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Allogeneic stem cell transplantation (alloSCT) is a curative procedure for myelofibrosis. Elderly people are mainly affected, limiting the feasibility of myeloablative regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible for older patients. Nevertheless, the incidence of myelofibrosis is not negligible in young patients, who are theoretically able to tolerate high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in younger myelofibrosis patients. This study included 56 transplanted patients aged

OBJECTIVES AND METHODS We analyzed the impact of pretransplant MRD level in bone marrow measured by flow cytometry using "different from normal" method on outcomes for 189 AML patients (108 males; median age, 58 (21-80) years). All patients were subdivided into negative (n = 96), "low" (0.1%-0.5%, n = 32), and "high" MRD (>0.5%, n = 61) groups. RESULTS In multivariate analysis, the hazard ratios for "high" and "low" MRD levels related to MRD negativity were 7.9 (95% CI 3.5-18.1, P

Severe aplastic anemia is a rare and potentially life-threatening disease of the bone marrow often requiring allogeneic hematopoietic stem cell transplantation. Pathogenesis of the disease can vary and often remains enigmatic. Occasionally, severe aplastic anemia is associated with prior severe acute hepatitis. Differential diagnosis of acute non-viral hepatitis challenges the physician as pathogenesis remains unclear.We here present a case of a young patient presenting with acute hepatitis followed by severe aplastic anemia successfully treated with allogeneic hematopoietic stem cell transplantation. Due to immunosuppressive treatment with azathioprine for acute hepatitis of putative autoimmune pathogenesis and coincident infection with parvovirus B19, diagnosis of the sequential disease of acute hepatitis followed by severe aplastic anemia was complicated. We discuss the caveats and present a review of the literature.Schwere aplastische Anämie (SAA) ist eine seltene und potentiell lebensbedrohliche Erkrankung des Knochenmarkes. Es gibt verschiedene Modelle zur Erklärung ihrer Pathogenese. Die Transplantation allogener hämatopoetischer Stammzellen ist die einzige kurative Therapiemöglichkeit. Selten ist eine schwere aplastische Anämie mit einer vorangehenden akuten Hepatitis assoziiert. Die Differentialdiagnose der akuten Hepatitis ohne Virusnachweis stellt den behandelnden Arzt häufig vor Probleme.Hier beschreiben wir einen Fall einer jungen Patientin mit akuter nicht-viraler Hepatitis, auf die eine SAA folgte. Letztere wurde erfolgreich mit einer allogenen Stammzelltransplantation behandelt. Infolge einer Immunsuppression mit Azathioprin für die zunächst als autoimmuner Genese behandelte Hepatitis sowie einer koinzidentellen Parvovirus-B19-Infektion gestaltete sich die Diagnosestellung der SAA schwierig. Interdisziplinäre Aufarbeitung führte zur Diagnosestellung des seltenen Syndromes der akuten Hepatitis gefolgt von schwerer aplastischer Anämie.

Acute graft-versus-host disease (aGVHD) is a serious complication after stem cell transplantation and is associated with high non-relapse mortality. If steroid treatment as first-line therapeutic approach fails, treatment options are limited. In retrospective studies, ruxolitinib, a selective Janus kinase 1/2 inhibitor as well as extracorporeal photopheresis (ECP) could show high efficacy in treatment of steroid refractory acute and chronic GVHD. Here, we report single-center experience of combining JAK-inhibitor treatment with ECP in 18 patients with severe steroid refractory aGVHD of lower GI-tract. The treatment was well tolerated and no severe cytopenia (grade IV) occurred, in three patients grade III cytopenia could be observed. Response was complete or partial in 44% and 11%, respectively, resulting in an estimated 2 year overall survival of 56%. Steroids were tapered rapidly with a median time of 2 days for halving of dosage avoiding additional steroid-associated side effects. Under treatment with ruxolitinib and ECP, an increased level of regulatory T cells could be observed elucidating direct effects of this treatment on immune response.

Introduction Myelofibrosis (MF) is a disease of elderly with median age of 65 years at diagnosis. Allogeneic stem cell transplantation (ASCT) currently is the only potentially curative option, although associated with treatment-related morbidity and mortality. Development of reduced intensity conditioning (RIC) regimens enabled transplant to be performed successfully in older patients. Objectives and methods To evaluate outcome of transplantation among elderly patients (≥65 years), we conducted retrospective analysis of results in 45 patients transplanted between 2002 and 2018 at the University Medical Center Hamburg. Median age at ASCT was 67 years (r: 65-74). The majority of patients (n = 43) received busulfan plus fludarabine RIC regimen and were classified as DIPSS intermediate-2 or high risk at time of transplantation. Results After a median follow-up of 4 years, 6-year estimated progression-free survival and overall survival were 60% and 64%, respectively. Cumulative incidence of non-relapse mortality was 21% at 1 year. Cumulative incidence of relapse at 6 years was 10%. Patients with Sorror score 3 or less had a significant better survival (73% vs 25%, P = .009). Conclusion Reduced intensity conditioning regimen followed by ASCT in older patients with myelofibrosis is a curative treatment option. Outcome is more favorable in patients with no or minimal comorbidities.

The major reason for treatment failure after allografting in multiple myeloma (MM) is relapse. Donor lymphocyte infusions (DLIs) are considered a valuable post-transplant strategy mainly for relapsed patients but using them to prevent relapse in MM has been reported rarely. In the present study, we examined the efficacy of prophylactic DLIs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in myeloma patients with a long-term follow-up of more than 5 years. A total of 61 patients with MM who did not relapse or develop disease progression after allo-HSCT were treated with prophylactic DLI in an escalating fashion (overall 132 DLI procedures) to deepen remission status and prevent relapse. Overall response rate to DLI was 77%. Thirty-three patients (54%) upgraded their remission status, 41 patients (67%) achieved or maintained complete remission, and 26% achieved a molecular remission. Incidence of acute graft-versus-host disease (GVHD) grade II to IV was 33% and no DLI-related mortality was noted. After a median follow-up of 68.7 months from first DLI the estimated 8-year progression-free survival (PFS), and overall survival (OS) in a landmark analysis was 43% (95% confidence interval [CI], 28% to 57%) and 67% (95% CI, 53% to 82%), respectively, with best outcome for patients who acquired molecular remission (8-year PFS was 62% and 8-year OS was 83%). Prophylactic escalating DLI in a selected cohort of MM patients to prevent relapse after allograft resulted in a low incidence of severe GVHD and encouraging long-term results, especially if molecular remission is achieved.

INTRODUCTION Allogeneic stem cell transplantation (alloSCT) is the only curative procedure for primary and secondary myelofibrosis (PMF, SMF). Elderly people are mainly affected, limiting the feasibility of intensive myeloablative chemotherapy regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible and effective for old patients. Nevertheless, the incidence of PMF and SMF is not negligible in young patients, theoretically able to tolerate also high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in the particular setting of young-aged MF patients. PATIENTS AND METHODS This study includes 56consecutive Myelofibrosis young patients (age RESULTS Engraftment rate was 98%, with a median neutrophil engraftment time of 15 days. Platelet engraftment was reached by 51 patients (91%) in a median time of 19 days. Four patients (7%) developed poor graft function, successfully treated with CD34+ selected PBSC boost. After a median follow up of 8.6 y estimated 5y PFS and OS was 68% and 82% respectively. DIPSS risk and donor HLA-matching resulted the only significant impacting factors on OS. Neither cytogenetic nor molecular abnormalities (included ASXL1) were significantly related to OS. Twenty-five patients (44%) experienced acute GVHD grade >1. Chronic GVHD was observed in 34 patients (65%), mostly (82%) beginning in the first 300 days after transplantation. Cumulative incidence of TRM was 7% at 1 year, with a plateau after the first year (5y TRM = 12%). TRM was observed only in patients with maximal grade (3) of marrow fibrosis (p=0.00). Furthermore, TRM never occurred in previously splenectomized patients (p=0.00), but no significant impact from splenectomy on OS was observed (p=0.32). After transplant, 11 patients (20%) relapsed: 1 died without any treatment because of infection, 9 received DLI with durable recovery of complete remission in 3 cases, 7 patients (6 after DLI) underwent a second alloSCT, with long-term survival in 5 cases. CONCLUSION Reduced intensity conditioning followed by allogeneic SCT is a curative treatment approach for younger patients with myelofibrosis with a low NRM. The most important outcome-determining factor is donor HLA-matching. Interestingly, marrow high grade fibrosis showed to significantly impact TRM. Biological markers such as ASXL1 mutation and cytogenetics, largely known as highly predictive for poor prognosis in the disease natural course, did not show any impact on survival, suggesting that patients harboring these abnormalities could get the greatest benefit from alloSCT. According to these data, RIC-alloSCT ensures optimal engraftment and low relapse rate, being able to lead also younger MF patients to cure. Further data collection, and a prospective randomized trial are needed to confirm our conclusion. Disclosures No relevant conflicts of interest to declare.

Introduction Myelofibrosis (MF) is predominantly a disease of the elderly with a median age of 65 years at diagnosis. Allogeneic stem cell transplantation (ASCT), which is associated with substantial treatment-related morbidity and mortality, is the only potentially curative option so far. The development of reduced intensity conditioning (RIC) regimens has enabled transplant to be performed successfully in older patients. To evaluate the outcome of transplantation among elderly patients, we conducted a retrospective analysis of results in 46 patients, aged 65 years or older, who were transplanted between 2002 and 2018 at the University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany. Patients and methods Retrospective data from 46 patients with primary or secondary MF, who underwent ASCT, were collected. Median age at ASCT was 67 years (r: 65-74). 76% of patients were classified as MF-3 according to the WHO criteria. DIPSS risk status was intermediate-1 in 4% of patients, intermediate-2 in 61% and high in 33%. 70% of patients had mutation in JAK2, 17% in CALR and 9% in MPL. All patients received peripheral blood stem cell (PBSC) as graft source. Stem cell donor was related in 9% of patients, unrelated in 91%; 74% of patients had a completely HLA-matched donor, whereas 26% had at least 1 allele or antigen mismatch. 85% of patients received busulfan 10 mg/kg orally (or 8 mg/kg intravenously) plus fludarabine (150 mg/m2) reduced intensity conditioning regimen, whereas 15% received myeloablative conditioning with busulfan 16 mg/kg orally (or 12.8 mg/kg intravenously) plus fludarabine (150 mg/m2). 96% of the patients received anti-T-lymphocyte globulin (Grafalon®, Neovii, Germany) at a cumulative dose of 30 mg/kg for matched related donor (MRD) transplants and 60 mg/kg for matched/mismatched unrelated donor (MUD/MMUD) transplants. Further GVHD prophylaxis consisted of cyclosporine A and mycophenolate from day +1 to +28. Results Engraftment rate was 94%, with a median time to neutrophil engraftment of 13 days (r: 10-19). Two patients (4%) experienced primary graft failure (PGF), one received a second ASCT with successful engraftment, while the other had further PGF after second ASCT and died of infection after third ASCT. Platelet engraftment rate was 87% and was reached in a median time of 21 days (r: 10-293). Five patients (11%) developed secondary poor graft function and four received CD34+ selected PBSC boost, two achieving complete remission (CR) and one obtaining CR with incomplete platelet recovery (CRp). 52% of patients experienced acute GVHD grade I to IV, while the overall rate of chronic GVHD was 56%, which was moderate disease in 24% and severe disease in 13%. After a median follow-up of 4 years, 6-year estimated progression-free survival (PFS) and overall survival (OS) were 60% (95% CI: 42-78) and 64% (95% CI: 48-80), respectively. In the univariate analysis, male donor sex was the only significant factor for improved OS and PFS at 6 years (P=.001 and P=.003, respectively). A positive impact on OS was observed for mutation in CALR (P=.05), as previously reported. Interestingly, survival was not significantly different in patients aged 65-70 years compared with those aged 71-74 years. Cumulative incidence of non-relapse mortality (NRM) was 29% at 4 years (95% CI: 13-45). Major causes of death were infections (n=4) and GVHD (n=3). The only significant factor for lower NRM in the univariate analysis was male donor sex vs female (NRM 17% vs 58%, P=.004). No NRM occurred in CALR-mutated patients (p=0.00). Cumulative incidence of relapse at 6 years was 10% (95% CI: 0-22): one patient durably restored molecular response after early tapering of cyclosporine, one died because of GVHD without any further treatment, one achieved a long-lasting CR after donor lymphocytes infusions (DLI), while two patients underwent a second ASCT after DLI alone in one case and DLI plus azacitidine in the other, with long-term CR in the former. Conclusion Our results show that RIC regimen followed by allogeneic stem cell transplantation in older patients with myelofibrosis is a curative treatment option. These results are encouraging for older MF patients with minimal comorbidities. In addition to Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), a comprehensive geriatric assessment could be a useful tool for a better selection of patients with the aim to further reduce NRM. Disclosures No relevant conflicts of interest to declare.

Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma cells. Some clinical studies have shown encouraging efficacy and acceptable safety profile of daratumumab, so that the drug became the first monoclonal antibody as single agent therapy approved by the FDA for the treatment of multiple myeloma. The role of allo-SCT in myeloma patients remains unclear; nevertheless, the registry study of European Society for Blood and Marrow Transplantation (EBMT) suggests an increasing rate of allografts in Europe in last years. Despite the potentially curative potential of this approach, the increased relapse rate and low PFS remain a central clinical problem. In this single center retrospective analysis, we report on our experience on the use of daratumumab in relapsed/refractory myeloma patients after allo-SCT. A total of 10 patients (male, n=5) with median age of 59 years (range, 37-69) relapsing after allo-SCTs that had been performed during a period 2008-2015 at the University of Hamburg and received daratumumab as single agent salvage therapy. Before allografting 8 patients received one and 2 patients ≥2 autografts, respectively. All but one patient received at least 1 salvage therapy line prior to the allo-SCT. The allografts were performed from unrelated donors (MUD, n=5; MMUD, n=3) or matched related donors (MRD, n=2). Five patients experienced early relapses (≤12 months) after allo-SCT. The median number of salvage lines post-transplant and prior to first daratumumab infusion was 3 (range, 1-4). The salvage regimens included bortezomib, lenalidomide, pomalidomide and carfilzomib. Daratumumab infusions were started at a median of 21 months (range, 2-30) after relapse/progress. The median number of infusions was 6 (range, 2-12). A total of 10 and 9 patients were available to safety and efficacy evaluation, respectively. The safety was assessed according to the Common Toxicity Criteria (CTC). A total of 14 adverse events were observed in 9 patients: dyspnea (CTC1, n=2; CTC2, n=1), bronchospasm (CTC2, n=1) shivering (CTC1, n=3), cough (CTC1, n=1; CTC2, n=1), musculoskeletal pain (CTC1, n=2), acute coronary syndrome (CTC3, n=1), skin rush (CTC2, n=1), pressure on eyes (n=1). There were no cases of hematologic toxicity. There were no cases of GvHD. The adverse events appeared in all patients after the first infusion, with improved tolerance of following infusions. There were no cases, where the therapy had to be stopped due to adverse events. Within a median follow-up of 25 months (range, 3-38) from the relapse/progression 9 of 10 patients remain alive. One patient died due to severe infection after progress of myeloma. A total of 5 of 9 evaluable patients responded (56%), of those 3 of 5 patients with early relapses (PR, n=2; vgPR, n=1). The responses (decrease of paraprotein and/or free light chains; reduction of extramedullary tumor in 1 patient) occurred at a median of 7 days (range, 7-22) after the first administration of daratumumab. The median response duration is 35 days (range, 7-84). All responding and 2 non-responding patients showed clinical improvement of constitutional symptoms. No patients required blood or platelets transfusions during and after the therapy. All responding patients maintain their responses 7, 14, 35, 54 and 84 days after the first administration of daratumumab. Daratumumab demonstrated encouraging efficacy in relapsed/refractory patients with myeloma after allo-SCT. The administrations of the drug in these heavily pre-treated patients were associated with good safety profile and development in majority of cases non-severe adverse events mostly after the first infusion. Further studies on the use of daratumumab in post-transplant setting are warranted. Disclosures Kröger: Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.

Introduction The Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib is approved for the treatment of symptomatic myelofibrosis (MF) regardless of the JAK2 mutational status. Ruxolitinib can reduce constitutional symptoms and spleen size resulting in an improvement of the performance status and also in a potential prolonged survival. Here we investigated the efficacy and toxicity of ruxolitinib in MF patients who relapsed after allogeneic stem cell transplantation. Patients and methods Between the years 2012 and 2016, 10 myelofibrosis patients of our department who relapsed after allogeneic stem cell transplantation received ruxolitinib. Stem cell donor was matched related (MRD) in two patients, matched unrelated (MUD) in six and mismatch unrelated MMUD in two patients. The median age of the patients was 61 years (r: 41-72). The median time from allogeneic transplantation until the start of ruxolitinib treatment was 23.8 months (r: 2.7-85.7). The median treatment duration was 143.5 days (r: 12-369). The median dose of ruxolitinib was 10 mg bid (r: 5-20mg) according to toxicity. Two patients had already received ruxolitinib prior to allogeneic transplantation. All patients had mixed chimerism at start of ruxolitinib. Two patients had already received donor lymphocyte infusions (DLI) prior to ruxolitinib. Two patients started with DLI beginning at day +30 and at day +147 within ruxolitinib treatment. Seven patients were positive for the JAK2V617 mutation and one patient for CALR mutation. Constitutional symptoms were observed in seven patients and splenomegaly in six patients before treatment start. One patient had aGvHD (skin) and three had cGvHD (oral mucosa, skin, liver) at the time of treatment start. In seven patients bone marrow histology was available before and during ruxolitinib treatment. Results We observed an improvement of constitutional symptoms in six patients (86%). The palpable spleen size was reduced in five patients (83%) with splenomegaly (≥50% n=4, Conclusion The Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib can lead to a reduction of spleen size, an improvement of MF-associated constitutional symptoms and a reduction of the blood transfusion-interval in patients with relapse after allogeneic transplantation. However, ruxolitinib does not lead to an increase of donor chimerism. It seems to have little impact on the JAK2V617F-allele level. A further aggravation of bone marrow fibrosis was seen in most of the patients. Despite of clinical improvement all patients experienced further progression of myelofibrosis and three patients even transformed to AML. Furthermore in those patients with GvHD an improvement or even complete resolution of the GvHD was seen. Disclosures Kroeger: Novartis: Honoraria, Research Funding.

Despite the significant improvement in outcomes for myeloma patients (pts) in the more recent years (yrs), the disease remains incurable. Because of high morbidity and mortality the role of allo-SCT in treatment of myeloma remains controversial. Registry data from the European Society of Blood and Marrow Transplantation (EBMT) suggest an increasing use of allo-SCT as salvage therapy after failure to auto-SCT. In present single center study we provide data on the use of allo-SCT focusing on pts with first relapse/progressive disease after autografting. A total of 89 pts (males, 62%) with median age of 53y (24-73) relapsed after an autograft (single, 64%; tandem, 36%) and received an allo-SCT during 2000 - 2015 yrs at University of Hamburg were included. The majority of the pts experienced advanced disease (stage III, 80%) and short remission duration after auto-SCT (≤24 mo, 81%) with median of 15 mo (2-91). A total of 76% of pts received a reinduction therapy prior to allo-SCT, whereas 24% did not. Twelve pts (14%) had high risk cytogenetics (defined as detection of del17p and/or t(4;14) by FISH). Twelve pts experienced extramedullary relapses. At time of transplantation pts were in CR (10%), vgPR (22%), PR (27%), SD (16%) or PD (25%). Allo-SCTs were performed mostly with peripheral stem cell (92%) and from unrelated (matched, 40%; mismatched, 32%) donors. Myeloablative conditioning was used in 70% of pts (busulfan-based, 61%; treosulfan-based, 9%). A total of 28 pts (31%) received a maintenance therapy (lenalidomide, 79%) starting at median 6 mo (4-8) post-transplant. Furthermore, 19 pts (24%) received DLIs (positive immunofixation, n=15; prophylaxis, n=4) within a median of 10 mo (4-27). The cumulative incidence (CI) of acute GvHD (grade II-IV) at d100 was 43% (32-55%). The CI of chronic GvHD at 5y post-transplant was 51% (39-63%; mild, n=19, moderate, n=12, severe, n=5). Of the 19 pts receiving DLIs, 5 (26%) developed GvHD (grade II-IV). Six (40%) of 15 pts responded (CR). The CI of TRM at d100 and at 5y were 8% (4-16%) and 19% (12-28%), respectively. We observed improved TRM in pts who didn't receive radiation before allo-SCT (p=0,03). The CI of relapses at 5y was 61% (49-72%). We observed a trend to lower relapse rate of 29% in pts with longer remission duration (>24 mo, p=0,07). The 5y probability of EFS was 28% (19-39%). The median EFS was 29 mo (22-36). In univariate analysis, we observed decreased survival probability for pts with high risk cytogenetics (p=0,026), remission duration ≤24 mo (p=0,008) and non-responders to salvage therapy (p=0,037). In multivariate analysis the negative impact of remission duration ≤24 mo (HR 6,9; 1,8-25,6; p=0,004) and failure to salvage therapy (HR 3,3; 1,2-9,0; p=0,021) were confirmed. In landmark analysis at d100 we observed improved survival for responding pts (p After a median follow up of 48 mo (6-170), the 5y probability of OS was 57% (46-78%). The median OS was 76 mo (42-110). In univariate analysis, we observed decreased survival probability for pts with extramedullary relapse (p=0,039), high risk cytogenetics (p=0,001), remission duration ≤6 mo (p=0,044) and those who received reduced intensity conditioning (p=0,022). In multivariate analysis the negative impacts of extramedullary relapses (HR 7,3; 2,7-20; p Allo-SCT being performed as salvage therapy after autograft failure resulted in around 30% 5y EFS. The response on d100 post-transplant, augmented by the MRD detection, seems to be prognostic important and might be used for planning further therapeutic strategies post-transplant. The use of DLIs and maintenance therapy post-transplant represent a possible approach to further improve survival. Disclosures Kröger: Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.