Azacitidine Initiation Research Articles

Real-world study of the use of azacitidine in myelodysplasia in Australia.

Hypomethylating agents are the most widely used upfront therapy for patients with myelodysplastic syndrome (MDS) who are not suitable for hematopoietic stem cell transplantation. In Australia, azacitidine was, until recently, the only approved and subsidized treatment for patients with intermediate-2 and high-risk MDS, chronic myelomonocytic leukemia, and low blast acute myeloid leukemia. We analyzed prescription data to evaluate the real-world persistence and overall survival (OS) of patients prescribed azacitidine for the first time in Australia. A retrospective cohort analysis of patients who had been prescribed Pharmaceutical Benefits Scheme (PBS)-listed azacitidine for the first time, between January 2016 and April 2021, was conducted using the PBS 10% dataset. Treatment persistence and OS were estimated using Kaplan-Meier methods. The impact of the number of treatment cycles and treatment adherence on OS was also estimated. There were 351 patients in the PBS 10% dataset who initiated treatment with azacitidine. The average age (standard deviation [SD]) at azacitidine initiation was 71.9 (11.1) years and the average number (SD) of azacitidine prescriptions was 5.6 (0.2). The median persistence on azacitidine was 15.6 months, and the OS was 13.4 months. The median OS for patients who had six or more cycles of azacitidine treatment was greater compared to patients who had five or less cycles of treatment. The data from this real-world study illustrate the unmet medical needs of patients with MDS treated with azacitidine in Australia. The majority of patients are not treated with the optimal number of cycles of azacitidine, which is negatively correlated with patient outcomes.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Efficacy of Azacitidine Post-Transplant Maintenance for FLT3-Negative Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: For patients with myeloid malignancies undergoing allogeneic hematopoietic transplantation (alloHCT), disease relapse remains the most common cause of transplant failure and mortality. Treatment of relapse after alloHCT remains extremely challenging. Post-transplant maintenance with fms-like tyrosine kinase 3 (FLT3) inhibitors has shown benefit in preventing relapse in the minority of patients with FLT3 mutated acute myeloid leukemia (AML). For the remaining patients, the efficacy of hypomethylating agents (HMA) as post-transplant maintenance yields conflicting results. There is a paucity of data regarding the role of HMA as post-transplant maintenance administered outside the context of a clinical trial. We aimed to evaluate the efficacy of azacitidine (AZA) as post-alloHCT maintenance in a real-world setting in patients with FLT3-negative AML or myelodysplastic syndrome (MDS). Methods: We conducted a single center retrospective matched-control comparative analysis. The study group (AZA group) included adults, aged ³18, with FLT3-negative AML or MDS who received their first alloHCT between 2013 and 2020; and were treated post-transplant with AZA maintenance therapy, initiated within 180 days after alloHCT. All patients in the AZA group initiated maintenance while in complete remission (CR) without minimal residual disease (MRD), assessed by multi-color flow cytometry. We compared the AZA group to a matched control group of contemporaneous patients with AML or MDS who did not receive any maintenance. We matched the control group according to disease type (AML or MDS), disease risk category (by ELN12 for AML and IPSS-R for MDS) and disease status at transplant. Matched controls were required to have count recovery (ANC>1000 X 106 cells/L and PLT>20K/µL) within ±7 days of initiation of AZA in their counterparts. We excluded controls if they had positive MRD, overt relapse or if they died prior to the initiation of AZA in their counterparts; grade 2-4 acute graft versus host disease (GVHD) within +/-7 days, or chronic GVHD within +/-15 days of initiation of AZA in their counterparts. The primary endpoint was disease progression, evaluated considering death before progression as a competing event. Results: We identified 93 consecutive patients who received AZA maintenance. A total of 357 unique matched controls were identified at a 2/1, 3/1, 4/1 matching ratio for 1 (1%), 13 (14%), and 79 (85%) of cases, respectively. The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, p=0.01) and lower hematopoietic comorbidity index (HCT-CI) (median: 2 vs. 3, p=0.04) in the AZA group (Table 1). Patients in the AZA group received a median of 8 (range 1-60) cycles of AZA. Outcomes were compared starting at the time of initiation of AZA in the case. Median follow-up among surviving patients was 35 and 44 months in the AZA and control groups, respectively. The 3-year cumulative incidence of disease progression was 29% and 33% (HR 0.7, 95% CI 0.4-1.1; p=0.09), respectively. Subset analyses showed that the protective effect of AZA on disease progression was limited to patients with high risk AML or MDS [HR 0.4, 95% CI 0.2-0.8, p=0.009] (Figure 1 B,D).There was no beneficial effect for AZA for patients with low or intermediate risk disease [HR 1.04, 0.6-1.8, p=0.9] (Figure 1 A,C). The use of AZA was also associated with a lower rate (4% vs. 22%, p=0.001) of non-relapse mortality independent of the disease risk category. These effects translated into a significantly superior overall (74% vs. 51%, p<0.001) and progression-free (67% vs. 46%, P<0.001) survival in the AZA group compared to the control group. Results were consistent when the analyses were repeated using a second independently selected matched control group (data not shown). Conclusion: Post-alloHCT AZA maintenance was associated with lower progression rate in patients with high-risk FLT3-negative AML or MDS. This effect is remarkable considering that matched controls had been in MRD-negative CR prior to initiation of AZA in their matched counterparts. Our results also indicate a low rate of non-relapse mortality associated with AZA maintenance which warrants evaluation in prospective studies. Collectively, our data suggest that AZA maintenance should be considered for post-alloHCT maintenance in high risk FLT3-negative AML and MDS patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II Trial of Venetoclax (Ven) in Combination with Azacitidine (AZA) As Maintenance Therapy for High-Risk Acute Leukemia Following Allogeneic Stem Cell Transplantation (SCT)

Introduction: Allogeneic SCT remains the only potentially curative therapy for acute leukemia patients but with inferior outcomes for high-risk patients. Prior data on maintenance therapies, including AZA, have yielded conflicting results on its efficacy to improve outcomes. Considering the clinical efficacy of VEN in acute myeloid and lymphoid leukemia (AML/ALL) with its known tolerability when used with AZA, we thought VEN and AZA might be an attractive maintenance strategy to improve outcomes after SCT. Methods: This is a single center, open label, Phase II clinical trial to assess the safety and efficacy of VEN with AZA as maintenance therapy after SCT. Inclusion criteria was 1) high risk AML or B cell and T cell ALL or mixed phenotype leukemia, 2) absolute neutrophil count >/= 1.0 x 109/L and platelet >/= 30 x 109/L without any support, 3) absence of active graft versus host disease (GvHD) and infection, 4) absence of minimal residual disease at enrollment. Treatment consisted of up to 12 cycles of VEN 100 mg on Days 1-7 with AZA 32 mg/m 2/day IV/SC on Days 1-5 every 28 days. VEN dosing was adjusted for patients on concomitant CYP3A inhibitors or those with severe cytopenias. After the first 11 patients enrolled, due to myelosuppression observed, VEN dose was changed to 50 mg on days 1-7 if patients were on posaconazole. Treatment delays, up to 70 days, were allowed by toxicity. The primary objectives are relapse-free survival (RFS) after initiation of VEN and AZA and the safety and tolerability of the combination. The study has been ongoing. Results: The study enrolled a total of 30 patients (27 AML, 3 ALL). Demographics across all AML patients included mean age 52 years (range: 40-74), 67% males, 15% second SCT, 48% in first complete remission (CR1) at SCT, 41% adverse risk by European Leukemia Net classification. The majority (63%) received a myeloablative intensity conditioning regimen using intravenous busulfan. The three ALL patients were younger with mean age of 35 and all were in CR1 at SCT. The median time to start the maintenance treatment was 70.5 days (range, 42-103). As of the data cutoff date of 13 July 2022, patients completed a median of 4 cycles (range, 1-12) of study treatment with 9 patients (30%) remaining on study treatment. The primary reasons for study treatment discontinuation among 21 patients were complications like myelosuppresssion, infections and GvHD in 11, relapse in 6 and completion of 12 cycles of treatment in 4. The median follow-up time was 8.67 months (95% CI, 7.23 to 13.6).The median RFS and OS were not reached. The estimates of RFS and OS at 1-year were 69.2% (95% CI, 52.1% to 91.8%) and 90.2% (95%CI, 78% to 100%), respectively, after the initiation of VEN and AZA maintenance (Figure 1&2). Assuming a Bayesian Poisson-Gamma Model with a Gamma (1,1) prior; the mean number of grade≥3 treatment related adverse events (AEs) per patient was estimated. The mean number of AEs were 1.87 (range, 0-8) for decreased white blood cell count; 1.68 (range, 0-7) for decreased absolute neutrophil count; 1.06 (range, 0-6) for decreased platelet count; 0.55 (range, 0-6) for anemia; 0.13 (range, 0-1) for pneumonia and 0.06 (range 0-1) for each event of febrile neutropenia, maculopapular rash, respiratory failure and secondary graft failure (GF). The secondary GF was observed in one patient after the 4th cycle of treatment leading to discontinuation of study treatment. No patient died to due to treatment related AEs. Due to frequent and prolonged myelosuppression observed, 9 patients (30%) required dose reduction of VEN; mostly right after the first cycle of treatment (6 of 9 patients). After the protocol amendment for VEN to be given as 50 mg on days 1-7 on posaconazole, the requirement for dose changes decreased though still some patients required lower doses of VEN (as 30 mg on days 1-5) on subsequent cycles. Conclusion: Post-SCT maintenance therapy with VEN/AZA was safe and tolerable with favorable results in patients with high-risk AML and ALL. The majority of reported AEs was related to myelosuppression which is a known complication of VEN. Many patients required dose modification of VEN and treatment delays between cycles, highlighting the importance of monitoring these patients very closely. On the other hand, the observed RFS and OS data were highly encouraging compared to the historical outcomes for this high-risk group of patients although longer follow-up is needed. The study has been ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Erythema nodosum after azacitidine in a patient with acute myeloid leukemia.

Nodular skin lesions in patients with acute myeloid leukemia (AML) raise clinical suspicion for leukemia cutis versus fungal infections. Here, we report a rare case of treatment-related erythema nodosum (EN) in a patient with AML. Approximately 5 weeks after the initiation of sorafenib and one week after azacitidine initiation, a 32-year-old man with primary refractory AML presented with several painful red nodules on the lower extremities. Histological examination established a diagnosis of EN. Treatment with topical and oral steroids led to complete resolution of the nodules. However, once the dose of steroids was reduced, the lesions rapidly recurred. Higher dose steroids were reinitiated, again with a resolution of the nodules, confirming steroid responsiveness of the underlying process. Given the onset of lesions one week after the initiation of azacitidine and 5 weeks after the initiation of sorafenib, azacitidine was considered the more likely culprit. Only 2 cases of EN-like eruption after azacitidine and 1 case after sorafenib have been reported. Although fungal infections and leukemia cutis are the top differentials considered for skin nodules in a patient with AML, EN should be considered as an alternative diagnosis. Correct diagnosis is critical because it will guide treatment.

Predictive Factors of Overall Survival and the Completion of Four Cycles of Azacitidine: An MDS-CAN Study

Predictive Factors of Overall Survival and the Completion of Four Cycles of Azacitidine: An MDS-CAN Study

Azacitidine for relapse of acute myeloid leukemia or myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation, multicenter PALG analysis

Relapse of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) belongs to the major causes of treatment failure. Retrospective multicenter analysis of patients diagnosed with AML or MDS who had hematological relapse after allo-HSCT and were treated with azacitidine for this indication. Twenty-three patients receiving azacitidine as the first treatment of relapse (Group_1) and 8 patients receiving azacitidine after other treatment of relapse (Group_2) were included. There were 68% males, median age at initiation of azacitidine was 53years (15-66). Median time to relapse was 3.5months and 6.3months in Group_1 and Group_2, respectively; median time from relapse to azacitidine 0.2 and 2.3months. Azacitidine 75mg/m2 , days 1-7, was administered in 78% and 75% of patients in Group_1 and Group_2, concomitant DLI in 48% and 50%. With median follow-up of 4.7 and 13.6months, the median overall survival was 5.9 and 9.5months. 17% and 37.5% patients proceeded to salvage allo-HSCT, with median OS of 11.6months and not reached respectively. Azacitidine treatment for hematological relapse is associated with poor outcome; nevertheless, a proportion of patients may benefit from it, including patients receiving subsequent salvage allo-HSCT.

Relationship between Low Pretreatment Geriatric Nutritional Risk Index and Poor Tolerability of Azacitidine in Patients with Myelodysplastic Syndromes

Background: Predicting tolerability and treatment-related risks associated with azacitidine (AZA) in patients with myelodysplastic syndromes (MDS) before the initiation of therapy is required for appropriate treatment. Thus, in this study, the nutritional status of patients with MDS prior to AZA treatment was evaluated using the geriatric nutritional risk index (GNRI). Tolerability and overall survival (OS) after AZA initiation were also investigated. Methods: This was a single-center retrospective observational study. A total of 59 patients with MDS treated with AZA were assessed using GNRI, and a comparison of undernourished (GNRI <92, n = 27) and non-undernourished (GNRI ≥92, n = 32) patients was performed. Results: The undernourished group had a significant reduction in the number of patients that successfully completed 4 cycles of AZA treatment compared with the non-undernourished group (undernourished group, 11/27 patients, 40.7% vs. non-undernourished group, 24/32 patients, 75.0%; p = 0.009). Factors associated with the difference included karyotype and GNRI. There was also a significant increase in the rate of infectious complications in the undernourished group compared with the non-undernourished group (undernourished group, 33/60 cycles, 55.0% vs. non-undernourished group, 31/92 cycles, 33.7%; p = 0.012). Lastly, a significant reduction in OS was observed in the undernourished group compared with the non-undernourished group (undernourished group, 11.5 months; 95% CI, 5.2–16.7 vs. non-undernourished group, 21.9 months; 95% CI, 13.8–24.0; p = 0.026). Factors associated with OS included both the revised International Prognostic Scoring System (IPSS-R) and GNRI. Conclusions: These results indicate that predicting treatment completion and adverse events in patients with MDS prior to AZA treatment is important. This study suggests GNRI may be a valuable nutritional assessment tool for determining tolerability and OS of AZA treatment.

Real-World Costs of Azacitidine Treatment in Patients With Higher-Risk Myelodysplastic Syndromes/Low Blast-Count Acute Myeloid Leukemia.

Azacitidine (AZA) is a standard of care for higher-risk myelodysplastic syndrome (MDS)/low blast-count acute myeloid leukemia (AML). Despite this, there is a paucity of data on the real-world health care resource utilization costs of AZA in this population. We linked the Ontario AZA MDS registry-higher-risk MDS/low blast-count AML-to population-based health system administrative databases. Patients were observed for 24 months after first AZA and censored at the earliest of 90 days after last AZA, date of death, time of AML induction/stem-cell transplantation, or March 31, 2016. Costs (2015 Canadian dollars) were expressed as standardized mean and median 28-day costs. Univariable quantile regression was used to explore the association of baseline patient and disease characteristics and median cost. Multivariable quantile regression was used to explore predictors of median costs. Among 877 patients in the registry, mean standardized 28-day cost per patient was $17,638 (median, $15,272; interquartile range [IQR], $11,869-$19,580) and $13,450 (median, $11,043; IQR, $7,981-$14,882) excluding the cost of AZA. Major nondrug drivers of cost were cancer clinic visits and inpatient care (mean standardized 28-day cost, $4,631; median, $1,558; IQR, $238-$4,961). Transfusion dependence at AZA initiation (P = .001) and greater comorbid disease burden (P = .009) were independently associated with increased cost. Our cohort of patients with uniformly higher-risk MDS/low blast-count AML treated with AZA demonstrates substantial costs of care above and beyond the cost of AZA alone. These results provide insight into the costs of AZA in the real world with implications for resource allocation.

Role of Post-Allogeneic Hematopoietic Stem Cell Transplantation Low-Dose Azacitidine for Prevention of Relapse in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Analysis

Introduction Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains a major cause of treatment failure with associated poor prognosis. Low-dose post-HSCT maintenance azacitidine (AZA) has proved to be beneficial in preventing relapses (de Lima et al. Cancer 2010). Herein, we retrospectively evaluated outcomes of patients (pts) treated with low-dose AZA post-HSCT. Methods Pts with AML and MDS who underwent allogeneic HSCT between 2012-2018 at two centers were evaluated and categorized into AZA group (with low-dose AZA maintenance) and control group (without AZA maintenance). In control group, pts who died or relapsed prior to day +100, had grade III-IV aGVHD or received maintenance therapy other than AZA (e.g. FLT3 inhibitors) were excluded. Using Kaplan-Meier method, event (defined as relapse or death) free survival (EFS) and overall survival (OS) were computed and compared using log-rank test. Results A total of 107 patients were included; 53 (49.5%) in AZA and 54 (50.5%) in control groups. Disease and transplant-related characteristics are shown in table 1. Both groups were comparable with respect to age, diagnosis, disease risk stratification, disease status at HSCT, and MRD status at day +30 and day +100 (table 1). More pts received reduced intensity conditioning (RIC) in the AZA group (71.6% vs 37%, p= Conclusions In our cohort, low-dose AZA maintenance was generally well tolerated. The results of this study indicate that AZA maintenance is feasible and associated with improved EFS and OS. In addition, AZA has the potential of improving relapse rates even in pts who are unable to receive myeloablative conditioning as a significant number of pts in AZA group in this study received RIC. The optimal timing, duration of treatment and selection of pts most suitable for AZA for maximum benefit, however, requires further studies.

PB2087 PROGNOSTIC VALUE OF CLINICAL AND CYTOGENETIC PARAMETERS IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES TREATED WITH AZACITIDINE

Background:Myelodysplastic syndromes (MDS) are characterized by cytopenia due to hematopoietic dysfunction and increased risk of transformation to acute myeloid leukemia. DNA hypomethylating agents such as azacitidine (AZA) significantly improve clinical outcomes in higher‐risk MDS and have become the standard therapy for this disease. However, prognostic factors for survival of patients with higher‐risk MDS treated with AZA remain largely unknown, and a prognostic scoring system for these patients in clinical practice has not been established. In addition, MDS occurs mainly in elderly patients, and cytotoxic drugs including AZA may cause frailty and impair quality of life. Therefore, identification of predictive factors related to response to AZA is needed.Aims:The goal of this retrospective study was to analyze a cohort of patients with higher‐risk MDS treated with AZA at a single institute.MethodsOutcomes of 68 patients with higher‐risk MDS treated with AZA between April 2011 and October 2018 at Saitama Medical Center, Saitama Medical University, Kawagoe, Japan were evaluated retrospectively. AZA was administered at a dose of 75 mg/m2 for 5 days. The study was approved by our Institutional Review Board, and the procedures followed were in accordance with the Helsinki Declaration of 1975. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression models. Overall survival (OS) was calculated from the date of initiation of AZA to the date of last follow‐up or death.Results:The median age was 70 years (range, 44‐86 years) and median OS was 14 months. The effects of cytogenetics, hemoglobin, neutrophil count, % circulating blasts, RBC transfusion dependency, serum albumin, IPSS‐R and WPSS on OS were examined. In univariate analysis, OS was significantly related to pretreatment low serum albumin (&lt;3.7 g/dL) (HR = 2.56, 95% CI 1.35 to 5; p = 0.05), pretreatment low hemoglobin (&lt;9 g/dL) (HR = 1.82, 95% CI 0.98 to 3.45; p = 0.057), and chromosome 7 deletion (HR = 2.29, 95% CI, 1.16 to 4.54; p = 0.018). In multivariate analysis, these three variables were shown to be independent prognostic factors for patients with MDS treated with AZA. We then classified the patients into three risk groups: low (score = 0), intermediate (score = 1), and high (score = 2 or 3), based on serum albumin (≥3.7 vs. &lt;3.7 g/dL), hemoglobin (≥9 vs. &lt;9 g/dL) and the presence or absence of deletion of chromosome 7. In evaluation of the prognostic value of this scoring system using a Cox regression proportional hazards model, patients in the three risk groups had significantly different OS (p&lt;.0001). The median OS was 30 (range: 11‐49), 16 (14‐29), and 7 (3‐8) months in the low, intermediate, and high risk groups, respectively.Summary/Conclusion:Low serum albumin and low hemoglobin before treatment and deletion of chromosome 7 are independent unfavorable prognostic factors in patients with MDS treated with AZA. Our scoring system based on these factors provides a simple practical approach to predict outcomes of these patients in routine clinical practice.

Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia

The administration of azacitidine (AZA) was found to be more effective than conventional care regimen (CCR) in patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) with lower blast count. We designed a study to determine efficacy and safety of AZA therapy in “real life” patients with MDS, CMML and AML. The study included 83 patients (65% male) with a median age at diagnosis of 68 years. 43 patients were diagnosed with higher-risk MDS, 30 had AML and 10-CMML. Median AZA dose was comparable between treated groups. AZA dose reduction was required for 44% of MDS, 17% of AML and 25% of CMML patients. Complete remission (CR) was achieved in 14% of MDS, 7% of AML and 10% of CMML patients. Overall response rate was following: 27% for MDS, 20% for AML and 20% for CMML. Estimated OS at 12 months was 75% for MDS, 60% for AML and 75% for CMML. Median follow-up for MDS/AML/CMML from AZA initiation to last follow-up was 9.0, 9.4 and 9.4 months, respectively. The most common toxicity of AZA therapy was myelosuppression and infections. AZA treatment was effective in a limited number of patients with acceptable safety profile.

Quantitative Modeling of Ineffective Hematopoiesis in Myelodysplastic Syndrome Patients Yields Distinct Clinical Phenotypes and Can Identify a State of Disease Predictive of Loss of Response to Azacitidine

Background: The implementation of genomic data from myelodysplastic syndrome (MDS) patients into clinical practice requires its association with MDS disease activity. However, the determination of a genotype-phenotype correlation in MDS where the disease phenotype is ineffective hematopoiesis, is not straightforward. Part of the problem may be that disease activity reflected by a change in blast count, a change in a peripheral blood count, or the acquisition of a new cytogenetic abnormality does not currently provide any information about the likely dynamics of hematopoietic progenitors underlying this change. Being able to reliably infer a change in the early hematopoietic progenitor compartment of MDS patients where the disease clone likely resides that can account for the phenotype of ineffective hematopoiesis is an important step in the development of a tool to measure disease activity over time.We aim to apply a quantitative model of hematopoiesis based on parameters known to affect hematopoietic progenitor population dynamics, including rate of self-renewal, rate of proliferation, rate of differentiation, and rate of apoptosis. The mathematical formulation based on delay-differential equations has been successfully used to model the peripheral blood counts of CML and cyclic neutropenia. The goal is to identify unique MDS disease states based on the parameters described in the model, and to correlate these with both genotype and clinical outcomes.Methods: MDS patients with IPSS intermediate-2/high diagnosed during the period 2010-2017 at the London Health Science Centre had their bone marrow aspirate and biopsy data at diagnosis, laboratory data while on treatment with azacitidine and following disease progression, and transfusion history collected. The time-dependence of the peripheral blood counts for each patient were modeled using a delay-differential equation (Colijn and Mackey, 2005), with parameters representative of rates of proliferation, self-renewal, differentiation, and apoptosis of the stem cell and progenitor compartments. The model was integrated with MATLAB's dde23 routine and the model parameters were fit to the peripheral blood counts using gradient descent for the constrained non-linear least squares problem. The patients were separated into two clusters using the k-means clustering of all the model parameters using the city-block distance measure. The number of clusters were determined using the Calinski-Harabasz criterion.Results: Seventy-seven patients with a diagnosis of IPSS intermediate-2/high risk MDS were included in the analysis. Model fitting of the peripheral blood count data of 1000 simulated healthy patients whose blood count parameters were within their respective normal ranges over time yielded baseline variability of hematopoietic kinetic parameters (Figure 1). Two main groups of MDS patients could be identified from model fitting: MDS 1 and MDS 2, both of which could be best distinguished from the simulated healthy patients based on the parameter for the rate of megakaryocytic differentiation. MDS 1 and MDS 2 also had distinct parameters for the rates of hematopoietic progenitor proliferation, describing two different phenotypes of disease activity. The red blood cell count of a representative patient in MDS 1 is shown in Figure 2, where application of the Akaike information criterion identified the most likely time point when the hematopoietic kinetic parameters accounting for the peripheral red blood cell count changed after initiation of azacitidine. This time point preceded proven disease progression by 40 days.Conclusion: Parameterization of hematopoiesis with a model that can infer the kinetics of hematopoietic compartments in the bone marrow provides a powerful tool for measuring ineffective hematopoiesis in MDS patients. The resulting kinetic parameters can identify distinct groups of MDS patients based on the phenotype of their disease. The next step would be to correlate the different kinetic parameters distinguishing these groups to their disease genotypes using next-generation sequencing. On an individual patient level, these parameters can identify the most likely time when the disease phenotype changes. The development of a dynamic score predicting the change in disease activity based on hematopoietic kinetic parameters derived from peripheral blood count data over time is ongoing. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Healthcare Utilization and Costs in Patients with Higher-Risk MDS/Low Blast Count AML Treated with Azacitidine in Ontario, Canada

Background: Azacitidine (AZA) use in higher-risk MDS has been adopted because it improves survival. Despite this, “real-world” data on the economic impact and resource utilization remains unknown. We used the Ontario provincial AZA MDS registry, which captures all AZA-treated patients in the province, to analyze “real-world” data on healthcare use, associated costs and their predictors in AZA treated higher-risk patients.Methods: We linked the provincial MDS AZA registry (single-payer/universal access), which captures baseline characteristics and treatment response for all AZA-treated patients in Ontario, to population-based health system administrative databases. Only higher-risk MDS patients (IPSS intermediate-2, high) and low blast count AML (21-30% blasts) treated from May 30, 2010 to March 16, 2015 were included. Patients were followed for 24 months following first AZA treatment and censored at the earliest of 90 days after last AZA treatment, date of death, time of acute leukemia induction/allogeneic stem cell transplant or March 31, 2016. We estimated healthcare resource utilization and the mean (and overall) standardized 28-day healthcare cost in Canadian dollars ($1 CDN = 0.76 USD$). Quantile regression was used to explore predictors of cost. Negative binomial regression models were used to explore predictors for higher rate of emergency department (ED) visits, and for longer length of stay, with the natural logarithm of length of follow-up as an offset variable in each model.Results: The registry had 652 higher-risk MDS and 225 low blast count AML patients (n = 877) with median follow up of 8 months (IQR 4-13). Median age was 73 years (IQR 66-79), 66.0% were male, 17.8% were secondary MDS and IPSS scores of those calculable were intermediate-2 (64.9%) and high-risk (35.1%). At the time of AZA initiation, 587 patients (66.9%) were transfusion dependent. The median number of cycles received was 6 (range 3 to 11) and median overall survival was 16.1 months (95% CI 13.9 to 18.3). Overall, 705 patients (80.4%) had at least 1 ED visit and 290 (33.1%) had an ED visit during their first cycle of AZA. In addition, 680 patients (77.5%) had at least 1 hospital admission with a mean hospital stay of 17.7 days (95% CI 16.3 to 19.1) over the entire study period. 141 patients (16.1%) required admission to an intensive care unit. Older age (Rate ratio [RR] = 1.33, 95% CI 1.09-1.62), rurality (RR=1.75, 95% CI 1.42-2.15), high IPSS score (RR=1.31, 95% CI 1.06-1.62), and increased comorbidity level were each independent predictors of increased ED visits; while higher comorbidity level (RR=1.51, 95% CI 1.08-2.11), high IPSS score (RR=1.39, 95% CI 1.01-1.92), and transfusion dependence (RR=1.51, 95% CI 1.13-2.01) were associated with longer hospital stays.The overall mean cost was $146,675 per patient (95% CI $139,537 to $153,812) including AZA and $103,580 (95% CI 98,675 to 108,486) excluding AZA drug costs. The mean standardized cost per 28-day period per patient was $17,638 (95% CI $16, 870 to $18,407) with AZA and $13,450 (95% CI $12,730 to $14,170) without AZA drug costs. Inpatient admissions ($4,631, 95% CI $4,010 to $5,251) and non-physician outpatient cancer clinic costs ($6,092, 95% CI $5,851 to $6,333) were the major cost drivers. Excluding AZA costs, the mean standardized 28-day costs were higher in those receiving less than 4 cycles of AZA (n= 295) at $19,408 (95% CI $17,568 to $21,248), compared with those receiving 4 or more cycles (n= 582) at $10,430 (95% CI $10,069 to $10,790) with inpatient admissions as the major driver (mean $10,192, 95% CI $8,594 to $ 10,192 vs. $1,812, 95% CI $1,558 to $2,065). On multivariable analysis, only greater comorbid disease burden (β = $2,074, 95% CI $665 to $3,483) and transfusion dependence (β = $2,402, 95% CI $1,190 to $3,613) were associated with higher median standardized 28-day cost.Conclusions: In our analysis of “real-world” patients with uniformly higher-risk MDS treated with AZA we demonstrate a significant economic impact above and beyond the cost of AZA alone. The costs are higher in patients who are transfusion dependent and have greater comorbidity and appear to be driven by inpatient care and outpatient non-physician ambulatory care. This group of patients are high users of healthcare resources with the majority having ED visits and inpatient admissions. These results will inform patients and providers about the “real-world” anticipated toxicities of AZA. DisclosuresBuckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A phase II/III, multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy.

TPS7068 Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a Phase 1/2 trial of FLT3 mutation-positive (FLT3mut+) relapsed/refractory AML. In FLT3mut+ AML cell lines, gilteritinib plus azacitidine (AZA) inhibited growth, and induced apoptosis and differentiation. This ongoing Phase 2/3 trial will examine the efficacy, safety, and tolerability of gilteritinib alone, gilteritinib plus AZA or AZA alone in newly diagnosed FLT3mut+AML patients ineligible for intensive induction chemotherapy. Methods: This open-label, 3-arm, 2-stage randomized trial (NCT02752035) will enroll ~540 newly diagnosed adults with FLT3mut+ (FLT3-ITD or -TKD) AML; those with APL, BCR-ABL+, or active CNS leukemia will be excluded. Before initiation, the safety and tolerability of gilteritinib plus AZA will be assessed in a Safety Cohort to establish the appropriate gilteritinib dose for combination therapy. Subjects will then be randomized 1:1:1 to receive oral gilteritinib alone (120 mg daily; Days 1–28), AZA alone (75 mg/m2 by subcutaneous injection or intravenous infusion on Days 1–7), or AZA (75 mg/m2; Days 1–7) plus oral gilteritinib (daily on Days 1–28 at the dose determined from the Safety Cohort), and stratified by age ( &lt; 75 vs ≥75 years). Subjects will continue treatment until a discontinuation event occurs. The primary endpoint is overall survival of subjects receiving gilteritinib or gilteritinib plus AZA versus AZA alone; the key secondary endpoint is event-free survival. Additional secondary endpoints: complete remission rate, leukemia-free survival, remission duration, composite remission rate, tolerability, and fatigue. Dose changes and interruptions are allowed in all treatment arms. A formal interim futility analysis by an Independent Data Monitoring Committee is planned when ~50 subjects in each treatment arm have either discontinued therapy or completed 2 treatment cycles. Enrollment began on November 21, 2016; as of January 31, 2017, the Safety Cohort is ongoing. Clinical trial information: NCT02752035.

Impact of Bone Marrow Fibrosis and Early Response on Outcome after Azacitidine Therapy in 94 Patients with Myelodisplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia

▪Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified.We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving > 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category [HR 2.24 (1.19-4.20) p=0.01], poor cytogenetics [2.19 (1.27-3.78) p=0.005], and lower ORR [0.46 (0.26-0.80) p=0.006] significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS [HR 0.86 (0.80-0.92) p<0.0001]. Notably, cases with pre-AZA fibrosis ≥MF-1 showed lower OS [2.26 (1.28-3.99) p=0.005]. In conclusion we provide evidence of no relationship between neutropenia and infections and of no impact of toxicities on dose-density and ORR to AZA treatment. Moreover, high marrow fibrosis and hypercellularity may affect response to AZA therapy. Further studies are needed to disclose the clinical/biological significance of marrow fibrosis/cellularity in the era of hypomethylating agents. [Display omitted] [Display omitted] DisclosuresReda:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.

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.

Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

Prospective Evaluation of Azacitidine Maintenance Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

▪Introduction and aim. Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is a major cause of treatment failure and is associated with a poor prognosis. Overall survivals are around 50% at 5 years following allogeneic HSCT in intermediate and high risk AML. Survivals remain less than 20% in poor-risk and very poor-risk patients based on the cytogenetic profile. Thus, prevention of relapse following allogeneic HSCT remains an unmet clinical need. Low-dose azacitidine maintenance post-HSCT has been shown to augment graft-versus-leukemia effect and may prolong survivals. We aim to prospectively evaluate the effect of azacitidine maintenance following allogeneic HSCT in high risk AML and MDS.Method. Consecutive patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in remission following first allogeneic HSCT or second allogeneic HSCT (from the original donor) were recruited. High risk AML in this study comprised patients with poor risk karyotype, secondary AML transformed from underlying MDS, presence of fms-like tyrosine kinase 3-internal tandem duplication (FLT3 -ITD) and non-remission before HSCT. Azacitidine was administered at 100mg daily for 3 days per cycle every 28 days until progression or a maximum of 8 cycles. The clinicopathologic and treatment characteristics were determined. The occurrence of graft-versus-host disease (GVHD) was determined. DNA chimerism was determined in the bone marrow before the initiation of azacitidine, after 4th and 8th cycles of azacitidine and at 1 year. DNA chimerism was determined by quantification of polymorphic short tandem repeat sequences. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier analysis.Results. Thirty-four patients with high-risk AML (N=31) and MDS (N=3) were recruited. The median duration of follow-up was 14 months (range: 2 - 44 months). Twenty-two patients received azacitidine maintenance after first allogeneic HSCT, whereas 12 patients received azacitidine maintenance after a second allogeneic HSCT from the same donor following relapse from a first allogeneic HSCT For patients receiving azacitidine after first HSCT, at a median follow-up of 18.5 months (range: 5- 36 months), the median PFS was not reached, and the median OS was 32 months (95% confidence interval [C.I.]: 24.85-39.15). The 24-month PFS and OS were 66.1% and 73.2% respectively. Acute and chronic GVHD occurred in 7 (31.8%) and 17 patients (77%). For patients receiving azacitidine after second HSCT, at a median follow-up of 14 months (range: 9 - 46 months), the median PFS and OS were 9 months (95% C.I.:6.94-11.04) and 14 months (range: 11.77 - 16.23 months). The 24-month PFS and OS were 25% and 14% respectively. Acute and chronic GVHD occurred in 1 (8.3%) and 5 (41.7%) patients respectively. In both groups, 100% donor chimerism was achieved during azacitidine maintenance.Conclusion. Azacitidine maintenance following first allogeneic HSCT resulted in favorable 2-year survivals in selected patients with high-risk AML and MDS. Nevertheless, survivals were poor despite azacitidine maintenance after second allogeneic HSCT from the same donor. Full donor chimerism was maintained during azacitidine maintenance. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Add-on Study of Vorinostat (VOR) in Higher Risk Myelodysplastic Syndrome with Failure of Hypomethylating Agents (HMA): The GFM Azavor Study

Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival.Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients.Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months.Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. DisclosuresPrebet:CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.