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: 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: 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. Extracorporeal photopheresis (ECP) is increasingly used in the treatment of acute and chronic graft versus host disease (aGVHD). It is recognized as an immunomodulatory therapy that can decrease inflammation and allow for immune tolerance. Interesting results have obtained using ECP as salvage therapy in patients with steroid-refractory GVHD after failure of one or more lines of immunosuppressive therapy. With this background, we hypothesized that incorporation of ECP as part of first line treatment for aGVHD may improve response rate and avoid the development of steroid-refractory or steroid-dependent aGVHD, mainly in cases of aGVHD with predominant skin involvement. Patients and methods. Forty consecutive patients who received ECP as part of their first line treatment of aGVHD with skin involvement between 2013 and 2016 were included in this single center analysis. 36 patients (90%) received granulocyte-colony stimulating factor mobilized PBSC as grafts, 3 patients (7.5%) received a bone marrow graft and one patient (2.5%) received an umbilical cord blood graft. Donor was a matched related one for 10 patients, haploidentical for 8 patients, matched unrelated for 16 patients and mismatched unrelated for 6 patients. 4 patients received a reduced intensity conditioning regimen and 36 a myeloablative reduced toxicity conditioning regimen. All patients received a combination of cyclosporine A (CsA) and mycophenolate mofetil for GVHD prophylaxis, except for patients with a matched related donor who received cyclosporine A alone. Patients transplanted with a haploidentical donor, received post-transplant cyclophosphamide (PTCy; 50mg/kg/d at d+3/d+5). ECP was initiated as soon as possible after the diagnosis of aGVHD with predominant skin involvement. The primary endpoint was to determine the best response achieved through the use of ECP for first line treatment of aGVHD. Results. Median age was 57 (range, 22-66) years, with 28 male patients (49%). Diagnoses were myeloid (n=32) or lymphoid malignancies (n=8) and disease status at transplant was complete remission in 23 patients, partial remission in 8 patients, relapse/progression in 8 patients and untreated in 2 patients. Patients developed aGVHD at a median of 31 days after alloHCT (range, 11-129). 5 patients had late onset aGVHD and two patients developed aGVHD after DLI. None of them had an overlap syndrome. aGVHD grade was I in 13 patients, II in 18 patients and III-IV in 9 patients. All patients had skin involvement and 10 patients had gut (n=8) and/or liver (n=5) involvement. All patients, but one, were still receiving CsA at time of aGVHD diagnosis. Systemic corticosteroids were initiated in 29 patients, while 11 patients received only topical dermo-corticoids. ECP was initiated at a median of 9 days (range, 0-83) after the diagnosis of aGVHD. ECP was performed weekly for 26 patients and twice weekly for 14 patients. Overall response rate (ORR) was 80% after a median of 3 (range, 1-9) weeks of treatment, including 24 complete responses (CR, 60%), 6 very good partial responses (VGPR, 15%) and 2 partial responses (PR, 5%). According to aGVHD grade, in patients with grade I aGVHD, the ORR was 92%, including 11 CR and 1 VGPR. In patients with grade II aGVHD, the ORR was 83%, including 8 CR and 7 VGPR/PR. In patients with grade III-IV aGVHD, ORR was 55%, all of them being in CR. In responding patients, 1 patient presented a recurrence of aGVHD and 15 developed chronic GVHD, including 4 overlap syndromes. Median follow-up was 32 months (range, 22-58) among surviving patients. At 24 months after transplant, the OS and PFS rates were respectively 78% (95% CI, 61%-88%) and 56% (range, 39%-70%). The 2-years cumulative incidence of relapse was 33% (95% CI, 19%-49%) and the 2-years cumulative incidence of non-relapse mortality was 10% (95% CI, 3%-22%). Conclusion. ECP is an effective and well-tolerated option for treatment of acute GVHD with predominant skin involvement with a 2 years cumulative incidence of NRM of 10% and an ORR of 80%. Best responses were seen in patients with grade I-II aGVHD, suggesting that ECP should be started as early as possible after the diagnosis of aGVHD. Incorporation of ECP as part of first line treatment for aGVHD may improve response rate and avoid the development of steroid-refractory aGVHD. Prospective randomized trial are warranted to evaluate ECP as adjuvant treatment for first line treatment of skin aGVHD. Disclosures Mohty: Celgene: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Molmed: Consultancy; Servier: Consultancy; Amgen: Consultancy, Honoraria.

Description: Introduction Although a large variety of conditioning regimens are used in autologous hematopoietic stem cell transplantation (autoSCT), including the widely used BEAM (carmustine, etoposide, cytarabine, melphalan), there is no consensus regarding a standard approach. In the context of a carmustine shortage, we replaced it with thiotepa. However, clinical data on the TEAM (thiotepa, etoposide, cytarabine, melphalan) conditioning regimen are sparse and only retrospective. Thus, we designed a multicenter prospective study (NCT02504190) to assess the efficacy and toxicity of a TEAM conditioning regimen. Patients and methods The TEAM regimen consisted of a total dose of thiotepa of 8 mg/kg on day -6; etoposide 100 mg/m2/12h and cytarabine 200 mg/m2/12h (day -5 to -2); melphalan 200 mg/m2 on day-1. Inclusion criteria were the following: age between 18 and 65 years, biopsy-proven Hodgkin or non-Hodgkin lymphoma, HIV seronegative, and first autoSCT. Results Seventy-four male and eighteen female patients with a median age of 53 years (range, 19-65) were included. Karnofsky score was 20 G/L was 13 days (range, 7-197). The most significant regimen-related toxicities were mucositis in 100% of patients (median grade=3, range, 1-4) and diarrhea in 98% of patients (median grade=1, range, 0-3). Other non-hematologic grade 3 adverse events occurred in 17 patients (18%). Blood cultures were positive for Staphyloccocus sp. in 27% patents, other Gram- positive bacteria in 5% and Gram negative in 6%. Central line-associated bloodstream infection occurred in 22 patients (24%). Invasive fungal infection occurred in 3 patients. Four patients required transfer to the intensive care unit. The median length of stay in hospital was 27 days (range, 16-62). At day+100, 89 patients were evaluable for response and all were in CR. Deaths directly attributed to disease progression or relapse occurred in 5 patients. After a median follow-up of 31 months (range, 15-48), the non-relapse mortality (NRM) was 3.3%. Two patients died of infection during aplasia and one patient died 67 days after autoSCT of necrotizing fasciitis. At last follow-up, 17 patients (19%) relapsed, 9 died and 83 were alive. The estimated 3-year overall survival (OS) and progression-free survival (PFS) were 90.2% and 77.2%, respectively. In patients with double expressor diffuse large B-cell lymphoma (n=15), the estimated 3-year OS and PFS were 93% and 73%, respectively. None of the 31 patients with intermediate or high-risk CNS international prognostic index experienced CNS relapse. Conclusion The TEAM conditioning regimen is a safe and valid platform in autoSCT for patients with high-risk or relapsed/refractory lymphoma. Although mucositis and diarrhea were frequent, the NRM was similar to that reported for BEAM conditioning. Most notably, no CNS relapse occurred in patients at intermediate or high-risk of CNS relapse. Disclosures Duléry: Keocyt: Honoraria. Choquet:Keocyt: Honoraria. Di Blasi:Novartis: Honoraria. Malard:Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria; Keocyte: Honoraria; Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria. Coppo:Ablynx/Sanofi: Consultancy; Shire: Consultancy; Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Description: Curative potential of allogeneic transplantation from related or unrelated donors is limited by tranplant related mortality (TRM) and donor compatibility. After reduced intensity conditioning regimens (RIC) transplantation can be extended to older patients, those with poor performance status, organ dysfunction or intensive prior therapy. In absence of HLA-matched donor, unrelated cord blood transplant (UCBT) is a possible source of hematopoietic stem cells. In order to confirm previous report of RIC after UCBT in adults we conducted a phase I–II trial. Primary endpoint was neutrophil recovery and chimerism. Secondary endpoints were early TRM, acute GVHD incidence, early relapse and survival. Between October 2003 and March 2005, 18 patients (pts) were enrolled: median age: 46y (19–64), weight: 62.5 kg(45–90), gender: 13 females and 5 males, CMV serpositivity in 8 pts, ABO major incompatibility in 8 pts. The median of follow-up was 4.5 mo (0.5–16). Disease status were 2 ALL (CR1: 1; CR2: 1), 10 AML (CR1: 3, CR2: 6, CR3: 1), 1 AP CML, 1 CLL, 1 Waldenström disease, 3 follicular lymphoma relapsed after autologous transplantation. Infused nucleated and CD34+ cells number were respectively: 2.3x107/kg (1.7–3.7) and 0.7x105/kg (0.4–1.2). Only a single cord blood was used. HLA disparity was 0/6 in 1, 1/6 in 6 and 2/6 in 11. RIC regimen consisted of cyclophosphamide 50 mg/kg D-6, fludarabine 200 mg/m2 and 2Gy TBI at D-1. CsA and MMF from D-3 were used in GVHD prophylaxis. Pts received GCSF until 5 G ANC/l. Results: Median day for 0.5 G/l ANC recovery was 14 days (0–28) and for 20 G/l platelets was 28 days (0–48). Mixt chimerism was present until D+56 and full chimerism at D+80/100 in all pts except 2 who relapsed. Mucositis was not observed, CMV reactivation in 2 pts, bacteremia in 3, SRV pneumonitis in 1 pt, bone aspergillosis in 1 pt. Regressive limbic encephalitis in 2 pts. Two pts recovered normal ovarian function 5 mo and 12 mo after UCBT. Grade 2 acute GVHD was observed in 2 pts and limited chronic GVHD in 3 out of 8 pts at risk. TRM was 0%. Two pts relapsed and died at D+100 and D+171. EFS was 80+/−13%. In conclusion, in spite of the short follow-up and few patients enrolled in this trial, these results confirm those reported by Barker J et al. Importantly there was a rapid neutrophil recovery with acquired late full chimerism and absence of early TRM. The encouraging results justify the use of cord blood cells in RIC and prospective trials in order to compare phenoidentical peripheral blood stem cell transplantation and UCBT with the same RIC regimen.

Description: Background: Pre- and post-transplant pulmonary function tests (PFT) have been previously analyzed in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). A deterioration in pulmonary function could be observed in this setting and accounts for higher morbidity and mortality. Haploidentical allogeneic stem cell transplantation (HAPLO) with post-transplant cyclophosphamide (PTCY) is increasingly used. Limited data exists on evaluation of PFT after HAPLO and the number of patients who underwent HAPLO in previously published studies is negligible. We report the evolution of PFT as well as pre-transplant characteristics and outcomes after HAPLO in the adult setting. Methods: We retrospectively analyzed 80 HAPLO performed in a single center between 2013 and 2019. All patients with available pre- and post-transplant PFT results were included in the study. The Friedman test was used for comparing PFT at baseline, 100 days and 1 year after HAPLO. Results: The median follow up was 32 (range: 12-74) months. CMV serology was positive in 45% and 65% of patients were male. The median age was 58 (range: 16-73) years. The proportion of surviving patients with available PFT at 3 months and 1 year were 86% and 68%, respectively. Diagnosis was acute myeloid leukemia in 51% and disease risk index was intermediate-low in 75% of the cases. Disease status before HAPLO was complete remission in 61%. Graft source was peripheral blood stem cells in 91% of the cases. Conditioning regimen was reduced intensity in 40% and the most frequent chemotherapy regimen was thiotepa, busulfan and fludarabine. Graft-versus- host disease (GvHD) prophylaxis consisted of Cyclosporine A (CsA) and mycophenolate mofetil in all but one patient who received methotrexate and CsA. All patients received PTCY, 64 (80%) at days 3 and 5 after HAPLO, 7 (9%) at days 3 and 4, and 9 (11%) at day 3 only. Seventy-three (91%) patients received anti-thymocyte globulin. In total, 24% of the patients had previously smoked, 8% had type 2 diabetes, and 23% suffered from hypertension. Three patients had a lung infection at baseline, of which one was bacterial and two were possibly aspergillosis. At screening for HAPLO, five (6%) patients had restrictive lung disease, nine (11%) met the criteria for obstructive lung disease, and diffusing capacity for carbon monoxide (DLCO) corrected for hemoglobin was impaired in 74% of the patients. The median forced expiratory volume in the first second (FEV1) was 100 (range: 58-146) before HAPLO, 93 (range: 42-10) at 100 days after HAPLO and 99 (range: 32-144) at 1 year. The median forced vital capacity (FVC) was 106 (range: 57-153), 98 (range: 44-148) and 106 (range: 31-153) at pre HSCT, 100 days and 1 year after HAPLO, respectively. FEV1 and FVC were significantly different over time during the 1 year follow up (p=0.01 and p=0.001, respectively). The median FEV1/FVC was 80 (range 51-105) before HAPLO, 77 (range: 54-103) after 3 months, and 75 (range: 43-100) after 1 year. FEV1/FVC, residual volume, and total lung capacity (TLC) remained stable from baseline to 1 year (p=0.27, p=0.84 and p=0.21, respectively). In contrast, DLCO remained impaired during the follow-up period (p