Lower-risk Non-del 5q Myelodysplastic Syndromes Research Articles

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.

Lenalidomide Treatment For Lower Risk Non-Deletion 5q Myelodysplastic Syndromes Patients Yields Higher Response Rates When Used Prior To Azanucleosides

▪ IntroductionLenalidomide (LEN) is the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndromes (MDS) with chromosome 5q deletion (del 5q). In the MDS-002 study, 26% of lower risk transfusion dependent MDS patients became red blood cell transfusion independent after LEN treatment. National Comprehensive Cancer Network (NCCN) clinical guidelines list LEN as a second line treatment alternative for transfusion dependent anemia in lower risk non-del 5q MDS after azanucleosides failure. The response rate to LEN after azanucleosides failure, however, is not known given that the MDS-002 study preceded FDA approval of azanucleosides. To address the best sequence of LEN to optimize response potential in lower risk MDS, we examined the response rates to LEN in non-del 5q lower risk MDS when offered as first line after (erythroid stimulating agents) ESA's or after azacitidine failure. MethodsThis was a retrospective study conducted using the Moffitt Cancer Center (MCC) MDS database. We identified patients with lower risk MDS who received both LEN and azacitidine as first or second line therapy after erythroid stimulating agents. Lower risk MDS was defined according to the international prognostic scoring system (IPSS) Low or intermediate-1 (int-1) risk groups. The primary endpoint was to compare rates of erythroid hematological improvement (HI-E) between the group of patients who received LEN as first line therapy followed by azacitidine as second line (LEN 1st line group) and those who received LEN as second line therapy after azacitidine (LEN 2nd line group). HI was defined according to international working group criteria (IWG 2006). Chi- square test was used for categorical variables, T-test was used for continuous variables, and Kaplan Meier estimates for overall survival. All analyses were conducted using SPSS statistical software (IBM version 21) ResultsWe identified 63 patients who received both azacitidine and LEN as first and second line where 37 patients were in group 1 (LEN 1st line) and 26 patients were in group 2 (LEN 2nd line). Baseline characteristics between the two groups are summarized in Table-1. There were no statistically significant differences between the 2 groups in terms of mean age at diagnosis, gender, WHO subtype, revised IPSS, or mean blood counts. The majority of patients had refractory cytopenia with multilineage dysplasia (RCMD) and had low risk revised IPSS .Table-1Baseline characteristicsLen 1st line(n=37)Len 2nd line(n=26)P-valueAGEMean66.365.70.85GenderMale26 (70%)18 (69%)0.6Female11 (30%)8 (31%)WHO subtypeRARARSRCMDRAEB-1CMMLMDS/MPN4 (11%)9 (24%)14 (38%)5 (14%)2 (5%)3 (8%)4 (15%)7 (27%)13 (50%)1 (4%)1 (4%)00.3Revised IPSSVery lowLowIntermediateHighVery High4 (11%)20 (57%)8 (23%)3 (9%)05 (19%)17 (65%)3 (12)01 (4%)0.25CBCHgb (g/dl)PlateletsANC9.12362.89.12332.30.90.90.47The rate of HI-E was 38% (n=14) among LEN 1st line group compared to 12% (n=3) in LEN 2nd line group. (p=0.04). There was no difference in overall survival (OS) among the two groups with a median OS of 104 months and 87 months, respectively, p=0.55. There was no difference in AML transformation rate, 5.4% (n=2) and 11% (n=3) among the two groups, respectively, p=0.33. There were no differences in response rates to azacitidine among the two groups. Among the Len 1st line group response to 2nd line azacitidine was 38% (n=14) compared to 35% (n=9) among those who received azacitidine as first line followed by LEN as 2nd line. (p=0.69). ConclusionLEN yields a higher rate of HI-E in non-del 5q lower risk MDS when used as first line therapy. If validated in a larger cohort, LEN should be considered for 1st line therapy after ESAs rather than after azacitidine failure. Responses to azacitidine were similar among the two groups, indicating no adverse effect of LEN on azacitidine response. Disclosures:Komrokji:Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.