Hypomethylating Agents Initiation Research Articles

Clinical Effectiveness of Hypomethylating Agents (HMAs) and Lenalidomide (Len) in Older Patients (pts) with Refractory Anemia with Ring Sideroblasts: A Large Population-Based Study in the United States (US)

Clinical Effectiveness of Hypomethylating Agents (HMAs) and Lenalidomide (Len) in Older Patients (pts) with Refractory Anemia with Ring Sideroblasts: A Large Population-Based Study in the United States (US)

The Prognostic Significance of Monocytopenia in Patients with Myelodysplastic Syndrome

The Prognostic Significance of Monocytopenia in Patients with Myelodysplastic Syndrome

Clinical Outcomes of Older Patients (pts) with Acute Myeloid Leukemia (AML) Receiving Hypomethylating Agents (HMAs): A Large Population-Based Study in the United States

Clinical Outcomes of Older Patients (pts) with Acute Myeloid Leukemia (AML) Receiving Hypomethylating Agents (HMAs): A Large Population-Based Study in the United States

Association of provider experience and clinical outcomes in patients with myelodysplastic syndromes receiving hypomethylating agents

Population level survival of patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) is inferior to clinical trials. Using SEER-Medicare data, we identified 2086 MDS patients diagnosed in 2004–13, aged ≥66 years at diagnosis, and receiving ≥1 HMA cycle after 2005. We used multivariate logistic regression and Cox proportional hazards models to assess the impact of provider experience on persistent HMA therapy and overall survival (OS), respectively. Median number of HMA cycles was 4 and median OS was 10 months. Thirty-two percent of patients were treated by providers with ≥1 prior HMA initiation in the last 2 years and were more likely to receive ≥4 cycles of HMA therapy (OR = 1.29, 95% CI = 1.06–1.57; p = .01). No significant association was found between MDS or HMA initiation volume and survival. In conclusion, while HMA initiation volume was associated with persistent HMA treatment, neither MDS nor HMA initiation volumes were associated with OS in older MDS patients.

RBC transfusion independence among lower risk MDS patients receiving hypomethylating agents: a population-level analysis

Most patients with lower risk myelodysplastic syndromes (LR-MDS) become red blood cell (RBC) transfusion dependent at some time during their disease course. Hypomethylating agents (HMAs) are frequently used in this setting; however, reported rates of in RBC transfusion independence (TI) achieved with HMA therapy vary significantly between studies. Here we study the real-life clinical effectiveness of HMA in inducing RBC TI in anemic LR-MDS patients using the Surveillance, Epidemiology and End Results (SEER)-Medicare database. We find that approximately 40% of LR-MDS patients who were receiving RBC transfusions and 33% who were dependent on RBC transfusions at HMA initiation ultimately achieved TI. The receipt of ≥3 transfusions in the 8-week period before HMA initiation was significantly associated with lower odds of achieving TI. Our study provides important population level estimates of clinical effectiveness of HMAs in LR-MDS.

Transfusion Independence in Lower-Risk, Non-del5(q) Myelodysplastic Syndromes (LR-MDS) Among Patients (pts) Initiating Hypomethylating Agents (HMAs) While Receiving Red Blood Cell (RBC) Transfusions

Background: HMAs were approved in the U.S. for treatment of MDS in 2004 (azacitidine) and 2006 (decitabine), and are used for upfront management higher risk disease and in LR-MDS at progression or after failure or low likelihood to respond to erythropoiesis stimulating agents (ESAs). Clinical trial data suggest that 24-50% of LR-MDS pts achieve RBC transfusion independence (TI) from prior transfusion dependence (TD) with HMA therapy. Response among older pts with LR-MDS treated with HMA in a real-world setting is unclear. We have previously shown that survival of higher risk MDS pts treated with HMAs in real-life setting is much shorter than clinical trial data. We therefore examined rates of achieving TI in LR-MDS pts receiving HMAs.Methods: We identified adults >65 years old diagnosed with LR-MDS (WHO categories RA, RARS, and RCMD) in 2004-2013 from the Surveillance Epidemiology and End Results Medicare claims data. Exclusion criteria include: pts with MDS diagnosed on autopsy report or death certificate, absence of continuous Medicare Part A and B coverage or presence of HMO enrollment from 12 months prior to diagnosis through death or end of study (12/31/2014). Pts had to initiate at least one cycle of HMA, defined as 3 to 10 doses of HMA within 28 days. A gap in treatment between 14 to 28 days indicates a new cycle. Pts were assessed for their transfusion status each week throughout the study period. We measured weekly transfusion status based on receipt of RBC transfusions (observed in Medicare claims) during the current and prior 7 weeks (8 weeks total). Transfusion status was defined as: transfusion receiving (TR), pts received at least one transfusion in each period; TD, patient received ≥2 transfusions over 8 weeks, with ≥2 transfusions ≥2 weeks apart; TI, no transfusions within the 8-week period. We required pts to be at least TR at HMA initiation. We censored observations one month prior to death and 4 weeks after the end of the last HMA cycle. TI duration is defined as number of weeks between last transfusion before achieving TI and first transfusion after TI. TI ends the week that the pt receives a transfusion. Time to achieve TI as well as duration of TI were assessed with Kaplan-Meier and Cox models, adjusting for patient's demographics, health status at HMA initiation, prior hospitalization for bleeding and infection, and prior erythropoiesis-stimulating agent and transfusion use. Analysis was also conducted among the subset of pts who were TD at time of first HMA.Results: Among 336 pts with LR-MDS who initiated HMA while RBC TR, median age was 76 years (interquartile range [IQR]: 71-81) and 87.2% were non-Hispanic white. Median time to HMA initiation from diagnosis of MDS was 44.3 (IQR: 13-117) weeks. 136 (40.5%) pts achieved RBC TI, with median time of 23 (95% confidence interval [CI]: 18-28) weeks (Figure 1a). Multivariate Cox model showed pts receiving ≥3 transfusions in the 8 weeks before HMA initiation were less likely to achieve TI (HR: 0.46, p<.01). Geographic region of residence also affected time to TI, with pts in the Northeast and West having lower probability of achieving TI compared to pts in the Midwest (hazard ratio [HR]: 0.44, 95% CI: 0.24-0.80 and HR: 0.56, 0.36-0.87 respectively). Medicaid dual coverage also had a positive association with achieving TI (HR: 1.92, p=.03). Median TI duration was 50 (95% CI:26-76) weeks (Figure 1b). Among 192 pts who were TD at HMA initiation, 64 (33.3%) achieved TI, with a median time to TI of 32 (95% CI: 24-71) weeks. Median TI duration was 60 (95% CI: 23-87) weeks. TD pts of older age (>85 years) showed a higher tendency of losing TI over younger pts (age 66-69) (HR: 4.50, p=.04).Conclusions: Achieving TI is an important quality of life outcome for MDS pts. Our results indicate that a substantial portion of HMA recipients who were RBC TD or TR at initiation achieved TI status, with slightly shorter time to achieve TI for those who initiated while TR compared to TD, and no significant difference in duration of TI. Our results are limited by inability to assess for lenalidomide use and lack of ascertainment of reason of HMA initiation (progression of LR-MDS versus ESA failure). Observed rates of achieving RBC TI in LR-MDS pts utilizing HMA were consistent with clinical trials. DisclosuresZeidan:Celgene: Consultancy; Gilead: Consultancy; Pfizer: Consultancy; Incyte: Employment; Abbvie: Consultancy; Ariad: Consultancy, Speakers Bureau; Agios: Consultancy; Novartis: Consultancy. Huntington:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy. Podoltsev:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Research Funding; Pfizer: Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Research Funding; Genentech: Research Funding; LAM Therapeutics: Research Funding; Daiichi Snakyo: Research Funding; Boehringer Ingelheim: Research Funding. Gore:Celgene: Consultancy, Research Funding. Ma:Celgene: Consultancy; Incyte: Consultancy. Davidoff:Celgene: Research Funding.

What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

What Is the Optimal Time to Initiate Hypomethylating Agents (HMA) in Higher Risk Myelodysplastic Syndromes (MDS)?

Risk of Invasive Fungal Infections in Patients with High-Risk MDS and AML Receiving Hypomethylating Agents

IntroductionAcute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients are at risk of invasive fungal infection (IFI) due to prolonged neutropenia related to the underlying diseases and the induction chemotherapy required to treat them. The risk of IFI specifically in AML or MDS patients treated with hypomethylating agents (HMA) has not been fully elucidated, with previous publications reporting various prophylaxis practices and IFI incidences from 3.3% to 14.4%. We sought to characterize the incidence of IFI in patients with MDS and AML who received azacitidine (AZA) or decitabine (DAC) at our institution.MethodsA retrospective cohort study was performed to evaluate the incidence of IFI in adults receiving between 10/1/10 and 10/1/17. Patients were included if they received at least two cycles of either drug and were diagnosed with AML, MDS with a revised international prognostic scoring system (R-IPSS) score of at least 3.5, or chronic myelomonocytic leukemia (CMML) categorized as intermediate 2 or higher risk using CMML-specific prognostic scoring system (CPSS). Patients were excluded if they received mold-active antifungal prophylaxis at any time during HMA therapy prior to the development of an IFI, or if they received mold-active antifungal treatment when starting a HMA. The primary endpoint was the incidence of IFI, defined as proven, probable, or possible using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria (EORTC).ResultsSix hundred and fifty-one consecutive patients were screened, and 203 patients met inclusion criteria. The three most common reasons for exclusion were incomplete data (n=158), receipt of fewer than two cycles of a HMA (n=138), and receipt of mold-active antifungal treatment at the time of HMA initiation or mold-active antifungal prophylaxis at any point during HMA therapy (n=86). Six patients had two distinct episodes of HMA therapy separated by either an allogeneic stem cell transplant or a treatment other than HMA; thus 209 episodes of treatment occurred amongst 203 patients. Overall, the study population was elderly with the median age of 69, and 59% of the patients were male. Fifty-one percent of patients had AML, while 49% had MDS or CMML; 72% received AZA. The median number of cycles of HMA utilized was five. Most patients were treatment-naïve (59% AML and 87% MDS had no prior therapy). A significant portion of the group (25.8%) was neutropenic on cycle 1 day 1 (C1D1) of HMA. Other pertinent baseline characteristics of the study population are displayed in Table 1. We identified 20 cases of IFI, with an overall incidence of 9.6%. Most IFI were possible cases according to the EORTC criteria (13/20, 65%), but there were 3 culture-proven cases. The possible cases all met the host criterion of neutropenia and 12 of 13 met the clinical criterion of lower respiratory tract infection based on imaging. Organisms isolated on culture included Aspergillus spp., Fusarium spp., and Scedosporium spp. A diagnosis of IFI was made at a median of 3 cycles of HMA, with the majority (85%) diagnosed within the first four cycles. Among the 20 cases of IFI, 12 were diagnosed while receiving AZA and 8 were receiving DAC. More than half of the patients who developed IFI were neutropenic on C1D1. These patients had a significantly higher risk of IFI compared to non-neutropenic patients (20.4% vs. 5.8%, p=0.0051). When other baseline characteristics were analyzed, patients with therapy-related MDS (t-MDS) compared to de novo MDS were more likely to have an IFI (20.8% vs. 5.1%, p=0.0314). Patients with de novo AML also had a higher incidence of IFI compared to AML from an antecedent MDS/MPN (15.4% vs. 2.4%), however this did not reach statistical significance (p=0.07). Additional comparisons are described in Table 2.ConclusionIFI occurred in 9.6% of patients treated with HMA, but was observed in 20.4% of those who were neutropenic on C1D1 of HMA. Another potential risk factor identified was t-MDS versus de novo MDS. Prospective evaluation of mold-active antifungal prophylaxis in patients with MDS or AML who are neutropenic at the start of HMA therapy is warranted. DisclosuresFrey:Novartis: Consultancy; Servier Consultancy: Consultancy. Perl:Arog: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Kite Pharma: Other: Advisory board; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment.

Evaluation of Salvage Induction Chemotherapy Regimens in Higher Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia after Hypomethylating Agent Treatment Failure

▪Background. Hypomethylating agents (HMA) are standard therapy for patients with higher-risk MDS and AML patients (pts) declining induction chemotherapy. However, >60% do not respond and all responding patients ultimately relapse. Prognosis after HMA failure is poor, with median overall survival (OS) of 4-6 months (m) and 2-year survival of 15%. Second-line intensive chemotherapy (IC) can reduce disease burden and serve as a bridge to allogeneic stem cell transplantation. To date, no large-scale study has focused on HMA failure pts and there is no standardized induction regimen. This retrospective, multicenter cohort study compared clinical responses, cumulative incidence of relapse (CIR), and median OS for different induction chemotherapy regimens given after HMA failure in MDS and AML pts.Methods. Pts from 11 centers treated between January 2005 to September 2015 were analyzed. Inclusion criteria was age 18 years or older, diagnosis of higher-risk MDS (IPSS Int-2 or high) or AML, failure to respond or progression of disease after at least 1 HMA cycle, and treatment with an intensive chemotherapy (IC) regimen after HMA failure. Response was evaluated per AML 2003 IWG criteria (CR + CRi), OS was calculated from time of induction to death or last follow-up, CIR was calculated from time of response to IC to relapse or last follow-up. All statistical analyses were adjusted on region (Europe vs US).Results. Of 366 included pts, 203 received 7+3, 56 received intermediate to high-dose Aracytine (IDAC), and 107 received a nucleoside analogue (NA)-based regimen (fludarabine, cladribine, clofarabine). Baseline demographics (sex, age, IPSS cytogenetic risk stratification, and prior number of HMA cycles) were similar between the treatment groups (table1). For the whole cohort, the overall response rate to chemo was 39.6%, 8-week mortality was 7.9%, the median OS was 10m (95%CI [8-12m]) and the cumulative incidence of relapse was 50% at 1 year and 71% at 2 years. In univariate analyses, history of therapy related myeloid neoplasm, adverse cytogenetic risk, and use of 7+3 or NA vs IDAC negatively impacted chance of response. Cytogenetic risk stratification was the only variable that impacted response in multivariate analyses (MVA) (45%, 46%, and 28% for favorable, intermediate, and unfavorable group respectively, p=0.005). Factors associated with significantly shorter median OS in MVA included diagnosis of AML at the time of initiation of HMA (6m vs 11m for AML vs MDS, p=0.006), adverse cytogenetics (15m, 10m, 7m for favorable, intermediate, and unfavorable groups, respectively, p=0.003), prior IC before HMA (8m with vs 11m without IC, p=0.001), and progression of disease at the time of HMA failure (9m with vs 20m without, p<0.001). There was no impact on OS of the induction regimen (Figure 1A). The cumulative incidence of relapse after IC was significantly increased for patients receiving IC before HMA (median CIR of 8m with vs 14m without, p=0.006) and progression at the time of HMA failure (9m with vs 17m without, p=0.05). Allogeneic transplantation was performed in 95 pts (26%), including 53 pts in complete response after induction (37% of responders). In a landmark analysis performed at 6 months after IC, transplanted pts had improved OS vs non-transplanted pts (25m vs 13m, p<0.001, Figure 1B). Moreover, no long-term survival was observed in the cohort of responding patients who were not transplanted.Conclusions. This large cohort of patients treated with IC after HMA failure confirms the relatively dismal outcome of this patient group. No induction strategy is superior for outcomes of interest, nor more toxic. IC-post-HMA is a valid treatment option, with response rates and transplant rates that exceed what is observed with other treatment modalities. The benefit of IC-post-HMA may be maximized by patient selection: non-adverse cytogenetics, no prior exposure to IC, and availability of an allogeneic donor seem to be the key factors. [Display omitted] [Display omitted] DisclosuresKomrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Ades:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pleyer:Celgene: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria. Vey:Sunesis: Honoraria. Almeida:Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Shire: Speakers Bureau. Gore:Celgene: Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

The Use of Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity ( 20%), BM blast percentage ( 20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Disclosures Podoltsev:Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Fusion Transcript Reduction in Core Binding Factor Acute Myeloid Leukemia: Maintenance Strategy with Hypomethylating Agents

Introduction: Recurrent translocations, t(8;21) or inv(16), in core binding factor acute myeloid leukemia (CBF-AML) are amenable to monitoring for minimal residual disease (MRD) with reverse transcriptase polymerase chain reaction (RTPCR). Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest. Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML. We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacytidine (AZA), can be used for MRD elimination to ultimately prolong relapse free survival.Methods: We performed a retrospective analysis of 23 patients with CBF-AML who received HMA after fludarabine, cytarabine and G-CSF (FLAG) with low dose gemtuzumab or idarubicin induction/consolidation. RTPCR from peripheral blood or bone marrow was obtained approximately every 3 months. Mutations in KIT, FLT3ITD, FLT3D835 and RAS genes were tested at baseline.Results: A total of 23 patients [t(8;21)=15 and inv(16)=8] received maintenance HMA. The reason for transition to HMA was persistent PCR positivity in 13 patients (57%), prolonged myelosuppression precluding chemotherapy based consolidation in 9 patients (39%), and molecular relapse after allogeneic stem cell transplant (SCT) in 1 patient (4%). Three of these patients received salvage clofarabine, cytarabine and idarubicin (CIA) for relapsed CBF-AML after FLAG based therapy and then went on HMA for molecular MRD. Of 23 patients, 21 received DAC and 2 received AZA. Median age at diagnosis was 53 (range, 23-70). Patients received a median of 6 cycles of FLAG based induction/consolidation (range, 1-7) prior to transitioning to HMA. The median number of HMA cycles received was 6 (range, 1-17). Seventeen patients had detectable MRD (RTPCR ≥ 0.01) at initiation of HMA maintenance with a median RTPCR of 0.06 (range, 0.03-0.91). All 17 patients were in morphologic and cytogenetic complete remission (CR) when HMA was initiated. Of these 17 patients, 5 patients (29%) had progressive disease post HMA initiation, including 1/7 with t(8:21) and 4/10 with inv(16). The RTPCR values preceding HMA in these 5 patients were 0.34, 0.06, 0.08, 0.01, and 0.01, respectively (median=0.06). All 5 patients had an increase in the RTPCR value soon after the initiation of HMA. RTPCR for these 5 patients following the first or second cycle of HMA was 3.84, >100, 77.48, 1.33, and 0.17, respectively. Four [inv(16)=3 and t(8;21)=1] of these 5 patients had a RAS mutation, while the patient with t(8;21) had a concomitant KIT mutation, and another patient with inv(16) had a FLT3D835 mutation. All five patients failing HMA proceeded to SCT, and 3 are alive and disease free post SCT. For the 12 patients without HMA failure, the median RTPCR at HMA initiation was 0.06 (range, 0.01-0.91). Unlike the HMA failure subset described above, 11 of these patients had a reduction in RTPCR by first or second subsequent measurement following initiation of HMA. One patient is in early follow up. All 6 patients who started HMA with undetectable MRD remain MRD negative (RTPCR < 0.01) and in remission. Eight patients continue on maintenance therapy. Median follow up is 11.3 months (range, 2.9-67.7).Conclusions: Despite a favorable prognosis in CBF-AML, relapse remains the primary cause of treatment failure. Identifying patients who are more likely to relapse will be beneficial in extending relapse free survival. Hypomethylating agents can potentially be used in patients with detectable RTPCR to prolong remission. Determining which patients would benefit most from this therapy is an important task. This data suggests that patients with low levels of RTPCR (between 0.01 and 0.05) following induction/consolidation chemotherapy might benefit most from maintenance HMA, particularly those that have a reduction in RTPCR on first or second subsequent measurement following initiation of hypomethylating agent therapy. DisclosuresDaver:ImmunoGen: Other: clinical trial, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria.

Clinical Outcome of Hypomethylating Agents in Hypocellular MDS: Mayo Clinic Experience

Introduction: Hypocellular myelodysplastic syndrome (h-MDS) represents only a small portion of MDS, of which, the clinical significance and outcomes are not well understood. Both laboratory and clinical evidence suggests that h-MDS shares immune-mediated pathogenic mechanisms similar to acquired aplastic anemia. As a result, immunosuppressive therapy (IST) has been the mainstay treatment. Since h-MDS is poorly understood and reported response rates to IST vary, we retrospectively reviewed the outcome of our patients with hypocellular MDS and identified the effectiveness of alternative therapy using hypomethylating agents (HMA).Methods: AllMDS patients over a 13-year period (June 1997 to May 2010) were captured after an IRB approval was obtained. Patients' demographics, labs, bone marrow aspirates and biopsies as well as cytogenetic data were collected. We used the currently accepted age-adjusted criteria to define hypocellularity as ≤ 30% in patients <70 years old, and ≤20% in >70 years old. Only patients with available response data were included in the final analysis. Survival estimates were calculated using Kaplan-Meier curves.Results: We identified 65 (8%) h-MDS patients from a cohort of 827 adult MDS. Median age was 68 years (range, 20-90), with 69% males. The largest group of patients were RAEB-1 at 9 (14%) and RAEB-2 at 14 (22%) along with RCMD at 18 (28%) and 15 (23%) MDS-U, 2 (3%) MDS 5q, 4 (6%) RARS and 2 (3%) were considered atypical. Cytogenetic analysis was normal in 17 (26%) with 7 (11%) having trisomy 8, and 11 (16%) and 14 (22%) having abnormalities of chromosome 7 and 5, respectively. IPSS-R were very low, low, intermediate, high, and very high in 4%, 30%, 28%, 21% and 17%, respectively. Leukemic transformation (LT) occurred in 6 (9%). The 4 year overall survival and progression free survival was 35% and 34%, respectively. Median overall survival and progression free survival was 30.2 and 29.7 months, respectively.Nine out 65 h-MDS patients were treated with a HMA, azacitidine (4) or decitabine (5). The median age of patients was 71 years (range, 66-85) with 6 (66%) being males. The median cellularity of the diagnostic bone marrow was 15% with the majority of patients presenting with RAEB-1 (11%) and RAEB-2 (55%) classification and 2 (22%) cases of RCMD as well as 1 (11%) case of MDS with isolated 5q. Cytogenetic analysis was normal in 3 (33%). IPSS-R were low in 1 (11%), intermediate in 4 (44%), high in 1 (11%) and very high risk in 3 (33%).The median time to initiation of a HMA from diagnosis was 5 months with response assessed at a median of 4.2 months. Two patients had received prior therapy including lenalidomide (for MDS 5q) and one had 1 cycle of trial therapy. Two patients (22%) achieved a marrow complete remission at a median time of 2.95 months; with one case of relapse at 9.8 months using HMA. Three patients (33%) had LT at a median time of 7.9 months post initiation of HMA. Median overall survival of patients with LT was 20 days. A total of 4 (44%) patients remain alive with a leukemia free survival of 67% at 2 years. In comparing to h-MDS patients without HMA treatment versus HMA treated, median OS was 28.2 vs 50.9 months (p=0.41) and PFS was 28.1 vs 40.6 months (p=0.69), respectively.Conclusions: The results from our clinical experience confirm that hypocellular MDS is a rare variant and that it is distinct from normocellular/hypercellular MDS. Two thirds of h-MDS received HMA for the treatment of higher risk disease (RAEB1-2). HMA has some efficacy in h-MDS. Further studies are warranted to better understand the clinical significance and outcomes of hypocellular MDS. DisclosuresBinder:American Society of Hematology: Research Funding. Al-Kali:Celgene: Research Funding.

Comparative Effectiveness of Azacitidine Versus Decitabine Among Older Adults Diagnosed with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Background: The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of MDS, but only azacitidine has been shown to have an overall survival (OS) advantage over conventional care in a randomized phase III trial for patients with HR-MDS. Azacitidine has not been directly compared to decitabine in clinical trials of patients with HR-MDS. In addition, it is unknown whether the OS observed with azacitidine in clinical trials would hold in "real-world" clinical practice.Methods: In a retrospective cohort study, patients were identifiedfromthe Surveillance, Epidemiology, and End Results-Medicare database using the following criteria: 1) having an International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) code for MDS; 2) diagnosedbetween 1/1/2005 and 12/31/2011; 3) aged ≥66 years at diagnosis; and 4) enrolled in Medicare Parts A and B continuously through death or end of study (12/31/2013). Patients with the ICD-O-3 code 9983 (RA with excess blasts) were classified as having HR-MDS. Healthcare Common Procedural Coding System codes identified outpatient treatment with azacitidine and decitabine. Patients who had <10 days of treatment with azacitidine or decitabine, and patients who received both HMAs were excluded. We used Medicare claims to calculate a modified Elixhauser comorbidity count and disability status. Median household income and percentage of adults with high school education or less were derived from census data. Kaplan-Meier analysis was used to estimate OS probabilities from date of HMA initiation until death or end of study. Multivariate Cox proportional hazard models were utilized to analyze covariate-adjusted survival and estimate hazard ratios. The covariates included year of diagnosis, age at diagnosis (66-69, 70-74, 75-79, and 80+ years), gender, race, % of adults with high school education or less, median household income, the modified Elixhauser comorbidity count and disability status score, time from MDS diagnosis to HMA initiation, and pre-HMA use of erythropoiesis-stimulating agents.Results: Of 27,422 patients diagnosed with MDS, 2,025 were eligible for inclusion; 1,580 (78%) received azacitidine and 445 (22%) received decitabine. Median age at diagnosis was 77 years, 64% were males, and 91% were white. Patients received a median of 6 cycles. A total of 1,205 patients (60%) received ≥4 cycles of either HMA. By end of follow-up, 1,729 patients (85%) had died. Median OS for the entire cohort from time of HMA initiation was 15 months (95% Confidence Interval [CI]: 14-15 months). Of the 532 HR-MDS patients who received HMAs, 76% received azacitidine and 24% received decitabine. The median OS for these 532 patients was 12 (95% CI: 11-14) months, and there was no statistical difference in median OS between patients who received different HMAs; 11 (95% CI: 10-14) months for azacitidine vs. 12 (95% CI: 11-16) months for decitabine, p = 0.26, Figure. In multivariate analysis of OS among patients with HR-MDS, the hazard ratio was 0.99 (95% CI: 0.78-1.24) indicating no significant improvement (or decrement) for decitabine compared to azacitidine.Conclusions: In this large cohort of HR-MDS patients treated with HMAs, we found no significant differences in OS between azacitidine versus decitabine. Additionally, we found significantly shorter OS for HR-MDS patients treated with azacitidine in real-world clinical practice compared to results from randomized trials (11 vs. 24.5 months). Although the shortened OS could be partly related to the older age of this patient cohort, our data provides a real-life reference for counseling older MDS patients regarding this drug's potential benefits. Additionally, these results provide rationale for older patients with HR-MDS to consider enrollment into clinical trials upfront, potentially in HMA-based combinations, rather than defaulting to the use of "standard-of-care" HMA monotherapy. [Display omitted] DisclosuresPrebet:CELGENE: Research Funding. Gross:21st-Century Oncology LLC: Research Funding; Johnson and Johnson: Research Funding; Medtronic: Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Ma:Incyte Corp: Consultancy; Celgene Corp: Consultancy. Davidoff:Celgene: Consultancy, Research Funding.

Use of hypomethylating agents and associated care in patients with myelodysplastic syndromes: a claims database study

Objective:The purpose of this study is to describe patterns of hypomethylating agents (HMA) use and to compare treatment outcomes of decitabine (DAC) and azacitidine (AZA) with respect to transfusion dependence and the use of erythropoiesis-stimulating agents (ESA) treatment in commercially-insured patients with Myelodysplastic Syndromes (MDS).Research design and methods:A retrospective study using MarketScan Research Data, a large claims database studied patients who received DAC, AZA, or Supportive Care (SC) with at least two claims for MDS between January 1, 2006 and December 31, 2008. Poisson regressions were used to compare DAC and AZA on post-index number of red blood cell/platelet (RBC/PLT) transfusions and ESA treatment, controlling for age, gender, Charlson Comorbidity Index (CCI), time to HMA initiation, number of HMA cycles, and pretreatment RBC/PLT or ESA claims. No other adjustment for disease severity was made.Results:Approximately 48% of the patients were males with a mean age of 73 years (N = 2525). There were 37 DAC-treated and 60 AZA-treated patients. The length of follow-up did not significantly differ between the DAC- and AZA-treated groups (DAC = 349.2; AZA = 350.5 days); however, the number of days from MDS diagnosis to HMA therapy initiation was longer in the DAC cohort than in the AZA cohort (mean 93.7 days vs. 50.8 days, respectively, p = 0.029). Both DAC- and AZA-treated patients received similar number of treatment cycles (mean: 4.8 vs. 5.6 in DAC vs. AZA, p > 0.05), with means of 4.6 days per cycle for patients receiving DAC and 7.4 days for those receiving AZA (p = 0.003). Following treatment with HMA using Poisson regression analysis, DAC-treated patients had significantly lower use of RBC/PLT transfusions (RR 0.206, p = 0.034) and similar use of ESAs compared with AZA-treated patients. Limitations of the study included the small sample size, and the fact that the majority of patients were unspecified regarding their International Prognostic Scoring System (IPSS) risk category, which did not allow for accounting for differences in disease severity.Conclusions:In MDS patients treated with an HMA, treatment with DAC was associated with less frequent transfusions than with AZA treatment. Further studies with the ability to control for disease severity are warranted.