A Pilot Study of Exjade (Deferasirox) As Monotherapy in Higher Risk MDS or Acute Myeloid Leukemia

Although deferasirox use is established in clinical practice for iron overload, there have been a spate of case reports describing hematologic improvement attributed to use of this agent in myelodysplastic syndrome (MDS) patients (Guariglia et al, Leuk Res, 2011, 35 (5), 566-570). In addition, a post-hoc analysis was conducted assessing hematologic improvement in patients enrolled on the Evaluation of Patients' Iron Chelation with Exjade (EPIC) trial of deferasirox chelation therapy in low or intermediate-1 risk MDS. Erythroid, platelet, and neutrophil responses were observed in 21.5%, 13.0%, and 22.0% of 341 patients after a median of 109, 169, and 226 days, respectively (Gattermann, N et al, Haematologica, 2012, 97 (9), 1364-1371). There has even been a case report of a patient with acute monocytic leukemia who achieved a complete remission after deferasirox therapy (Fukushima et al, Anticancer Res, 2011, 31 (5) 1741-1744). Preclinical data has suggested potential mechanisms for hematologic improvement, including modulation of reactive oxygen species and activating the MAP kinase pathway (Callens et al, J Exp Med, 2010, 37 (4), 731-750), increased labile plasma iron leading to reactive oxygen species induction (Naka K et al, Antiox Redox Signal, 2008, 10 (11) 1883-1894), or inhibition of nuclear factor Kappa B (Messa et al, Haematologica, 95 (8) 1308-1316). Given these intriguing findings, we performed a single-center, investigator-initiated pilot study of deferasirox in MDS International Prognostic Scoring System (IPSS) 1.5 or greater, intolerant of or with lack of response to hypomethylating agents, and acute myeloid leukemia (AML), either relapsed or refractory after treatment with a non-intensive regimen or newly diagnosed and not appropriate candidates for induction chemotherapy. As an inclusion criterion, baseline serum ferritin was > or = to 500 ng/mL. Prior therapy with iron chelating agents within the last 6 months was an exclusion criterion. Current therapy for AML or MDS, including hydroxyurea to control leukocytosis, was prohibited. Thirteen patients consented to the study. There was one screen failure and one patient withdrew from the study after one day. Eleven patients received deferasirox at an initial dose of 10 mg/kg/day which was increased to 20 mg/kg/day if tolerating well. Three of 11 patients (27%) responded. One of the three responding patients achieved red blood cell (RBC) transfusion independence (no RBC transfusions for 6 weeks before death related to infectious complications), one improved bone marrow blasts from 57% to 30% after one month of therapy and the third patient improved bone marrow blasts from 13% to 8% after one month of therapy. The patient who achieved RBC transfusion independence did not achieve any other measures of response. The two patients who responded in the bone marrow did not achieve a concomitant hematologic response. Of the 8 non-responding patients, one patient had stable disease and was on study for one year. One patient withdrew in the setting of neutropenic fever and mild transaminitis that was possibly attributable to deferasirox and was terminated from the study. One patient withdrew from the study due to personal choice and the remaining 5 patients came off study in the setting of complications from progressive disease. Study drug was generally well tolerated. Grade 3 adverse events (AEs) included three patients with elevated creatinine (27%) and 2 patients with diarrhea (18%). One responding patient had a lower gastrointestinal bleed that was possibly attributable to deferasirox and was terminated from the study for this reason. One patient had grade 4 dry mouth immediately after drinking deferasirox slurry that resolved by 30 minutes after ingestion. No other significant AEs occurred that were possibly attributable to deferasirox. In conclusion, deferasirox was generally well tolerated and showed modest activity as a single agent in higher risk MDS or non-proliferative acute myeloid leukemia. Further study of deferasirox in the phase II setting as monotherapy or in combination with other therapies such as hypomethylating agents (HMAs) or HMAs in combination with venetoclax is probably warranted. Disclosures Frey: Novartis: Research Funding. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Luger:Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding. OffLabel Disclosure: Presentation will discuss the off-label use of Exjade (deferasirox) as therapy for higher risk MDS or AML. Deferasirox on-label use is for iron chelation.

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EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps7054 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS7054-TPS7054

Author(s):

Amer Methqal Zeidan ◽

Jacqueline Suen Garcia ◽

Pierre Fenaux ◽

Uwe Platzbecker ◽

Yasushi Miyazaki ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Hypomethylating Agents ◽

Newly Diagnosed ◽

Phase 3 ◽

Transfusion Independence ◽

Treatment Naïve ◽

The U.S ◽

Acute Myeloid

TPS7054 Background: Patients with higher-risk myelodysplastic syndromes (HR-MDS) experience peripheral cytopenias, disease progression to acute myeloid leukemia, and high mortality with expected median overall survival of less than 2 years. Allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative treatment. Patients ineligible for transplantation are treated with hypomethylating agents such as azacitidine (Aza), which is not curative and provides limited improvement in clinical benefit. Venetoclax (Ven) is a selective, potent, oral B-cell lymphoma-2 (BCL-2) inhibitor that is approved in the U.S. in combination with hypomethylating agents for treating older or co-morbid patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Ven is approved in the U.S. as first-line treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. For patients with treatment-naïve HR-MDS, Ven + Aza demonstrated manageable safety and a combined complete remission (CR)/marrow CR (mCR) rate of 79% in a single arm phase 1b study (NCT02942290). To confirm these benefits, the VERONA study, a randomized, double-blind, phase 3 study (NCT04401748) of patients with treatment-naïve HR-MDS, will assess the safety and efficacy of Ven combined with Aza including CR rate and overall survival. Methods: Patients (≥18 years) with newly diagnosed HR-MDS per WHO 2016 classification with = 20% bone marrow blasts per marrow biopsy/aspirate at screening will be enrolled at ̃200 sites globally (̃500 patients). Patients must have intermediate risk or higher IPSS-R (score > 3), ECOG ≤2, and be hematopoietic stem cell transplant (HSCT) eligible without any pre-arranged donor, or HSCT ineligible without a plan for HSCT at Study Day 1. De novo patients without prior hypomethylating agents, chemotherapy for MDS, or allogenic stem cell transplantation are eligible. Patients will be randomized 1:1 to receive placebo or Ven 400 mg oral tablet once daily on Days 1-14, both in combination with Aza 75 mg/m2 (intravenous or subcutaneous) on Days 7-0-0 or Days 5-2-2 per 28-days. Patients will receive study treatment until disease progression, unacceptable toxicity, HCT, withdrawal of consent, or discontinuation. The primary endpoints are CR rate (as adjudicated by investigator) per IWG 2006 criteria and overall survival. Secondary outcomes are red blood cell transfusion independence, platelet transfusion independence, change in fatigue as measured by Patient-Reported Outcomes Measurement Information System (PROMIS)-fatigue SF 7a scale score, time to deterioration in physical functioning domain of EORTC QLC-C30 scale, overall response (CR + partial response), and modified overall response (CR + mCR + partial response). Exploratory objectives are predictive biomarkers and pharmacokinetics. Clinical trial information: NCT04401748.

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Targeted Intravenous Busulfan and Fludarabine Allogeneic Transplantation Conditioning in Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.2290.2290 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2290-2290

Author(s):

Joseph A. Pidala ◽

Jongphil Kim ◽

Claudio Anasetti ◽

Melissa Alsina ◽

Ernesto Ayala ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Large Series ◽

Myelogenous Leukemia ◽

Secondary Aml ◽

Relapsed Disease ◽

Acute Myeloid

Abstract Abstract 2290 Poster Board II-267 Reduced and intermediate intensity conditioning with allogeneic hematopoietic cell transplantation (HCT) offers promise to effectively control hematologic malignancies, while limiting treatment related toxicity and mortality (TRM). We aimed to examine the efficacy of IV targeted Busulfan and Fludarabine (IV-Bu/Flu) in a large series of adults with exclusively acute myelogenous leukemia (AML). One hundred adults (median age 48) with AML (CR1 49, CR2 25, REL1 8, REL2 1, PIF 16, untreated 1) were treated with Busulfan 130-145 mg/m2/day for four days with pharmacokinetic targeting on the final two days to achieve an area under the curve (AUC) of 5300 (+/-10%) μmol*min/L/day and Fludarabine 40mg/m2/day for 4 days, followed by transplantation of G-CSF mobilized peripheral blood stem cells (PBSC) (N=98) or unstimulated bone marrow (BM) (N=2) from allogeneic donors (MRD 38, MUD 38, MMUD 24). Acute GVHD prophylaxis consisted of tacrolimus/methotrexate (N = 77), tacrolimus/mycophenolate mofetil (N = 22), or tacrolimus/sirolimus (N = 1). Median time to neutrophil and platelet engraftment was 16 and 12 days, respectively. Non-relapse mortality was 3% at 100 days, and 15% by 1 year. The cumulative incidence of relapse was 41%. Overall survival (OS) was 59% (95% CI: 48.1 – 67.5) at 1 year, and 42% (95% CI: 30.8-53.3) at 4 years. OS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 52.9%, 40.1%, 41.2%, and 57.5% respectively; none with relapsed disease survived to 4 years (log-rank p = 0.0014). Progression-free survival (PFS) was 53% (95% CI: 42.8 – 62.2) at 1 year, and 32.3% (95% CI: 21.8 – 43.2) at 4 years. PFS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 44.1%, 33.4%, 33.9%, and 33.1%, respectively, while none with relapsed disease at transplant reached this endpoint (p = 0.0264). On multivariable modeling, remission status at HCT (relapsed disease HR 14.85 (95% CI: 2.12 - 104.2), p = 0.007), moderate/severe cGVHD (HR 0.281, 95% CI: 0.10 - 0.76; p = 0.013), and day 90 bone marrow (BM) chimerism ≥ 90% (HR 0.245, 95% CI: 0.08 - 0.79; p = 0.018) predicted overall survival, and day 90 BM chimerism ≥ 90% (HR of 0.18 (95% CI: 0.08 - 0.45), p = 0.0002) predicted PFS. The following were not significantly related with OS or PFS: age, cytogenetics, donor relation, number of induction cycles, aGVHD prophylaxis regimen, maximum aGVHD grade, WBC at diagnosis, time in first CR, or % BM blasts prior to transplant. Day 90 BM chimerism and cGVHD were significantly related with relapse. Maximum grade of aGVHD predicted non-relapse mortality. These data support the low TRM and efficacy of IV-Bu/Flu in a large series of exclusively AML patients, and demonstrate the impact of day 90 bone marrow chimerism as an important prognostic factor. Further efforts to mitigate relapse risk after HCT are warranted, particularly in those with advanced disease at time of transplant. Disclosures: Off Label Use: IV busulfan and fludarabine for the treatment of acute myeloid leukemia. Alsina:Ortho Biotech: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau. Field:PDL BioPharma: Research Funding. Fernandez:Otsuka: Honoraria.

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Lack of Association of Mutations in IDH1, IDH2, DNMT3A with Outcome in Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents (± Histone Deacetylase Inhibitors).

Blood ◽

10.1182/blood.v120.21.2483.2483 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2483-2483

Author(s):

Farhad Ravandi ◽

Keyur P. Patel ◽

Rajyalakshmi Luthra ◽

Sherry A. Pierce ◽

Gautam Borthakur ◽

...

Keyword(s):

Valproic Acid ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Histone Deacetylase ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Hypomethylating Agents ◽

Idh Mutations ◽

Acute Myeloid

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

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High Expression of Myocyte Enhancer Factor 2C (MEF2C) Is Associated with Adverse Risk Features and Poor Outcome in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽

10.1182/blood.v126.23.2570.2570 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2570-2570

Author(s):

George S. Laszlo ◽

Todd A. Alonzo ◽

Chelsea J. Gudgeon ◽

Kimberly H. Harrington ◽

Alex Kentsis ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Event Free Survival ◽

Free Survival ◽

Expression Levels ◽

Acute Myeloid ◽

Enhancer Factor

Abstract Background: Myocyte enhancer factor 2C (MEF2C) was initially identified as essential transcription factor for cardiac muscle development. However, subsequent studies have indicated that MEF2C plays a much broader biological role, including in the normal hematopoietic system. Recent studies have now identified MEF2C as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML. These findings raised the possibility that MEF2C could serve as marker of poor-risk disease and, therefore, have prognostic significance in AML. To test this hypothesis, we retrospectively quantified MEF2C expression in participants of the AAML0531 trial and correlated expression levels with disease characteristics and clinical outcome. Patients and Methods: AAML0531 (NCT00372593) was a multicenter phase 3 study that determined the addition of gemtuzumab ozogamicin to intensive chemotherapy among 1,022 eligible patients aged <30 yearswith newly diagnosed de novo non-APL AML, excluding those with bone marrow failure syndromes, juvenile myelomonocytic leukemia, or Down syndrome (if ≤3 years of age) between 2006 and 2010. Cryopreserved pretreatment ("diagnostic") specimens from patients enrolled on AAML0531 who consented to the biology studies and had bone marrow samples were available were included in this study. Total RNA from unsorted specimens was extracted, quantified, and subjected to quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) using TaqMan primers to determine expression of MEF2C and, for normalization, the housekeeping gene, β-glucuronidase (GUSB). Patient samples were run in duplicate, and the ΔΔCT method quantified as 2(-ΔΔCT) was used to determine the expression levels of MEF2C relative to GUSB. Results: In all 751 available patient specimens, MEF2C mRNA was detectable and varied >3,000-fold relative to GUSB (0.0091-29.1272 [median: 0.7978]). Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67% vs. 78%, P=0.005). They also had an inferior overall survival (P=0.014; at 5 years: 55±8% vs. 67±4%), inferior event-free survival (P<0.001; at 5 years: 38±7% vs. 54±4%), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P<0.001; at 5 years: 53±9% vs. 35±5%). Of note, exploratory multiple cutpoint analyses for overall and event-free survival indicated that the most statistically significant results were centered around the Q4 cutpoint region, supporting our approach of comparing patients with the highest quartile of relative MEF2C expression with those having lower relative MEF2C expression. Importantly, MEF2C expression was strongly associated with cytogenetic and molecular abnormalities. Specifically, patients with high MEF2C expression less likely had CBF translocations (inv(16): P=0.007, and t(8;21): P<0.001) or normal karyotype AML (P<0.001); conversely, they were more likely to have leukemia with monosomy 7 (P<0.001) and abnormalities involving 11q23 (P<0.001). Furthermore, patients with high MEF2C less likely had a FLT3/ITD (P =0.018) or a mutation in either NPM1 (P=0.010) or CEBPA (P =0.002). Consistently, patients with high MEF2C expression less likely had low-risk disease (16% vs. 46%, P<0.001) and more likely had standard-risk disease (68% vs. 42%, P <0.001) than those with lower MEF2C expression. Indeed, after adjustment for disease risk, age, FAB category, and treatment arm, high MEF2C expression was no longer statistically significantly associated with inferior overall survival (hazard ratio [HR]=0.99 [95% confidence interval: 0.72-1.36], P=0.929), inferior event-free survival (HR: 1.14 [0.86-1.49], P=0.365), or higher relapse risk (HR: 1.32 [0.91-1.92], P=0.137), suggesting that MEF2C cooperates with additional pathogenic abnormalities. Conclusion: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. These findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. Disclosures Walter: AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

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Genetic Dissection of p53 Driven Senescence of Bone Marrow Mesenchymal Cells in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-117585 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2625-2625

Author(s):

Rasoul Pourebrahim ◽

Peter P. Ruvolo ◽

Steven M. Kornblau ◽

Carlos E. Bueso-Ramos ◽

Michael Andreeff

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Bone Marrow Mscs ◽

Advisory Committees ◽

Equity Ownership ◽

Bone Marrow Mesenchymal Cells ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by bone marrow infiltration of abnormally proliferating leukemic blasts which results in fatal anemia, bleeding and infectious complications due to compromised normal hematopoiesis. Patients with complete remission (CR) but incomplete blood cell count recovery (CRi) have significantly shorter survival compared to CR patients. Although there is a correlation between CRi and minimal residual disease (MRD), the two variables were shown to be independent risk factors for relapse development (1). The mechanism by which AML induces bone marrow failure in patients is largely unknown. Here, we demonstrate that AML derived MSCs highly express p53 and p21 proteins and are more senescent compared to their normal age-matched controls as demonstrated by high β-galactosidase staining (figure 1. A, B&C). Emerging evidence indicates that the aging of endosteal niche cells results in lower reconstitution potential of hematopoietic stem cells (2). To functionally evaluate the effects of AML on bone marrow MSCs, we utilized a murine leukemia model of the AML microenvironment. We transplanted Osx-Cre;mTmG mice with AML cells and compared the senescence of MSCs in normal bone marrow (Figure 1.D) with AML (Figure 1.E). Consistent with our initial findings in human, AML strongly induced senescence of osteoblasts. This suggests that AML suppresses normal hematopoiesis by inducing senescence in the hematopoietic niche. To address the role of p53 signaling in senescence of MSCs we generated a traceable conditional p53 gain/loss model specifically in bone marrow MSCs using Osx-Cre;mTmG; Mdm2fl/+ and Osx-Cre;mTmG;p53fl/fl mice respectively (Figure 1.F). Deletion of p53 in bone marrow MSCs resulted in an increased population of osteoblasts (GFP+) in Osx-Cre;mTmG;p53fl/fl mice in comparison to Osx-Cre;mTmG mice suggesting that p53 loss in osteoblasts inhibits senescence of osteoblasts. In order to evaluate p53 activity after recombination of p53fl alleles in the osteoblasts, we isolated MSCs from bone marrows and analyzed the expression of p21.P21 was significantly down regulated in osteoblasts (GFP+) derived from Osx-Cre;mTmG;p53fl/fl mice whereas its expression in the hematopoietic cells from same tissue (tdTomato+) remained comparable to p53 wild type suggesting that p21 as the master regulator of senescence is regulated by p53 in bone marrow mesenchymal cells. To evaluate the effect of p53 loss in osteoblasts and its impact on hematopoietic cells, we isolated the GFP+ cells (osteoblasts) and RFP + cells (hematopoietic) by FACS. Senescent cells, non-cell autonomously, modulate the bone marrow microenvironment through the senescence-associated secretory phenotype (SASP). We analyzed the expression of fifteen SASP cytokines by QPCR. Deletion of p53 in bone marrow mesenchymal cells strongly abrogated the expression of several SASP cytokines. Interestingly several Notch target genes such as Hey1 and Hey2 were highly induced in MSCs following p53 deletion suggesting a role for Notch signaling in hematopoietic failure following AML induced MSCs senescence. Our data suggest that AML induces senescence of endosteal niche resulting in hematopoietic failure. These findings contribute to our understanding of the role of p53 in leukemia MSCs and could have broad translational significance for the treatment of hematopoietic failure in patients with AML.Chen X, et al. (2015) Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol 33(11):1258-1264.Li J, et al. (2018) Murine hematopoietic stem cell reconstitution potential is maintained by osteopontin during aging. Sci Rep 8(1):2833. Disclosures Andreeff: Astra Zeneca: Research Funding; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Celgene: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SentiBio: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Jazz Pharma: Consultancy; Reata: Equity Ownership.

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Development of Somatic NRAS Mutation Associated with Rapid Transition from Germline GATA2 Mutation Associated Myelodysplastic Syndrome to Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.3616.3616 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3616-3616 ◽

Cited By ~ 1

Author(s):

Yanqin Yang ◽

Yubo Zhang ◽

Jun Zhu ◽

Catherine E. Lai ◽

Jingrong Tang ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Research Funding ◽

Bone Marrow Aspirate ◽

Nras Mutation ◽

Trisomy 8 ◽

Acute Myeloid

Abstract There is increasing recognition of the role of inherited germline predisposition for myeloid disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The additional somatic genetic events required for development of a malignant phenotype are however poorly understood. A 25 year old woman was referred to the NHLBI hematology branch in March 2014 for a seven year history of pancytopenia. Her medical history included recurrent pneumonias, oral ulcers, severe varicella infection and arthralgias. Prior bone marrow examinations at ages 21 and 23 at outside institutions reported normocellular marrow, tri-lineage hematopoiesis and mild dyspoiesis. Cytogenetics were remarkable for trisomy 8 in 80% (aged 21) or 90% (aged 23) of metaphases. Previously unrecognized lymphedema was noted on examination. Peripheral blood counts showed WBC 2.28 K/ul [normal range: 3.98-10.04], HGB 9.9 g/dL [11.2-15.7], PLT: 67 K/ul [173-369], ALC: 0.36 K/ul [1.18-3.74] and AMC: 0.06 [0.24-0.86]. Peripheral blood flow cytometry demonstrated decreased CD3+ CD4+ (T) cells, CD19+ (B) cells and NK cells. HLA-DR15 negative. Bone marrow examination showed trilineage hematopoiesis, 50-60% cellularity, mild erythroid predominance and mildly increased, mildly atypical megakaryocytes. Blasts less than 5%. Bone marrow flow cytometry revealed severely decreased B-cells and monocytes, absent B-cell precursors, absent dendritic cells, inverted CD4:CD8 ratio, and atypical myeloid maturation pattern. Cytogenetics demonstrated stable trisomy 8 in 90% of metaphases. On the basis of this assessment the diagnosis of MDS was confirmed. Sanger sequencing revealed a GATA2 L375S mutation in the second zinc finger of known pathogenic significance. Four months later she developed increased fatigue and easy bruising with worsening thrombocytopenia (PLT: 10K/ul). Bone marrow was dramatically changed; now markedly hypercellular (90-100%) with diffuse sheets of immature cells consistent with blasts having fine chromatin, distinct or prominent nucleoli, and visible cytoplasm. Blasts were positive for CD33, CD56, CD64, CD123, and CD163; and were negative for CD34, CD14, and myeloperoxidase. Cytogenetics showed a new trisomy 20 in 65% of metaphases, in addition to previously seen trisomy 8 in 100%. A diagnosis of acute monoblastic leukemia (M5a subtype) was made. At both clinic visits bone marrow aspirate was collected on an IRB approved research sample acquisition protocol. Whole exome sequencing of 1ug DNA was performed using Agilent SureSelect v5 Exome enrichment Kits on an Illumina HiSeq 2000 with 100-bp paired-end reads (Macrogen, Rockville, MD). Data was mapped to hg19 (BWA) and processed using an in-house pipeline (Samtools/Picard/GATK/VarScan/Annovar). Mean read depth of target regions was 157 and 149. There was high correlation between both samples with the exception of a NRAS:NM_002524:exon3:c.C181A:p.Q61K mutation (57 of 180 reads) seen only in the later sample. Confirmatory ultra-deep sequencing for NRAS was performed using Illumina TruSight Myeloid Sequencing Panel on an Illumina MiSeq. No evidence of the NRAS Q61K mutation was found in the earlier March MDS bone marrow sample even when sequenced to a depth greater than 1750 reads (see figure). The mutation was confirmed in the August AML sample at a variant allele frequency of 35%. If heterozygous this would reflect a clone size of 70%, consistent with data from both cytogenetics (new trisomy 20 in 65% of metaphases) and the 76% blasts documented by bone marrow aspirate smear differential. We report here the rapid progression to AML in a patient with germline GATA2 MDS associated with development of a new trisomy 20 karyotype and a NRAS Q61K mutation. The NRAS mutation was not detectable after the patient achieved a complete remission following induction chemotherapy further supporting this association. This NRAS mutation has been implicated in the pathogenesis of multiple cancers by constitutive activation of proliferative signaling. GATA2 associated MDS is a high-risk pre-leukemic condition with the potential for rapid evolution to AML. This is the first report of acquired somatic mutations in the RAS/RTK signaling pathway in the context of germline GATA2 insufficiency associated with acute leukemic transformation. Figure 1. Figure 1. Disclosures Townsley: Novartis: Research Funding; GSK: Research Funding.

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Outcomes and Predictors of Relapse with Use of Hypomethylating Agents in Combination with Venetoclax Prior to Allogeneic Transplant in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-150815 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2327-2327

Author(s):

Imran Nizamuddin ◽

Timothy Seijung Oh ◽

Yazan Numan ◽

Max Farber Kelsten ◽

Madelyn Burkart ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Maintenance Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Intermediate Risk ◽

Hypomethylating Agents ◽

Significant Difference ◽

Acute Myeloid

Abstract Introduction The treatment of acute myeloid leukemia (AML) has evolved tremendously. Recently, venetoclax with hypomethylating agents (HMA/ven) demonstrated durable responses in the frontline and relapsed/refractory (R/R) settings. This regimen is now standard of care for older adults or those unfit for intensive induction chemotherapy (DiNardo CD, N Engl J Med, 2020). Our institution also often uses HMA/ven to treat fit patients (pts) with high risk disease characteristics. Because HMA/ven was studied in transplant-ineligible pts, outcomes following potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) remain unknown. This retrospective study aims to describe characteristics and outcomes of pts treated with HMA/ven who proceeded to HSCT. Methods Adult pts diagnosed with AML and treated with HMA/ven either in the frontline or R/R setting between 1/2010 and 2/2020 at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University were identified. Hypomethylating agents included either azacitadine or decitabine. Data were collected and analyzed based on demographics, laboratory and clinical characteristics, and disease and toxicity outcomes. Efficacy endpoints included complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with incomplete platelet recovery (CRp). Survival curves for overall survival (OS) and leukemia-free survival (LFS) were calculated using the Kaplan-Meier method. Univariate analyses were performed to determine impact of clinical variables on outcomes (significance defined as p≤0.05). Cohorts were compared using χ 2 or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. Results Clinical and demographic features at time of diagnosis are listed in Table 1. In total, 257 pts received HMA/ven. Of these, 36 pts received a HSCT, which was the population analyzed in this study. In the front-line setting 11 (31%) pts received HMA/ven and 25 (69%) pts received HMA/ven for R/R disease. 25 (69%) pts received azacitadine and 11 (31%) pts received decitabine (5 days, n=5, 14%; 10 days, n=6, 17%). Based on ELN guidelines, 23 (64%) pts had adverse risk disease at diagnosis. Response to HMA/ven in the pre-transplant setting is shown in Table 2. Of 35 evaluable pts, 34 achieved remission (CR, n=32, 91%; CRi, n=1, 3%; CRp, n=1, 3%). Table 3 shows outcomes following HSCT. 14 (39%) pts relapsed post HSCT and 13 (36%) pts received treatment for relapse. With a median follow-up of 11.6 months, median LFS from time of transplantation was 11.2 months. Median OS was not reached over follow up period but estimated to be 25.4 months. There was a significant difference in rates of relapse based on ELN classification at diagnosis (p=0.0296). In comparison, presence of complex/monosomal karyotypes (p=0.593), blast percentage at diagnosis (p=0.456), donor type (p=0.484), and number of previous lines of therapy (p=0.822) did not predict for relapse. Median LFS in adverse and favorable/intermediate risk ELN groups was 5.8 and 19.8 months, respectively. Median OS in adverse and favorable/intermediate risk ELN groups was 25.4 and 29.5 months, respectively. Following transplant, 10 (28%) pts received maintenance therapy with a median of 5 cycles (range 1-14); 8 pts (22%) received HMA/ven maintenance following HSCT. There was no significant difference in relapse rates between those who received maintenance therapy (n=6, 43%) and those who did not (n=8, 57%) (p = 0.107). Median time to relapse from HSCT was 4.42 months in those who received maintenance therapy compared to 2.98 months in those who did not receive maintenance therapy (p=0.370). Following relapse, 10 (28%) pts were retreated with HMA/ven, but less than half (n=4, 40%) had a response. To date, 22 (61%) pts are alive with the majority (n=19, 86%) in remission. 14 (39%) pts died with half in remission at the time of death. Conclusions Our study showed that HMA/ven can feasibly be used not only to bridge to transplant, but to achieve durable remissions post HSCT. For those pts that relapsed post HSCT, duration of remission was very short. ELN classification was the only factor that informed relapse risk. Prospective studies must be done to understand which cytogenetic and molecular subgroups benefit the most from HMA/ven prior to transplant. Figure 1 Figure 1. Disclosures Abaza: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Altman: Biosight: Consultancy, Other: Travel fees, Research Funding; Fujifilm: Research Funding; Kura: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Daiichi Sankyo: Consultancy; ALZ Oncology: Research Funding; Theradex: Consultancy, Other: Advisory boards; Syros: Consultancy; Amgen: Research Funding; Aprea: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; GlycoMimetics: Other: Participation on an advisory board; AbbVie: Consultancy, Other: Advisory Board, Research Funding; BMS: Research Funding; Kura Oncology: Consultancy. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria.

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Efficacy of Venetoclax Combination Therapy with Hypomethylating Agents in Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2019-129514 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5089-5089 ◽

Cited By ~ 1

Author(s):

Varun Mittal ◽

Mimi Lo ◽

Lloyd E. Damon ◽

Karin L. Gaensler ◽

Thomas G. Martin ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Hypomethylating Agents ◽

Advisory Committees ◽

Allogeneic Hct ◽

Acute Myeloid

Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) has high efficacy in treatment-naïve elderly patients with acute myeloid leukemia (AML). The role for VEN in patients with relapsed/refractory (R/R) AML, myelodysplastic syndrome (MDS), or other myeloproliferative neoplasms remains incompletely defined. In particular, the efficacy of VEN+HMA has not been studied systematically in patients who experience AML relapse following allogeneic hematopoietic cell transplantation (HCT). Method: All patients treated with VEN+HMA (azacitidine or decitabine) for R/R de novo or secondary AML or progressive MDS following allogeneic HCT were identified and reviewed retrospectively. All included AML patients had overt clinical relapse with ≥ 5% bone marrow blasts or extramedullary disease biopsy proven to be AML. Patients were included in this analysis if they received at least 14 days of VEN therapy. Results: Eleven patients with median age 66 (range 25-75) were treated for R/R AML post-allogeneic HCT. Transplant characteristics included use of reduced intensity conditioning in 10/11 (91%), matched sibling donors in 5/11 (45%), matched unrelated donors in 5/11 (45%), and cord blood in 1/11 patients. The median time from HCT to relapse/disease progression was 7 months (range 3-36). Two patients had extramedullary relapse only, and the remainder had marrow involvement. Eight patients (73%) received azacitidine and 3 (27%) received decitabine in combination with VEN. All but two patients (82%) had prior HMA exposure and most received VEN+HMA as initial post-transplant salvage therapy (64%). Only one patient received donor lymphocyte infusion in conjunction with VEN+HMA therapy, and none proceeded to a second allotransplant. Nine patients (82%) experienced an objective response, which included 4 CR/CRi (36%) and 5 PR/SD (45%). In patients with CR/CRi, three patients had adverse risk cytogenetics and one had a favorable risk profile at diagnosis consisting of normal cytogenetics with an isolated NPM1 mutation. All patients who failed to remit with VEN+HMA had intermediate- or high-risk genetic features. The median number of treatment cycles given was 3 (range 1-20). Median survival was 11 months and estimated 6-month and 12-month survival was 82% and 36%, respectively. Three patients remain alive with median 16.5 months follow-up (range 2.5-32). Conclusion: Venetoclax in combination with HMA is a viable salvage option in patients with relapsed AML or progressive MDS after allogeneic HCT, including those with prior exposure to HMA. Although one patient in this cohort sustained long term complete remission, overall prognosis remains dismal in this high-risk patient population and improved treatment options for relapsed/refractory AML following alloHCT remain needed. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; AstraZeneca: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Mirati Therapeutics: Research Funding; Spectrum: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding. Logan:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pharmacyclics: Research Funding; Astellas: Research Funding; Jazz: Research Funding; Kite: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; TeneoBio: Consultancy; Kiadis: Consultancy; Kadmon: Research Funding; Abbvie: Consultancy.

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Chronic Myelomonocytic Leukemia Is Associated with More Frequent and More Rapid Progression to Acute Myeloid Leukemia and Shorter Survival Than Myelodysplastic Syndrome, but Is Less Frequently Treated: Analysis of Surveillance Epidemiology and End Results Data Linked to Medicare Enrollment Claims

Blood ◽

10.1182/blood.v118.21.2784.2784 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2784-2784

Author(s):

Dan Zandberg ◽

Ting-Ying Huang ◽

Xuehua Ke ◽

Maria R. Baer ◽

Steven D. Gore ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Population Based ◽

Chronic Myelomonocytic Leukemia ◽

Rapid Progression ◽

Hypomethylating Agents ◽

Equity Ownership ◽

Myelomonocytic Leukemia ◽

Acute Myeloid

Abstract Abstract 2784 Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder that displays features of both a myelodysplastic syndrome (MDS) and a myeloproliferative neoplasm (MPN). Originally classified as an MDS subtype in the French-American-British (FAB) classification system, it was reclassified as an MDS/MPN in the World Health Organization (WHO) system. Based on SEER and NAACCR data, CMML is associated with shorter survival than MDS and MPN, but no other population-based data have been available to date. We used the Surveillance Epidemiology and End Results (SEER) dataset linked to Medicare enrollment and claims data to compare patient demographics, baseline characteristics, treatments received, progression to acute myeloid leukemia (AML) and survival between CMML and MDS. The sample included 792 CMML and 6,588 MDS patients diagnosed from 2001 through 2005. MDS cases were 34.6% low-risk [RA, RARS, RCMD, del (5q)], 13.7% high-risk (RAEB), 1.4% therapy-related and 50.4% not otherwise specified. CMML and MDS patients did not differ in age (peak proportion at 80–84 years in both) or race distribution (90% and 88% white non-Hispanic, respectively). Male predominance was greater in CMML than in MDS (59.2% vs. 53.8%; p =.004). Baseline renal disease was more common among CMML patients (13.0% vs. 7.4%; p <.0001), while CHF/ischemic heart disease (37.4% vs. 44.6%; p =.000) and liver disease (2.8% vs.4.3%; p=.041) were more common in MDS. There was no difference in the proportion with poor performance status, diagnosis of other cancers within 5 years of CMML/MDS diagnosis, health care use prior to diagnosis or median household income. More CMML than MDS patients received no treatment (25.25% vs. 15.7%; p <.0001). Among patients who were treated, fewer CMML patients received blood transfusions (59.5% vs. 70.4%; p <.0001), erythropoiesis-stimulating agents (46.3% vs. 62.4; p <.0001) and granulocyte colony-stimulating factor (7.32% vs. 16.9%; p <.0001), while more CMML patients were treated with cytarabine (2.02 vs. 0.87; p =.002), etoposide (1.01 vs. 0.36%; p = 0.009) and bone marrow transplantation (1.14% vs. 0.47%; p =.016). There was no difference in treatment with hypomethylating agents between CMML and MDS patients (5.81% vs. 7.64%; p =.064). A higher percentage of CMML patients progressed to AML (42.6% vs. 16.3%; p < .0001) and progression occurred earlier (median 8 vs. 33 weeks; p < .0001). CMML patients had a lower survival probability at 1 year (51% vs. 66%; p <.0001) and at 3 years (19% vs. 37%; p <.0001), and a shorter median survival (13.3 vs. 24 months; p <.0001). Survival remained significantly lower across gender, age and race groups. In this population-based study, we have demonstrated that CMML patients less frequently receive therapeutic interventions, in relation to MDS patients, but in fact have a higher rate of progression to AML, more rapid progression to AML and shorter survival. The percentages of patients receiving hypomethylating agents for both diseases was low in our dataset and has likely increased following FDA approval of azacitidine in 2004 and decitabine in 2006. Our data support early application of disease-modifying therapies in CMML, and also support the need for clinical trials focused on this disease entity. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Davidoff:Cellgene: Equity Ownership, Research Funding.

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