Haploidentical Allogeneic Stem Cell Transplantation Research Articles

High plasma IL-6 levels following haploidentical allogeneic hematopoietic stem cell transplantation post-transplant cyclophosphamide as predictor of early death and worse outcome

IntroductionHaploidentical hematopoietic stem cell transplantation (haplo-HSCT) can be used as an alternative procedure in the absence of HLA-compatible donors. The use of high doses of cyclophosphamide after infusion improves the prognosis and eliminates the need for T cell depletion in vivo. Among the main complications of haplo-HSCT are acute graft-versus-host disease (a-GVHD) and cytokine release syndrome (CRS). This is a systemic inflammatory response that leads to the release of inflammatory proteins, including IL-6. This syndrome has several clinical features, with mild to severe symptoms. This study aimed to compare plasma IL-6 levels in patients submitted to different HSCT types and to associate them with the presence of acute graft versus host disease (a-GVHD), CRS and survival. MethodsA total of 84 patients (22 haploidentical and 62 non-haploidentical) were evaluated at different times. The IL-6 levels in haplo and non-haplo-HSCT recipients were measured before transplantation and on days D7, D14, D28, D60, and D100. ResultsIL-6 levels were higher in haplo-HSCT recipients than in non-haplo-HSCT recipients, remaining elevated from D14 until D100 (P = 0.006) and a cut-off ≥11 pg/mL on D7, which is related to worse overall survival. In our study, we found no association with a-GVHD (P = 0.239), a common complication of this type of transplant, but we found a relationship between the increase in IL-6 and CRS (P = 0.021). ConclusionIL6 can be used as a biomarker for patients submitted to haplo-HSCT, allowing clinical interference in patients having levels of IL-6 times larger than normality values, avoiding early death in this group of patients.

Cytokine Release Syndrome in the Immunotherapy of Hematological Malignancies: The Biology behind and Possible Clinical Consequences.

Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction associated with (i) chimeric antigen receptor (CAR)-T cell therapy, (ii) therapeutic antibodies, and (iii) haploidentical allogeneic stem cell transplantation (haplo-allo-HSCT). Severe CRS can be life-threatening in some cases and requires prompt management of those toxicities and is still a great challenge for physicians. The pathophysiology of CRS is still not fully understood, which also applies to the identifications of predictive biomarkers that can forecast these features in advance. However, a broad range of cytokines are involved in the dynamics of CRS. Treatment approaches include both broad spectrum of immunosuppressant, such as corticosteroids, as well as more specific inhibition of cytokine release. In the present manuscript we will try to review an update regarding pathophysiology, etiology, diagnostics, and therapeutic options for this serious complication.

Development and validation of a mortality predicting scoring system for severe aplastic anaemia patients receiving haploidentical allogeneic transplantation.

Haploidentical allogeneic haematopoietic stem cell transplantation (haplo-HSCT) is a significant alternative treatment for severe aplastic anaemia (SAA). To improve this process by modifying the risk stratification system, we conducted a retrospective study using our database. 432 SAA patients who received haplo-HSCT between 2006 and 2020 were enrolled. These patients were divided into a training (n=288) and a validation (n=144) subset randomly. In the training cohort, longer time from diagnosis to transplantation, poorer Eastern Cooperative Oncology Group (ECOG) status and higher haematopoietic cell transplantation-specific comorbidity index (HCT-CI) score were independent risk factors for worse treatment-related mortality (TRM) in the final multivariable model. The haplo-HSCT scoring system was developed by these three parameters. Three-year TRM after haplo-HSCT were 6% [95% confidence interval (CI), 1-21%], 21% (95% CI, 7-40%), and 47% (95% CI, 20-70%) for the low-, intermediate-, and high-risk group, respectively (P<0·0001). In the validation cohort, the haplo-HSCT scoring system also separated patients into three risk groups with increasing risk of TRM: intermediate-risk [hazard ratio (HR) 2·45, 95% CI, 0·92-6·53] and high-risk (HR 11·74, 95% CI, 3·07-44·89) compared with the low-risk group (P=0·001). In conclusion, the haplo-HSCT scoring system could effectively predict TRM after transplantation.

Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with AML/MDS Demonstrates Excellent Long Term Overall Survival, Results from the Australasian Bone Marrow Transplant Recipient Registry

Background: Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HCT) is an established therapy using alternative donors for patients with Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS). There is a limited body of evidence for older patients undergoing Haplo-HCT in AML and MDS. Studies describing Haplo-HCT in older patients have used a high proportion of bone marrow (BM) derived grafts and a variety of conditioning regimens. In this setting, Haplo-HCT demonstrates acceptable Non-Relapse Mortality (NRM) and chronic Graft Versus Host Disease (cGVHD) rates of less than 10% (Ciurea. Biology of Blood and Marrow Transplantation. 2018 Jun 1;24(6):1232-6.). In Australia and New Zealand, Haplo-HCT is predominantly performed using peripheral blood (PB). We performed a retrospective national registry study to examine the outcomes of Haplo-HCT using PB in older patients.Methods: Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB Haplo-HCT for AML/MDS between January 2010 and July 2020. Cumulative incidence functions were used for engraftment, CMV reactivation, acute GVHD, chronic GVHD, relapse, and NRM. The competing risk for engraftment, CMV reactivation and GVHD was death. Relapse and NRM were competing risks for each other. Overall survival (OS), relapse-free survival (RFS), and composite GVHD and RFS (GRFS) were calculated using Kaplan-Meier analyses. The impact of pre-transplant factors on these endpoints was analyzed using Cox regression.Results: A total of 44 patients were included in the analysis. The median follow-up time was 734 days. The median age was 68 (range 65-74) with a median Karnofsky Performance Status of 90. Thirty patients (68.2%) had AML while 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was non-myeloablative fludarabine, cyclophosphamide and TBI (73.8%), the remainder of the patients received either melphalan or busulfan based regimens, the majority were reduced intensity with only 2 patients undergoing myeloablative conditioning. All patients received post-transplant cyclophosphamide and mycophenolate mofetil with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporin (9.5%). No patients received anti-thymocyte globulin.Neutrophil engraftment was achieved in 97.6% of patients, at a median of 18 days while platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of CMV reactivation and CMV disease were 52.5% and 5.1% at 1 year The incidence of Grade 2-4 aGVHD was 18.2%. The incidence of cGVHD at 2 years was 40.7%, with extensive cGVHD occurring in 17.7% of patients. The incidences of relapse and NRM at 2 years were 8.8%. and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year OS was 74%. RFS and GRFS at 2 years was 70% and 48% (Figure 1). Recipient age, donor age or disease type (AML vs MDS) had no significant impact on OS or GRFS.Conclusion: These results confirm the safety and effectiveness of Haplo-HCT for AML/MDS in older patients. The rates of cGVHD were higher than expected given the lower rates reported in other studies using PTCy GVHD prophylaxis. Haplo-HCT using a PB graft demonstrates good long-term disease control with reasonable rates of NRM and cGVHD for older patients with AML/MDS. [Display omitted] DisclosuresBajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Perera: Abbvie: Speakers Bureau; BMS: Speakers Bureau. Greenwood: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Hemophagocytic lymphohistiocytosis, what about hair?

A 1-month-old boy, born to nonconsanguineous parents, without notable family health history, presented with febrile pancytopenia and splenomegaly. Clinical examination disclosed no other anomaly, notably no neurological alteration. His initial complete blood count showed normocytic anemia (hemoglobin 105 g/L), thrombocytopenia (84 × 109/L), and neutropenia (0.8 × 109/L) without lymphopenia. Upon worsening of this pancytopenia, associated with persistent fever despite antibiotics, a bone marrow aspirate revealed no blasts but the presence of histiocytes with hemophagocytosis (Image 1A). High serum triglycerides, ferritin, and lactic dehydrogenase were observed at respectively 3.3 mmol/L, 71 000 μg/L, and 788 U/L together with hypofibrinogenemia (1.1 g/L). Molecular tests for toxoplasmosis, HSV, EBV, CMV, HHV6, and parvovirus B19 were negative. Clinical examination revealed the presence of partial albinism with silver-gray hair. This feature associated to the biological anomalies, evoked a diagnosis of Griscelli or Chediak Higashi syndrome. However, bone marrow cells did not contain giant cytoplasmic granulations. Moreover, microscopic analysis of hair revealed clumps of melanin of various sizes irregularly distributed throughout the hair shaft, suggestive of Griscelli syndrome (Image 1B,C). Cerebrospinal fluid (CSF) analysis revealed hyperproteinorachia (0.73 g/L) and 20/μL leucocytes (92% lymphocytes CD4+, CD3+, DR+, CD25−) in favor of asymptomatic central nervous system hemophagocytic lymphohistiocytosis (HLH). Sequencing of the RAB27 gene in a blood sample finally revealed a homozygous missense mutation in exon 3, confirming the diagnosis of type 2 Griscelli syndrome.1 Corticosteroid therapy was initiated followed by alemtuzumab administration. The patient then underwent a haplo-identical allogeneic hematopoietic stem cell transplantation and is well 8 months later. Children with GS2 indeed present with partial albinism, associated with hemophagocytic lymphohistiocytosis. RAB27A deficiency is responsible for a defective exocytosis of cytotoxic granules from T cells and natural killer cells, which may cause secondary immune overactivation leading to HLH. In the absence of treatment, the evolution is rapidly fatal. Although poorly codified, treatment consists in suppression of the triggering factor, control of HLH with chemotherapy or immunotherapy followed by an allo-HSCT.2 The pejorative evolution of this pathology makes its early recognition essential. Thus, children presenting with HLH must systematically benefit from a search for partial albinism. The presence of silver-gray hair makes necessary microscopic examination. The authors declare that they have no conflict of interest. ME and EC performed analyses. BLC, AH and CT treated the patient. BLC, MCB and ME wrote the manuscript.

Possible Reactivation of SARS-CoV-2 in a Patient with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: a Case Report

Reactivation or reinfection cases of SARS-CoV-2 are known but there is scarce evidence about reactivation in immunocompromised patients. Here, we report the case of a 61-year-old male undergoing a conditioning regimen with fludarabine, cyclophosphamide, and 2-Gy total body irradiation in preparation of a haplo-identical allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). He received the first dose of a COVID-19 vaccine 6 weeks prior allo-HSCT and was hospitalized a month prior because of a COVID-19 bilateral pneumonia. On discharge, he showed two negative SARS-CoV-2 nasopharyngeal PCR swabs as well as a high SARS-CoV-2 antibody titer. On admission for allo-HSCT, he tested negative for SARS-CoV-2 again. Conditioning with fludarabine, cyclophosphamide, and 2-Gy total body irradiation was started and the patient developed lymphopenia. During his hospital stay, he tested positive for SARS-CoV-2 in a PCR test twice but remained asymptomatic. The conditioning regimen was continued as planned. Later during his stay, the patient showed undetectable SARS-CoV-2 load four times. This case documents possible reactivation of SARS-CoV-2 and raises questions about reactivation risks among recipients of stem cell transplants and other immunocompromised patients.

Successful haploidentical transplantation using plasma exchange and post-transplantation cyclophosphamide for severe aplastic anemia patients with anti-human leukocyte antigen donor-specific antibodies

Haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HSCT) has emerged as a novel strategy to treat patients suffering from severe aplastic anemia (SAA) who lack matched donors due to the availability and easy access to sources of donors. Anti-human leukocyte antigen donor-specific antibodies (DSAs) have been found to influence the outcome of Haplo-HSCT. Between March 2016 and March 2020, 7 SAA patients with DSAs underwent Haplo-HSCT in our center. We employed a modified protocol of post-transplantation cyclophosphamide and plasma exchange aiming to decrease the levels of DSAs. All 7 patients successfully achieved hematopoietic reconstruction. The median follow-up is 31 (range, 8 to 45) months. They survived and were transfusion-independent in the absence of clonality. No occurrence of primary or secondary graft failure has been noted among any of the patients. There was no severe acute and chronic GVHD occurred. This protocol is effective for Haplo-HSCT in SAA patients with DSAs, which provides an option for the SAA patients without other alternative donor.

Mixed Chimerism of Bone Marrow CD34+ Sorted Cells after Matched or Haploidentical Allogeneic Stem Cell Transplantation for Myeloid Malignancies Is Predictive of Relapse

▪IntroductionThe assessment of donor chimerism after allogeneic stem cell transplantation (ASCT) is a useful tool to monitor engraftment and predict relapse. The detection of mixed donor chimerism in CD34+ sorted cells from ASCT patients has been reported in small series in the literature (Bornhäuser M et al. Haematologica. 2009; Hoffmann JC et al. Ann Hematol. 2014) to be sensitive to detect relapse. Investigating these progenitors could indeed allow to suspect an upcoming relapse earlier than assessing chimerism in whole blood (WB) or sorted WB CD3+ T-cells. We report on the predictive impact on survival of chimerism assessment in CD34+ sorted cells from patients' bone marrow (BM) on day +90 after matched or haploidentical ASCT.Patients, materials and methodsAll ASCT recipients (n=168), between October 2009 and April 2017, treated for acute myeloblastic leukemia (n=115) or chronic myeloid disease (n=53) were reviewed, focusing on those having benefited from CD34+ chimerism assessment in BM around day +90 (50-150). The 20 cases of relapse before this evaluation were excluded. A cohort of 148 grafts was retrieved, and 145 were informative with enough cells for DNA extraction after magnetic CD34+ cell-enrichment.Chimerism was assessed by quantitative PCR using specific donor/recipient markers (Alizadeh et al. Blood, 2002). Data from chimerism assessed on CD3+ sorted cells or whole blood, performed at the same period, were also retrieved. Receiving Operator Characteristics (ROC) curves were drawn based on the presence or absence of relapse. No significant threshold appeared for CD3+ cells chimerism but a threshold of 95% was retained by convention. Conversely good specificity was obtained with a 95% threshold for whole blood (86%) and 80% for CD34+ sorted cells (97%). Event-free survival (EFS) was calculated from the date of the ASCT until the date of either relapse, progression, death or last news. Overall survival (OS) was calculated from the date of ASCT until the date of death or last news.ResultsThe whole cohort comprised 57% of males and had a median age of 60 years old (24-74) at the time of ASCT. Reduced-intensity (RIC), myeloablative (MAC) or sequential (SEQ) conditioning was used in 82%, 12% and 6% of the cases respectively. Donors were familial (73%), from registry (70%) or unrelated cord blood (5%). Post-transplant cyclophosphamide (PTCY) was used in 31 procedures (22 haploidentical-ASCT and 9 matched donors). The median follow-up of the cohort was 13 months (1-88) and the rates of relapse and death were 29% and 24% respectively.The 95% threshold for WB and WB CD3+ chimerisms had no impact on neither EFS nor OS.Conversely, full donor chimerism (>80%) was observed in CD34+ cells in 91% and 86% of all cases and PTCY procedures respectively (P=0.4) with 91% for haploidentical ASCT. Full CD34+ engraftment was observed in 91% of the cases after MAC, 93% after RIC and only 67% after SEQ (p=0.03, yet no difference between MAC and RIC). The presence of a mixed CD34+ chimerism was associated with more relapses (77% vs 25%, p<10-4) in the whole group as well as when considering only PTCY procedures (75% vs 31%) or haploidentical grafts (100% vs 30%) although this did not reach statistical significance because of the small size of these subgroups. The presence of a mixed CD34+ chimerism at day+90 was associated with a significantly worse EFS (median: 5 vs 79 months, HR 0.2 [95%CI: 0.06-0.6] p<10-4) and OS (median: 12 months vs not reached (NR), HR 0.4 [95%CI: 0.1-1.1] p=0.007). Of interest, patients who received ASCT while not in complete remission had a better EFS (median NR vs 5 months, HR 3.1 [95%CI: 1.1-9.2] p=0.005) if they achieved a full CD34+ chimerism at day +90.DiscussionIn this large series, the feasibility of BM CD34+ cells' sorting at day +90 after ASCT appears highly feasible with 98% of informative patients. BM CD34+ cells chimerism stands out as a more robust marker than CD3+ or whole blood chimerism to predict relapse when using the 80% threshold determined here. It could be of value to decide whether or not to prescribe donor lymphocytes infusions as ASCT consolidation. Moreover, since CD34+ mixed chimerism appears here of high predictive value for relapse, it could be used as a surrogate prognostic factor for patients without minimal residual disease molecular markers. Finally, of interest, this marker is valid whatever the type of donor, and can be used even after hapoloidentical ASCT and/or PTCY administration. DisclosuresMoreau:Amgen: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceutical: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Mohty:Sanofi: Honoraria, Speakers Bureau.

Successful Salvage Therapy by Second Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation in a Severe Aplastic Anemia Patient Presenting Donor-Specific Anti-HLA Antibodies After Graft Failure From Matched Sibling Donor HSCT: A Case Report and Review

Hematopoietic stem cell transplantation (HSCT) is potentially curative for severe aplastic anemia (SAA). Graft failure (GF) remains a life-threatening complication after HSCT. Preexisting anti-HLA antibodies, especially HLA-specific antibodies (DSA), have been demonstrated as a risk of GF. This report describes a woman with acquired SAA who presented with anti-HLA antibodies and GF. After the treatment of anti-HLA antibodies, engraftment was achieved through a second alternative donor HSCT. This work complied with the Declaration of Helsinki and the Declaration of Istanbul. Based on our experience in treating this case, we hold that the presence of preoperative anti-HLA antibodies could discount the efficacy of HSCT and anti-HLA antibody screening should be performed before HSCT. Additionally, a second HSCT is feasible to prolong survival.

Current Use of Total Body Irradiation in Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation.

Total body irradiation (TBI) is included in the conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT), with unique advantages such as uniform distribution over the whole body and decreased exposure to cytotoxic chemotherapeutic agents. For individuals who lack matched sibling or matched unrelated donors, the use of haploidentical donors has been increasing despite challenges such as graft rejection and graft-versus-host disease (GVHD). Although a limited number of studies have been performed to assess the clinical role of TBI in haploidentical HSCT, TBI-based conditioning showed comparable results in terms of survival outcomes, rate of relapse, and GVHD in diverse hematologic malignancies such as leukemia, lymphoma, and multiple myeloma. Advances in supportive care, along with recent technical improvements such as restriction of maximum tolerated dose, appropriate fractionation, and organ shielding, help to overcome diverse adverse events related to TBI. Post-transplantation cyclophosphamide was used in most studies to reduce the risk of GVHD. Additionally, it was found that post-transplantation rituximab may improve outcomes in TBI-based haploidentical HSCT, especially in patients with B-cell lymphoma. Along with the advances of techniques and strategies, the expansion of age restriction would be another important issue for TBI-based haploidentical HSCT considering the current tendency toward increasing age limitation and lack of matched donors. This review article summarizes the current use and future perspectives of TBI in haploidentical HSCT.

Stable Pulmonary Function after Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide: A Single Center Experience

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&amp;lt;0.001). The median DLCO was 72 (range: 39-105), 64 (range: 16-105) and 66 (range: 26-104) at baseline, 3 months and 1 year after HAPLO. Twenty-nine patients had an infectious respiratory complication during the follow-up period. Of these, 19 were bacterial, three were viral, two were fungal and five had no microbial documentation. During the 1-year follow-up period, four patients met the criteria for bronchiolitis obliterans syndrome and two for interstitial lung disease. Of these, only one had died at last follow-up. The cumulative incidence of grade II-IV acute GvHD was 21% (95% CI 14-33%). At 1 year, the cumulative incidence of chronic GvHD was 26% (95% CI 18-39%). Non-relapse mortality was 9% (95% CI 4-18%) at 100 days and 14% (95% CI 8-24%) at 1 year. Relapse incidence was 3% (95% CI 1-10%) and 14% (95% CI 8-24%) at 100 days and 1 year, respectively. Overall survival was 73% (95% CI 62-82%). In all, 22 patients died. Cause of death was relapse of hematological disease in 7 (35%), infection in 7 (35%), GvHD in 2 (9%), multi organ failure in 4 (20%) and other causes in 2. Conclusion: We observed a significantly impaired DLCO at baseline, which remained impaired at 3 months and 1 year after HAPLO, but with a substantial stable pulmonary function at 1 year. Disclosures Malard: Theralos/Mallinckrodt: Honoraria; Sanofi: Honoraria; Keocyt: Honoraria; Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Biocodex: Honoraria; Janssen: Honoraria.

Personalized Risk-Profiling for Acute Leukemia Patients Undergoing Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation: A Study on Behalf of the Acute Leukemia Working Party of the EBMT

Background: Prediction of patient outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) remains a tenacious problem. An important limitation of current prediction models is the heterogeneity in outcome even among similar cases. We introduce a novel approach to individualizing estimates of leukemia-free survival (LFS) in acute leukemia patients undergoing haploidentical (haplo) HSCT. Methods: Data were obtained from the registry of the European Society for Blood and Marrow Transplantation for all cases of haplo HSCT for acute leukemia performed between 2011 and 2017. Patients receiving ex-vivo T-cell depleted grafts were excluded. Acute myeloid leukemia patients were classified by clinical disease ontogeny (de novo vs. secondary), cytogenetics, and FLT3-ITD/NPM1mut status; acute lymphoblastic leukemia patients by disease status and the presence of the Philadelphia chromosome. Common patient and transplantation parameters including recipient age, Karnofsky performance status (KPS), time from diagnosis to transplantation, conditioning and graft-versus-host disease (GvHD) prophylaxis were included. Data were split into training and geographic validation sets. Results: A total of 2,001 patients was included in the training set and another 270 in the validation cohort. In the training set, the median age was 50 years; 68% of patients were in complete remission, and 69% had a KPS ≥ 90; 87% received post-transplant cyclophosphamide and 13% antithymocyte globulin for GvHD prophylaxis. To provide the clinician insight on outcomes of similar patients, we developed a descriptive tool to visually explore outcomes of cases with comparable features. We next generated 50 random survival forest models for the prediction of 1-year LFS. In contrast to single point-estimates, the ensemble of 50 models generates a prediction interval accounting for predictive uncertainty. There was heterogeneity of variable importance between models, with either disease status or KPS leading in all models (Figure A). The model was well calibrated (Figure B); the median c-statistic was 0.64 on the validation set. An online interface presents the individual outcomes of the fifteen patients most similar to the index case, the prediction interval, and a visualization of all 50 survival forest predictions. Predictions for a sample patient are shown in Figure (C). Conclusions: We present the first system for individualized prediction of leukemia-free survival following T-cell replete haplo transplantation. A key, novel component of the model, distinguishing it from standard risk scores, is that it provides a measure of predictive certainty. This is essential for judging the robustness of prediction. Our approach is applicable to other clinical settings and can be used for designing risk-guided interventions and for informing patients and clinicians. Figure Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau.

An Encouraging Successful Result of Allogeneic Hematopoietic Stem Cell Transplantation in a Boy Both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta : A Case Report

Background: Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in young children that is classified as a myelodysplastic/myeloproliferative neoplasm and not only characterized by young age, hepatosplenomegaly, thrombocytopenia and monocytosis, but also by molecular aberrations in the RAS-RAF-MEK-ERK signaling pathway and GM-CSF-hypersensitivity. Most children with JMML experience an aggressive clinical course and the only curative treatment option for these children is stem cell transplantation (SCT). Osteogenesis imperfect (OI) is also an orphan inherited monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities. Current multidisciplinary management could only improve quality of life for patients, including physical therapy, drug treatment and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell or bone marrow transplantation, targeting the specific altered pathway rather than the symptoms, may develop new curative treatments. Here we report a 3-year-old boy who suffered from both JMML and OI, was successfully transplanted and kept presenting an encouraging outcome up to now. Aims:To investigate the possible efficacy and safety of Allogeneic Hematopoietic Stem Cell Transplantation in a boy both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta. Methods:A 3-year-old boy presented with fatigue, fever, petechia and rash in Aug 2019, accompanying with loss of appetite, joint pain and severe hepatosplenomegaly. The boy had a special appearance of short stature and blue sclerae, meanwhile he suffered intermittent eczema and bone fracture twice since he was 2 years old. Similar characteristics were also positive in his grandmother, father and father's sister. The blood cell counts revealed anemia, thrombocytopenia and leukocytosis especially monocytosis. Bone marrow aspirate showed excessive proliferation of myelomonocytic cells and hypersensitivity to granulocyte-macrophage colony-stimulating factor in vitro. Somatic mutation of gene NF1, PTPN11 and COL1A1 were identified by Next Generation Sequencing.Therefore, the little boy was diagnosed with two rare diseases of Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta at the same time. After 4 courses of hypomethylating agents therapy, the boy underwent haploidentical allogeneic bone marrow stem cell transplantation combined with allogeneic single umbilical cord blood transplant in May 2020. The myeloablative conditioning regimen was composed of Decitabine (20mg/m2/day, days -13 to -9), Cyclophosphamide (25mg/kg/day, days -8 and -7), Busulfan(100mg/m2/day, days -6 to -3), Fludarabine (40mg/m2/day, days -6 to -2) and Cytarabine (100mg/m2/day, days -6 to -2). Post-Cyclophosphamide (50mg/kg/day, days +3 and +4), tacrolimus and mycophenolate mofetil were used for prophylaxis of graft-versus-host disease (GVHD). Results:The number of infused TNCs from haplo-bone marrow and cord blood unit was 41.4×10^8/kg and 9.72×10^7/kg, respectively, while the number of infused CD34+ cells was 11.84×10^6/kg and 2.33×10^5/kg, respectively. The boy achieved sustained engraftment of both neutrophils and platelets at 16 days and 24 days, respectively, with complete haplo-donor chimerism of confirmed at 14 days. He developed grade III acute GVHD (skin, gut and liver) and recovered at 39 days after transplant. Clinical symptoms such as rash, joint pain and hepatosplenomegaly got complete remission, and the mutated genes like NF1, PTPN11 and COL1A1 all disappeared at 30 days. At the time of this report, the boy was alive with negative MRD and good quality of life with a follow-up of 3 months after HCT. Conclusion:To our knowledge, this is the first report that a child both with Juvenile Myelomonocytic Leukemia and Osteogenesis Imperfecta was cured by allogeneic hematopoietic stem cell transplantation.Our experience suggests that allogeneic bone marrow transplantation may be a novel safe and effective therapeutic strategy for OI patients. Disclosures No relevant conflicts of interest to declare.

CD34+ cell dose effects on clinical outcomes after T-cell replete haploidentical allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia using peripheral blood stem cells. A study from the acute leukemia working Party of the European Society for blood and marrow transplantation (EBMT).

Previous observations have reported controversial conclusions regarding cell dose and survival endpoints after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis on 414 adult patients (median age 54 years, range, 18-74 years) with acute myeloid leukemia (AML) in first and second complete remission. They received a T-cell replete allogeneic HSCT from haploidentical donors, using peripheral blood stem cells, between 2006-2018. Median number of infused CD34+ was 6.58 × 106 /kg (range, 2.2-31.2 × 106 /kg). Graft-vs-host disease (GVHD) prophylaxis was post-transplant cyclophosphamide in 293 patients and anti-lymphocyte serum in 121 patients. Conditioning was myeloablative in 179 patients and reduced-intensity in 235 patients. After a median follow-up of 23.3 months (range, 12.1-41.8 months), 2-year overall survival (OS) was 64.5% (95% CI 59.3%-69.7%) with leukemia-free survival (LFS) of 57.3% (95% CI 51.8%-62.7%) and non-relapse mortality (NRM) of 23.3% (95% CI 19%-27.7%). Grades III-IV acute GVHD day+100 incidence was 14.6% while extensive chronic GVHD was 14.4% at 2-years. Thirteen (3.2%) patients experienced graft failure. We found the optimal CD34+/kg threshold defining high (n = 334) vs low cell dose (n = 80) at 4.96 × 106 . Recipients of >4.96 × 106 /kg CD34+ cells experienced less NRM (Hazard ratio [HR] 0.48; 95% CI 0.30-0.76) and prolonged LFS (HR 0.63; 95% CI 0.43-0.91) and OS (HR 0.60; 95% CI 0.40-0.88) compared to those in the lower cell dose cohort. Larger cohort studies are needed to confirm these findings.

Incidence, risk factors, and clinical outcomes associated with Epstein-Barr virus-DNAemia and Epstein-Barr virus-associated disease in patients after haploidentical allogeneic stem cell transplantation: A single-center study.

Human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective alternative to HLA-matched transplantation. However, Epstein-Barr virus (EBV) infection causes morbidity and mortality in patients undergoing haplo-HSCT. Here, we retrospectively evaluated the incidence and risk factors of EBV-DNAemia and EBV-associated diseases in 131 patients who underwent haplo-HSCT. Patients were classified into the no EBV infection groups, EBV-DNAemia group and EBV-associated disease group. Cumulative incidences of acute graft-vs-host disease, EBV infections, overall survival (OS), and relapse were analyzed. The cumulative incidences of EBV-DNAemia and EBV-associated disease were 26.9% and 33.3%, respectively. In multivariate analysis, cytomegalovirus (CMV)-DNAemia was confirmed as an independent risk factor associated with EBV-DNAemia and EBV-associated disease. Patients with EBV-associated disease had higher transplant-related mortality (TRM) rates and lower OS rates, but similar relapse rates. Overall, these findings demonstrated the cumulative incidences of EBV-DNAemia and EBV-associated disease and identified correlations of EBV infection with TRM, relapse, and OS. Additionally, CMV-DNAemia was a risk factor for EBV-DNAemia and EBV-associated disease.

Reconstitution of cytomegalovirus-specific T-cell immunity following unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with posttransplant cyclophosphamide.

Cytomegalovirus (CMV) DNAemia and CMV disease have been reported as more frequent in patients undergoing haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HSCT) than in those receiving HLA-matched allografts. This could be due to impaired CMV-specific T-cell reconstitution. Here, we conducted a multicenter observational study to assess CMV pp65 and IE-1-specific T cells kinetics in patients undergoing unmanipulated Haplo-HSCT with posttransplant cyclophosphamide (PT/Cy-haplo) and compared it with patients allografted with HLA-matched donors. Plasma CMV DNA load was monitored by real-time PCR and enumeration of CMV-specific IFN-γ-producing CD8+ and CD4+ T cells was performed by flow cytometry for intracellular cytokine staining at days +30, +60, +90, and +180 after transplantation. CMV DNAemia developed in 62 patients, occurring with comparable frequency in PT/Cy-haplo and MRD/MUD recipients (P = 0.14). There were no significant differences across groups in the number of patients either displaying detectable CMV-specific CD8+ and CD4+ T-cell responses or acquiring CMV-specific T-cell levels conferring protection against subsequent infection. CMV-specific T-cell counts were comparable between groups at most time points examined, irrespective of whether CMV DNAemia occurred or not prior to monitoring. Collectively the data suggest that PT/Cy-haplo recipients may reconstitute CMV-specific T-cell immunity to the same extent as patients undergoing HLA-matched allo-HSCT.

STAPHYLOCOCCUS HAEMOLYTICUS: AN EMERGING THREAT IN CANCER PATIENT

Staphylococcus haemolyticus, a coagulase-negative Staphylococcus, is an opportunistic bacterial pathogen that colonizes human skin and is known for its high antibiotic resistance. After Staphylococcus epidermidis, the second most frequently isolated coagulase-negative Staphylococcus is S. haemolyticus. Increasing clinical significance of S. haemolyticus could be due to the great adaptability and the ability of the organism to survive in the hospital environment, especially on indwelling catheters, and the ability to acquire multidrug resistance against available antimicrobial agents. We report a case of a 40-year-old female diagnosed with mixed-lineage leukemia-positive pre-B acute lymphoblastic leukemia. The patient had undergone myeloablative T-replete haploidentical allogeneic stem cell transplantation. Later on, she developed skin graft versus host disease on day 83 and S. haemolyticus was isolated from the skin cultures. The patient was successfully managed with injection teicoplanin and skin care, but subsequently, she succumbed to multidrug-resistant Klebsiella pneumoniae infection.

Incidence, features, and outcomes of cytomegalovirus DNAemia in unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with post-transplantation cyclophosphamide.

Conflicting data have been published as to the risk of cytomegalovirus (CMV) DNAemia and CMV disease in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide. We conducted a multicenter retrospective study including 118 patients subjected to unmanipulated haplo-HSCT to further clarify this issue. An historic cohort comprising 165 patients undergoing other transplant modalities (HLA-matched related, matched unrelated or mismatched) was built for comparison purposes. Plasma CMV DNA monitoring was performed using two highly sensitive real-time PCR assays. Overall, the cumulative incidence of CMV DNAemia, recurrent CMV DNAemia, and CMV DNAemia requiring preemptive antiviral therapy in patients undergoing haplo-HSCT was 63.9%, 34.9%, and 50.1%, respectively. These figures were rather comparable for other transplant modalities (P=.22, P=.13 and P=.72, respectively). A trend toward longer duration of episodes and shorter CMV DNA doubling times was observed in haplo-HSCT patients in comparison with other transplant modalities. Furthermore, median CMV DNA peak load was significantly higher in haplo-HSCTs (P=.008), yet overall mortality by day 180 and 365 was the same across comparison groups. There were five cases of CMV disease, and all occurred in haplo-HSCT patients. This latter observation is worrying and merits further investigation. The incidence of initial and recurrent episodes of CMV DNAemia either requiring or not antiviral therapy in unmanipulated haplo-HSCT was comparable to other transplant modalities in our cohort.

Risk Factors and Different Therapeutic Patterns of Late-Onset Hemorrhagic Cystitis after Haploidentical Allogeneic Stem Cell Transplantation

Introduction Late-onset hemorrhagic cystitis (LOHC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with an incidence ranging from 6.5% to 70% and leads to prolonged hospitalization and even death (Silva Lde P et al, Haematologica, 2010; LAM et al, Transpl Infect Dis, 2017). The pathogenesis of LOHC remains obscure, but in our previous study, viral infections and acute graft-versus-host disease (aGVHD) have frequently been shown to be associated with its development (Han et al., Am. J. Hematol, 2014). Therapeutic strategies for LOHC are still not standardized due to the complicated clinical background and given the paradoxical phenomenon that immunosuppressive agents, such as steroids, are necessary for aGVHD but cause an immunosuppressive state. We aimed to investigate the incidence, risk factors and outcomes of LOHC after allogeneic stem cell transplantation. Additionally, for the first time, we propose four therapeutic patterns and their impact on prognosis of LOHC to aid in clinical decision making. Methods This retrospective, nested, case-control study reviewed data from 2158 patients who received allo-HSCT from January 2014 to December 2018. In total, 364 (16.87%) patients were diagnosed with LOHC. Individual matching was performed by randomly selecting 3 controls from the same cohort for each identified LOHC patient according to the time of allo-HSCT. Standard basic measures included hyperhydration, forced diuresis, insertion of a vesical catheter for intermittent or continuous bladder irrigation and evacuation of clots. Patients with grade III-IV LOHC were divided into four groups according to immunosuppressant use (steroid, MMF and Basiliximab) 1 week before and after the onset of LOHC: an intensified-intensified (I-I) group, intensified-not intensified (I-N) group, not intensified-intensified (N-I) group and not intensified-not intensified (N-N) group. "Intensified" was defined as an increase in any immunosuppressant, and "not intensified" was defined as maintenance or tapering of all immunosuppressants. Data concerning the baseline characteristics, incidence, treatment patterns and outcomes were recorded. Results In total, 364 patients developed LOHC at a median of 29 days (range, 23-37.75 days), with a cumulative incidence of 16.87%. AML (HR =0.493 95% CI, 0.244-0.997; p=0.049), AA (HR =0.444, 95% CI,0.18-1.096; p=0.078), HLA match(HR =0.149, 95% CI, 0.036-0.616; p=0.009), days to platelet engraftment(HR =1.023, 95% CI, 0.998-1.049;p=0.069)and CMV viremia (HR =2.365, 95% CI, 1.179,4.733;p=0.015)were associated with LOHC. Only HLA match (HR =0.111, 95% CI, 0.014-0.878; p=0.037)remained significant in the multivariate analysis. 6.5%, 12.9%, 48.39% and 32.26% patients with III-IV LOHC were divided into I-I, I-N, N-I and N-N groups, respectively. There were no significant differences in overall survival (p=0.05) and the incidence of CMV viremia (p=0.187) among the four groups. The incidence of relapse (p=0.007) and the incidence of aGVHD (p=0.01) was highest in the I-I group, followed by the N-I, I-N and N-N groups. 50% of the patients in N-I group showed the improvement of LOHC, which is significantly highest among the four groups(p=0.000). However, no statistical significance was found regarding the CMV viremia turning shade or the improvement of aGVHD. Non-relapse mortality (NRM) was observed in 25% of patients without resolution of LOHC. NRM was 0% among patients without intensified immunosuppression but was 25%, 0% and 50% among those with intensified immunosuppression before LOHC, after LOHC and before and after LOHC, respectively. Conclusion The independent risk factors for LOHC after allo-HSCT were HLA mismatch. Avoiding intensified immunosuppression that damages endothelium or reactivates the related virus may improve transplant outcome. The N-N pattern could reduce the incidence of CMV viremia or aGVHD in the LOHC patients, and the N-I pattern might be more promising as a therapeutic strategy for LOHC. Disclosures No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

Head-to-Head Comparison of Haploidentical HSCT Strategies for Hematologic Malignancies: Phase III Hatcy Study of T-Cell-Depleted HSCT with Adjunctive ATIR101 Versus T-Cell-Replete HSCT with Post‐Transplant Cyclophosphamide

Rationale: Haploidentical allogeneic hematopoietic stem cell transplantation (haplo HSCT) is increasingly used for the treatment of high-risk hematologic malignancies and overcomes limitations of finding a human leukocyte antigen (HLA)-matched donor in a timely manner. Although the most frequently used approach is a T-cell-replete stem cell source followed by in vivo depletion of alloreacting T cells using post-transplant chemotherapy with cyclophosphamide (PTCy), several other approaches have emerged, providing selected or manipulated donor-derived T cells to a T-cell-depleted or alpha/beta T-cell-CD19-depleted stem cell backbone. Here, we present the approach involving T-cell-depleted haplo HSCT complemented by ATIR101, an adjunctive infusion consisting of ex vivo selectively allodepleted, donor-derived, T-cell-enriched leukocytes. ATIR101 can facilitate early immune protection and provide anti-infectious and anti-leukemic activity while minimizing the risk of acute and chronic graft-versus-host disease (GVHD) without the need for post-transplant immunosuppression. ATIR101 is manufactured through the ex vivo use of TH9402 (a rhodamine derivative) and photodynamic treatment, selectively depleting the donor T cells that were activated by the recipient cells. The safety and efficacy of ATIR101 treatment following T-cell-depleted haplo HSCT have been investigated in Phase I and II studies in patients with hematologic malignancies (Roy DC et al. Br J Haematol 2019; ASH 2016, 2018). This strategy is currently being explored in a large, global, randomized Phase III study against a strategy of T-cell-replete HSCT with PTCy as the most commonly applied approach in haplo HSCT. Trial Overview: A randomized, multicenter, open-label Phase III trial (HATCY; CR‐AIR‐009; NCT02999854) is currently enrolling 250 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) to undergo either T-cell-depleted haplo HSCT with adjunctive ATIR101 treatment or T-cell-replete haplo HSCT with PTCy. Trial Design and Methods: Inclusion and exclusion criteria are listed in Table 1. All patients undergo total body irradiation (TBI) or non-TBI myeloablative conditioning. Patients in the ATIR101 arm receive anti-thymocyte globulin (Sanofi, 2.5 mg/kg once daily for 4 days) prior to HSCT and an ATIR101 infusion at a dose of 2 × 106 viable T cells/kg between 28 and 32 days post HSCT. In this group, no post-HSCT immune suppression is administered. Patients in the PTCy arm receive cyclophosphamide (50 mg/kg) on Day 3 and 4 (or 5) post HSCT, with subsequent use of immune suppression for GVHD prophylaxis based on institutional guidelines. The primary endpoint of the study is GVHD- and relapse-free survival (GRFS), a composite endpoint defined as time from randomization until Grade III/IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs first. GRFS was selected because it encompasses overall post-transplant health status, thereby closely reflecting a successful transplant outcome (Holtan SG, Blood 2015). Key secondary endpoints are overall survival, progression‐free survival, relapse‐related mortality, and transplant‐related mortality. A further objective of the study is to compare the effects of the two treatment strategies on quality of life. Approximately 50 sites are planned globally. The analysis is event driven: an interim analysis is planned at 105 GRFS events and the final analysis at 156 GRFS events. All patients will be followed up for at least 24 months post HSCT. Conclusion: This study will determine whether a strategy with a T-cell-depleted HSCT with adjunctive ex vivo selectively allodepleted, donor-derived, T-cell-enriched leukocytes (ATIR101) results in improved outcomes over a strategy with T-cell-replete HSCT with PTCy in patients undergoing haploidentical transplantation. The use of GRFS as a composite endpoint involving freedom of relapse and severe GVHD will allow a unique health-economic assessment and definition of value-based healthcare. Disclosures Roy: Kiadis Pharma: Other: Travel support; University of Montreal: Patents &amp; Royalties: Author on patent; Hopital Maisonneuve-Rosemont: Patents &amp; Royalties: Author on patent. Sanson:Kiadis Pharma: Employment. Hylton:Kiadis Pharma: Employment. Sandler:Kiadis Pharma: Employment. Mielke:Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; IACH: Other: Travel support; DGHO: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; EBMT/EHA: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; ISCT: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau.