation in the expression of the IGF1 and CXCL12 genes in 19 of those studies. Intriguingly, the highest IGF1/CXCL12 correlations were observed in indications, including AML (ρ=0.698, p<0.001), in which activity of tipifarnib as monotherapy has been previously reported (AML, breast and urothelial cancer). Based on these results, we investigated the effect of IGF1/CXCL12 co-expression on pt outcome in tipifarnib studies. In previously untreated AML, 3 subsets of pts were identified with respect to bone marrow (BM) IGF1/CXCL12 expression: (1) high IGF1, high CXCL12 with predominantly hematological improvement or stable disease (SD) as best response, (2) intermediate IGF1, low CXCL12, with predominantly disease progression (PD), and (3) low IGF1, variable CXCL12, with 6 complete responses in 15 pts that were associated with CXCL12 expression (p=0.013), supporting the notion that CXCL12 pathway activation determines objective responses with tipifarnib while IGF1 mediates drug resistance. Barely detectable levels of IGF1 (and IGF2) were observed in the BMs of CMML pts in whom only 1 best response of PD was reported. In contrast, elevated levels of both CXCL12 and IGF1 were observed in PTCL pts responding to tipifarnib. Further investigation revealed that tumors of PTCL pts experiencing a partial response (PR) with tipifarnib expressed high levels of IGFBP7 (p=0.03), a natural inhibitor of the IGF1 receptor. Sequencing of the CXCL12 and IGF1 genes in PTCL samples revealed the presence of polymorphisms in non-responding pts: 8 pts, 7 carrying CXCL12 rs2839695 and 1 with a novel 3UTR variant, experienced a best response of PD. No pts with a best response of PR or SD carried 3UTR variants in CXCL12 (0% vs 80%, p=0.007). No pt with a best response of PR, 1 of 4 pts with SD and 6 of 10 pts with PD carried the IGFBP7 variant L11F (rs11573021) (16% PR/SD vs 60% PD, p=0.15)ConclusionsPre-treatment tumor CXCL12, IGF1 and IGFBP7 expression may enable the identification of pts susceptible to experience objective responses with tipifarnib monotherapy. These data may contribute to the understanding of the mechanism of action of FT inhibitors. DisclosuresGualberto:Kura Oncology: Employment, Equity Ownership. Mishra:Kura Oncology: Employment, Equity Ownership. Janes:Wellspring Biosciences: Employment, Equity Ownership. Kessler:Kura Oncology: Employment, Equity Ownership.

Leukocytosis Is Associated with End Organ Damage in Chronic Myelomonocytic Leukemia (CMML) and Can be Mitigated with Cytoreductive Therapy

Introduction: CMML is a myeloid neoplasm hallmarked by cytopenias and a peripheral monocytosis. Although uniformly fatal, many patients (pts) are diagnosed incidentally and are monitored without treatment. Therapy is implemented when symptomatic cytopenias, splenomegaly, or bone marrow progression occur. Higher white blood cell count (WBC) and absolute monocyte count (AMC) are associated with inferior OS, however, they are currently not an indication for treatment. Case reports have demonstrated a putative link between CMML monocytes and end organ damage (EOD), which has not been systematically explored. We hypothesize that CMML cases with higher WBC and/or AMC will be at increased risk for EOD and that cytoreductive therapy could mitigate this risk.Methods: CMML pts with at least 2 measures of creatinine and liver function tests were retrospectively identified from the Moffitt Cancer Center CMML database. EOD was defined as the interval development of chronic kidney disease (CKD), acute kidney insufficiency (AKI) by Kdigo criteria, liver dysfunction, pleural effusion, or cardio-vascular events (CVE). CKD was defined by a GFR<60 for greater than 3 months. Those pts with preexisting EOD, to include CKD or history of AKI, transformation to Acute Myeloid Leukemia, or allogeneic transplant were excluded from this study. Categorical variables were compared with the Fisher's exact test and quantitative variables compared utilizing the Mann-Whitney test. The Kaplan-Meier method and log-rank test were used to estimate overall survival (OS).Results: Between 1/1/2000 and 1/1/2018, 313 CMML cases were identified that met the above criteria for study entry. The median age of pts in this cohort was 70 (31-95 range) with a male predominance (66%). 168 pts were classified as WHO CMML-0 (54%), 78 as CMML-1 (25%), and 67 as CMML-2 (21%). The majority of cases were intermediate risk by the Global MDACC score (30% INT-1, 28% INT-2). The most common somatic mutations included TET2(64%), ASXL1(44%), and SRSF2(45%). AKI was the most common type of EOD that occurred in 37% of cases, with new CKD in 8.6% of pts. Pleural effusions, defined by radiographic evidence by X-ray or CT-scan occurred in 29% of cases. Liver dysfunction, defined as transaminitis or hyperbilirubinemia 1.5x the upper limit of normal, occurred in 14% of cases, and CVE were recorded in 4.5% of cases. Development of new CKD (9.2% v 1.2%, p=0.012) and liver dysfunction (13.2% v 3.5%, p=0.012) were significantly more common in myeloproliferative-CMML (MPN) defined by FAB criteria. Because the FAB criteria relies solely on WBC, we explored the impact of WBC and AMC on EOD. To account for variability of longitudinal measures, we isolated the patient-specific peak WBC and AMC along with the corresponding markers of EOD for each peak, respectively. Using these variables WBC (Spearman r-value 0.25, p<0.0001), and to a greater extent AMC (Spearman r-value 0.30, p<0.0001), linearly correlated with creatinine and were associated with AKI (median AMC 11.7 vs. 5.5, p< 0.0001; median WBC 54.7 vs. 35.6, p <0.0001) and CKD (median AMC 19.7 vs. 6.5, p = 0.0002; median WBC 73.1 vs. 40.7, p = 0.002). This association remained significant when combining all EOD events (median AMC 11.4 vs 4.5, p <0.0001; median WBC 54.4 vs. 29, p < 0.0001). To identify a WBC and AMC within MPN-CMML that could be targeted for therapeutic intervention, we divided our cohort into WBC and AMC quartiles. Importantly, only the first quartile, defined by an upper boundary of 33.95 cells/dL for peak-WBC and 5.4 cells/dL for peak-AMC was statistically associated with a lower creatinine (p<0.004), AKI (p<0.0008), CKD (p<0.0003), or combined EOD events (p<0.002). MPN-CMML pts with new AKI had an inferior OS (17.1m v 30.7m, HR=1.51, p=0.0007) as did patients with a baseline WBC >33.95 (19.8m v 29.6m, p = 0.004). Patients with a baseline WBC at diagnosis >33.95 cells/dL treated with hydroxyurea had improved overall survival (22.6m vs. 12.4m, HR 0.35, p= 0.0006). This survival advantage did not hold in CMML patients with baseline WBC lower than 33.95 cells/dL suggesting that treatment may only mitigate poor outcomes in high WBC CMML patients (Figure 1).Conclusions: MPN-CMML is associated with EOD that includes AKI/CKD, pleural effusions, LFT abnormalities, and CVE. Those cases with a WBC >33.95cells/dL are at particularly high risk for EOD and cytoreductive therapy should be routinely considered to mitigate this risk. [Display omitted] DisclosuresSweet:Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy; BMS: Honoraria; Agios: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Phizer: Consultancy; Agios: Consultancy; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.

A Two-Gene Classifier for Chronic Myelomonocytic Leukemia (CMML) Patients Treated with Hypomethylating Agents (HMA): A Report By the GFM

▪Context: Mutations in epigenetic regulators such as TET2 or ASXL1 predict response but do not appear to impact overall survival (OS) in MDS patients (pts) treated with HMA. Somatic mutations are highly frequent in CMML, where ASXL1 confers independent poor prognosis (GFM score; JCO,2013;31:2428). Both azacitidine (AZA) and decitabine (DAC) are active in CMML. The prognostic value of gene mutations in CMML pts treated with HMA has not been analyzed so far.Methods: Retrospective analysis of advanced CMML pts treated with AZA (within EMA label) or DAC (in GFM trials) in GFM centers and Dresden University. Screening for mutations was based on Sanger sequencing (JCO, 2013;31:2428). All statistical analyses were stratified on HMA.Results: Mutation status was available for 79 pts (M/F: 57/22, median age 71y), prior to onset of AZA (n= 46) or DAC (n= 33). Median time from diagnosis to HMA onset was 8 months. At HMA onset, WHO diagnosis was CMML-1, CMML-2 and CMML having progressed to AML in 47%, 39% and 14%, respectively (resp). Pts received a median of 9 cycles for both drugs (range: 1-55). Median follow-up was 50 months.Compared to AZA pts, DAC pts had poorer cytogenetic risk according to CMML Prognostic Scoring System (CPSS, Such Blood 2013: DAC: fav/int/poor in 49/21/30% vs AZA: 78/9/13%, p=0.009), and higher WBC (median 20.6 vs 13.4 G/L p=0.06).The most frequently mutated genes were ASXL1 (47%), SRSF2 (47%), TET2 (40%), NRAS (20%), RUNX1 (19%), KRAS (10%) and CBL (10%). The mutation spectrum was similar in AZA and DAC groups.Overall Response Rate (ORR) was 58% (AZA: 61%, DAC: 55%, p=NS), including CR in 26% and 15%, resp. (p=NS) according to IWG 2006 criteria. In univariate analysis, no single mutation significantly affected ORR, but KRAS-mutated pts tended to have higher ORR than KRAS -wildtype (wt) pts (88 vs 55%, p=0.08). Mutation in either KRAS or NRAS conferred significantly higher CR rate (36%, vs 14% in pts with NRAS/KRAS -wt, p=0.04).Median OS was 27.5 months. In univariate analysis, ASXL1 (HR=2.10, p=0.008), SRSF2 (HR=2.97, p=0.008), RUNX1 (HR=2.40, p=0.01) and to a lesser extent CBL (HR=2.22, p=0.054) mutations conferred poorer OS. TET2 mutations had no prognostic impact. The higher CR rate in pts with KRAS/NRAS mutations did not translate into prolonged OS. There was a significant interaction between ASXL1 and SRSF2 status (p=0.0009). A two-gene classifier could stratify patients with significantly different 3y-OS estimates of 80.8%, 44.1%, and 23.6% in pts with neither, either, or both ASXL1/SRSF2 mutated (Figure; p<0.0001).Other variables associated with worse OS in univariate analysis were age, WBC, peripheral immature myeloid cells (IMC), peripheral blasts, and high risk cytogenetics by CPSS. Splenomegaly, Hb and Plt levels, transfusion dependency (TD) or marrow blast % (hence WHO category) had no impact.CPSS, which includes cytogenetics, WBC, TD and WHO, had thus significant but relatively limited prognostic value, with worse outcome in high vs low risk pts (p=.04), but no difference between low and int-1 or int-2 pts (both p>.2).GFM risk system which includes ASXL1 and WBC, Hb and Plt, also had prognostic value restricted to high vs low risk comparison (p=0.04).In multivariate analysis, the two-gene classifier retained significant prognostic impact (1 mutation: HR=3.5, p=.05; 2 mutations: HR=9.4, p=.001), together with increasing IMC (HR=1.05, p=.04), independently of age, WBC, peripheral blasts and cytogenetic risk. The classifier also had prognostic value independent of CPSS (p=.001).Median OS was 18.4 vs 32.3 months in DAC vs AZA treated pts (p=0.01), but this difference was not significant after adjusting for CPSS cytogenetic risk (p=0.19). Heterogeneity analyses did not identify any significant interaction with the type of HMA independent of cytogenetics or WBC, suggesting no genotype predicted better outcome with one HMA over the other.Conclusion: In this retrospective cohort of CMML pts treated with AZA or DAC, response to HMA could not be predicted by frequently mutated genes, except for a higher CR rate in RAS -mutated pts. Treatment with HMA did not abrogate the poor prognostic value of ASXL1 mutations in CMML. A two-gene classifier based on ASXL1 and SRSF2 could stratify the prognosis of CMML treated with HMA independently of clinical variables. Finally, there was no evidence that genotype should influence the choice of HMA (AZA vs DAC) in CMML. [Display omitted] DisclosuresOff Label Use: Decitabine off label to treat CMML. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding; Amgen, Inc.: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Park:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. De Botton:Agios Pharmaceuticals: Research Funding. Fenaux:JANSSEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding. Itzykson:Oncoethix: Research Funding.

Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Additional Analyses of a Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Somatic Mutations of ASXL1, RUNX1 and SETBP1 Improve Prognostic Stratification of Patients with Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by a highly variable clinical course. Based on clinical, hematologic and cytogenetic parameters, we previously developed a CMML-specific Prognostic Scoring System (CPSS) that stratifies patients into 4 different risk groups [Blood 2013;121:3005-15]. Recently, recurrent somatic mutations have been identified in CMML, and preliminary evidence suggests that selected mutated genes may provide useful prognostic information.In this study, we performed a comprehensive mutation analysis of genes implicated in myeloid malignancies in a large and well characterized cohort of CMML patients with the aim to dissect relationships between genotype and disease phenotype and to integrate somatic mutations into a clinical/molecular prognostic model.Thirty-eight genes were analyzed by high throughput sequencing (Illumina MiSeq, San Diego, CA) in a cohort of 199 CMML patients (pts) diagnosed according to WHO classification, and in 12 pts with monocytosis not fulfilling WHO diagnostic criteria. Myelodysplastic and myeloproliferative subtypes (CMML-MD and CMML-MP, respectively) were defined according to FAB criteria. Least absolute shrinkage and selection operator (Lasso) and Cox proportional hazards methods were adopted to select and weight variables for prognostic scoring.Ninety-three percent of pts showed at least one somatic mutation (median number per patient: 2, range 0-6). The most frequently mutated genes were TET2 (44%), SRSF2 (43%), ASXL1 (34%), KRAS (11%), NRAS (10%), CUX1 (10%), CBL (9%), RUNX1 (7%), SETBP1 (7%), JAK2 (6%), SF3B1 (6%), and U2AF1 (5%). A significant association was found between mutations in TET2 and RNA splicing factors (P=.037), 42 of 199 CMML pts (21%) showing co-occurrence of TET2 and SRSF2 mutations. Mutations in genes involved in signaling were significantly associated with CMML-MP (P=.002), whereas SF3B1 mutations were associated with CMML-MD (P=.024).The number of mutations per patient inversely correlated with overall survival (OS) (HR=1.32, P=.021). In univariate analysis, mutations in ASXL1 (HR=2.31, P=.026) , RUNX1 (HR=3.53, P=.02) and SETBP1 (HR=3.85, P=.005) significantly affected OS. Focusing the analysis on disease subtype, ASXL1 mutations significantly affected survival in CMML-MD (HR=3.45, P=.025), whereas CUX1 and SETBP1 had a significant prognostic value in CMML-MP (HR=4.33, P=.013 and HR=4.4, P=.025, respectively).In order to investigate the additive value of somatic mutations to current prognostic assessment, we first fitted a Lasso Cox regression model for genetic variable selection. The selected variables were then included in an unpenalized Cox regression in order to obtain unbiased coefficients. The statistically significant variables were CPSS-specific cytogenetic risk groups (HR=2.49, P=.001), mutations in ASXL1 (HR=2.77, P=.018), RUNX1 (HR=5.39, P=.009) and SETBP1 (HR=3.96, P=.013). Based on regression coefficients, we defined a CMML-specific genetic risk score that was able to identify three different groups (Low risk: normal karyotype and –Y; Intermediate: other abnormalities, mutations in ASXL1; High: trisomy 8, complex karyotype, mutations in RUNX1 or SETBP1), with significantly different OS (HR=2.24, P<.001). The Akaike information criterion showed that this genetic risk score performed better than the original CPSS cytogenetic risk classification (AIC 274 vs. 282, respectively). According to the CMML-specific genetic risk score, 36% of patients had a shift toward a higher risk category compared with cytogenetic risk classification. Then, the new genetic risk categories were integrated in the CPSS (CPSS-Mol), which was able to identify 4 risk groups with different OS (HR=2.29, P<.001) and risk of disease progression (HR=2.62, P<.001). As a robustness analysis, we also fitted a Lasso Cox regression model including clinical and genetic variables, and all variables included in the clinical/molecular score were confirmed. The Akaike information criterion showed that the CPSS-Mol performed better than the original CPSS (AIC 251 vs. 253, respectively).In conclusion, this study showed that mutation pattern in CMML significantly correlates with disease phenotype. The integration of somatic mutations in current scoring systems significantly improves prognostic stratification of patients. DisclosuresNo relevant conflicts of interest to declare.

FLT3 mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).

6597 Background: FLT3 mutations occur in one third of acute myeloid leukemia (AML) patients (pts) and predict poor outcome. The incidence and impact of FLT3 in MDS/ CMML is unknown. Methods: We conducted a retrospective review at MDACC to identify FAB MDS/ CMML pts with FLT3 mutations at diagnosis. Results: From 1996 to 2010; 2052 MDS/ CMML pts had mutation analysis. 45 (2.2%) had FLT3 mutations (internal tandem duplication-ITD or D835) at diagnosis. 29 pts had MDS and 16 had CMML. Median (Med) age was 64 years (21 to 83) and 69% were males. FAB groups: 3 pts with refractory anemia (RA), 11 pts with refractory anemia-excess blasts (RAEB), 18 pts with refractory anemia-excess blasts in transformation (RAEB-T) and 13 pts with CMML. IPSS: 3 in Low (7%), 16 in Int-1 (36%), 11 in Int-2 (24%), and 15 in High (33%). Med white count, hemoglobin, platelet count and marrow blast percent at diagnosis were 5.2 x 109/l (1.2 to 211), 10.0 g/l (6.8 to 14.9), 78 x 109/l (8 to 429), and 14% (1 to 28), respectively. FLT3 ITD and FLT3 D835 mutations were present in 32 (71%) and 13 pts (29%), respectively. Karyotype was diploid in 30 (66%); -5/-7 in 5 (11%), 11q in 1 (2%), and others in 9 pts (19%). All 5 pts with -5/ -7 had the ITD mutation. Concurrent mutations were identified in RAS, NPM1 and C-Kit in 6 (13%), 3 (7%) and 1 (2%) pt, respectively. Med overall survival (OS) for FLT3 pts was 15 months compared to 17 months for non FLT3 pts (P=0.9). 18 pts had RAEB-T: 13 (72%) received AraC-based therapy and 3 (17%) received hypomethylating therapy (HMT) with complete remission (CR) in 14 pts (78%). 14 pts had RA/ RAEB: 5 (36%) received AraC-based therapy and 7 (50%) received HMT with CR in 5 (37%) and hematological improvement (HI) in 4 (28%). 13 pts had CMML: 4 (31%) received AraC-based therapy and 6 (46%) received HMT with CR in 3 (23%) and HI in 3 (23%). Repeat FLT3 was available on 16 pts achieving any response and was absent/ decreased in 14 (88%), stable in 1 (6%) and increased in 1 (6%). Notably, the 14 pts with absent/ decreased FLT3 had med OS of 27 months versus 12 months for remaining group (P=0.004). Conclusions: FLT3 occurs in MDS/ CMML at a lower frequency than AML and does not predict poor outcome. Pts who achieve absent/ decreased FLT3 seem to have significantly improved overall survival.