ALBERT

Description: Abstract 4496 Purpose: To investigate the impact of pre-transplant CMV serostatus of donor or recipient on outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). Patients and methods: We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer centre at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R]-) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk – either (D-/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%). Results: Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs intermediate: 29% vs high: 50%; p=0.001) and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively. Conclusion: Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients, warranting further prospective studies. Legend: CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; Flu, fludarabine; Bu, busulfan; ATG, antithymocyte globulin; CR, complete remission; VGPR, very good partial remission; PR, partial remission, PD, progressive disease; MRD, matched related donor; URD, unrelated donor; GVHD, graft versus host disease; CSA, cyclosporine A; MMF, mycophenolate mofetyl. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Incidence of most myeloid malignancies increases with age. Although allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative option for most of myeloid diseases, conventional myeloablative regimens are associated with considerable toxicity in older patients and high rate of non-relapse mortality (NRM). Thus, such standard approach is very rarely performed in the setting of older patients. Recent developments and introduction of reduced intensityoxicity (RIC/RTC) and non-myeloablative (NMAC) regimens have allowed the extension of Allo-HSCT to these older patients. This study aims to report our experience of Allo-HSCT in patients 〉 55 years of age. Patients and Methods: From 2005 to 2014, 171 patients 〉 55 years of age with myeloid malignancies underwent first allogeneic HSCT at our center, with a median age of 63 years (56-72 years). Sixty-five patients (38%) had 65 years or more. Data had been double-checked using individual institutional files along with HSCT database of the IPC. Of all patients 117 had AML, 49 had MDS and 5 had MPN. They were conditioned by RIC (120 patients, 70%), RTC (16 patients, 9%) or NMAC (35 patients, 21%) regimens. One hundred and nineteen patients (70%) were transplanted with HLA-identical donor (sibling donor, n=66; unrelated donor; n=53), while 52 patients (30%) received transplantation from alternative donor (mismatched unrelated donor, n=18; cord blood, n=14; haploidentical donor, n=20). We found that 91 patients (53%) have a hematopoietic cell transplantation comorbidity index (HCT-CI) between 0 and 2, while 80 patients (47%) had a HCT-CI ≥ 3. Disease risk index (DRI) was low, intermediate, high and very high in 4 (2%), 108 (63%), 55 (33%) and 4 (2%) patients, respectively. Results: NRM at day+100 and 3 years were 7% and 23%, respectively. Cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 20% and 28%, respectively. With a median follow-up of 32 months (3.3-99.5), 3-years cumulative incidence of relapse (CIR), overall survival (OS) and progression free-survival (PFS) were 32%, 52% and 45%, respectively. Although we found a trend for higher NRM in patients aged above 65 years (〈 65 vs. 〉= 65 years: 20% vs. 28%, p=0.056), no impact of age was found on PFS (〈 65 vs. 〉= 65 years: 44% vs. 46%, p=0.662) and OS (〈 65 vs. 〉= 65 years: 50% vs. 54%, p=0.750). DRI significantly influenced outcome (low + intermediate vs. high + very high: PFS: 53% vs. 28%, p=0.011; OS: 60% vs. 34%, p=0.020) while patients who received NMAC regimens had significantly lower PFS (NMAC vs. RIC vs. RTC: PFS: 26% vs. 50% vs. 50%, p=0.028) and OS (NMAC vs. RIC vs. RTC: PFS: 30% vs. 57% vs. 63%, p=0.031).There were no significant differences of OS or PFS among patients groups classified according to type of donor, sex mismatch, donors' age, donors' sex, donors' CMV antibodies positivity, patients' sex, HCT-CI, disease classification, graft's source or whether they were transplanted before or after 2010. In multivariate analysis model including conditioning type (NMAC vs. RIC vs. RTC), DRI (low + intermediate vs. high + very high), HCT-CI (0-2 vs. 〉=3), patients' age (continuous) and donors' type (HLA-identical vs. alternative donor), high/very high DRI as well as the use of NMAC regimens were independent poor predictive factor associated with higher CIR and shorter PFS (HR, 95%CI=1.77, 1.16-2.72; p=0.009 for DRI; HR, 95% CI=1.87, 1.11-3.13; p=0.018 for NMAC) and OS (HR, 95% CI=1.75, 1.11-2.75; p=0.016 for DRI; HR, 95% CI=1.98, 1.14-3.45; p=0.016 for NMAC). Patient's age was associated with higher NRM (HR, 95% CI=1.10, 1.01-1.19; p=0.027). Conclusion: Our data shows that though aged patients still generally at a higher risk of NRM, Allo-HSCT using adapted conditioning regimen can provide low NRM and prolonged survival. Beyond the feasibility, disease relapse appears as the major issue after Allo-HSCT. To optimize conditioning regimen for older patients may be a viable option to enhance disease control without raising toxicity. Indeed, the development of RIC/RTC regimens may improve overall outcome of older patients suffering from myeloid diseases. In contrast, truly NMAC regimens may provide insufficient disease control. The optimal conditioning intensity in the setting of older patients with myeloid malignancies remains undefined and should be evaluated in further prospective trials. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION. In the setting of T-cell replete haploidentical transplantation, the question about the best stem cell donor is still open. Cytomegalovirus (CMV) serostatus represents one of the main factors affecting outcome, however its role has to be yet characterized after haploidentical stem cell transplantation with post-transplant high-dose cyclophosphamide (haplo-SCT with PT-Cy). METHODS. Four cohorts were followed up, according to patient/donor CMV serostatus, on a total of 207 haplo-SCT with PT-Cy performed at two institutions (Institut Paoli-Calmettes, Marseille and Istituto Clinico Humanitas, Milano) from September 2009 to April 2015; cohort 1, patient/donor CMV-/- (n=36); cohort 2,-/+ (n=26), cohort 3,+/+ (n=110), cohort 4,+/- (n=35). CMV reactivation, OS and TRM were observed in the four cohorts and the adjusted effect of patient/donor CMV serostatus was evaluated through multivariate Cox regression on OS and TRM. RESULTS. Median follow-up from transplant was 660 days (range: 42-1826). The main characteristics (patient/donor gender, diagnosis, patient's age, disease status before transplant, DRI, AB0 matching, source of stem cells, conditioning intensity, HCT-CI, year of transplant) were analyzed and did not significantly differ among the groups except for the source of stem cells that was unbalanced in cohort 1 (approx. ratio PBSC:BM of 3:1) vs. the cohorts 2,3,4 (ratio 1:1, p=0.04). The rate of CMV reactivation was 42% for the entire population and 0%, 45%, 52%, 51% in cohorts 1 to 4, respectively, with a longer time to first reactivation in the cohort 2 vs. 3 and 4: day+63 vs. +41 and +42. Two-year OS was 62%, 65%, 50%, 42% in cohorts 1 to 4, respectively (64% vs. 48% in cohorts 1+2 vs. 3+4, p=0.01); TRM was 9%, 17%, 24% and 31% in the same groups. After adjustment, OS was not significantly impaired if a CMV seropositive donor was used for a CMV seronegative patient instead of a CMV seronegative donor (table 1); mortality risk was higher among CMV+ patients, without differences according to donor CMV serostatus. Results on TRM were similar (table 1). Of note, no significant differences of acute or chronic GvHD were observed among the 4 cohorts (p=0.86 and p=0.12, respectively). CONCLUSIONS: for a CMV- patient, the use of a CMV+ donor did not appear to impair survival after haplo-SCT with PT-Cy. Outcome of CMV+ patients is worse than CMV- patients, without significant differences according to donor CMV serostatus. Further studies with larger series (i.e. collaborative and/or registry studies) are warranted to better clarify this issue. Table 1. Multivariate Cox regression on OS and TRM. OS TRM Patient/donor CMV serostatus HR 95% CI P HR 95% CI P -/- 1 1 -/+ 0.98 0.37-2.54 0.96 1.41 0.28-7.02 0.68 +/+ 2.28 1.16-4.47 0.02 3.64 1.09-12.20 0.04 +/- 2.18 1.01-4.69 0.05 3.80 1.02-14.09 0.05 Variables with p

Description: Abstract 3031 Introduction: The use of hematopoietic stem cells from partially matched family donors has become an alternative transplant option for patients with no HLA identical donor available. It might be even a first choice, especially in advanced hematological maligancies, because of the presumed stronger graft versus tumor effect relied to the partial HLA identity. However, haplo-SCT is associated with high risk of graft rejection (GR) and severe graft versus host disease (GvHD), especially after non NMA. High dose posttransplant Cyclophosphamide (Cy) has been shown to prevent GvHD and GR. Aim: This retrospective analysis report the outcome of 15 patients (pt) using posttransplant Cy after a NMA in our center. Results: Fifteen adult pt (Male=9) with high risk lymphoid malignancies for whom a HLA matched related or unrelated donor were not available, underwent haplo-SCT from February 2011 to June 2012. The median pt age was 41years (y) (range, 20–60). Diagnosis were Hodgkin Lymphoma in 5 pt, Non Hodgkin Lymphoma in 4 pt, Chronic Lymphatic Leukemia in 2 pt, Multiple Myeloma in 2 pt and Acute Lymphoblastic Leukemia in 3 pt. All pt were heavily pretreated with a median of 3 or more chemotherapy regimens including failure of previous autologous (12pt) or allogeneic transplantation (3pt). At time of transplant 9pt (60%) were in complete remission (CR1=6, CR2=3). The NMA consisted in Fludarabine 30mg/m2 iv on days -6 to -2, Cyclophospamide 14.5mg/kg iv from days -6 and -5 and Total Body Irradiation 200cGy on day -1. For Graft versus Host Disease prophylaxis all pt received postransplant Cy 50mg/kg iv on days + 3 and +4 with Mesna. One day later, all pt started with Cyclosporine (CSA) 3mg/kg/day and Mycophenolatemofetil (MMF) 15mg/kg/day and Filgrastim 5ug/kg/day until neutrophil recovery. MMF was stopped at day+35 and CSA was given until day +180 in the absence of GvHD. Ten pt (67%) received bone marrow (BM) and 5 pt (33%) G-CSF mobilized peripheral blood stem cells (PBSC) as graft source. All donors were HLA haploidentical first degree family donors (Male=8) including brothers (7), sisters (2), mothers (4) and son (1). Median donor age was 49 y (range, 23–66). Pt had HLA typing at the allele or antigen level (A, B, Cw, DRB1, DQ) whereas 8 pt were mismatched at 5 loci, 1 pt at 4 loci, 4 pt at 3 and 2 pt at 2 loci. BM grafts contained a medium of 2×106/kg CD34+ cells and 22×106/kg CD3+ cells. PBSC grafts contained a medium of 6×106/kg CD34+ cells and 298×106/kg CD3+ cells. The engraftment rate was 93%, with a median time to neutrophil recovery (〉500 G/l) of 20.5 days (range, 14–26) and to platelet recovery (〉20 000 G/l) of 28.5 days (range, 14–41). Compared to BM recipients, pt receiving PBSC experienced faster neutrophil [(17 days (range, 14–23) vs 21 days (range, 18–26), p=0.04] and platelet recovery [(23 days (range, 14–30) vs 30 days (range, 23–41), p=0.04)]. One pt with ALL did not engraft and died at day +40 for infectious complication. One pt died of treatment related mortality with a cumulative incidence of 7% [96%CI (0–20)]. Two pt developped acute GvHD grade 2. No chronic GvHD was observed in pt surviving beyond day 100. Four pt exerienced relapse or progression of the underlying disease. After a median follow up of 197 days (range, 40–518) the actuarial overall survival and event-free survival at 2 years were 87% [95% CI (70–100)] and 51 % [95% CI (16–85)], respectively. Conclusion: NMA haplo-SCT with postransplant Cy in pt with advanced lymphoid malignancies is associated with low NRM, low acute GvHD and low graft rejection. However, better disease control in selected pt is needed to overcome early relapse or progression. Even if follow-up is short, PBSC seems to be an promising option to bone marrow as stem cell source. Disclosures: No relevant conflicts of interest to declare.

Description: INTRODUCTION: Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a major therapeutic challenge: outcome is very poor, without curative option in most cases. Second alloHSCT may be considered in few selected patients because of anticipated limitations: 1) donor availability; 2) high toxicity due to previous treatments; 3) low efficacy considering the very advanced disease situation. We hypothesized that the use of post transplantation Cyclophosphamide (pCY) haplo-SCT may be an interesting alternative to overcome these limitations. In particular, the presence of full haplotype HLA mismatch could provide a decisive antileukemic effect relative to alloreactivity. In absence of large series in this setting, we report here the outcome after HaploSCT for patients who relapse after a first alloHSCT. METHODS: We retrospectively studied adult patients, who received a second pCy Haplo-SCT for hematological malignancies. Patients were treated between 2009 and 2016. The objective was to assess both the feasibility and the efficacy of HaploSCT in this setting. RESULTS: Twenty seven patients were included: median time between first alloHSCT and relapse was 11 months (range: 1-82). Median age at second transplantation was 49 years old (range: 21-61). Most of patients had acute myeloid leukemia (n=12, 44%) or Hodgkin lymphoma (n=6 patients, 22%). Fifteen patients (55%) were in complete remission at the time of pCY Haplo-SCT. Hematopoietic cell transplantation-comorbidity index was ≥ 3 in 20 patients (74%). Thirteen patients (48 %) received non-myeloablative conditioning regimen (as Baltimore schema, Luznik et al. BBMT 2008) prior to HaploSCT while remaining patients received busulfan-based regimen. Day+100 cumulative incidence of grade 2 to 4 and 3 to 4 acute GVHD was 15% and 7%. 2-year cumulative incidence of chronic GVHD was 12%. The cumulative incidence of non-relapse mortality and relapse at 2 years were 38% and 27%, respectively. With a median follow up of 25 months (range: 4-63), 2-year progression-free and overall survivals were 36% and 39%, respectively. Disease status at the time of HaploSCT was a major determinant for outcome. Indeed, 2-year NRM and OS were 58% and 25% in patients transplanted with active disease, respectively, while corresponding values in patients transplanted in CR were 21% (p=0.036) and 49% (p=0.041), respectively (Figure 1A and 1B). CONCLUSION: We can conclude that in selected patients who could be candidate for second transplantation, HaploSCT is feasible and may represent a curative option. The overall incidence of relapse of 27% is promising in this situation for which no alternative for cure is available, with relatively good survival in patients transplanted in CR. However, the very high NRM (58%) in refractory patients should make us consider second transplant with caution in this setting. For these patients, specific developments are needed to avoid procedure-related toxicity. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p

Description: Abstract 4545 The monitoring of chimerism is a standard procedure for assessing hematopoietic engraftment and achievement of full donor lymphoid chimerism after RIC based Allo-SCT. Post graft donor lymphocyte infusions are often decided on this evaluation. These studies have however a cost issue, all the more no consensus presently exists on when and how often to perform them. We retrospectively analysed the impact of acute GvHD in the prediction of allograft chimerism in our RIC program where TCC was serially assessed at 30, 60 and 90 days after Allo-SCT. We selected patients with hematologic malignancies (with the exclusion of myelofibrosis) transplanted between 2001 and 2010 after Fludarabine-Busulfan-ATG RIC from a HLA identical donor. 115 patients fulfilled all criteria including at least one T cells chimerism (TCC) determination between day 30 and 120. Allo-SCT was performed from familial donor in 92 patients (80%) and from MUD in 23 patients (20%). The conditioning regimen consisted of fludarabine (90 to 180 mg / m2), Busulfan (8 mg / kg orally or 6.4 mg / kg IV) and rabbit anti-thymocyte globulin (ATG) (2.5 or 5 mg /kg). As for chimerism study, recipient peripheral blood T lymphocytes were positively sorted by a mix of anti-CD4 and CD8 immunomagnetic beads (Dynal, Compiègne, France). T-cell purity was controlled by flow cytometry and was always 〉 or =95%. Genomic DNA was amplified using fluorescent PCR primers for polymorphic variable number tandem repeats (VNTR) or short tandem repeats (STR). Mixed T-cell chimerism was defined as between 5 and 94% recipient cells, and full chimerism was defined as the presence of more than 95% donor cells. Full TCC was achieved in 94 patients (82%) at a median of 77 (30–120) days post transplant. Fifty eight patients (50.4%) developed acute GvHD. The cumulative incidence of Grade 2–4 GvHD in our population is 32% (95% CI 23–41). Overall the results showed that each of the 37 patients developing grade ≥ 2 AGVHD had a Full TCC prior day 120. On the other hand, all mixed chimerism were documented in patients not presenting Grade≥2 AGVHD (21 of the 78 patients (27%) without grade ≥ 2 AGVHD) (p=.002). No other parameter (ATG dose, Donor type…) achieved this level of individual prediction. These results, in a very homogenous population, are in line with the concept that full TCC is more likely to occur when patient develops significant aGVHD. Although they deserve further and deeper confirmation in different populations, they address the value of systematic routine chimerism surveillance (outside clinical studies) in patients presenting acute GvHD following RIC Allo-SCT. The modulation of TCC determination might represent an interesting cost and resources saving. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Allogenic hematopoietic stem cell transplantation (SCT) is often the only curative treatment for a part of patients with malignant or benign hematological disorders. The availability of a HLA matched related or unrelated donor remains a major obstacle which can be resolved by the presence of alternative donors, like umbilical cord blood, partially matched unrelated or haploidentical family donors. T cell repleted SCT using haploidentical donors (H-SCT) has considerably improved over the last years due to better control of Graft Versus Host Disease (GVHD) using post-transplantation cyclophosphamide (PTCY). Our study aims to shed light on the interest of chimerism evaluation after H-SCT and to elucidate the cause of graft failure (GF) in our H-SCT recipients. Patients and methods: We conducted a retrospective study of 179 patients (pts) who received a H-SCT in our center from august 2009 to march 2016. The pts characteristics are reported in Table 1 and 2. One hundred sixty pts received a Reduced Intensity (RIC) and 19 pts a MyeloAblative Conditioning (MAC) regimen. Twenty-eight pts had refractory or relapsed acute myeloid leukemia. All pts received PTCY on days 3 and 4 and Ciclosporine A and mycophenolate of mofetil since day 5 for GVHD prophylaxis. Twenty pts received H-SCT for relapse after a first SCT with a HLA identical donor. Stem cell sources were bone marrow (BM) for 19 pts, peripheral blood stem cells (PBSC) for 157 pts and BM+PBSC for 3 pts. The donors were children (79 daughters sons), parents (4 fathers, 14 mothers), family members (75 siblings, 1 cousin, 1 nephew) and 5 unknown. Chimerism analysis: The peripheral blood CD3 positive cells were selected using the kit Human CD3 Positive selection (Stemcell) and genotyping was performed with the PowerPlex 18D System (Promega), a multiplex STR system allowing the co-amplification of 18 loci. DSAs (donor-specific anti-HLA antibodies): The DSAs were identified with the use of highly sensitive solid-phase immunoassays. Desensitization therapy with Bortezomib, Rituxan and plasmapheresis was performed in two patients with a high level of DSAs. Results: Chimerism could be evaluated in 167 patients, where 162 had ≥ 98% of donor cells at a median time of 35 d post-transplant (range 15-170) without secondary GF. One patient suffering from sickle disease had stable mixed chimerism (82% donor). Only 4 pts had primary GF (2%), all of donor-recipient pairs were ABO compatible, all of them received a Baltimore conditioning whereas 2 pts had BM as SC source. Recipients with PBSC as SC source had poor CD34+ cells infused (1,2 and 2,3 x 106/kg). One of the 4 pts had a high level of DSAs. A patient with mycosis fungoide had secondary GF after relapse (PBSC/DSAs negative). One patient with a high level of DSAs (78%) had a primary graft failure. Two pts with a high level of DSAs who were desensitized by the described procedure. Forty-five patients had a positive anti-HLA antibody no specific to donor with a median level of 3% (range: 1-45%) with no impact on engraftment (Anti-HLA antibody class I in 30 pts, class II in 11 pts and mixed in 4 pts). The median number of CD34+ cell count was 5,2x 106/kg (range: 1,3-17) in 160 pts who had PBCS as SC source. With a median follow up of 532 d (range: 164-1587d), 123 pts are alive and 116 of them are in CR. Conclusion: Full donor chimerism is obtained in almost all pts after T cell repleted H-SCT with PTCY. Primary graft failure occurred principally in pts with high levels of DSAs and poor graft CD34+ cells. Chimerism analysis post H-SCT is not crucial and might focus on a small group of high-risk pts. Detection of DSAs is crucial in HLA mismatched transplants not only to select the most appropriate donor but also to include a pre-transplantation strategy of desensitization to minimize the risk of graft failure. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: The conditioning regimen (CR) is crucial for outcome and disease control after allogenic hematopoietic stem cell transplantation (AHSCT). Especially high risk and older patients (pt) represent a major challenge because of the need to intensify the CR for better disease control and the risk of regimen related toxicity. Busulfan (Bu)-based CR are widely used for AHSCT and pharmacokinetic (PK) studies have established that an optimal therapeutic window for a delivered high dose Bu exists. Bu Pk directed dosing targeting a per day area under the curve (AUC) may further optimize the antitumor effect and minimize toxicity. However, reported PK procedures are not optimal either using a test dose (Andersson Blood 2004) or done on the first administration day (d) allowing to get the results just before the 3rd administration in a 4 d Bu schedule and leaving only 2 d for adaptation with potential high variations. We report here the results of an ongoing prospective monocentric study evaluating the efficacy and toxicity of a myeloablative (MA) CR with iv Bu dose adjustment by PK analysis following an original schedule. Patients and methods: From December 2014 to July 2016, 13 pt over the age of 55 years were included. All received a GCSF mobilized peripheral blood stem cell graft from a HLA identical 6/6 matched sibling or 10/10 matched unrelated donor (MUD). CR consisted in Fludarabine 30 mg/m2 given once daily on d -6 to -2 which each infusion followed immediately once daily by iv Bu for 4 d and Thymoglobuline 2.5 mg/kg on d -3 and -2.Graft versus host disease (GVHD) prophylaxis was assured by cyclosporine A. The first dose of Buat d -6 was 130 mg/m2 given over 3 hours followed by 3 dose adjusted administrations on d -4 to -2 after 1 d of rest at d -5. Blood samples were drawn for each pt at d -6 and -2 for a total of 12 samples: just before the start of the Bu infusion, 15 minutes after the end of the infusion and then at 2, 4, 6 and 9 hours. PK parameters and AUC calculation were performed by compartimental analysis using Kinetic Pro software. Bu doses were adjusted at d -4 to -2 to achieve an average daily AUC of 5300 µM.min. Adjustments were made if the first-dose AUC was below or above the target interval of 4770-5830. The samples at d -2 were analyzed to control the BuSE after the 4 infusions and to determine the real AUC obtained. Results: Ten of the 13 pt enrolled were evaluable. Median age was 63 years (range, 57-68). Diagnosis was acute leukemia in 6 pt [4 ALL, 2 AML], multiple myeloma in 2 pt, and myelodysplastic and myeloproliferative syndrome in 1 pt respectively. Disease risk according to Armand (Blood 2014) was intermediate in 8 and high in 2 pt [MPS, ALL]. Seven pt were in complete remission at time of transplant [5 CR1, 2 CR2], 2 pt in partial remission [1 PR1, 1 VGPR] and 1 pt with SMP in accelerated phase. The comorbidity index according to Sorror was 3 (range, 0-7). Donors were siblings in 6 and MUD in 4 pt. Bu dose adjustment was performed in 7 pt, whereas 5 pt required an increase and 2 pt a decrease in dose to achieve the average target AUC of 5300 (table 1). The remaining 3 pt did not require dose adjustments as their first Bu dose AUC felt within the target range. The median AUC at the first Bu dosing was 4894 (range, 3477-6759). After Bu dose adjustment, the final BuSE at the last dosing showed 5 pt with increased AUC outside the range, from whom the 3 pt who did not require dose adjustment. The median AUC at the last Bu dosing was 5330 (range, 4335-5987). Most common toxicities were transient grade 1-3 mucositis, enteritis and liver transaminases or bilirubin elevation. All pt engrafted with a median time to neutrophil recovery to an ANC 〉 500 x 106/L of 15 d (range, 11-21) and to platelet 〉 20 x 109/L (range, 8-19) of 14 d. Two pt developed grade 1 acute GVHD and 1 pt showed overlap GVHD. With a median follow up of 180 d (range, 30-573) no regimen related mortality occurred. Three pt with ALL relapsed at a median time of 127 d (range, 72-183). Conclusion: Despite the small pt population and the short follow-up, the preliminary results of our study shows the feasibility and safety a high dose Bu MA CR in older pt with comorbidities and different hematologic malignancies. Bu PK guided dose escalation was not associated with severe acute toxicities or early regimen related mortality. Strategies to target BuSE individually according to disease risk and integrate early posttransplantation drug interventions associated with donor lymphocyte infusions may further prevent relapse. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: allogeneic transplantation (allo-HSCT) is a curative treatment for patients with advanced lymphoma. Haploidentical (haplo-SCT) transplantation extended the accessibility to allo-HSCT, overcoming the issue of donor availability. However, alternative donor allo-HSCT is still considered at higher risk of non-relapse mortality due to the HLA disparity and thus an anticipated higher incidence of GVHD. In this context, the use of a non myeloablative conditioning (NMAC) regimen combined with post transplantation cyclophosphamide (PT-Cy) based GVHD prophylaxis may reduce procedure related toxicity. The aim was to evaluate the toxicity and efficacy of haplo-SCT using NMAC with PT-Cy in advanced lymphoma patients. Methods: We here report the retrospective experience of a bicentric transplantation program. We analyzed a cohort of lymphoma patients undergoing Haplo-SCT and homogeneously receiving NMAC and PT-Cy. Inclusion criteria were: 1) first allo-HSCT for advanced lymphoma between 2009 and 2018; 2) haploidentical donor; 3) NMAC (fludarabine cyclophosphamide and 2 gray TBI GVHD prophylaxis consisted of PT-Cy day+3 and +4 , cyclosporine A and MMF starting from day +5. Multivariate analyses included age, disease type (NHL vs HL), HCT-CI (〈 vs ≥ 3), graft source (PBSC vs BM), disease status at haplo-SCT (CR vs other). Results: One hundred forty seven patients (73 NHL; 74 HL) with a median age of 46 years (range: 19-71) were included. PBSC (peripheral blood stem cell) was used as graft source in 96 patients (65%). Patients received a median number of 3 conventional chemotherapy lines before haplo-SCT (1-8). Sixty-five (44%) had relapse after Auto-HCT. At the time of haplo-SCT, 96 patients (66%) were in complete remission. The cumulative incidences of day+100 grade 2-4 and 3-4 acute GVHD were 30% and 3%, respectively. The cumulative incidences of 2-year chronic and moderate or severe chronic GVHD were 13% and 8%, respectively. With a median follow up of 39 months (6-114), 2-year NRM was 14%, with a trend for higher risk in patients with HCT-CI ≥ 3 (HR 0.39, 95CI [0.15-1.04] p = 0.061) while age was not associated with an increased risk of NRM (HR 1.01, 95CI [0.98-1.05], p = 0.450). Two-year cumulative incidence of relapse (CIR) was 21% and 18% in HL and NHL patients, respectively. Disease status at the time of haplo-SCT was strongly associated with relapse (HR 2.99, 95CI [1.41-6.35], p = 0.004) In HL patients, 2-year PFS, OS and GRFS were 65%, 77% and 57%, respectively, while corresponding values in NHL patients were 65%, 69% and 55%, respectively. Two-year PFS and GRFS were significantly higher in patients who underwent haplo-SCT in CR (PFS: CR vs. no CR: 72% vs. 55%, p=0.045; GRFS: CR vs. no CR: 63% vs. 42%, p=0.010). There was a trend for better 2-year OS in CR (OS: CR vs. no CR: 78% vs. 63%, p=0.063. Conclusion: We confirm the feasibility of haplo-SCT using NMAC and PT-Cy with low incidence of GVHD (notably severe forms) and NRM. In addition, we observed a relatively low incidence of relapse (19%) in this cohort of heavily pretreated patients, underlining a potent graft-versus-lymphoma effect after haplo-SCT, leading to promising survivals, including high rate of GRFS (〉50%), suggesting a preserved long term quality of life in survivors. We conclude that NMAC haplo-SCT with PT-Cy should be considered as a valuable curative option for advanced lymphoma patients, with a favorable toxicity profile and promising long term survival. Figure Disclosures Stoppa: celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Carlo-Stella:MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Boehringer Ingelheim: Consultancy; Genenta Science sr: Consultancy; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Other: Travel, accommodations; Janssen Oncology: Honoraria; AstraZeneca: Honoraria. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities. Santoro:Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Blaise:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria.