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Background: Multiple myeloma (MM), is a clonal plasma cell neoplasm characterized by destructive bony lesions, anemia, and renal impairment. MM is a global disease - worldwide in 2016, there were 138509 incident cases with an age standardized incidence rate (ASIR) of 2.1 per 100 000 persons, with a 126% global increase in incident cases from 1990 to 2016 (Cowan AJ et al JAMA Oncology 2018). Access to effective care, including proteasome inhibitors, immunomodulatory agents, and autologous hematopoietic stem cell transplantation (HSCT) is largely limited to high-income sociodemographic index (SDI) countries. SCT remains the standard of care for eligible patients, and in general is more affordable and accessible worldwide than novel therapies. We sought to evaluate the rates and utilization of ASCT globally from 2006-2015 to better characterize access to SCT for patients with MM. Methods: This was a new analysis of a retrospective survey of WBMT sites, conducted annually between 2006-2015, as described previously (Niederwieser et al BMT 2016). Incidence data estimates were reported from the Global Burden of Disease study (Institute for Health Metrics and Evaluation. 2019 'GBD Results Tool.' Global Health Data Exchange. Seattle WA: University of Washington. Accessed 1 June 2019). South Asia and East Asia regions were combined for this analysis. Outcome measures included total number of autologous and allogeneic stem cell transplants by World Bank (WB) regions, and percentage of newly diagnosed MM patients who underwent ASCT, calculated by the number of transplants per region in calendar year / gross annual incidence of MM per region. Results: From 2006 to 2015, the number of autologous HSCT performed worldwide for MM increased by 107% (Figure 1). Activity increased in each region from 2006 to 2015 from 56% in USA and Canada to 335% in Latin America. Utilization of autologous HSCT was highest amongst the Northern America and European WB regions, with an increase from 13% to 24% in Northern America, and an increase from 15% to 22% in Europe. The activity increased considerably in the Latin American countries (335,46% increase) and the utilization reached >10%. In contrast, the utilization of autologous HSCT was much lower in the Africa/Mediterranean and Asian/Pacific region, with autologous HSCT utilization only changing marginally from 1.8% in 2006 to 4% in 2015 despite increase in activity. The number of first allogeneic HSCT performed globally for MM declined after a peak in 2012 by -3% since 2006 mostly in North America. Allogeneic HSCT remains highest amongst the European WB region (increase 8%). The increase in activity was accompanied by an increase in team numbers from 1327 in 2006 to 1581 in 2015 but also by an increase of activity in the teams. Discussion: Autologous HSCT utilization has increased worldwide in high-income SDI WB region countries for MM yet has not increased proportionally amongst low-middle income WB regions. There is a disparity in autologous HSCT utilization amongst high-income regions, exceeding 20% in North America and Europe, while remaining poorly utilized in Africa and the East Mediterranean. Latin America has increased their utilization and is for the first time above 10%. However, we are limited with respect to use of incidence data in LMIC countries from the GBD, likely due to under reporting. Conflicting clinical trial data likely contributed to the decline in some regions for first allogeneic HSCT in MM. More work is needed to improve access to transplantation services for MM patients, especially in low to middle income countries. Conclusion: Although autologous HSCT numbers and rates have increased globally, there are marked disparities in usage amongst high versus low to middle income countries. More work is needed to improve access to HSCT for MM globally. Figure 1 Disclosures Cowan: Celgene: Consultancy, Research Funding; Cellectar: Consultancy; Juno: Research Funding; Sanofi: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Atsuta:Janssen Paharmaceutical K.K.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Pasquini:Novartis: Research Funding; Kite Pharmaceuticals: Research Funding; BMS: Research Funding; Medigene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Galeano:Szabo SA: Other: (Equity interest). Szer:Amgen: Honoraria, Other: Travel, Research Funding; Alexion: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding. Kroeger:Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Sanofi-Aventis: Honoraria; Novartis: Honoraria, Research Funding; Medac: Honoraria; DKMS: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Incyte: Research Funding; Pharmacyclics: Consultancy. Niederwieser:Cellectis: Consultancy; Daichii: Speakers Bureau.

HSCT is the only curative option for many malignant and non-malignant diseases. The WBMT was founded as an umbrella organization of societies involved in cellular therapies with the mission of promoting excellence in HSCT. As a non-governmental organization in official relation with the World Health Organization (WHO), the WBMT assisted in the founding of regional societies (Latin America Blood and Marrow Transplantation Group and African Blood and Marrow Transplantation Group), performs global activity surveys, conducts workshops and provides expert support for programs in evolving countries. In this retrospective evaluation we analyzed worldwide activity trends in HSCT up to the year 2016 and evaluated possibilities of improving availability of HSCT by the use of telemedicine. Methods: HSCT activity was collected annually from member societies, national registries and individual centers including donor type (allogeneic/autologous), stem cell source (bone marrow/peripheral blood stem cells/cord blood) and indications for transplant. Transplant rates (TR) were calculated as HSCT/10 million inhabitants without adjustment for patients transplanted in a country other than that of primary residence. Country team density (TD) was defined as teams/10 million inhabitants. Workshops were organized in a number of locations where there was little or no HSCT activity or where improvement in one or more aspect of local or regional HSCT activity was requested, including Vietnam, Brazil, China, South Africa and Morocco. Other countries were paired with established centers using WBMT affiliated partners. In two countries, a pilot program was established involving a 6 month physician training in a JACIE/FACT accredited center followed by daily telemedicine-guided supervision of clinical activities. Results: From 1957-2016 a total of 1,298,897 HSCT (57.1% autologous) procedures were collected. By the end of 2016, HSCT activity was reported from 87 of the 195 WHO member states. A total of 89,070 HSCT from 1662 centers was reported in 2016. Assuming a frequency of 84,000/year, 1.5 million HSCT will be reached in 2019, only 7 years after the 1 million report in 2012 (Figure 1). The global activity/year increased continuously from 10,000/year in 1991 to 82,718 first HSCT/year in 2016 with a global increase of >7% (7.0% in autologous and 7.8% in allogeneic HSCT). As in previous years, slightly more autologous (53.5%) than allogeneic and more related (53,6%) than unrelated HSCT were reported. The further increase in related HSCT was caused mainly by an increase of non-identical family donors (39.5% of related HSCT). Increase in activities according to regions is given in Figure 2. TR and TD varied according to region and are highest in Nord America with 511.2 TR, followed by Europe with 390.9 TR, Latin America with 63.9 TR, APBMT with 46.2 TR and Africa/EMRO with 32.8 TR. In contrast, TD was highest in Europe (7.5 TD) followed by Nord America (6.0 TD), APBMT (1.9 TD), Latin America (1.9 TD) and Africa/EMRO (0.4 TD). Commonest indications were lymphoproliferative diseases for autologous and leukemia for allogeneic HSCT and continue to rise (Figure 3 autologous and Figure 4 allogeneic HSCT). Graft source were predominantly peripheral blood in autologous (99.7%) and 65% in unrelated HSCT, while umbilical cord blood as a stem cell source (13.8% of all unrelated) declined. More than 150 HSCT were performed in one country and one center without activities using daily telemedicine-guided supervision. In conclusion, the global distribution and activities are increasing continuously by more than 7,0% per year with numbers currently running at app. 90,000/year. Of note is the increase of haploidentical HSCT activity, while the use of umbilical cord blood HSCT continues to decrease. TR data show significant gaps between regions. Supervisory telemedicine is a powerful tool to overcome lack of experience and establish JACIE/FACT compatible new programs with collateral benefits for conventional hematology, blood banking, microbiology and virology. Abbreviations: EUR, Europe; AMR/PHA, America; SEAR/WPR, South-East Asia/Western Pacific; AFR/EMRO, African/Eastern Mediterranean. Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. Galeano:Szabo SA: Other: (Equity interest). Novitzky:Astellas, Roche: Consultancy. Szer:Prevail Therapeutics: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Alexion: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Weisdorf:Incyte: Research Funding; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy. Pasquini:Amgen: Consultancy; BMS: Research Funding; Medigene: Consultancy; Pfizer: Other: Advisory Board; Novartis: Research Funding; Kit Pharma: Research Funding.

Background: Therapies involving adoptive transfer of chimeric antigen receptor-modified T-cells (CARTs) targeting CD19-expressing B-cells have shown remarkable efficacy in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). We hypothesized, that a higher fraction of more differentiated, senescent and exhausted T-cells affects negatively ex vivo T-cell expansion in the manufacturing phase of CARTs and the in vivo function of CARTs after infusion. Of note, naïve CD4+ T-cells were shown to uniformly express the co-stimulatory receptors CD27 and CD28, while repeated cycles of activation led to their progressive loss (van Leewen et al, J. Immunol, 2004), accompanied by telomere erosion and replicative senescence (van Baarle et al., Immunol. Lett. 2005; Effros RB et al., Dev Comp Immunol 1997). CD28 expression on T-cells within the tumor environment was shown to be a decisive factor for the efficacy of anti-PD-1 therapy (Kamphorst RO et al, Science 2017). We have therefore analyzed the CD27 and CD28 expression status of CD3+ T-cells from the peripheral blood and apheresis products of adult r/r DLBCL patients at the day of leukapheresis. Methods: Peripheral blood and apheresis samples of 22 consecutive r/r DLBCL patients scheduled for CART therapy were analyzed by flow cytometry to assess their CD27 and CD28 expression status on CD3+ T-cells. Samples were stained with fluorochrome conjugated antibodies (anti-CD3 PerCP, anti-CD27 FITC, CD28 PE, anti-CD4 FITC, BioLegend) and analyzed using a FACScalibur flow cytometer supported by CELLQUEST software (Becton Dickinson, BD, Palo Alto, CA). Results: To rule out an apheresis-related bias within cell populations we analyzed peripheral blood and apheresis samples for each patient. No differences in the distribution of CD27-, CD28-, CD27-/CD28- or CD27+/CD28+ T-cells between peripheral blood and apheresis product were detected. Mean CD3+ cell count in blood samples before apheresis was 624±399/µl (range, 75-1853cells/µL) with only about 25% of the patients presenting with CD3+ cell counts within the normal range (690-3320/µL) and 70% of the patients showed an inverse CD4/CD8 ratio (1.0) CD4/CD8 ratio (Figure 1c) in responding patients. Furthermore, we did not observe significant differences in CD27-and CD28- expression in samples derived from patients who died prior to receiving CART therapy (n=6) when compared to patients responding or progressing after CART therapy. Three patients have not been infused yet. Conclusion: We demonstrate in this small patient cohort that individuals with a lower percentage of more differentiated, senescent or exhausted T-cells are more likely to respond to CART therapy. Our observation underscores the importance of T-cells with normal replicative capacity in the apheresis material for consecutive CART production to achive therapeutic success. Further analysis is needed to determine the effect of cytotoxic pretreatment on the fraction of immunosenescent/exhausted T-cells. However, to confirm our findings additional investigations including the T-cell status of manufactured cells are warranted. Disclosures Worel: Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau; Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Hopfinger:Celgene, Gilead, GlaxoSmithKline, Janssen, Novartis, Roche, Takeda,: Honoraria; Gilead: Research Funding.

To the editor: B lymphocytes are increasingly assigned an important role in the pathogenesis of auto-and alloimmune diseases including chronic graft-versus-host disease (cGVHD)[1][1][⇓][2][⇓][3]–[4][4] where abnormalities of B-cell homeostasis in patients with active cGVHD have been observed

Relapse is the major cause of death after allogeneic hematopoietic cell transplantation (HCT) for hematological malignancies and can be treated with donor lymphocyte infusions (DLI). Initial low dose DLI followed by escalating DLI doses have been used to minimize the risk of graft-versus-host disease (GVHD) in patients with relapsed chronic myeloid leukemia (CML). The impact of initial CD3+ cell dose on outcome after DLI in patients treated for other hematological malignancies is limited. We retrospectively analyzed data of 75 patients who were treated with DLI after HCT at our institution over the last 20 years. The primary objective of this analysis was to determine the effect of the initial CD3+ cell dose in DLI on overall survival (OS). The median age of the cohort was 43 (range, 18 - 71) years, 60% were male. Patients received transplants from related (n=53) or unrelated (n=22) donors for treatment of CML (n=18), acute myeloid leukemia (n=29), myelodysplastic syndrome (n=3), acute lymphoblastic leukemia (n=9), multiple myeloma (n=8), lymphoma (n=7) and paroxysmal nocturnal hemoglobinuria (n=1). Thirty-three patients (44%) received reduced-intensity conditioning regimens. DLI were given for mixed chimerism (n=5), relapse/progression (n=58) or prophylactically in patients with high risk disease (n=12). The median time intervals from HCT to relapse/progression and HCT to DLI for mixed chimerism were 15 (range, 1-80) and 20 (range, 1-169) months, retrospectively. Prophylactic DLI were given between 1 and 25 months after HCT. Therapy prior to DLI consisted of cytoreductive chemo-/radiotherapy with or without tyrosine kinase inhibitors (TKI) in 33 (44%) patients, TKIs alone in 10 (13%) and immunomodulatory drugs in 3 (4%) patients. Twenty-nine (39%) patients received DLI alone. Initial DLI CD3+ cell dose/kg was 1.0 to 10x107(n=16; Group C), in 3 patients the cell dose was not available. Of note, 24 patients received escalating doses of CD3+ cells. Response evaluation three months after DLI for evaluable patients with relapse/progression or mixed chimerism (n=60) revealed complete response (CR) in 30 (47%) and no response in 28 (44%) patients. Two patients developed aplasia and were rescued with second HCT. After prophylactic DLI 6/12 (50%) patients remained in CR whereas 6 (50%) experienced relapse between 3 and 21 months after DLI. Twenty-nine (39%) patients are currently alive including eight with malignant disease after a median follow-up of 69 months (range, 1-193). Seventeen (24%) patients developed acute or chronic GVHD after DLI. The risk for GVHD was significantly higher in patients receiving higher (Group B and C) compared to lower doses (Group A; p=0.04) of CD3+. Eight patients died due to severe GVHD. Higher CD3 cell doses did not result in lower relapse rates or better response (p=0.23). OS rates at 5 years were 50%, 45%, and 6% for Groups A, B, and C, respectively. Compared to lower doses initial DLI CD3+ cell dose of >10x107/kg was significantly associated with a reduced overall survival after DLI (p=0.003, Figure 1). Of note, conditioning regimen applied, donor type and reason for DLI administration had no significant influence on overall survival. Our results show that an initial DLI CD3+ cell dose of >10x107/kg is associated with reduced survival rates. These findings are clinically relevant, and support a recommendation to infuse Disclosures: No relevant conflicts of interest to declare.

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT) requiring prolong immunosuppressive therapy and increasing non-relapse mortality. Immune mechanisms underlying cGVHD have remained elusive. Recently, we reported a severe disturbance in B cell homeostasis seen in a significant expansion of immature/transitional B lymphocytes (CD21−) and a significant decrease of non-class switched (CD19+/IgD+/CD27+) and class-switched memory B cells (CD19+/IgD−/CD27+) in patients with active chronic GVHD. In long-lasting cGVHD irreversible tissue damage cannot be distinguished from active cGVHD with certainty since no biomarkers for monitoring of cGVHD activity as well as for assessment of therapeutic response are available. We investigated serially every 3 to 6 months B cell subpopulations in the peripheral blood (PB) of 47 patients (median age 40 years, range 18–62 years) given extracorporeal photopheresis (ECP) as first line (n=13) or salvage therapy (n=34). Twenty-nine patients (64%) had more than 2 organs affected by cGVHD and in 21 patients (45%) severity of organ involvement was grade 3 according to the NIH Consensus. Duration of cGVHD before ECP was a median of 2.5 years. ECP was performed initially every two weeks on 2 consecutive days and monthly thereafter until improvement. The median duration of ECP was 30 (range, 8–50) cycles during a median of 13 (range, 3–36) months and ECP is still ongoing in 14 patients. A total of 257 samples with a median of 6 analyses per patient (range, 3 to 10) was assessed. PB leukocytes were analyzed by multiparameter flow cytometry after staining for CD19, CD27, CD21 and surface Ig. Patients were scored for cGVHD activity and response evaluation according to the NIH Consensus Development Project criteria at every sampling event. Thirty-five patients (75%) responded to ECP, including 22 with complete resolution, whereas 12 (25%) were nonresponders. Retrospective correlation of clinical response to ECP with B cell subpopulation numbers revealed that patients not responding to ECP had a significantly higher number of immature/transitional B cells (CD19+/CD21−) (mean 16.6%, range 0.8–57%) in PB samples taken prior to start of ECP compared to responders (mean 13%, range 1–54%, p 0.0001). The numbers of both non-class-switched and class-switched memory B cells were significantly higher in ECP-responders, mean 5.1% (range 1–21%) compared to a mean of 4.2% (range 0.3–14%) in nonresponders (p 0.041) The CD21−/CD27+ ratio was significantly higher in nonresponders with a mean of 8.6 (range 0.5–50) compared to a mean of 6.6 (range 0.3–89) in the responding group(p 0.0005). Three months after start of ECP patients responding to therapy had a decrease in their CD21−/CD27+ ratio (mean 3, range, 0.3–18, p=0.05) whereas in nonresponders B cell subpopulations were unchanged. After 6 months a significant decrease in immature/transitional B cell numbers (CD19+/CD21−) compared to baseline (p=0.03) values was observed in ECP responders whereas ECP nonresponders presented a further increase in immature/transitional B cell (CD19+/CD21−) numbers. One year after start of ECP 22 patients with durable complete responses had a further decrease of the CD21−/CD27+ ratio (mean 1.6, range 0.2–5.4) comparable to patients with resolved cGVHD as previously reported (Greinix et al, BBMT14:208–219, 2008). In contrast, nonresponders to ECP with persistent active cGVHD had a significantly higher CD21−/CD27+ ratio (mean 3.3, range, 0.1–11, p=0.08) in PB samples. In conclusion, determining the degree of disturbance of B cell homeostasis as seen in elevated numbers of immature/transitional B cells and decreased memory B cell subsets during active cGVHD could be used for predicting therapeutic response to ECP. Moreover, 3 to 6 months after start of ECP distribution of B cell subpopulations differed significantly between ECP responders and nonresponders. Thus, B cell subsets serially assessed could serve as possible biomarkers of response to ECP in cGVHD. Our preliminary findings should be confirmed in a larger prospective patient cohort receiving ECP.

Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Second-line therapies for steroid-refractory acute GVHD have been used with limited success. Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing agent 8-methoxypsoralen and UV-A radiation (ECP) has been shown to be effective in the treatment of selected diseases mediated by T cells. We have reviewed the responses and long-term outcome of 59 hematopoietic stem cell transplant (HSCT) patients treated from 1996 to 2003 with ECP for steroid-refractory acute GVHD, defined as progression or no improvement of acute GVHD after a minimum of 4 (range, 4–49, median 17) days of treatment with prednisone (n=37) or steroid-dependent acute GVHD, defined as flare-up of GVHD during prednisone taper (n=22). Patients received HSCT from 17 related and 42 unrelated donors. In 28 cases an HLA-mismatch between recipient and donor was present. Prior to ECP, grade III–IV GVHD was observed in 23 patients (39%) and grade II GVHD in 36 (61%). Organs involved included skin in 97% of patients, liver in 39%, and GI tract in 17%. Treatment consisted of ECP on two consecutive days per week (=1 cycle) for a median of 7 (range, 1–45) cycles administered within a median of 3 (range, 0.5–31) months in addition to cyclosporine A and prednisone. Three months after initiation of ECP complete resolution of GVHD was achieved in 82% of patients with cutaneous, 61% with liver, and 61% with gut involvement. Complete responses were obtained in 86% of patients with grade II, 55% of patients with grade III, and 30% of patients with grade IV acute GVHD. Probability of transplant-related mortality (TRM) at 4 years after HSCT is 15% in patients with complete response to ECP compared to 88% in patients not responding completely. After a median follow-up of 46 (range, 9–45) months since discontinuation of ECP, 28 (47%) patients are alive including 22 without chronic GVHD. Probability of survival (OS) at 4 years after HSCT is 59% in patients with complete response to ECP compared to 11% in patients not responding completely. Besides response to ECP only organ involvement and grade of GVHD at start of ECP, and ability to timely taper steroids during ECP had a significant impact on both TRM and OS. Thus, ECP is an effective adjunct therapy for acute steroid-refractory and steroid-dependent GVHD. Our long-term results demonstrate durability of responses without adverse events.

Thrombotic microangiopathy (TM) is a severe complication of stem cell transplantation (SCT) associated with high mortality rates. One of the major risk factors for the development of TM is the toxic effect of high-dose chemo-radiotherapy, heavy pretreatment and the use of unrelated donors (URD) grafts. To reduce transplant related mortality in patients at risk non myeloablative conditioning regimens have been introduced. We reviewed data on 83 consecutive patients given sibling (n=44) and URD (n=39) SCT after reduced intensity conditioning and graft versus host (GvHD) prophylaxis with CsA and mycophenolate mofetil with respect to occurence of TM. Diagnoses consisted of ALL (n=5), AML (n=31), CML (n=8), MDS (n=6), MM (n=11), NHL (n=17), renal cell cancer (n=4) and n. ovarii (n=1). A group of 565 patients undergoing high-dose conditioning followed by sibling (n=372) an URD (n=193) SCT served as control. The majority of these patients received CsA and MTX as GvHD prophylaxis. The diagnoses of TM was confirmed by renewed thrombocytopenia, coombs negative hemolysis, increased LDH-levels and fragmented red cells in peripheral blood smears. TM occured in 9 of 83 patients (11%) after RIC compared to 25 of 565 patients (4,4%) after high-dose conditioning, respectively. All but one patient in the RIC group received an ABO-incompatible stem cell graft (p< 0.05). The median time of onset of TM was 62 days after SCT (range, 9 to 906 days) in this group. Donor source (sibling/URD) had no influence on the risk of developing TM (p=0.07). TM was associated with severe acute GvHD (n=2), chronic extensive GvHD (n=3), sepsis (proteus mirabilis n=1), herpes virus infection (n=1), severe hemolysis after minor ABO-incompatible SCT (n=1) and computed tomography approven atypical pneumonia (n=1). First line treatment consisted of withdrawal of cyclosporine A and plasmaexchange treatment (median exchange procedures 14, range 8 to 30). Overall, 5of 9 (55%) patients responded, 3 patients died due to GvHD and TM, 1 of multi- organ failure. One patient who responded to plasmaexchange died 1 year later due to relapse. Posttransplant TM is a common severe complication and seems to increase after reduced-intensity conditioning. Fludarabin, a major constitute of RIC, is not reported to cause TM. How far GvHD-prophylaxis without MTX plays a role in the development of TM remains unclear. Of particular importance is that patients receiving ABO-incompatible stem cell grafts have a significant higher risk to develop TM after allogeneic SCT following reduced-intensity conditioning.