ALBERT

Description: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of a variety of hematologic diseases. However, allo-HSCT can be associated with many complications, including poor graft function early after transplant requiring long-lasting supportive care. In the literature, the incidence of poor graft function post allo-HSCT has been reported to range from 4 to 27%. Here, we retrospectively studied 10 patients (male/female: 4/6, median age: 45 years, range 19 to 67) who received a boost of CD34+ selected cells for poor graft function after allo-HSCT (of whom 4 cases of haplo-identical allo-HSCT with post-Cy prophylaxis), between January 2014 and January 2016. Patients' disease and transplant characteristics are summarized in the below table. Patients were selected for the CD34+ cells "boost" therapy after eliminating other causes that could explain a poor graft function (eg. drug toxicity, infections, disease relapse, etc.) The same original allo-HSCT donor was used to collect the CD34+ cells after mobilization with G-CSF and positive selection. The patients did not receive any prior conditioning therapy prior to CD34+ cells boost infusion. At time of the boost, all patients were in full donor chimerism. The number of infused CD34+ cells differed from one patient to another ranging from 2.91 to 7.99 x106 cells/kg recipient body weight. The median day of infusion post- allo-HSCT was 120 (range, 76-352). Among these 10 patients, 7 patients had full counts recovery at a median of 15 days (range, 7-30) post-infusion, while 3 patients had an incomplete response with persistent anemia and/or thrombocytopenia. None of the patients experienced clinically significant GVHD symptoms after the boost. At last follow-up, 7 patients were alive whereas 3 patients died of severe infections after 1, 6 and 13 months post-boost. Based on these results, we concluded that boost therapy can be used in the treatment of poor graft function post-allogeneic HSCT, including in those patients who received a haplo-transplant. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclophosphamide is widely used for the treatment of patients with hematologic malignancies especially in patients who lack related or unrelated donors. Several factors were shown to affect hematopoietic recovery after allogeneic hematopoietic stem cell transplantation, including age at transplant, initial diagnosis, stem-cell source, CD34 count in the graft, conditioning regimen intensity, infections, etc. The aim of this study was to evaluate immune reconstitution, neutrophils and platelets recovery, transfusion needs and main transplant outcomes after Haplo-SCT and to identify factors correlated with improved or worsened recovery. Methods: This study included 72 consecutive patients who underwent haploidentical stem cell transplantation between December 2012 and March 2018, in a single center. Graft was either bone marrow (n=21) or peripheral blood stem cells (n=51). Patients were given PT-Cy (50mg/kg/d) for one (n=20) or two days (n=52), cyclosporine, mycophenolate mofetil and ATG for GvHD prophylaxis. Conditioning regimen was reduced toxicity one (RIC) in 69% (n=50) of patients, and a myeloablative one (MAC) in 31% (n=22) of cases . Main transplant outcomes, neutrophil and platelets recovery, and needs for transfusion were evaluated at day +30, day +60 and day +90 after Haplo-SCT. Results: The median CD34+ cells infused was 10.62 x106/kg (range, 1.02-15.06). The median time to neutrophil recovery (〉500/µL) was 16 days post-transplant (range, 5-29). The median time to neutrophil count 〉1000/µL was 17 days post-transplant (range, 5-32). Platelets recovery (〉20.000/µL) was observed at a median of 13 days post-transplant (range, 10-193). Platelets recovery (〉50.000/µL) was documented at a median of 60 days post-transplant (range, 10-193). Forty-five (63%) and 49 (68%) patients had a platelets count 〉50.000/µL at days +30 and +60 post-transplant respectively. At day +90 post-transplant, 61 patients were assessable with 56 (92%) of them having a platelets count 〉50.000/µL. In this series, 61 patients (85%) needed platelets transfusion with a median number of 13 units (range, 2-60), transfused for a median of 26 days (range, 5-198) post-transplant. Similarly, 59 patients (82%) needed RBCs transfusion and received a median of 6 RBCs packs (range, 1-60) for a median duration of 31 days (range, 5-147) post-transplant. 23 patients (32%) had anemia and/or thrombocytopenia requiring the administration of growth factors, either erythropoietin in 14 patients (19%) (Epoetin, n=8 or Darbepoetin, n=6) and/or Thrombopoietin in 15 patients (20%) (Romiplostim, n=13 or Eltrombopag, n=2). In all, 6 patients received unmanipulated CD34+ donor stem cell ("boost" procedure), 5 of them for poor graft function and 1 patient as a consolidation after immunosuppressive therapy for relapse after Haplo-SCT. Such boost proved to be successful in 4 patients while 2patients had an incomplete response with persistent anemia and/or thrombocytopenia. In the multivariable analysis, donor age (〉40 years) and CMV reactivation within the first 3 months were shown to meaningfully affect day +90 platelets recovery 〉100 x109/L (HR 4.86, 95%CI 1.08-21.80, p=0.04 and HR 5.15, 95% CI, 1.22-21.7, p=0.03). Number of CD34, conditioning regimen, stem cell source, donor age and disease status at transplant have no impact on platelet recovery at day +90. Conclusion: In conclusion, our data show that Haplo-SCT is associated with a fast hematopoietic recovery with an acceptable rate of transfusions. While the adverse impact of CMV reactivation on platelet recovery was expected, the relation between donor age (〉40 years) and platelets recovery is new. This finding should guide in selection of potential donors for Haplo-SCT. Disclosures Mohty: Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Molmed: Consultancy; Bristol Myers: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Background. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated with calicheamicin, used in acute myeloid leukemia (AML) either as monotherapy or in association with chemotherapeutic agents (Hamann et al. Bioconjug. Chem 2002). It is known to induce a significant liver toxicity that might increase the risk of sinusoidal obstruction syndrome (SOS), especially in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Risk is especially high in patients transplanted within a short interval from last GO dose (≤ 3.5 months) (Wadleigh et al. Blood 2003). The current retrospective analysis aimed to assess the incidence of SOS and the outcome of AML patients receiving GO before allo-HSCT. Patients and methods. The primary endpoint of the study was the assessment of SOS incidence in a series of 146 adult patients (71 women and 75 men) with AML undergoing allo-HSCT after prior exposure to GO. Relevant data were captured by a specific designed questionnaire focusing on SOS (Med C) that was distributed to all EBMT centers. Secondary endpoints were engraftment, non-relapse mortality (NRM), graft-versus host disease (GVHD), leukemia-free survival (LFS) and overall survival (OS). Median age was 50 years (range 19-70). In most cases (n=127 out of 137 for which the information was available, 93%) GO was administered in parallel with other chemotherapeutic agents. Median GO dose was 3 mg/m2. Median number of cycles before allo-HSCT was 1 (range 1-6). The majority of the patients (n=79, 54%) received GO as induction treatment, while 51 (35%) and 16 (11%) received GO for relapsing or primary refractory disease, respectively. At time of allo-HSCT 97 (66%) patients were in complete remission. Of note, 11 patients underwent prior allo-HSCT and 8 patients prior auto-HSCT. Most patients received a reduced intensity conditioning (RIC) regimen pre allo-HSCT (n=84, 58%). SOS prophylaxis was given in a total of 69 patients (heparin n=57, ursodeoxycholic acid n=8, and defibrotide n=4). Cumulative incidence (CI) and Kaplan-Meier estimates were used when appropriate; Cox model was used for multivariate analysis. Results. Overall, cumulative incidence of SOS was 7.75% (95% CI 4.1-12.9) (n=11). Among patients receiving RIC, 4 (4,9%) developed SOS as compared to 7 (11,5%) among patients receiving MAC regimen (p=NS). SOS was the main cause of death in 3 out of 11 cases. Median interval between last GO dose and allo-HSCT was 130 days (range 13-1126). Neither OS nor SOS incidence differed significantly for patients receiving GO shortly before allo-HSCT (≤ 3.5 months) as compared to the others. None of the analyzed risk factors had an impact on the risk of SOS in our study. With a median of 15 days, CI of neutrophil and platelet engraftment was 93.8% (95% CI 88.1-96,8) and 89% (95% CI 82.3-93.3), respectively. CI of acute GVHD at day 100 was 30.6% (95% CI 23-38.2), occurring in 84 patients (out of them 45 had grade II-IV GVHD), while CI of chronic GVHD at 5 years was 25.5% (95% CI 18.6-33). With a median follow-up of 64 months the probability of OS and LFS at 5 years was 40% (95% CI: 31-48) and 37% (95% CI: 29-45), respectively. Cumulative RI and NRM at 5 years were 42% (95% CI: 34-50%) and 21% (95% CI: 14-28), respectively. In multivariate analysis patients transplanted with an active disease relapsed more often and had worse LFS and OS, while patients presenting with liver abnormalities before allo-HSCT had a worse OS (p

Description: Background Graft-versus-host disease (GvHD) is a major limitation after allo-HSCT and remains a frequent cause of death. The 5-years survival is 25% and 5% for grade III and IV, respectively. Acute GvHD occurs in up to 45% of HLA-matched and up to 75% in case of unrelated donors. The standard-treatment consists of methylprednisolone (usually 2 mg/kg/day) and a calcineurin-inhibitor. No standardized second-line treatment for acute GvHD exists. Here, we report a pilot single-centre experience with extracorporeal photopheresis (ECP) for acute GvHD: the objective was to investigate the efficacy of ECP for patients with steroid-refractory/-dependent acute GvHD as well as an early intervention in patients with low-grade acute GvHD to avoid/taper steroids. Furthermore, we evaluated the reduction of immunosuppressive therapy. Patients' characteristics Between 2013 and 2014, 17 patients with acute GvHD (of whom two patients developed GvHD after donor lymphocyte infusion) were treated. Eight patients had a maximum grade of GvHD I/II (2/6 patients) and nine patients were graded as III/IV (6/3 patients). Organ involvement was as follows: skin only in 10, skin and liver in one, skin and gastrointestinal tract in two and all three organs were involved in four patients. Treatment before ECP consisted of topical steroids in one and 0.5 mg/kg methylprednisolone (due to side-effects of calcineurin-inhibitor) in the other patients with grade I. Six patients received 1 mg/kg and eight patients received 2 mg/kg methylprednisolone. One patient was treated with 2 mg/kg methylprednisolone and weekly methotrexate. Before start of ECP, one patient was steroid-free, six patients were steroid-refractory and nine patients were steroid-dependent. Thus, we treated patients with acute GvHD not only for steroid-refractory disease but also steroid-dependent disease and grade I GvHD to avoid a treatment with steroids. Results The median number of ECP sessions per patient was 12 (range, 5 - 36), seven patients received ECP twice a week. Best response to ECP was complete remission in 71%, partial response in 12% and no response in 17%, after a median number of 6 treatments (range, 2 - 9). Response was better for grade I/II: 87.5% received complete remission compared to 56% with grade III/IV, partial response was observed in 12.5% in patients with grade I/II versus 11% with grade III/IV. No responders comprised 33% with grade III/IV and 0% with grade I/II. Immunosuppressive therapy could be tapered successfully: mean reduction of steroids was 95% (range, 60 - 100) and mean reduction of calcineurin-inhibitor was 83% (range, 40 - 100). Six patients developed a rebound of GvHD during tapering (two patients) or after discontinuation (four patients) of ECP. Eleven patients (78%) developed chronic GvHD (two patients with severe grade), whereas it appeared in four patients during tapering of ECP and in seven patients after discontinuation of ECP after a median time of 116 days (range, 30 - 287). We could observe seven bacterial, 14 viral and one fungal infection in 14 patients, which are expected rates after allo-HSCT in patients with acute GvHD. After a median follow up of one year, two patients relapsed from their underlying disease and five patients died (one due to relapse and four due to infections). Conclusion In this single-centre pilot experience, we could show that ECP is an efficient and safe treatment in patients with steroid-refractory or steroid-dependent acute GvHD as well as an upfront-treatment in patients with low-grade GvHD. We were able to taper immunosuppressive therapy with a mean reduction of steroids of 95% and mean reduction of calcineurin-inhibitor of 83%. Best responses were seen in patients with I/II grade GvHD which concludes that ECP should be started as early as possible. Further studies are warranted to investigate a schedule to reduce the risk of rebound of acute GvHD (42% in our cohort) and development of chronic GvHD (78%). Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria.

Description: The refined endpoint of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents an important measure of outcomes of allogeneic hematopoietic stem cell transplant (HSCT) including both clinical results and quality of life without ongoing morbidity. We analyzed the refined GRFS in 5059 patients with de novo acute myeloid leukemia (AML) with intermediate and unfavorable cytogenetics in first complete remission (CR1), undergoing HSCT from a matched sibling (MSD, n=3731) or unrelated donor (UD, n=1328). HSCT were performed between 2000 and 2015 and reported to EBMT. Median age for the whole population was 49 years (range 18-76) There were statistical differences between the 2 groups: compared to MSD, UD recipients were younger (60 vs 32 years, p

Description: Introduction: Despite allogeneic hematopoietic stem cell transplantation (HSCT), prognosis of fms-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML) remains poor due to the high risk of relapse. Sorafenib, a multikinase inhibitor active on FLT3, has shown encouraging results in these patients. Patients and methods: Here, we report the use of sorafenib as a maintenance agent after HSCT in 28 adults with FLT3 positive AML treated in three hematologic departments. Results: A total of 18 males and 10 females were included. All but one patient (pt) underwent their first HSCT between 2012-2016. Median age at HSCT was 45 years (range 16-57). A normal karyotype was detected in all but 5 pts. Ten pts showed FLT3-ITD as sole molecular abnormality, thirteen with concomitant NPM-1 mutation, associated to WT1 overexpression in 1 case and to CEBP-α double mutated in two. Association of FLT3 and WT1 overexpression was observed in 3 pts. Two more pts presented a FLT3-TKD with concomitant NPM-1 mutation. At time of HSCT, all but 1 pt were in complete remission (CR; CR1, n=23; CR2=3; CR3=1). Thirteen pts in CR had a detectable minimal residual disease (MRD) before HSCT. Median interval from CR to HSCT was 74 days (d, range 6-220). The majority of the pts (n=26) received peripheral blood as stem cell source, 19 from a matched sibling, 4 from a matched unrelated, 3 from a haploidentical donor. A bone marrow unit was used in 2 pts, one matched sibling and one haploidentical donor. Conditioning regimen was myeloablative in 21 pts, while reduced intensity regimen was used in 5 pts, and 2 receiving a sequential regimen. All pts achieved neutrophil engraftment in a median of 16 d. Median time to sorafenib introduction as a maintenance agent after HSCT was 70 d (range 17-645). Seven pts were out of immunosuppressive treatment (IST) without graft-versus host disease (GVHD) at time of sorafenib start. Sorafenib was started at a dose of 400 mg twice a d (n=13), 200 mg twice a d (n=14) or 200 mg once a d (n=1). Sorafenib was used as primary prophylaxis in 25 pts, or as secondary prophylaxis in three relapsed pts who received it first in combination with salvage chemotherapy and then, after obtaining subsequent CR, as a maintenance treatment. Median duration of treatment was 179 d (range 4-1219). Dose reduction or withdrawal due to toxicities was needed in 5 and 3 pts, respectively. These included gastrointestinal (GI, n=3), cardiac (n=1), skin (n=3, 1 with GI), biochemical (n=1) and hematological toxicities (n=2, 1 with GI). Despite dose reduction, persistence of toxicities prompted to treatment withdrawal in 1 pt. Disease relapse occurred in 2 pts: in both sorafenib was withdrawn and then resumed after salvage chemotherapy. One pt died for disease progression, the other from non-relapse mortality. Twelve pts experienced GVHD (limited, n=6; extensive, n=6), resulting in dose reduction in 5 pts, followed by withdrawal in 1 pt. Nine pts required systemic IST. Dose reduction was made in 1 pt due to financial reasons. Three pts received donor lymphocyte infusion (DLI), without experiencing GVHD. Leukemia-free (LFS) and overall survival at one year were 91±6% and 89±7%, respectively. Probability of LFS with undetectable MRD at one year was 87±7%. With a median follow-up of 15 months (range 4-44), all but 2 pts are alive, all in CR. Sorafenib treatment is ongoing in 18 pts (with 7 at reduced doses) with a median of 15 months (range 1-41). Conclusion: Our findings suggest that a post-transplant prophylactic strategy is safe and may markedly improve the poor outcome of FLT3 positive AML. A large prospective randomized clinical trial is warranted in order to confirm our results and to determine the optimal treatment modalities. Although the optimal starting dose still remains unclear, dose individualization according to patient tolerability might be considered. Further analysis is needed to evaluate the immunomodulating role of sorafenib post HSCT. Figure 1 year Leukemia-free and overall survival Figure. 1 year Leukemia-free and overall survival Disclosures No relevant conflicts of interest to declare.

Description: Background: Allogeneic hematopoietic stem cell transplantation using a related haploidentical donor (Haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. However, use ofperipheral blood stem cell graft (PBSC) is associated with an increased risk of acute GvHD (aGvHD) compared to bone-marrow graft. Therefore, while cyclosporine A (CsA) and mycophenolate mofetil (MMF) are traditionally initiated after completion of PT-Cy at day +5, we decided to initiate them at day -3 before transplant and to add a low dose of ATG to reinforce GvHD prophylaxis in those patients. With this background, we analyze retrospectively the impact of early initiation of CsA and of CsA concentration on patients' outcome in all patients who underwent Haplo-HCT with PBSC grafts and PTCy. Patients and Methods: Sixty-one consecutive patients who underwent Haplo-HCT for hematological malignancies between October 2013 and August 2017 were included in this retrospective single-center study. All patients received G-CSF mobilized PBSC as grafts and post-transplantation immunosuppression with CsA and MMF. CsA was administered at a dose of 3mg/kg by continuous intravenous infusion starting from D -3 and changed to twice daily oral dosing as soon as tolerated.MMF was administered at a fixed oral dose of 2g per day starting from day 6 without adjustment. In the absence of GvHD, MMF and CsA were tapered over 4 weeks starting from day 30 and day 60, respectively. CsA blood trough concentrations were monitored 3 times per week during the intravenous treatment and at least once per week after switch to oral dosing. CsA doses were adjusted to achieve blood levels between 200 and 300 ng/mL and to prevent renal dysfunction. The primary endpoint was to determine the impact of the CsA concentration on the risk of grade II-IV and III-IV aGvHD. Results: Median age was 53 (range, 15-72) years, with 16 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid (64%) or lymphoid malignancies (36%). According to the Disease Risk Index, patients were considered as low-risk, intermediate-risk, high-risk or very-high-risk (respectively 8%, 56%, 31% and 5%). Twenty-five patients (41%) with refractory disease received a sequential conditioning regimen while the remaining (n=36, 59%) received a RIC/RTC regimen based on fludarabine, busulfan and thiotepa. 51 patients (83%) received ATG (2.5-5 mg/Kg total dose) as part of the conditioning regimen. All patients received standard PTCy, nine at D+3 (15%) and 52 at D+3 and D+5 (85%). All patients engrafted at a median of 18 (range: 13-35) days after Haplo-HCT and the median follow-up among surviving patients was 21 (range: 13-53) months. The median concentrations of CsA at 1, 2, 3, and 4 weeks after Haplo-HCT were 272 (range: 114-911), 296 (range: 132-516), 251 (range: 111-485), and 246 (range: 36-375) ng/mL, respectively. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. The CIs of chronic GvHD (cGvHD), extensive cGvHD and relapse were 41%, 19% and 35% at 18 months after Haplo-HCT, respectively. At 18 months after the transplant, the OS, PFS and GPFS rates were respectively 60%, 55% and 48%. In univariate analysis, patients having the lowest CsA concentration in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (49% vs 18%; P= .02), severe grade III-IV aGvHD (26% vs 0%; P = .03), cGvHD (P= .02) and extensive cGvHD (P= .04). We do not find statistically significant correlation between CsA concentration and relapse incidence, NRM, PFS, GPFS or OS. In multivariate logistic regression analysis, higher CsA concentration (〉 301 ng/ mL; the cut-off value defined by ROC analysis) during the first week following Haplo-HCT was the only independent parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (respectively P = .04; RR .11; 95% CI, 0.05-0.94; and P 〈 .0001; RR 〈 .001; 95% CI, 0.000007-0.00006). There was no association with extensive cGvHD (P = .14; RR .11; 95% CI, 0.06-1.48). Conclusion: We conclude that achievement of high concentration of CsA early after Haplo-HCT using PBSC graft is associated with a low incidence of aGvHD and that CsA should be initiated at time of transplant with adequate monitoring during the engraftment period to reduce the risk of grade II-IV aGvHD. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria.

Description: Rationale: FLT3 in mutated in 30% of AML and is associated with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR) is recommended in FLT-3 ITD AML. However frequent and early post-transplant relapse leads to poor outcome. Several small studies suggested the efficacy of sorafenib as prophylactic or preemptive therapy or as treatment for relapse post allo-HCT. The purpose of this study was to assess the impact of sorafenib on outcomes of FLT3 mutated AML post allo-HCT. Patients and Methods: We identified 462 adult patients (51% males) with FLT3 mutated AML (FLT3 ITD-95%) allografted at EBMT participating centers between 2010 and 2015. Median age was 50 years (range 18-75). Patients mostly belonged to the intermediate cytogenetic risk group (82%) and 55% of those with available data had NPM1 mutation. Disease status at allo-HCT was CR1 (72%), CR2 (10%) or active disease (18%). Donors were matched related (MSD, 40%), matched unrelated (49%) or haploidentical (11%), respectively. Preparative regimens were myeloablative (MAC) in 53% and reduced intensity conditioning (RIC) in 47% of allo-HCT. Sixty two patients received post-transplant sorafenib either as prophylactic (n=19) or preemptive therapy (n=9) or as treatment for relapse (n=34). Median time from allo-HCT to initiation of maintenance sorafenib was 55 days (1-173). Median follow-up for alive patients was 39 months (range 1-87). Results: The 2-year leukemia free survival (LFS), overall survival (OS) and GVHD relapse free survival (GRFS) was 51%, 59% and 38%, respectively. In multivariate Cox analysis, sorafenib maintenance (either prophylactic or preemptive) significantly improved OS (HR=0.36; p=0.03). OS was also positively affected by NPM1 mutation, allo-HCT in CR1, and in vivo T cell depletion, but negatively affected by the need for 〉1 induction. Similarly, sorafenib maintenance significantly improved GRFS (HR=0.44; p=0.02). GRFS was also positively affected by NPM1 mutation (HR=0.66; p=0.002), haploidentical donors compared to MSD (HR=0.61; p=0.04), and in vivo T cell depletion (HR=0.55; p=0.00001), but negatively affected by the need for 〉1 induction (HR=1.5; p=0.005) or active disease at transplant (HR=2.5; p than 50 years), disease status at allo-HCT (CR1 Vs CR2 Vs active disease), conditioning (RIC Vs MAC), and time from allo-HCT to relapse (+/- 1 month). One year and 2 year OS were 41% and 30% for patients treated with sorafenib versus 14% and 14% for controls (P=0.0015). Conclusion: For AML patients with FLT3 mutation, post-transplant sorafenib whether given as prophylactic or preemptive therapy or as treatment for relapse, significantly improves OS and may be considered as standard of care in that setting. Disclosures Mohty: MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Bristol Myers: Consultancy, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Molmed: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau.

Description: Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical donor (haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. We recently noticed a relatively high incidence of infectious complications, especially Epstein-Barr virus (EBV) reactivation after haplo-HCT. However, the mechanisms underlying the increased incidence of this complication in the haplo-HCT setting are unknown. We hypothesized that the use of PTCy may be associated with a deficit in innate-like effector T cells essential for preventing EBV reactivation.This study aimed to analyze immune reconstitution following haplo-HCT using peripheral blood stem cells (PBSC) grafts and to evaluate the correlations with EBV reactivation and outcomes. Patients and Methods: One hundred and twenty-three consecutive patients who underwent allo-HCT for hematological malignancies between 2013 and 2016 were included in this single-center retrospective study. All patients received G-CSF mobilized PBSC grafts and ATG 2.5-5 mg/Kg total dose. All patients received a combination of cyclosporine A and mycophenolate mofetil for GvHD prophylaxis, except for patients with a matched related donor (MRD) who received cyclosporine A alone and patients with an haploidentical donor who received PTCy (50mg/kg/d at d3+/-d5). α/β T cells (CD3+, CD4+ and CD8+), γ/δ T cells (pan γ/δ and Vδ2+), mucosal-associated T cells wich express a highly restricted TCR comprising a semi-variant Vα7.2-Jα33 (MAIT), invariant NK T cells, NK cells, B cells, Tregs, monocytes subsets and dendritic cells (myeloid DC, plasmacytoid DC and Slan-DC) were analyzed by multi-color flow cytometry at months (M) 1, 3, 6 and 12 following allo-HCT. Clinical data [acute GvHD (aGvHD), relapse incidence, chronic GvHD (cGvHD), viral reactivations, bacterial and fungal infections, non-relapse mortality (NRM), progression-free survival (PFS), refined GvHD-free and progression-free survival (GPFS), overall survival (OS)] were assessed together with sequential quantitative evaluation of immune subsets. Results: Median age was 55 (range, 17-70) years, with 32 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid malignancies (66%) or lymphoid malignancies (34%). Thirty-three patients (27%) received a graft from a MRD, 65 from an unrelated donor (MUD, 53%), and 25 from a haplo-identical donor (20%). Thirty patients (24%) with refractory disease received a sequential conditioning regimen while the remaining (n=93, 76%) received a RIC/RTC regimen based on fludarabine, busulfan +/- thiotepa. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 34% and 5%, respectively. The 2 years CIs of cGvHD, extensive cGvHD and relapse were 23%, 8% and 17%, respectively. At 2 years, NRM was 7%, PFS was 77%, GPFS was 66% and OS was 83%. The rate of EBV reactivation was significantly increased in haplo-HCT recipients as compared to fully-matched donor recipients (respectively, 68% versus 26%, P〈 .001). At one month after allo-HCT, the median counts of all immune cells subsets (except monocytes) was significantly lower in haplo-HCT recipients as compared to MRD or MUD recipients. At 3 months, α/β T cells, iNK T cells, NK cells, B cells, Tregs and Slan-DC reached similar median counts in haplo-HCT recipients as compared to MRD or MUD recipients. In contrast, Vδ2+ T cells and MAIT cells median counts remained significantly lower at 3, 6 and 12 months in haplo-HCT recipients compared to MRD or MUD recipients (at M1, M3, M6, M12, the median Vδ2+ T cells counts were 0.05/µL, 0.24/µL, 1.38/µL and 2.97/µL, and MAIT cells were 0.07/µL, 0.70/µL, 1.00/µL and 1.21/µL, respectively). Lower Vδ2+ T-cells and MAIT cells counts at one month was associated with a significantly increased CI of EBV reactivation (respectively, P=.04 and P

Description: The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.