ALBERT

Description: Abstract 5070 In 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. 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.

Description: Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach for a wide range of hematologic malignancies. However, the period of prolonged immunodeficiency after this procedure results in significant morbidity and mortality from infectious complications. Epstein-Barr virus (EBV) is a latent γ-herpes virus with B lymphocyte-specific tropism that infects more than 90% of healthy individuals. Following allo-HSCT, EBV reactivation and EBV-related proliferations may be associated with a spectrum of clinical presentations, going from fever to lymphoproliferative diseases (LPD), which arise as a consequence of an outgrowth of B cells latently infected with EBV in the setting of loss or suppression of normal cytotoxic T-cell surveillance. Reduction in immunosuppression and/or pre-emptive therapy with rituximab are strategies nowadays employed to prevent or to treat EBV-associated LPD, which have led to a significant improvement in patient outcome. While the role of T cells and NK cells in graft-versus-leukemia (GVL) immune responses has been established, recent studies have shown a potential contribution of B cells on GVL responses. In this context, the impact of the use of monoclonal antibodies targeting B cells lines on disease control has not been evaluated yet. The aim of this study is to evaluate the incidence of EBV reactivation in patients with hematological malignancies after allo-HSCT, the use of rituximab for its treatment and its impact on the transplantation outcomes. Patients and methods: We evaluated 359 consecutive patients with hematological malignancies who received allo-HSCT and were followed in our center between January 2008 and June 2015; there were 218 (61%) males and 141 (39%) females with a median age of 48 years (range: 18-70), 182 (51%) had acute myeloid leukemia, 44 (12%) multiple myeloma, 34 (9%) myelodysplastic syndrome, 30 (8%) Non-Hodgkin lymphoma, 7 (2%) chronic lymphocytic leukemia, 21 (6%) myeloproliferative syndrome, 14 (4%) Hodgkin disease, 13 (4%) chronic myeloid leukemia and 14 (4%) aplastic anemia. At transplantation, 227 (63%) patients were in complete response (CR) or chronic phase (CP) and 132 (37%) were in less than CR or CP. For conditioning regimen, 171 (48%) were myeloablative and 188 (52%) were reduced intensity. EBV DNA levels in blood were detected by quantitative real-time polymerase chain reaction (RQ-PCR) after weekly monitoring up to 3 months after allo-HSCT. EBV-DNA was considered positive when the copies exceeded 1000 copies/ml. EBV therapeutic intervention, firstly concerned gradual reduction of the doses of immunosuppressive drugs, and then rituximab infusion (375 mg/m², four injections weekly) was administered when the copies exceeded 10 000 copies/ml. Results: Among 359 patients, 222 patients had EBV reactivation after a median time of 1.3 months (0.7-2.5) after allo-HSCT with a cumulative incidence of 48 % (47-50) at 3 months. Among the 222 patients with EBV reactivation, only 35 (15.7%) needed treatment with rituximab. Rituximab was introduced after a median time of 55 days after transplantation with a median number of 5 infusions and a median dose of 2025 mg/m². EBV treatment was successful in all patients, none progressed to LPD. The cumulative incidence of relapse at one and two years for the whole population was 27% (26-28) and 34% (33-35) respectively and the cumulative incidence of transplant-related mortality (TRM) was 22% (21-23) and 25% (24-26) respectively. The multivariate analysis taking into account the type of disease, the type of conditioning, the use of ATG, the disease status at transplantation, the presence of GVHD and the EBV reactivation with/without rituximab, showed that the presence of EBV reactivation was associated with a significant lower relapse rate, HR= 0.52 [0.35-1], p=0.05. The use of rituximab did not compromise the GVL effect and thus had not impact on relapse or overall survival. Conclusion: We showed a positive impact of EBV reactivation on relapse incidence which could be explained as a stimulation of both function and amplification of NK compartment. The strict monitoring of the viral load and therapeutic intervention using rituximab enable a full viral control without any progression into LPD and without any compromise on GVL effect. Figure 1. Figure 1. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Nicolini:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction Tacrolimus is a widely used calcineurin inhibitor in solid organ transplantation and in allogeneic HCST for prophylaxis and treatment of GvHD. Recently, several transplantation centers showed advantageous effects for patients with tacrolimus in comparison with cyclosporin A (CsA) regarding renal function after renal and heart transplantation. Based on these observations, we have conducted a prospective study in wich CsA is switched for tacrolimus (Prograf or Advagraf ER) in case of renal impairment due to CsA after allogeneic HSCT. Patients, Method We enrolled 31 consecutive patients between March 2012 and March 2016 from two centers in France (Lyon and Nancy) with renal impairment due to CsA (serum creatinine 〉 90 µMol/L), the conversion dose was established on an mg:mg basis 1 :100 from CsA total daily dose to a total daily dose of tacrolimus. In this cohort, 27 patients received oral formulation Advagraf and 4 received Prograf initially i.v. and then converted to oral form. The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L.We evaluated the tacrolimus blood trough level changes after conversion, serum creatinine, potassium, one time a week from one week after switching to discontinuation. Before the switch, 22 patients (70%) had CsA for GvHD prophylaxis and 9 patients (30%) for acute GvHD treatment in association with prednisone. Results All patients had hematological malignancies, the median age was 54 years (range, 17-67). Twelve patients (39%) had a matched related donor, 19 patients (61%) had a HLA-10/10 matched unrelated donor .The stem cell source was bone marrow for 11 patients (35.5%), PBSC for 18 patients (58%) and cord blood for 2 patients (6.5%). Fifteen patients (48%) received a myeloablative regimen and 16 patients (52%) a reduced intensity regimen. ATG was administrated in 28 patients and 10 patients received 12Gy TBI. The status at transplantation was CR1 for 13 patients (42%), CR2 or more for 10 patients (32%), partial response for 5 patients (16%) and 3 patients (10%) had a refractory leukemia. The median follow-up after transplantation was 35.6 months (range, 1-51,7). The median time of switch for tacrolimus was 40 days (range, 3-1286) and the median of serum creatinine in wich the switch was realized was 110 mol/L (range, 94-262). Concerning creatinine level, the median of serum creatinine was 105 µmol/L (range, 51-262) with CsA and 84 µmol/L (range, 50-129) with tacrolimus (p

Description: Abstract 4549 Introduction Patients with high risk AML have poor outcomes. However, the only approach with curative potential remains allogeneic HSCT. With the aim to improve the effect of allogeneic HSCT by sequential use of chemotherapy, RIC regimen and pDLI, we are currently conducting a prospective pilot study for high risk AML. High risk AML was defined by unfavorable cytogenetics, adverse molecular abnormality, secondary AML, and AML requiring 2 induction courses to obtain CR1. After identification of a HLA 10/10 donor, patients are received the sequential regimen consisted of fludarabine (30mg/m2/d), Ara-c (2g/m2/d) and amsacrine (100mg/m2/d) (FLAMSA) chemotherapy for 4 days. After 3 days of rest, RIC regimen consisted of 4 Gy TBI, cyclophosphamide for 2 days (40 mg/kg in case of matched related donors, and 60 mg/kg for unrelated or mismatched donors), and ATG (5mg/kg total dose) (German regimen) or Busulfan 3.2mg/kg/d during 4 days followed by ATG (5mg/kg total dose) (French regimen). The modified regimen has been established after our results in refractory AML patients (ASH 2011, poster 1957). Prophylactic donor lymphocyte transfusion was given from day +120 in patients who were not receiving immunosuppression and were free of GvHD. Our objective is to include 20 patients and to compare with a control cohort of patients with the same high risk AML treated according to the conventional strategy during the same period. Results Between August 2010 and November 2011, we have included 12 consecutive patients in first complete response who underwent an allogeneic HSCT after sequential FLAMSA-RIC regimen with a median follow-up of 12 months (range [7–22]). Nine patients were 〈 55 years old (median age: 54 [28–64]), 7 patients had an unrelated donor and 5 patients had a related donor. The stem cell source was PBSC for 11 patients and two cord blood unit for 1 patient. Before FLAMSA-RIC regimen, 3 patients had received two induction courses to obtain CR1. All patients had adverse cytogenetics or molecular abnormalities and 1 patient had a secondary AML. At the last follow-up, 6 patients (50%) are alive in CR. (Figure 1.) Four patients (33.3%) died in remission. The cause of death was infection for 2 patients, aGvHD for 1 patient and graft failure for 1 patient. Only one patient died from relapse 6 months after transplantation. Five patients (41.6%) experienced aGvHD and 2 patients (16.6%) had an extensive cGvHD including the patient who has been transplanted with 2 cord blood unit. Six patients (75%) in a group of 8 patients aged 〉 45 years experienced complications (infection (n=3) and GvHD (n=3)). One patient (25%) from a group of 4 patients aged 〈 45 years had infectious complication after transplantation. Prophylactic donor lymphocyte transfusion was given in 6 patients, the causes of no administration were GvHD for 2 patients, cord blood unit as stem cell source for 1 patient and 3 patients were dead before 120 days after transplantation. From the 6 patients who had received pDLI, 5 patients are alive in CR and 1 patient died from GvHD. Conclusion The FLAMSA-RIC regimen before allogeneic HSCT is a new approach for high risk AML. Between 2012 January and 2012 July, 8 additionnal patients have been included and the results for the whole study will be communicated later. Our primary results are promising especially for young patients (〈 45 years) who seem to better profit from this sequential FLAMSA-RIC regimen. 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.

Description: Introduction Tacrolimus is a widely used calcineurin inhibitor in allogeneic HCST for prophylaxis and treatment of GvHD. This molecule is now available in both standard-release (Prograf, twice-daily tacrolimus, Astellas Pharma) and extended-release (Advagraf, once-daily tacrolimus, Astellas Pharma) formulations. Compared with the standard-release formulation, the extended-release (ER) tacrolimus has been shown in previous pharmacological studies to provide bioequivalent drug exposure, efficacy and safety. Moreover, this formulation of tacrolimus was followed by a clinically significant improvement in kidney graft function for kidney recipients. Based on these observations, we have conducted a prospective study in wich ciclosporine A (CsA) (Neoral) is switched for tacrolimus ER (Advagraf) in case of renal impairment after alloHSCT. Method We enrolled 16 consecutive patients with renal impairment (serum creatinine 〉110 µMol/L) from May 2012 to May 2013 during the follow-up at outpatient clinic, the conversion dose was established on an mg:mg basis 1:100 from CsA total oral daily dose to a single dose of oral tacrolimus ER formulation. The dose was readjusted to obtain a tacrolimus blood trough level between 5 and 15 µg/L. Tacrolimus ER was given at noon in a single dose one hour before lunch. We evaluated the tacrolimus blood trough level changes after switch, serum creatinine, glycemia, potassium, acute and chronic GvHD. A satisfaction survey for tacrolimus ER treatment was performed 3 months after the switch, the questionnaire included administration compliance questions. Results All patients in this cohort had hematological malignancies, the median age was 52 years (range, 28-66). Eight patients (50%) had a matched related donor, 7 patients (43.75%) had a HLA-10/10 matched unrelated donor and 1 patient underwent alloHSCT with two cord blood units. Seven patients (43.75%) received a myeloablative regimen with 12 Gy TBI and 9 patients (56.25%) a reduced intensity regimen. The stem cell source was bone marrow for 7 patients (43.75%), PBSC for 8 patients (50%) and cord blood for one patient. The status at transplantation was CR1 for 6 patients (37.5%), CR2 or more for 6 patients (37.5%) and partial response for 4 patients (25%). The median follow-up of the cohort was 7 months (range,2-14). Non-parametric tests such as exact Wilcoxon Mann-Whitney test or Kruskal Wallis were performed for the analysis of the physiological parameters. The median of serum creatinine was 112 µmol/L (range, 51-262) with CsA and 87 µmol/L (range, 50-125) with tacrolimus ER (p 4.5 mmol/L after the switch for tacrolimus ER. The median blood trough level was 300 µg/L (range,100-438) for CsA 14 days after starting and 7.2 (range,3-15) for tacrolimus ER 20 days after starting (Figure). The cumulative incidence of aGvHD grade 〉1 at 3 months was 25% (95%CI,14-36). After the switch for tacrolimus ER, no patient developped aGvHD. Eight patients (50%) developed aGvHD grade 〉1 during the prophylaxis with CsA. For 6 patients (37.5%), aGvHD was resolutive after the switch for tacrolimus ER with an association of tacrolimus ER and prednisone or tacrolimus ER alone. For 2 patients (12.5%), aGvHD was resolutive with CsA and prednisone before the switch for tacrolimus ER. Two patients in this study developed severe chronic GvHD after the discontinuation of prophylaxis (5 months and 10 months). One patient received tacrolimus ER with a complete resolution of cGvHD and the second patient is now on therapy with everolimus. All patients in this cohort are alive and all patients except two are still in complete response. Moreover, the satisfaction survey demonstrated that the patients were satisfied with the switch and the one daily formulation of tacrolimus. Conclusion The conversion from oral CsA to oral tacrolimus ER formulation was followed by a clinically significant improvement in kidney function with stable tacrolimus blood trough levels. The patients were satisfied with this formulation of tacrolimus. We have now extended this study to several centers in the aim to confirm these observations. Disclosures: No relevant conflicts of interest to declare.

Description: Long-term multiple myeloma therapy by immunomodulatory drugs (IMiDs) raises the question of management of adverse effects. The aim of this study is to assess the impact of an educational session for patients on the acquisition of knowledge to manage hematologic and thromboembolic adverse effects of IMiDs. In this prospective single-center study, patients attended an educational session with a hospital clinical pharmacist and a nurse. The primary endpoint was the patient’s level of knowledge for the management of IMiDs adverse effects, assess with a dedicated questionnaire administered before the session then 1 and 6 months after. Assessment of knowledge was combined with self-assessment of certainty. The secondary endpoints were adherence and IMiD treatment satisfaction. 50 patients were included. Patient knowledge increased at 1 month (p