Azacitidine Use Research Articles

Treatment strategy at the decision for allogeneic transplantation in patients with myelodysplastic syndrome in the era of azacitidine: A KSGCT prospective study

The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses.In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.

CPX351 Has Short Remission Duration but Is an Effective Bridge to Allogeneic Transplant in High Risk AML: Results from Canadian Real-World Multi-Centre Study

Background and objectives: CPX-351 is a liposomal formulation of daunorubicin and cytarabine in a fixed synergistic ratio of 5:1. It has been approved by both the FDA and EMA for use in high risk AML including therapy related AML (t-AML) and AML with myelodysplastic related change (AML-MRC). When compared with '3+7', CPX-351 resulted in superior OS (9.56 vs 5.96 months) and overall response rate (47.7% v 33.3%; P = .016; Lancet JCO 2018). However, this is little data of CPX-351 in a real world setting. The primary objective of our multi-centre study was to assess outcomes and associated toxicities of CPX-351 in these high risk AML patients. Methods: Patients aged 18 and over who were treated with CPX-351 and who met the WHO criteria for t-AML and AML-MRC were included in the study. Retrospective data was collected from 6 centres throughout Canada. Targeted sequencing was performed on DNA samples using the TruSight Myeloid Sequencing Panel isolated from peripheral blood or bone marrow samples at diagnosis. Overall survival (OS) and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Results: Fifty patients treated with CPX-351 were identified from six centres. Baseline characteristics are seen in Table 1. Cytogenetics was available in 45 (90%) patients and an abnormal karyotype was seen in 30 (60%) patients. Monosomal (33%) and complex (28%) karyotype were the most common chromosomal abnormalities seen. Targeted sequencing was performed on 64% patients (32/50) and the average number of mutations was 2(0-7). RUNX1 was the most commonly mutated gene found in 22% (7/32), followed by SRSF2 in 19% (6/32) with ASXL1 and NRAS both at 16% (5/32). Other commonly mutated genes were NPM1, IDH2, DNMT3a and TP53 all occurred at a frequency of 12% (4/32). Of the 10 patients (20%) that were FLT3 mutated (80% ITD and 20% TKD), 5 patients received the FLT3 inhibitor midostaurin in combination with CPX-351. Assessing treatment responses, 50% (25/50) of patients achieved a complete remission (CR) or a complete remission with incomplete recovery (CRi). Median neutrophil recovery (≥500/μl) was 32 days (range 18-68) and median platelet recovery (≥50 000/μl) was 34 days (range 19-70). Proven or probable fungal infection was seen in 10 (20%) patients. 30 day mortality was 4% (2/50) and 60-day mortality was 10% (5/50). The median CR duration was short at 7.17 months. Of the 25 patients who did not achieve a CR, 6 (24%) had prior azacitidine use for MDS suggesting CPX-351 may not have activity in this group of patients. Median follow up was 7.43 months (range 0.2 to 18 months). OS was 44% at 12 months (0.28-0.58 95% CI) and 29% at 18 months (Fig 1; 0.13-0.46 95% CI). PFS was 28% at 12 months (0.15-0.43 95% CI) and 18% at 18 months (0.06-0.39 95% CI). There were no differences in OS when stratified by ELN risk (p=0.25), adverse risk cytogenetics (p=0.1485), or poor risk mutations such as FLT3-ITD (p=0.29), RUNX1 (p=0.123) or ASXL1 (p=0.06). This is consistent with previous studies, which suggest that CPX-351 overcomes the poor prognosis associated with these mutations. 18 (36%) patients received an allogeneic stem cell transplant (ASCT) in CR1. Patients who received a allogeneic transplant had significant improvement of OS of 62% at 18 months compared to those who did not receive a transplant of 14.5% at 18 months (Fig 2; p=0.0008). Conclusion Our study reveals that CPX-351 produces high remission rates in patients with AML with a similar efficacy and toxicity profile seen in the Phase 3 trial data (Lancet JCO 2018). However, response rates are short and therefore CPX-351 is most effective when used as a bridge for allogeneic stem cell transplantation in this high risk population. Disclosures Assouline: AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding. Brandwein:Celgene: Honoraria; Astellas: Honoraria; Taiho: Honoraria; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer: Consultancy; Takeda: Research Funding; Novartis: Honoraria. McNamara:Novartis: Honoraria. Sanford:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Schimmer:Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria.

Continuity and efficacy of real-world use of azacitidine.

Long-term azacitidine (AZA) treatment is necessary for its maximal therapeutic effect. This study examined the continuity and efficacy of AZA treatment in real-world use. We conducted a retrospective study in 38 patients who had completed AZA treatment at the Ogaki Municipal Hospital between April 2011 and August 2019. The median number of AZA received cycles was 4. The number of AZA treatment cycles received was 1-3 cycles in 15 (39.5%), 4-6 cycles in 15 (39.5%), and ≥ 7 cycles in 8 (21.1%). The most common reason for discontinued AZA treatment was infection. Overall response rate was 33.3% in patients with discontinued AZA use (< 4 cycles) and 56.5% in patients with continued AZA (≥ 4). Median overall survival (OS) was 124 (15-529) days and 391 (132-2,825) days in the respective groups (p<0.01). The presence of peripheral blood blasts (PBs) was a prognostic factor for continuation of treatment (p =0.03). Discontinued AZA treatment due to infection (p <0.01), and PBs (p =0.03) were unfavourable prognostic factors for OS. Long-term AZA use is beneficial for improvement and survival. Infection control and presence of PBs were important factors for continuing AZA. These data support the idea of long-term continued treatment with AZA for optimal benefit to patients.

Azacitidine Improves Outcome in Patients with MDS and AML with High Risk Cytogenetics - a Single Center Experience

Azacitidine is a novel hypomethylating agent shown to improve leukaemia free survival and overall survival in comparison with other modalities of treatment in MDS and AML patients. There is proven reduction in transfusion requirements by improvement in haematological parameters with continuous azacitidine use. However azacitidine benefit in high risk cytogenetics group is unclear. Recent retrospective study from GESMD and GFM registries showed that Azacitidine improves outcome in higher‐risk MDS patients with chromosome 7 abnormalities. Here we report our experience in high risk cytogenetics group including complex karyotype.Methodology:-We retrospectively reviewed patients with MDS and AML who received Azacitidine at the Heart of England NHS Foundation Trust from April 2012- January 2018. Patient's demographic data, disease characteristics, treatment, outcome and follow up data were obtained and all patients were included irrespective of the number of the cycles.Results57 patients were included in the analysis. Median age of treatment was 73.9 years. Median number of cycles was 6 (range from 1 to 43). There were 68% of MDS patients, 22.8% of AML and 8.8% of CMML2 patients in the cohort .Varying degree of performance stage was noted including ECOG 0,1 and 2 at 40.4%,43.9% and 7.7% respectively. 9 patients had monosomy 7 and 11 patients had complex karyotype (3/>3). 42.1% had high risk cytogenetics.At presentation, median Hb was 9g/dl, Neutrophil count was 0.7x109/l and platelet count was 41x109/l. Median bone marrow blast percentage was10% and median RIPSS score was 6.5. Causes of death were mainly disease progression and sepsis. 42.2% died due to disease progression and 35.1% died due to sepsis.Overall survival was not affected by age, Bone marrow median blast percentage and median neutrophil count, however, survival was affected by presenting peripheral blast percentage, cytogenetic risk group and was statistically significant (P<0.05)Overall, median progression free survival (PFS) was 19monts while median overall survival (OS) was 12 months. There was no statistically significant PFS or OS difference for patients who had varying performance stage.High risk cytogenetics group:Among high risk cytogenetics group, 21% Patients had red cell transfusion independence at 6 months, 28% had an improvement in the neutrophil count to >1x10^9/L at 6 months. 25% patients had doubling of platelet count at 3 months leading to platelet independence and 17.8% maintained platelet transfusion independence. A significant difference was noted in the group of who had high risk cytogenetic versus other cytogenetic risks with PFS of 15 and 29 months respectively, OS of 8 months and 15 months respectively. with high risk cytogenetics still had a PFS advantage with treatment.ConclusionAzacidine therapy has benefited for the patients who had advanced age AML CMML and MDS who has non high risk cytogenetic based on IPSS-R risk categorization. However, the group of patients with high risk cytogenetic considered historically very poor survival had considerable PFS and OS benefitting treatment rather than best supportive care. DisclosuresMurthy:celgene: Consultancy, Other: Travel grant for educational meeting; Abbview: Other: Travel grant for Educational meeting. Kartsios:Bayer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Boehringer Inglelheim: Consultancy, Honoraria, Speakers Bureau. Nikolousis:Celgene: Consultancy, Other: Travel grant for educational meetings.

62 - Real-World Azacitidine use does not Replicate AZA-001 Results in Higher-Risk MDS/Low-Blast Count AML: Audit of 1101 Patients in Ontario, Canada

62 - Real-World Azacitidine use does not Replicate AZA-001 Results in Higher-Risk MDS/Low-Blast Count AML: Audit of 1101 Patients in Ontario, Canada

Deficiency of Current Acute Myeloid Leukemia (AML) Response Criteria to Predict Response to Hypomethylating Agent Therapy: The Value of Long-Lasting Stable Disease

Background: International Working Group (IWG) has set criteria in 2003 for response assessment in patients with AML; at which time intensive chemotherapy was the main therapy (Cheson, JCO 2003). Hypomethylating agents (HMA) were approved shortly after for the treatment of elderly AML (Fenaux, JCO 2009; Dombret et al Blood 2015). Although few patients achieve a deep response, the majority will have stable disease (SD), some of which could last several months while patients continue to receive HMA and gain clinical benefit. We hereby describe outcomes for patients who achieve SD with HMA for the treatment of elderly unfit AML patients.Methods: A total of 56 AML patients’ data from Feb 2007 to June 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients were considered for our study if they received HMA as frontline therapy for their AML. Patients who received HMAs after induction chemotherapy failure or for their MDS were excluded. Response was identified based on 2003 IWG AML response criteria. Patients with SD were categorized into short-lasting (<6 cycles of HMA, cohort 1) or long-lasting (≥6 cycles of HMA, cohort 2) SD.Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10.Results:i)Characteristics: Fifty six AML patients were treated with HMA as frontline therapy with median age of 76 years (range, 59-91), 68% of which were males. Therapy related AML (T-AML) was seen in 2% of the cases. Cytogenetics were favorable risk in 2%, intermediate in 62%, and poor in 36%. Complete remission (CR) was found in 10 (18%) patients, CR with incomplete count recovery in 3 (5%), partial remission (PR) in 3 (5%) patients. Forty patients were non-responders (SD).ii)Characteristics of HMA SD cohorts: Upon comparison of cohort 1 versus cohort 2 there was no statistical significance in median age, white blood count, absolute neutrophil count, platelets, peripheral blood and bone marrow blasts, bone marrow cellularity and sex. Median number of cycles was expectedly higher in cohort 2 vs 1 (9 vs 2, p<0.0001). Intermediate cytogenetic risk was more common in cohort 2 vs 1 (90% vs 43%, p=0.006), while poor risk was more common in cohort 1 vs 2 (57% vs 10%, p=0.006). Only 10% had complex karyotype in cohort 2 compared to 50% in cohort 1 (p=0.017). NPM1 mutation was absent in all cases, while FLT3 mutation was present 30% in cohort 1 and 25% in cohort 2 (p = 0.9). Decitabine was more commonly given in cohort 1 vs cohort 2 (80% vs 50%, p =0.07).iii)Clinical outcome of HMA SD cohorts: Median overall survival was higher in long-lasting SD patients (cohort 2) vs short-lasting SD (18 vs 4 months, p = 0.0002). Upon multivariate analysis, both age (p <0.0001) and long-lasting SD (p =0.01) were statistically significant for overall survival but not cytogenetics risk grouping nor type of HMA administered.Conclusions: Standard response criteria for AML by IWG were developed for intensive chemotherapy and do not apply to newer agents, specifically HMA. Stable disease (SD) could be meaningful to some elderly AML patients when treated with HMA. Intermediate cytogenetics and azacitidine use were more frequent in patients with long-lasting SD. Long-lasting SD did confer a survival benefit in elderly AML patients. Newer response criteria for assessing novel agents' efficacy are needed in this population. [Display omitted] DisclosuresTibes:Italfarmaco S.p.A.: Consultancy, Honoraria. Foran:pfizer: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; medscape: Honoraria; karyopharm: Honoraria; novartis: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Al-Kali:Novartis: Research Funding; Celgene: Research Funding.

Azacitidine Use in a Low Income Country, Effectiveness of a 100mg Fixed Dose

Azacitidine, a pyrimidine nucleoside analog of cytidine, causes hypomethilation of DNA. Currently FDA approved for treatment of low and intermediate MDS with complete responses around 50%. And Acute myeloid leukemia (AML) in the elderyIn the CALGB studies, the usual dose is 75mg/m2 in 28 day cycles, with dose modifications according to toxicity.In low income countries such as Mexico, one course of Azacitidine is around 500 dollars, median income in Mexico is 4,910 PPP (purchasing power parity); vs 30,616 in the USA. So, azacitidine treatment is far from reach for most of the common population, particularly those who do not have insurance.This is a retrospective observational study, of a compassionate use program of a fixed dose of Aza at 100mg. We analyzed data from patients that were treated with Aza between 2012 and 2016, and collected data in 2016. The aim of the study was to assess the effectivity of the fixed dose. For that purpose, we collected information from the physical and electronic file. We analyzed: Hemoglobin level before and after treatment, independence of transfusion, ANC recovery, number of courses, and overall survival. We conducted our research in a public institution in Mexico (Instituto Nacional de Cancerología) and a private institution (Medica Sur).We included acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients, regardless of age, previous treatment and comorbidities (we included patients with renal failure, hypertension etc.)We included 8 patients in our study, 6 males and 2 females, with a mean age of 69.9 years (49-87). We had 2 AML and 6 MDS.We had 2 high risk AML and according to IPSS-R: 1 very low, 2 low, 1 intermediate, 1 high and 1 very high risk MDS. As for the Karyotype we had 1 complex KT, 4 normal KT and 1 Del 7q Del 5q +8.All patients received at least one dose of Aza, with mean number of cycles of 4. We have a mean survival of 439 days (110-1385). 6/8 patients achieved transfusion independency within 3 doses of Aza. 6/8 patients achieved ANC but lost eventually lost response. 5/8 patients are alive in follow up. 3 patients died of infectious complications. 2 patients never achieved transfusion independence or ANC.The information recovered suggests that a fixed dose of 100mg is as feasible as a higher dose, at least when no other treatment or higher dose can be administered. We still are analyzing the survival data in order to find other bad prognosis factor within this population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Azacitidine Use in the Real World Does Not Replicate AZA-001 Results in Higher Risk MDS/Low Blast Count AML: An Audit of 1101 Patients in the Cancer Care Ontario Registry

▪Background: In the AZA-001 trial, azacitidine (AZA) altered the natural history of patients with higher-risk MDS (Fenaux et al., Lancet 2009) by significantly improving overall survival compared to conventional care regimens (24.5 months versus 15.0 months). Once approved for drug reimbursement by the provincial health ministry, Cancer Care Ontario (CCO) mandated that all eligible patients be enrolled in a prospective registry to ensure compliance with eligibility criteria and schedules of drug administration. Baseline characteristics were recorded and treatment response were to be submitted every 6 cycles of treatment. Our objectives were to audit this clinical program for results after 6 years and identify the prognostic markers for survival in a homogenous higher-risk MDS/low blast count AML patient population.Methods: Only higher-risk MDS patients (intermediate-2, high) as defined by the International Prognostic Scoring System (IPSS) and low blast count AML (20-30% blasts) treated with AZA in Ontario, Canada from June 1, 2010 to March 2, 2016 were eligible and included. Our primary outcome was overall survival (OS) from date of first AZA treatment. Our secondary outcomes were overall response rates and the predictors of OS including administration schedules, centre size or type (regional cancer versus community). Univariate and multivariable Cox proportional hazard model were used to determine the predictors of OS. Hazard ratios and generalized R2 (higher the R2, stronger association with OS) were also calculated.Results: 825 higher-risk MDS and 276 low blast count AML were included (n = 1101 total). Median age was 74 years (range 19 to 99), 65.2% were male and the IPSS scores were intermediate-2 (64.3%) and high-risk (35.7%). Sixty-six percent of patients were transfusion dependent (TD) at time of AZA initiation and 15.5% had received previous chemotherapy. By dosing schedule, 24.7% received AZA for 7 consecutive days (7d), 12.4% for 6 consecutive days (6d) and 62.9% by the 5-2-2 schedule. Overall, the median number of cycles received was 6 (range 1 to 67) and 8 (range 6 to 14) when restricted to the 692 (63%) patients who received at least 4 cycles of treatment. Dose reductions were seen in 33.3% of patients (mean 11.1 mg/m2 in those with reductions) and were more common over time (negative slope 0.178; p < .0001). Of those with repeat bone marrow (n = 293) best response was complete response (CR) in 16.7% and partial response (PR) in 10.6%. Of those without CR/PR/progressive disease on bone marrow (n = 814), 20.4% experienced hematologic improvement including those with marrow CR and marrow stable disease. The actuarial median survival was 11.6 months (95% CI 10.7- 12.4) with a significantly longer OS for MDS compared with low blast count AML (12.4 months vs. 9.6 months; p = .0002) and 16.7 months (95% CI 15.2-18.1) for those receiving at least 4 cycles. There was no difference in OS between the 3 dosing schedules (11.7 months (7d) vs. 10.2 months (6d) vs. 12.0 months (5-2-2); p = .87; figure 1A), regional cancer centre vs. community (11.3 months vs. 11.7 months; p = .19; figure 1B) or by centre volume (11.4 months < 50 patients vs. 11.6 months > 50 patients; p = .38; figure 1C). On univariate analysis, the following were predictive of OS: blast percentage, number of cytopenias, karyotype, IPSS, WHO classification, TD, greater transfusion burden and secondary MDS. The multivariate model with the highest R2 (13.5%) included blast percentage (p < .0001), karyotype (p < .0001), cytopenias (p = .038), TD (p < .0001) and secondary MDS (p = .0006) as summarized in the table below.Conclusions: In our large real world evaluation of AZA use in higher-risk MDS/low blast count AML, we validated the expected overall response rates to AZA but demonstrated a lower than expected OS compared to the AZA-001 trial. Reassuringly, survival did not differ by dosing schedules, centre volumes or center type (regional cancer vs. community). OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realized. This represents the largest real world evaluation of AZA in higher-risk MDS/low blast count AML and additional analyses are underway. [Display omitted] [Display omitted] DisclosuresMozessohn:Celgene: Honoraria. Buckstein:Celgene: Honoraria, Research Funding; Novartis: Honoraria.

Azacitidine Use After Allogeneic Stem Cell Transplantation—Results From the Polish Adult Leukemia Group

BackgroundRelapse of primary hematologic disease constitutes an important reason for failure of allogeneic hematopoietic stem cell transplantation (alloHSCT). There are very few treatment modalities for this indications. Therefore, there is a need for novel effective therapies and even more for the prevention of relapse. There are scarce data that azacitidine can be used for these purposes. MethodsAt the Polish Adult Leukemia Group, we retrospectively analyzed the results of azacitidine treatment after alloHSCT. Relapsing patients, patients with minimal residual disease/mixed chimerism, and patients in complete remission with high risk of relapse were analyzed separately. There were 17 patients, 6 with myelodysplastic syndrome, 11 with acute myeloid leukemia, 8 male, and overall median age of 56 years (range, 15–78); 7 patients received donor lymphocyte infusion (DLI). ResultsPatients treated because of relapse received a median of 3 (range, 1–6) cycles of azacitidine, patients receiving preemptive treatment received a median of 4 cycles (range, 2–6), and those on maintenance received a median of 5 cycles (range, 3–5). Toxicity was considerable, especially in relapse—neutropenia (67%), anemia (67%), thrombocytopenia (100%), serious infections (78%)—and preemptive settings. Median overall survival of patients treated for relapse reached 6.8 months (95% confidence interval [CI], 0.7–∞), with better survival observed in patients with temporary disease control (7.7 vs 4.7 mo) and without previous exposure to azacitidine (7.7 vs 3.4 mo). One-year overall survival reached 75% (95% CI, 13%–96%) for preemptive and 50% (95% CI, 0%–91%) for maintenance treatment. DLI did not aggravate graft-versus-host disease. ConclusionsEffectiveness of azacitidine in relapsing patients is disappointing. Azacitidine seems to be promising in preemptive and maintenance settings. Toxicity is considerable. Further research is needed.

Descriptive Analysis of Azacitidine Use in Four Adult University Teaching Hospitals in Quebec, Canada

Background: Azacitidine (5-AZA; Vidaza®), a pyrimidine nucleoside analog, is used in the treatment of myelodysplastic syndrome (MDS) and other hematological malignancies. Pharmacy directors gave the Therapeutic Drug Management Program (TDMP - www.pgtm.qc.ca) the mandate to evaluate 5-AZA use in four University Hospitals in Quebec, Canada.Objectives: Describe and review 5-AZA use for all indications in our hospitals.Methods: A review of pharmacy databases was performed to identify patients who received 5-AZA between January 1st 2010 and May 31st 2013. Files and medical records of every patient who received 5-AZA during the study period were reviewed to assess diagnostic (including International Prognostic Scoring System (IPSS) scores), treatment, response and non-hematological adverse events.Results: A total of 77 patients received 5-AZA during the study period, 56 (72.7 %) for the treatment of MDS, 15 (19.5 %) for acute myeloid leukemia (AML) and 6 (7.8 %) for chronic myelomonocytic leukemia (CMML). At the end of the study period, 31 patients were alive (14 were still on treatment), 35 patients had died and 11 were lost to follow up. Excluding the 14 patients still on treatment, 32 patients (50.8 %) received at least 6 cycles of 5-AZA.In the MDS population (76.7 % with an intermediate-2 or higher IPSS score), patients received a mean of 8.0 cycles (median = 6) and the overall benefit rate (OBR) (complete remission, partial remission, hematological improvement or stable disease) was 48.2 %. The median overall survival (OS) was 17.8 months and the median time to progression (TTP) was 9.7 months. MDS transformation to AML occurred in 16 patients after a mean of 9.9 months. Median time to transformation or death in the MDS population was 14.4 months.In the AML population, patients received a mean of 6.6 cycles (median = 5) and the OBR was 26.7 %. The median OS was 12.2 months and the median TTP was 6.5 months.In the CMML population, patients received a mean of 10 cycles (median = 5.5) and the OBR was 50% (3 of the 6 patients achieved stable disease).Across all patient populations, a 5-AZA dose of 75 mg/m2 for 7 days every 28 days was used in 77.8% of patients. Non-hematological adverse events were seen in 67 patients (87 %) but were mostly mild and most did not lead to delays or dose reductions (treatment intensity of 96 %).Conclusions: Our results show that 5-AZA had a more limited benefit in our real-life population when compared to published clinical trials (OBR of 44.2 % in MDS, AML and CMML populations combined compared to 60% and 61% and a mean exposition of 8.1 months compared to 10.3 to 11.4 months in the pivotal clinical studies (AZA-001 and CALGB 9221 respectively)). Considering that 5-AZA is often the only treatment we can offer these patients and considering its high cost, it would be of highest importance to wisely choose patients to whom we offer this treatment and to periodically re-evaluate its use (at least after the 6th cycle) to confirm the patient is benefiting from treatment. DisclosuresOlney:Cellgene: Honoraria; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy.

Lenalidomide Treatment for Lower Risk Nondeletion 5q Myelodysplastic Syndromes Patients Yields Higher Response Rates When Used Before Azacitidine.

Lenalidomide and azanucleosides are commonly used to treat anemic patients with lower-risk myelodysplastic syndromes (LR-MDS) without chromosome 5q deletion (non-del5q) after failure of treatment with erythropoiesis-stimulating agents (ESAs). Nonetheless, response rates to lenalidomide after azanucleosides treatment failure and their optimal sequencing after failure of treatment with ESAs is unknown. We identified patients with LR-MDS in the Moffitt Cancer Center Clinical Database who received lenalidomide and azacitidine after ESA treatment failure. Rates of erythroid hematologic improvement (HI-E) in patients who received lenalidomide first followed by azacitidine (group 1) and those who received lenalidomide after azacitidine (group 2) were examined according to the International Working Group 2006 criteria. Sixty-three patients (37 in group 1 and 26 in group 2) were identified. The HI-E rate with lenalidomide as first-line therapy was 38% versus only 12% when lenalidomide was used as second-line therapy (P= .04). There were no significant differences in overall survival (OS; median OS, 104 vs. 87 months, respectively; P= .55), rates of leukemic progression, or in HI-E rates after azacitidine use (38% when azacitidine was used after lenalidomide vs. 35% when azacitidine was administered before lenalidomide, P= .69). Lenalidomide appears to yield a higher HI-E rate in non-del5q LR-MDS when used as first-line therapy after ESA treatments failure. If validated in larger cohorts, lenalidomide rather than azacitidine should be considered for first-line therapy after ESA treatment failure.

Azacitidine Use in MDS and AML Patients: Best Selection for Better Results

AbstractAbstract 5070In a recent phase III trial, azacitidine was demonstrated to significantly prolong OS compared with conventional care regimens in patients classified in intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) (Fenaux et al. 2009). This study used the French- American-British (FAB) classification for MDS and included approximately one third of patients with refractory anemia with excess blasts in transformation (RAEB-t; 20% to 30% bone marrow blasts). WHO criteria now define AML as ≥20% BM blasts. Using those criteria, RAEB-t is now considered as AML.We conducted a retrospective analysis on patients who received azacitidine between August 2005 and November 2011 at our institution for MDS or AML. Patients were identified through the hospital database and individual charts were reviewed. The primary objective was to investigate the outcome of patients receiving azacitidine in a daily clinical practice in high risk MDS and AML patients and to evaluate its impact on overall survival (OS). Secondary objectives were hematological response rate and transfusion spare. Patients were included if they received at least one cycle of azacitidine. Disease status was defined by both the French American British (FAB) and the World Health Organization (WHO) classification systems, and risk was scored by the International Prognostic Scoring System (IPSS). All analyses were conducted using R statistical software. Descriptive statistics were used for baseline characteristics. Kaplan-Meier estimates were used to calculate overall survival (OS).There were 79 patients, 51 (65%) males and 28 (35%) females with a median age of 70 years (32–85). The indication of azacitidine was the first line treatment use for MDS, mainly refractory anemia with excess blasts, in 40 (51%) patients (group1) and treatment for patients who had AML and transformed, in 39 (49%) patients (group2). (post chemotherapy: n=16, first line: n=23). Patient characteristics, prognostic factors according to FAB classification, ISPP risk and cytogenetics for both groups are shown in table1. The median number of azacitidine cycles in groups 1 and 2 was 8 (1–30) and 3 (1–29) respectively. Evaluation after 6 cycles showed 55% of responders in group 1 and 31% in group 2; the rest of patients have progressed. The median OS for the group 1 was 24. 5 months (17. 8-NR) while in group2; it was 15. 5 months (11. 2-NR) for patients who received AZA in first line and 6 months (3. 9-NR) for patients with previous chemotherapy. In terms of transfusions number, we did not find any significant spare in terms of both RBC and platelets transfusion in group1 while there was a significant spare of 33% of red blood cells transfusions (p=0. 05) and 42% of platelets transfusions only in group 2 (p=0. 04). The multivariate analysis studying the impact of different variables on OS showed: a worse OS in AML patients with previous chemotherapy (HR= 9. 84 [ 3. 56 – 27. 19 ], p< 0. 001), a worse OS in patients with unfavorable caryotype (HR= 7. 30 [ 2. 13 – 24. 98 ], p< 0. 001), and a better OS in female patients (HR= 0. 31 [ 0. 14 – 0. 68 ], p= 0. 003).Our study confirmed results from previous prospective study in MDS patients while AML patients not receiving azacitidine in first line do not seem to benefit from this treatment. Cytogenetics remain a major factor impacting OS with no significant impact of IPSS. [Display omitted] [Display omitted] Disclosures:Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Azacitidine-associated Sweet’s syndrome

Sweet's syndrome (also known as acute febrile neutrophilic dermatosis) in two patients receiving azacitidine therapy is reported. The development of Sweet's syndrome in association with azacitidine use is rare (three published case reports since the drug's U.S. marketing approval in 2004), and the syndrome is not listed as a potential adverse reaction in the product packaging. In one of two cases of probable azacitidine-related Sweet's syndrome reported here, a 64-year-old man with myelodysplastic syndrome (MDS) developed a severe erythematous and nodular rash with peeling on his arms, legs, and face after receiving the drug (75 mg/m(2) subcutaneously daily) for three days; the second case involved a 67-year-old man with chronic myelomonocytic leukemia (CMML) who experienced a similar skin rash, as well as chills and an elevated body temperature, after five days of treatment with azacitidine. In both cases, the results of dermatologic or pathologic examination and skin biopsies were consistent with Sweet's syndrome. Perhaps the strongest evidence of a drug-induced etiology in these cases was the close temporal relationship between the initiation of azacitidine use and the development of Sweet's syndrome, with prompt symptom resolution after the discontinuation of azacitidine use and administration of appropriate corticosteroid therapy. Azacitidine was the apparent cause of Sweet's syndrome in a patient with MDS and another with CMML. Both responded well to corticosteroid therapy. After resolution of the reaction, decitabine was given to the first patient and azacitidine to the second, without complications.

Therapeutic Response to Azacitidine (AZA) In Patients with Secondary Myelodysplastic Syndromes (sMDS) Enrolled In the AVIDA Registry

Therapeutic Response to Azacitidine (AZA) In Patients with Secondary Myelodysplastic Syndromes (sMDS) Enrolled In the AVIDA Registry