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Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA-class Ib molecule HLA-G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo-HSCT setting, HLA-G mismatches may negatively impact the HLA-G-mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA-G on host cells by the immune cells of the donor.In order to explore this hypothesis, we investigated the impact of HLA-G mismatching in 2.083 10/10 matched high resolution HLA-typed allo-HSCT transplants.We found that the risk of chronic GvHD was significantly higher in HLA-G-mismatched transplant cases as compared with the HLA-G-matched control group (HR: 1.46, 95%CI = 1.11-1.91, p = 0.006). Sub-analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39-2.57, p 0.001) but not the HvG direction (HR: 1.01, 95%CI = 0.63-1.63, p = 0.967). In addition, the negative impact of HLA-G mismatching on chronic GvHD was only significant in younger patients (30y HR: 3.02, 95%CI = 1.25-7.28, p = 0.014;29y HR: 1.28, 95%CI = 0.94-1.72, p = 0.113).Our results indicate that HLA-G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible.

A common genetic variant within the T cell receptor alpha (TCRA)-T cell receptor delta (TCRD) locus (rs2204985) has been recently found to associate with thymic function. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient’s outcome after unrelated hematopoietic stem cell transplantation (uHSCT). 2016 adult patients were retrospectively analyzed. rs2204985 genotyping was performed by next generation sequencing, p < 0.05 was considered significant and donor rs2204985 GG/AG genotypes were set as reference vs. the AA genotype. Multivariate analysis of the combined cohort regarding the impact of donor’s rs2204985 genotype indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations. A subanalysis on account of HLA incompatibility revealed that donor AA genotype in single HLA mismatched cases (n = 624) associated with significantly inferior overall- (HR: 1.48, p = 0.003) and disease-free survival (HR: 1.50, p = 0.001). This effect was driven by a combined higher risk of relapse incidence (HR: 1.40, p = 0.026) and non-relapse mortality (HR: 1.38, p = 0.042). This is the first study to explore the role of rs2204985 in a clinical uHSCT setting. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely impact post-HSCT outcome and should thus be avoided., publishedVersion

Herpes zoster (HZ) is a frequent complication after autologous stem cell transplantation (ASCT). The option of zoster prophylaxis with an antiviral drug is described in the literature, but there is no consensus on the drug and the dosage.We analyzed the records of 310 patients treated with ASCT who were controlled regularly regarding HZ inter alia for at least 24 months following ASCT. Since 01/2015 patients received prophylactic low-dose acyclovir (400 mg per day) during the first 12 months following discharge after ASCT (n = 107).Twenty percent of patients without this kind of prophylaxis and 2.8% of patients with prophylaxis developed HZ (p .001). No patient with this prophylaxis developed HZ in the first year after ASCT, 2.8% of patients in the second year after ASCT. A prognostic factor was the kind of diagnosis: 30% of lymphoma patients and 14% of myeloma patients developed HZ in the first 24 months after ASCT without prophylaxis, but only 6.3% and 0% of patients with prophylaxis, respectively. Neither an increase of HZ cases following prophylaxis nor acyclovir refractory HZ cases were observed.Zoster prophylaxis with low-dose acyclovir over 12 months after ASCT is effective and well tolerated.

Purpose Treosulfan and fludarabine (Treo/Flu) were successfully introduced into toxicity-reduced conditioning for SCT. However, the risk of post-SCT relapse remains a matter of concern. We report the results of a novel individual treatment approach with Treo/Flu and cytarabine (Treo/Flu/AraC) conditioning prior to allogeneic SCT in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasms (MPN). Methods Seventy-seven patients (median age 54 years) at high risk of disease relapse due to unfavorable cytogenetics or failure to achieve complete remission prior to SCT were included. Median follow-up was 3.2 years. Results The 1-, 2- and 3-year RFS rates were 49.4%, 41.7%, and 37.6% and OS rates were 59.3%, 49.3%, and 45.4%, respectively. Cumulative incidence of NRM was 10% at 100 days, 18.8% at 1 year and 20.1% at 2 years. The cumulative incidence of relapse increased from 31% at 1 year to 38.5% after 3 years. The cumulative incidences of engraftment, chimerism, graft-versus-host disease (GvHD) and toxicities were acceptable and comparable with similar patients conditioned with Treo/Flu or FLAMSA-RIC. Conclusion In conclusion, Treo/Flu/AraC provides tolerable, feasible, and effective conditioning for patients with AML, MDS or MPN, even in advanced disease states. The incidence of NRM and relapse is acceptable in this heavily pre-treated population with high-risk disease. Future research will aim to confirm these initial findings and include a larger number of participants in a prospective trial.

OBJECTIVE To contribute data on long-term outcome and potential curative impact of ASCT in FL, especially following HDT with the BEAM protocol (BCNU, etoposide, cytarabine and melphalan), given very limited data on this topic in the literature. PATIENTS AND METHODS Patients with FL (n = 76) were treated in our institution with HDT and ASCT. In the case of long-term remission (≥8 years), peripheral blood was tested for minimal residual disease by t(14;18)- and IGH-PCR, including the last follow-up. RESULTS 10-year overall survival, progression-free survival, and freedom from progression (FFP) after first-line ASCT (n = 20) were 80%, 60%, and 69%, after second-line ASCT (n = 48, following BEAM) 66%, 38%, and 41%, after third/fourth-line ASCT (n = 8) 33%, 25%, and 25%, respectively. Prognostic factors for FFP were treatment line and FLIPI (Follicular Lymphoma International Prognostic Index). 10-year FFP for second-line ASCT and low-risk FLIPI at relapse was 69%, intermediate-risk 28%, and high-risk 25% (P

The prognosis of an early relapse of diffuse large B-cell lymphoma (DLBCL) appears to be poor following autologous stem cell transplantation (ASCT). The aim of this study is to contribute data to the open question on whether additional radiotherapy can improve the outcome. Forty-eight patients with an early relapse (median 4 months after the end of initial immunochemotherapy, range 1–11) of DLBCL have been treated in our institution with high-dose therapy (usually the BEAM protocol) and ASCT since 2008 (median age 61 years, range 28–73). Twenty-three patients received ASCT in a second treatment line, 25 in a third line (19 refractory to second-line salvage therapy, 5 after second relapse). Fifteen of these 48 patients received radiotherapy (36–50 Gy, median 40) of residual masses after ASCT. Three-year overall survival (OS) and progression-free survival (PFS) after second-line ASCT were 61 and 57%, after third-line ASCT 47 and 44%, respectively, without significant differences. A prognostic factor was the International Prognostic Index (IPI) at the start of salvage therapy. Three-year OS and PFS in low-risk patients were 69 and 69%, in low-intermediate-risk 63 and 53%, and in high-intermediate-risk 23 and 23%, respectively (p = 0.033). Twenty-three patients achieved a sustained complete remission (13–146 months, median 62). Sustained long-term remissions can be achieved in patients with early relapse of DLBCL following ASCT in a second or third treatment line, particularly in patients with low- and low-intermediate-risk IPI, following radiotherapy of residual disease after ASCT. Further investigations are required to clarify which patients need an alternative therapy (potentially CAR T‑cells or allogeneic transplantation).

Pathogen reduction (PR) technologies for blood components have been established to reduce the residual risk of known and emerging infectious agents. THERAFLEX UVPlatelets, a novel UVC light-based PR technology for platelet concentrates, works without photoactive substances. This randomized, controlled, double-blind, multicenter, noninferiority trial was designed to compare the efficacy and safety of UVC-treated platelets to that of untreated platelets in thrombocytopenic patients with hematologic-oncologic diseases. Primary objective was to determine non-inferiority of UVC-treated platelets, assessed by the 1-hour corrected count increment (CCI) in up to eight per-protocol platelet transfusion episodes. Analysis of the 171 eligible patients showed that the defined non-inferiority margin of 30% of UVC-treated platelets was narrowly missed as the mean differences in 1-hour CCI between standard platelets versus UVC-treated platelets for intention-to-treat and perprotocol analyses were 18.2% (95% confidence interval [CI]: 6.4%; 30.1) and 18.7% (95% CI: 6.3%; 31.1%), respectively. In comparison to the control, the UVC group had a 19.2% lower mean 24-hour CCI and was treated with an about 25% higher number of platelet units, but the average number of days to next platelet transfusion did not differ significantly between both treatment groups. The frequency of low-grade adverse events was slightly higher in the UVC group and the frequencies of refractoriness to platelet transfusion, platelet alloimmunization, severe bleeding events, and red blood cell transfusions were comparable between groups. Our study suggests that transfusion of pathogen-reduced platelets produced with the UVC technology is safe but non-inferiority was not demonstrated. (The German Clinical Trials Register number: DRKS00011156).

Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts

Introduction: A common genetic variant within the TCRA-TCRD locus has been recently identified as a predictive factor of thymic function and T cell repertoire diversity (Clave et al., 2018). Specifically it was shown in a mouse model that transplantation of rs2204985 AA human hematopoietic stem cells (HSC) into immunodeficient mice led to lower thymocyte counts and poorer TCR diversity. T cell mediated pathways are known to play a significant role in immunological processes affecting HSCT outcome like GvL, GvH and infection. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient's outcome after unrelated HSCT. Methods: The study included 2,016 adult patients with hematologic malignancies who received their first unrelated (10/10 or 9/10 HLA matched) graft between 2000 and 2013 in a German transplant center. Patients with refractory disease at time of transplantation were excluded from the analysis. Both donors and patients were retrospectively genotyped for the TCRA-TCRD rs2204985 polymorphism by next generation sequencing using a validated protocol on an Illumina Miseq platform. Overall survival (OS), disease free survival (DFS), relapse (RI), non-relapse mortality (NRM), acute GvHD (aGvHD) and chronic GvHD (cGvHD) were evaluated; p Results: The rs2204985 genotype frequencies found in both patients and donors were in line with those previously reported for Caucasian populations indicating a codominance of the two alleles (i.e. A and G). Regarding the impact of this genetic variation on outcome, multivariate analysis of the combined cohort indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations, therefore subanalysis on account of HLA incompatibility was performed. Analysis in the subgroup of single HLA mismatched cases (n=624) revealed that donor AA genotype associated with markedly inferior OS (55.1% vs 70.6%, p=0.004, Fig. 1) and DFS (47.6% vs 63.4%, p=0.002, Fig. 2) one year after HSCT as compared to the donor AG/GG genotypes. These results were confirmed in the corresponding multivariate models (OS HR: 1.48, p=0.003; DFS HR: 1.50, p=0.001) which are visually displayed as forest plots in Fig. 3 and Fig 4, respectively. The adverse effect of donor AA genotype on survival appears to be driven by a combined higher risk of RI (1Y after HSCT: 29.3% vs 18.3%, p=0.048; HR: 1.38, p=0.035) and NRM (1Y after HSCT: 28.6% vs 19.9%, p=0.043; HR: 1.38, p=0.042) as shown by both the univariate and multivariate analyses for the two respective endpoints. No association was found between donor rs2204985 genotype and risk of acute or chronic GvHD. The donor rs2204985 genotype had also no significant impact on any outcome endpoint in the 10/10 HLA matched subgroup. Last, no significant interactions were observed between this variable and the other adjusted covariates in the multivariate models. Conclusion: To our knowledge this is the first study to date investigating the potential effect of donor's genotype regarding a common genetic variant within the TCRA-TCRD locus on the outcome of patients receiving unrelated HSC grafts. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely affect the outcome of HSC transplanted patients and should therefore be avoided. It is of note that one in four unrelated donors of Caucasian origin is expected to carry the AA genotype. A weaker relapse and -presumably- infection control, especially in the early post-transplantation period, due to compromised T cell reconstitution as a result of the unfavorable donor AA genotype may account for these findings. Confirmatory studies in larger independent cohorts are warranted before final conclusions are drawn. Figure 1 Figure 1. Disclosures Platzbecker: Geron: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria. Sala: Celgene/BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Kroeger: Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Gilead/Kite: Honoraria; AOP Pharma: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Hertenstein: Novartis: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; BMS: Honoraria. Schrezenmeier: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria; Novartis: Honoraria; Apellis: Honoraria; Sanofi: Honoraria.

Currently, sunitinib is a standard of care in first-line treatment for metastatic renal cell carcinoma (mRCC). However, with the standard 4/2 schedule (sunitinib 50 mg/day; 4 consecutive weeks on treatment; 2 weeks' rest), 50% of patients require dose reductions to mitigate toxicity, highlighting the need to investigate alternative dosing schedules that improve tolerability without compromising efficacy. Areas covered: We present a concise critical review of published studies comparing the efficacy and safety of the 4/2 and 2/1 schedule (2 weeks on treatment; 1 week rest) for sunitinib. While all studies evaluating the 2/1 schedule have a low level of evidence, the results indicate that the 2/1 schedule improves tolerability compared with the 4/2 schedule, including significant reductions in the incidence of specific adverse events. It was not possible to make any definitive conclusions regarding efficacy due to methodologic limitations of these studies. Expert commentary: In the absence of strong evidence supporting the safety and efficacy of the 2/1 schedule, we recommend that patients should be initiated on sunitinib therapy with the standard 4/2 schedule and only be switched to the 2/1 schedule after the development of dose-limiting toxicities from weeks 3-4 (cycle 1) of the 4/2 schedule cycle.

Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting.AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors.Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments.In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.

705 Background: Using sunitinib (SUN) as the comparator, two out of three recent phase III clinical trials have shown an overall survival (OS) benefit in the alternative treatment arm (Checkmate 214 (C), Keynote 426 (K)). The Javelin 101(J) trial has yet to show a significant improvement. Methods: A cross-study comparison of OS for the sunitinib arms of C, K and J was carried out. Special focus was given to risk group stratification and subsequent therapies. Data from the SUN pivotal trial (SP) was also taken into account. Results: Across the C, K and SP trials, OS was similar at approximately 78%. Despite a lower percentage of favourable risk patients compared to K and SP, an OS of 82% was observed in J. At 18 months, OS survival curves split ranging from 65% ©, 72.1% (K) to 76% (J). OS in the SUN arm in J at 18 months was comparable to OS of Nivolumab/Ipilimumab in C (78%). The rate of subsequent therapies ranged from 34.3% (K), 39.2% (J) to 54% (C) in the SUN arms. At the time of the SP trial almost no subsequent therapy options existed. In the experimental arms, the rate of subsequent therapies was 51.8% ©, 20.5% (K) and 20.8% (J). The existing data give no clear evidence of a correlation between subsequent therapies and OS. However, an analysis of the subsequent therapies/patients discontinuing therapy ratio (ST/DIS) and type of subsequent therapy (PD1/L1 directed or therapy with proven OS benefit (pOS) in randomized trials) in the SUN arms may be more conclusive (see table). The rate of subsequent therapies (ST/DIS) as well as PD(L)1 or pOS therapies were highest in J, followed by K and C. Conclusions: Despite the difficulties of a cross trial comparison, this data should raise awareness of the influence of a more intense subsequent therapy. It points to the necessity to standardize subsequent therapies in 1st line trials if OS is a primary study aim. Given this analysis, it may be pertinent to ask if an optimal or near optimal subsequent therapy following SUN might be equal to a 1st line IO/IO therapy with regards to OS.[Table: see text]

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20–80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0–13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3–34) and 19 months (range 7–110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1–135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia, (c) presentation in chronic or blast phase, (d) rapid responses and long-term remission on low-dose imatinib, and (e) possible adverse prognostic impact of a complex karyotype.

Background Mitochondrial (mt) DNA markers have been identified as potential targets for the quantification of endogenous and allogeneic platelets (PLTs) in the blood of individuals who received transfusions. Our goal was to develop a routine polymerase chain reaction (PCR) assay for ex vivo monitoring of PLT survival in patients after transfusion. Study Design and Methods Targets were selected for real-time (RT)-PCR of mt DNA based on the frequency distribution of nucleotide polymorphisms and assay sensitivity in vitro. The assays were then evaluated with ex vivo samples to measure PLT survival and recovery of therapeutic doses of apheresis PLTs in hematooncologic patients with thrombocytopenia. Results Nucleotides in two positions (73/310 hypervariable region [HVR] 2) and three positions (295 HVR 2, 16069/16311 HVR 1) had allele frequencies of approximately 0.5 and 0.85, respectively, in a population of 960 Caucasian PLT donors. They provided targets for sensitive assays detecting at least 1 × 103 PLTs per whole blood sample with adequate reproducibility (interassay coefficient of variation

Background:Long-term clinical and molecular remissions in patients with MCL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for remission duration over 5 years. So the curability of this disease remains an open question. Patients and methods:Altogether 61 patients with MCL were treated in our institution with ASCT from 1998 to April 2019 (50 1st-line ASCT, ten 2nd-line ASCT, one 3rd-line ASCT). The data were collected retrospectively in 29 and prospectively in 32 patients who participated in two clinical trials: the 1st-line therapy trials of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Dreyling M, Blood 2005] and the European Mantle Cell Lymphoma Network [Hermine O, Lancet 2016], respectively. The diagnosis was regularly approved by the reference pathology of the GLSG (W.K.). The induction therapy before 1st-line ASCT consisted of 6 courses CHOP (n=11), mostly combined with rituximab and followed by Dexa-BEAM, and 6 alternating courses of R-CHOP and R-DHAP (n=39), respectively. For the salvage treatment patients usually received three to four courses of the DHAP protocol or the ESHAP protocol, since 2001 also combined with rituximab.Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols in remission. High-dose protocols: 1) total body irradiation with cyclophosphamide or melphalan and cytarabin (n=32) or 2) BEAM (n=29). Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible (n=4). Since 09/2016 patients received a maintenance therapy with rituximab after ASCT (every 2 months, planned for 3 years, n=14). Further details are described in an earlier publication of our first 36 patients (Metzner B, Ann Hematol 2013). Response assessment was performed by careful clinical examination and by ultrasound, chest x-ray and partly CT at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 5 years; n = 18), peripheral blood was regularly tested twice a year for minimal residual disease (MRD) by quantitative t(11;14) or allel specific IGH RQ-PCR and/or IGH-consensus PCR.Calculations were done using IBM SPSS Statistics Version 25. Data were analysed as of 01 July 2019. Results:With a median follow-up of 5 years (range 0.1-20) 10-year overall survival, progression-free survival (PFS) and freedom from progression (FFP) after 1st-line ASCT were 54%, 46% and 52%, respectively, after 2nd-line ASCT 42%, 20%and 20%, with a significant difference for PFS (p=0.045) and FFP (p=0.014) between 1st-line and 2nd-line cohort.Further prognostic factors (like sex, age, MIPI, bone marrow involvement, remission grade at ASCT: CR vs. PR, type of HDT: TBI vs. BEAM…) seemed to be without relevance (considering the small subgroups). Only one clinical relapse occurred after 5 years following ASCT in 1stor 2ndremission, respectively (one patient 6 years after 1st-line ASCT and another patient 7 years after 2nd-line ASCT and subsequent radiotherapy). So far, 18 patients experienced long-term remissions of at least 5 years (median 9 years, from 5 to 16 years). Fifteen of 17 tested patients were MRD negative at last follow-up, the two MRD positive patients (positive at a low level below the quantitative measuring range) had no clinical signs of relapse at last follow-up. None of these 18 patients had received rituximab maintenance therapy. None showed clinical criteria of "smoldering mantle cell lymphoma" at induction therapy. Treatment-related mortality at 100 days after ASCT was 1.6% (pneumonitis following TBI). One patient developed a secondary invasive malignancy in remission after ASCT (acute myeloid leukemia 4 years following TBI). Conclusion: Sustained long-term clinical and molecular remissions up to 16 years can be achieved following ASCT (without rituximab maintenance therapy), indicating the potential curative impact of 1st-line ASCT in MCL. The 2nd-line ASCT was obviously less effective. Disclosures Dreyling: Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Acerta: Other: scientific advisory board; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.

Background Allogeneic hematopoietic stem cell transplantation (HCT) remains a challenge in elderly and comorbid AML and MDS patients. This patient population is at increased risk for non-relapse mortality (NRM) when treated with standard myeloablative conditioning and was selected to compare a newly developed treosulfan-based with a well-established reduced intensity busulfan-based preparative regimen in a prospective randomized clinical phase III trial. Methods Adult patients with AML in remission or MDS scheduled for HCT from matched related or unrelated donors, aged ≥50 years or with a comorbidity index (HCT-CI) of >2 were enrolled by a central stratified randomization procedure. Treatment arms consisted of intravenous (IV) treosulfan (10 g/m²/day [d-4 to d-2]) or IV busulfan (3.2 mg/kg/day [d-4 to d-3]), both combined with IV fludarabine (30 mg/m²/day [d-6 to d-2]). The primary objective was to compare event-free survival (EFS) at two years with relapse/progression of disease, graft failure, or death reported as events. Secondary endpoints were safety evaluation (according to CTCAE v4.03), engraftment, chimerism, overall survival (OS), relapse/progression incidence (RI), NRM and acute or chronic GvHD. After a previously conducted confirmatory interim analysis (based on 476 patients), which resulted in early termination of patient accrual due to significant non-inferiority of treosulfan treatment with improved EFS, NRM and OS (Beelen et al., ASH 2017), results of the final analysis of all 570 randomized patients including post surveillance data are provided here. Results Median age of the 551 patients (352 AML; 199 MDS) included in the full analysis set (268 treosulfan; 283 busulfan) was 60 years (range: 31, 70). Frequencies of early adverse events (d-6 to d+28) and incidences of acute and chronic GvHD were largely comparable between the two regimens, while extensive chronic GvHD was numerically in favor of treosulfan (19.7% vs. 26.7%; p=0.0750). Primary neutrophil recovery at day +28 was comparable, while the rate of complete donor-type chimerism (day +28) was higher after treosulfan (93.2% vs. 83.3%; p Conclusions Final evaluation of this phase III trial substantiates the previous confirmatory analysis resulting in significantly improved survival after treosulfan-based conditioning. Due to the reduction of NRM a major clinical benefit of the new treosulfan conditioning regimen was demonstrated in the selected AML/MDS patient population.

Since the outcome of relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (>1 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (P

Long-term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Thirty-six patients with MCL received ASCT in our institution (27 patients undergoing first-line therapy, 8 patients undergoing second-line therapy, and 1 patient undergoing third-line therapy). In the case of long-term remission (≥5 years; n = 8), peripheral blood was tested for minimal residual disease (MRD) by t(11; 14) polymerase chain reaction (PCR) and immunoglobulin heavy-chain (IGH) PCR at the last follow-up. Ten-year overall survival (OS), progression-free survival (PFS), and freedom from progression (FFP) after first-line ASCT were 42 %, 43 %, and 54 %; after second-line ASCT, these were all 0 %. Four-year OS, PFS, and FFP for the first-line cohort were 75 %, 48 %, and 61 %, respectively. Four-year OS, PFS, and FFP after second-line ASCT were 55 %, 30 %, and 30 %, respectively. Treatment-related mortality (3 months after ASCT) was 0 %. The only prognostic factor for OS, PFS, and FFP was treatment line (p = 0.011, p = 0.046, and p = 0.023, respectively). No relapses occurred after 5 years following ASCT. So far, eight patients developed sustained long-term clinical and molecular complete remissions of up to 14.6 years following ASCT in the first treatment line. Sustained long-term clinical and molecular remissions can be achieved following ASCT in the first treatment line and apparently less frequent in the second treatment line.

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% [n = 127]; 9/10, 22.3% [n = 142]; 8/10, 38.2% [n = 60]; MICA-129 mismatched 10/10, 3.9% [n = 54]; 9/10, 10.2% [n = 65]; 8/10, 17.2% [n = 27]). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio [HR], 1.77; confidence interval [CI], 1.22-2.57; P = .003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P = .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup.

Single-dose pegylated filgrastim (pegfilgrastim) after autologous hematopoietic stem cell transplantation (AHSCT) showed similar efficacy compared to daily lenograstim. To address the question of the optimal application time, we randomly assigned patients (pts) to pegfilgrastim on day + 1 (Peg1) or day + 4 (Peg4) after AHSCT.Fifty-three pts with different hematological malignancies were included in this prospective randomized multicenter study. Primary endpoint of this study was time to neutrophil recovery (500 Gpt/l), and secondary endpoint was time to neutrophil recovery (1,000 Gpt/l), platelet recovery (20,000 Gpt/l), number and duration of febrile episodes, i.v. antibiotics, and number of transfusions. Time to engraftment endpoints were estimated according to Kaplan-Meier.Median time to neutrophil recovery (500 Gpt/l) was 10 days (95% CI: 10-11) in Peg1 versus 10 days (95% CI: 10-11) in Peg4 (P = 0.68, logrank test; hazard ratio: 0.93). The corresponding mean values were 10.2 and 10.4 days. Median time to platelet recovery (20,000 Gpt/l) was 10 (95% CI: 10-11) in Peg1 versus 10 (95% CI: 9-11) in Peg4, again not significantly different (P = 0.54). There was no difference regarding the incidence (67% vs. 60%, P = 0.77, Fisher's exact test) or duration of febrile neutropenia episodes in both groups (median: 1 vs. 1; mean: 2.8 vs. 2.4 days; P = 0.73, Wilcoxon test).In terms of neutrophil or platelet recovery after AHSCT, number and duration of febrile episodes, the use of i.v. antibiotics, early and late administration of pegfilgrastim are equally effective.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis, with noncodified therapeutic management and high mortality. No treatment has yet been shown to improve survival in these patients. We conducted a multicenter prospective observational cohort study to assess whether extraskeletal manifestations and interferon-α treatment would influence survival in a large cohort of ECD patients. To achieve this goal, we thoroughly analyzed the clinical presentation of 53 patients with biopsy-proven ECD, and we performed a survival analysis using Cox proportional hazard model. Fifty-three patients (39 men and 14 women) with biopsy-proven ECD were followed up between November 1981 and November 2010. Forty-six patients (87%) received interferon-α and/or PEGylated interferon-α. Multivariate survival analysis using Cox proportional hazard model revealed that central nervous system involvement was an independent predictor of death (hazard ratio = 2.51; 95% confidence interval, 1.28-5.52; P = .006) in our cohort. Conversely, treatment with interferon-α was identified as an independent predictor of survival (hazard ratio = 0.32; 95% confidence interval, 0.14-0.70; P = .006). Although definitive confirmation would require a randomized controlled trial, these results suggest that interferon-α improves survival in ECD patients. This may be seen as a significant advance, as it is the first time a treatment is shown to improve survival in this multisystemic disease with high mortality.

Background: The combination of treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS. Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%). Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV. Conclusion: The combination of cytarabine with the established conditioning of treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning. Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. Disclosures Hilgendorf: Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding.

Myelodysplastic syndromes (MDSs) often occur in older adults with significant comorbidities. Therefore, a reduced-toxicity conditioning regimen may be more suitable than standard conditioning regimens before allogeneic blood stem cell transplantation. Here, we retrospectively compare the outcome of a treosulfan-based conditioning regimen with standard myeloablative TBI-based conditioning regimens in patients (pts) with MDS. A total of 48 pts with MDS were included in the study, of which 29 (60%) pts received TBI-based and 19 (40%) pts received a treosulfan-based conditioning regimen. A significantly lower relapse incidence (5% vs 34% at 3 years, P=0.019) resulting in a better, but not statistically significant relapse-free survival (RFS) (57% vs 31%, P=0.086) was observed after treosulfan-based conditioning. In pts with increased risk for significant side effects due to comorbidities (haematopoietic stem cell transplantation specific comorbidity index), the estimated 3-year RFS was significantly better in the treosulfan group: 54% (95% confidence interval (CI), 17-90%) compared with pts in the TBI group: 11% (95% CI, 0-44%; log-rank test P=0.0455). Treosulfan-based conditioning therapy is a feasible and effective regimen for pts with MDS, especially in pts with preexisting comorbidities.

608 Background: Approximately 15% of nephrectomised patients who are diagnosed with loco-regional renal cell carcinoma (RCC) are considered to be at high risk of recurrence according to the postoperative UCLA Integrated Staging System (UISS) and 60% of these patients are expected to recur within five years of diagnosis. This study aimed to develop a conversation aid tool to improve knowledge about RCC for post-nephrectomy RCC patients who are at high-risk of recurrence. Specifically, to enable patients to make an informed decision about whether to proceed/not proceed with adjuvant therapy, should adjuvant therapy become standard-of-care in the future. Methods: A review of existing evidence relating to the development of conversation aid tools and previously developed tools was undertaken. Following the review, a focus group with a steering committee (RCC patients, caregivers and a clinician), and semi-structured interviews were conducted with clinicians to identify information currently provided as standard of care. Additional interviews were conducted with post-nephrectomy patients, to identify information patients would prefer to have been given post-nephrectomy. Results: The evidence review of 10 articles provided a framework for the development of a tool to enable better patient/clinician communication. Clinicians described a typical post-nephrectomy consultation and highlighted key topics of discussion, which included recovery, risk of relapse and ongoing care. The research highlighted that patients are expected to absorb a significant amount of information during consultations in order to take an active role in their care. Findings from the focus group and clinician/patient interviews led to the development of a conversation aid tool providing patients with key questions to ask their clinicians to increase knowledge of RCC post-nephrectomy and also the information they may require when considering adjuvant therapy, including: prognosis, risk of relapse, and the risk/benefit profile of available treatment options. Conclusions: The conversation aid tool may be useful for patients to improve knowledge of RCC and help make informed decisions about their future treatment and care.

589 Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) is continuously evolving, with several new first-line (1L) and second-line (2L) treatment options. In the AXIS trial, axitinib resulted in significantly longer progression-free survival (PFS) vs sorafenib in the 2L treatment of mRCC. In these post-hoc exploratory analyses of AXIS, possible key drivers for successful 2L treatment with axitinib after sunitinib were evaluated. Methods: AXIS was an open-label, randomized, phase III trial (NCT00678392) in patients (pts) with mRCC who failed 1 prior systemic therapy. Univariate and multivariate analyses evaluated potential predictive factors for improved PFS (investigator-assessed) and overall survival (OS) with axitinib. PFS (independent review), OS and objective response rate (ORR) for axitinib vs sorafenib according to these predictive factors were assessed. Results: In all, 389 pts received 1L sunitinib: 194 and 195 pts received 2L axitinib and sorafenib, respectively. Based on multivariate analyses of PFS and OS, predictive factors favoring 2L axitinib treatment were identified as: non-bulky disease (sum of the longest diameter < 98 mm), favorable/intermediate (Fav/Int) risk (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), no bone and no liver metastases. Thus, pts were grouped according to these factors. In pts with favorable risk factors (n = 86), a significantly longer median (95% confidence interval [CI]) PFS was observed in axitinib (n = 39; 13.9 [7.8–17.7] mo) vs sorafenib pts (n = 47; 4.7 [3.5–6.7] mo; hazard ratio [HR] 0.476 [95% CI 0.263–0.863]; P= 0.0126). Median (95% CI) OS (32.4 [23.8–not evaluable] mo vs 35.0 [23.9–35.0] mo; HR 0.902 [95% CI 0.457–1.780]; P= 0.7661) and ORR (both 12.8%) were similar between the 2 groups. More pts had stable disease ≥20 weeks with axitinib (38.5%) vs sorafenib (21.3%). Conclusions: In the continuously changing treatment landscape for mRCC, axitinib remains a suitable 2L treatment option, particularly in pts with non-bulky disease, Fav/Int risk and no bone nor liver metastases, characterized by an impressive PFS. Clinical trial information: NCT00678392.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long-term efficacy in chronic myeloid leukaemia (CML), although high non-relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 x 14 g/m(2) and fludarabine 5 x 30 mg/m(2), in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92.5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non-haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2.5%). The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 22.5% and extensive chronic GVHD, 14%. The 2-year probability of overall survival, leukaemia-free survival and NRM was 85%, 82.5% and 15% respectively. At 1 year post-transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low-toxicity regimen with high anti-leukaemic potential that seems feasible in CML patients referred for alloHSCT.

In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II-IV acute and chronic graft-versus-host disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60-1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.

BACKGROUND AND OBJECTIVE Allogeneic transplantation can not be offered to many patients due to potential side-effects of conventional conditioning. Dose-reduced conditioning approaches improve tolerability, however, treatment efficacy may be reduced as well. We have, therefore, developed a dose intense but toxicity reduced conditioning regimen based on treosulfan and fludarabine and report first results. PATIENTS AND METHODS 65 patients with a median age of 50 years were transplanted from related (n = 21) or unrelated donors (n = 44) after conditioning with treosulfan (3 x 10, 3 x 12 or 3 x 14 g/m(2) i. v.) and fludarabine (5 x 30 mg/m(2) i. v.). 21 patients were in complete remission (CR) and 44 patients had not reached a CR at the time of transplantation. 59 of 65 patients were considered unfit for a conventional conditioning regimen. RESULTS The actuarial overall survival after 3 years is 59.2 %, the event-free survival 40.1 %. Patients with a related donor or transplantation in CR had a better overall (85.4 resp. 74.2 %) and event-free survival (52.2 % resp. 61.9 %). The cumulative incidence of relapse at 3 years was 26.2 %. Non-relapse mortality at day 100 is 17.4 % (cumulative incidence). In stepwise Cox regression analyses for overall survival, event-free survival and non-relapse mortality the covariables transplantation in CR vs. not in CR and the donor status were shown to be influential. CONCLUSIONS These results with a conditioning therapy of treosulfan and fludarabine indicate that patients despite higher age, concomitant disease or after intensive pretreatment can be successfully transplanted without increased treatment-related mortality.

Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 x 12 or 3 x 14 g/m2) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progression-free survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications.

New conditioning regimens are being explored to reduce toxicity and enable allogeneic bone marrow transplantation in patients not eligible for conventional transplantation. We have investigated treosulfan, an alkylating agent, with the aim of developing an efficient and reliable but less-toxic conditioning regimen. A series of 30 patients who were not eligible for standard conditioning therapy received transplants from HLA-matched related (n = 14) or unrelated (n = 16) donors after administration of treosulfan 10 g/m2 intravenously daily for 3 days and fludarabine 30 mg/m2 intravenously daily for 5 days. Patients receiving grafts from unrelated donors also were given rabbit antithymocyte globulin 10 mg/kg intravenously daily for 3 days. All patients achieved prompt neutrophil and platelet recovery. Extramedullary toxicity was generally mild with Common Toxicity Criteria (CTC) grade 3 or 4 attributable to the conditioning seen only with transaminases. Complete donor chimerism was achieved by 90% of the patients. Acute graft-versus-host disease (GVHD) grade III or IV developed in 14% of the patients and chronic GVHD in 39%. An estimated overall survival rate of 73% and an event-free survival rate of 49% have been reached after a median of 22 months (range, 7.4-33.4 months). In summary, the combination of treosulfan and fludarabine is a safe and efficient conditioning regimen.

The graft vs. leukemia (GVL) effect is one of the most important factors of anti-tumor activity after allogeneic hematopoetic stem cell transplants (alloSCT). Its effectiveness depends mainly on the tumor biology as well as the tumor burden. Patients with a high tumor burden may not respond to GVL-effect despite otherwise sensitive biology. Campath-1H is known as an effective treatment of chronic lymphocytic leukemia (CLL). Due to its ability to induce profound immunosuppression, it has also been used as part of conditioning regimens before alloSCT. We report a patient, who received campath-1H in combination with docetaxel for treatment of chemotherapy and donor lymphocyte infusion resistant CLL after alloSCT, who developed shortly after discontinuation of treatment with campath-1H severe eosinophilia of the peripheral blood and typical clinical as well as histological signs of cutaneous chronic graft vs. host disease followed by complete clearance of CLL. The clinical course demonstrates the impact of the tumor burden on the GVL-effect, as well as the effectiveness of campath-1H in the presence chemo-resistance in a patient with CLL. Furthermore, the GVL effect was not abrogated by the use of campath-1H.

We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.

The aim of this study was to identify treatment strategies and therapeutic or clinical factors that predict for response to salvage therapy and survival in patients with metastatic ‘Indiana advanced’ or International Germ-Cell Cancer Collaborative Group (IGCCCG) poor prognosis’ germ cell cancer (GCT) failing first-line sequential high-dose chemotherapy plus autologous stem cell support (HD-CT). A total of 58 ‘poor prognosis’ patients who had relapsed after HD-CT were identified within two large prospective German first-line HD-CT trials ( n =286) performed between March 1993 and March 2001. Salvage treatment consisted of the following: cisplatin-based conventional dose CTx±resection (19/58; 33%), non-cisplatin based CTx (16/58; 28%) or salvage HD-CT (14/58; 24%)±resection; resection ( n =3) and/or radiation ( n =5) only: 7 patients (12%); no specific therapy: 2 patients. 21 (38%) patients responded favourably (Complete Response (CR)/Partial Response (PR) marker–negative) to salvage therapy. The use of salvage HD-CT (2-year survival 48%; P =0.03, the complete resection of residual masses (2-year survival 42%; P =0.015) as well as a favourable response to salvage therapy (2-year survival: 31%, P =0.014) were the only variables on univariate analysis associated with an improved survival. The estimated 2-year overall survival rate is 32% (95% Confidence Interval CI: 29–45%). Approximately 30% of patients relapsing after first-line HD-CT will survive>2 years, particularly those patients who can be treated with a second HD-CT +and/or surgical resection. If feasible, complete surgical resection of residual tumours appears to be the most efficient treatment.

Peripheral T-cell lymphomas (PTCL) are a rare entity of non-Hodgkin's lymphomas (NHL). Despite the poor outcome after conventional chemotherapy, the impact of high-dose chemotherapy (HDCT) and autologous or allogeneic stem cell transplantation is not well defined in these patients. In a retrospective study, we evaluated the outcome of 15 patients (9 male, 6 female) with PTCL after HDCT with autologous (10 patients) and allogeneic (5 patients) stem cell transplantation between 1996 and 2001 at our department. At the time of transplantation three patients were in second remission, seven patients were in partial remission (PR), and three patients had refractory disease. Two patients were treated with sequential HDCT (cyclophosphamide, adriamycin, vincristine, etoposide, prednisolone, m-CHOEP). The conditioning regimes were heterogeneous. After HDCT ten patients (67%, autologous 7, allogeneic 3) achieved CR, two patients (13%, autologous 2, allogeneic 0) had refractory disease, and three patients (20%, autologous 1, allogeneic 2) died because of toxic side effects before evaluation of response was performed. The median overall survival (OS) was 12 months. The 1-year probability of survival for the autologous and allogeneic groups was 58% and 40%, respectively. At the time of evaluation, six patients are alive and nine patients have died (four severe infection, one late toxicity, two disease progression, and two relapse). Despite the small number of patients in this study, HDCT with autologous or allogeneic hematopoietic transplantation seems to be an effective treatment option that can achieve CR for patients with PTCL. Because of the poor outcome of these patients after conventional chemotherapy, HDCT seems to be a rational option in first-line therapy. Whether it improves survival in these patients should be further investigated.

Anliegen der vorliegenden Untersuchung war es, die nationale Entwicklung der allogenen Stammzelltransplantation (alloSZT) und den Effekt der Etablierung lokaler Transplantationszentren zu erfassen. Dazu erfolgte eine Auswertung der Daten aller Patienten mit Wohnsitz in Mecklenburg-Vorpommern von 1991–2000 bezuglich Datum und Ort der Transplantation, Diagnose und Alter des Patienten sowie in Hinblick auf das Spenderverwandtschaftsverhaltnis. Im untersuchten Zeitraum erhohte sich die Zahl von alloSZT in Mecklenburg-Vorpommern von funf (1991) auf 30 (2000). Aufgrund des Fehlens lokaler Transplantationszentren erfolgten alloSZT von 1991–1997 ausschlieslich in Transplantationszentren auserhalb des Landes. Im Jahr 2000 wurden hingegen nur noch zwei von 30 Patienten aus Mecklenburg-Vorpommern (MV) in einem anderen Bundesland transplantiert. Gleichzeitig wurde mit der Eroffnung lokaler Transplantationszentren die Frequenz von alloSZT dem bundesdeutschen Durchschnitt angeglichen (1991: Deutschland: 4,17 Transplantationen/1 Mio. Einwohner (EW), MV: 2,67 Transplantationen/1 Mio. EW; 2000: Deutschland: 17,4 Transplantationen/1 Mio. EW, MV: 16,7 Transplantationen/1 Mio. EW). Die Daten demonstrieren zudem einen deutlichen Anstieg in der Gesamtzahl der in Deutschland durchgefuhrten allogenen Stammzelltransplantationen wahrend der letzten zehn Jahre. Dieser Anstieg ist hauptsachlich auf den vermehrten Einsatz hamatopoetischer Stammzellen nicht verwandter Spender zuruckzufuhren (1991: 0; 2000: Verwendung bei zwolf von 30 alloSZT). Ein weiterer Faktor ist der Anstieg des Altersbegrenzung zur alloSZT. Das Durchschnittsalter der Patienten erhohte sich von 32 Jahre (1991) auf 43 Jahre (2000).

The treatment of refractory or relapsed non-Hodgkin lymphoma (NHL) remains challenging. In this retrospective study, 88 patients with refractory or relapsed NHL received treosulfan and fludarabine as a reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Of the 88 intensely pre-treated patients, 73 experienced a relapse, with 18 of the 88 patients experiencing an early relapse (ER

Ten consecutive patients in our unit who had failed to mobilize a sufficient stem cell yield after either an initial or several mobilization regimens received high-dose etoposide phosphate (1500-2000 mg/m2) followed by granulocyte colony-stimulating factor (G-CSF; 10 micrograms/kg per day) to stimulate mobilization. Eight of the ten patients were apheresed. A median of 2.1 x 10(6) CD34+/kg (range 0-5.2) was collected. The number of CD34+ cells/microliter peripheral blood (pB) was significantly increased compared to the first-line mobilization [median 13.0 (range 2.68-29) versus median 4.76 (range 1.36-12); P0.05]. Besides hematotoxicity and four cases of infection (WHO grade 3), no major side effects were seen. The median duration of neutropenia was short (5 days, range 0-10), which is important in heavily pretreated patients. These results indicate that high-dose etoposide phosphate with G-CSF is safe, well tolerated, and may be effective in peripheral blood stem cell (PBSC) mobilization in patients who had previously failed to mobilize.