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Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678., (© 2015 by The American Society of Hematology.)

Principles: High-dose chemotherapy with subsequent autologous stem cell transplantation (ASCT) is an important treatment option in younger patients with multiple myeloma (MM). We analysed the outcome of patients treated at our institution outside the clinical trials framework and tried to identify risk factors prognostic for survival., Methods: Medical histories of the patients were screened for response, event-free survival (EFS) and overall survival (OS). Pre-transplant variables were analysed to identify possible prognostic risk factors., Results: Overall, 182 ASCT were performed in 120 patients with MM from 2002 to 2007. Treatment-related mortality (TRM) was 0.5%. Median EFS was 23.1 months (95% confidence interval [CI]: 19.4-28.4) and median OS was 49.8 months (95%CI: 43.7 - not reached) in the whole patient population. The median OS in patients who received one ASCT was 46.4 months (95%CI: 35.2 - not reached), and 63.7 months (95%CI: 48.9 - not reached) in patients who underwent double ASCT. Patients who already achieved a complete remission (CR) before ASCT had a longer EFS (p = 0.016) than patients without CR. Additionally, patients who achieved a CR after ASCT had a longer EFS (p = 0.0061) and OS (p = 0.0024) than patients without CR. ISS stage

Background: Non-HLA immunogenetic polymorphisms may influence outcome of hematopoietic stem cell transplantation (HSCT). In this study, we have determined the role of TNFa, TNFd, IL-10, IL-1, IL-1Ra, and IL-4R polymorphisms in patients transplanted with HSC of an unrelated donor., Methods: The allelic variants of four SNPs (IL-10-1082, IL-1beta-511, IL-4R-3223, IL-4R-1902) and four microsatellites (TNFa, TNFd, IL-10-1064, IL-1Ra) were determined in 131 unrelated patient/donor pairs typed for HLA-A/B/C/DR/DQ (four digits)., Results: The allelic distribution of the polymorphisms was similar to that previously reported in Caucasoid populations. Patient and donor TNFd and patient IL-10-1064 polymorphisms correlated with mortality in univariate analysis. Patients with TNFd1/d2/d3 genotypes had 3-year survival rates of 65%. A gradual decrease in survival rates was observed for patients with TNFd3/d3 genotypes (50%, p=n.s.), TNFd4 (46%, P=0.08), and TNFd5 (33%, P=0.03). A multivariate analysis of 10/10 matched patients revealed that the following patient genotypes correlated with lower survival: TNFd3/d3 (RR 4.08, P=0.026) TNFd4 (RR 3.78, P=0.032) and TNFd5 (RR 6.69, P=0.021) all compared to TNFd1/d2/d3 genotypes. Patient IL-10 (12, 14, 15) microsatellite alleles correlated with lower 3-year survival (28%) when compared to IL-10 (<12) (56%, P=0.052) and to Il-10 (13) alleles (60%, P=0.0023). In multivariate analysis this correlation remained significant only in recipients of HSCT of 10/10 HLA matched donors (RR=2.96, P=0.038)., Conclusion: The data demonstrate a significant correlation of the TNFd and IL-10-1064 microsatellite polymorphisms with mortality after unrelated HSCT. They support the hypothesis that simple genomic tests, in addition to precise HLA matching, may contribute to determine prognosis in patients undergoing unrelated HSCT.

Background: Allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease (CGD) is associated with a significant risk of transplant-related mortality. Adult age, overt infection, and residual inflammatory disease at transplant are major risk factors., Methods: Here we report the favorable outcome after bone marrow transplantation in three high-risk adult CGD patients (ages 18, 35, and 39) with severe disease-related complications (overt pneumonia, liver abscess, steroid-dependent granulomatous colitis, diabetes, restrictive lung disease, renal insufficiency, epilepsia). Bone marrow donors were human leukocyte antigen-matched related or unrelated. The conditioning regimen consisted of 2 x 4 mg/kg oral busulphan (d -3, -2), fludarabine 6 x 30 mg/qm (d -7 to -2), rabbit anti-T-cell-globulin (Fresenius) 4 x 10 mg/kg (d -4 to -1). Graft versus host disease prophylaxis consisted of cyclosporine A and mycophenolate-mofetil., Results: Mean neutrophil and platelet engraftment was observed at day +18.5 and +22.5, respectively. All infectious and inflammatory lesions resolved and restrictive lung disease improved. No signs of grade II-IV acute or chronic graft versus host disease were observed. With a follow-up of 12 to 27 months, all patients are alive and well with full donor chimerism, normalized superoxide production, and documented T- and B-cell function., Conclusion: This modified reduced intensity conditioning protocol is a promising treatment modality for high-risk adult CGD patients.

Background: Nephrotoxicity is an important side effect of amphothericin B deoxycholate (ampho B) and cyclosporine A (CsA). The combined administration of these drugs is frequent in patients with haematological diseases undergoing allogeneic stem cell transplantation., Aim: To assess the additional renal toxicity of ampho B given as a continuous infusion in addition to CsA., Methods: In a retrospective study renal function was investigated in patients receiving CsA alone or in combination with ampho B (24-hour infusion) after allogeneic stem cell transplantation between January 1998 and April 2001., Results: Of a total of 84 patients, 22 were treated with ampho B. There was a statistically significant decline in renal function in comparison to the 62 patients receiving CsA alone. However, renal insufficiency in all patients remained in a clinically acceptable range and was reversible. The residual renal dysfunction at the end of the hospitalisation was mainly due to continuing therapy with CsA., Conclusion: Amphotericin B deoxycholate in addition to CsA leads to a statistically significant but clinically tolerable worsening of renal function. Using a 24-hour infusion and strict salt repletion, amphotericin B can be administered safely as deoxycholate in bone marrow transplant patients in conjunction with CsA for proven or suspected fungal infections.

There is increasing evidence that therapy-related acute lymphoblastic leukemia (trALL) resulting from chemo- and/or radiotherapy represents a distinct entity. However, apart from KMT2A rearrangements, which have been repeatedly reported in this subgroup, the relevance of other aberrations remains controversial due to divergent study results and sparse molecular analyses. Within our ALL patient cohort, 15% (n = 19/131) met the criteria for trALL with a high proportion of Ph + and KMT2A rearrangements. On the molecular level, the most frequently observed mutation was KMT2D, followed by CDKN2A, KRAS and DNMT3A. No TP53 mutation was detected. Outcome was particularly poor in Ph + trALL compared to Ph+ de novo ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL. [ABSTRACT FROM AUTHOR]

We investigated ≥ grade 3 (CTC-AE) organ toxicities for commercial CD19 chimeric antigen receptor T cell (CAR-T cell) products in 492 patients (Axi-Cel; n = 315; Tisa-Cel; n = 177) with Large B-cell Lymphoma in the European Society for Blood and Marrow Transplantation (EBMT) CAR-T registry. The incidence of ≥ grade 3 organ toxicities during the first 100 days after CAR-T was low and the most frequent were: renal (3.0%), cardiac (2.3%), gastro-intestinal (2.3%) and hepatic (1.8%). The majority occurred within three weeks after CAR-T cell therapy. Overall survival was 83.1% [79.8-86.5; 95% CI] at 3 months and 53.5% [49-58.4; 95% CI] at one year after CAR-T. The most frequent cause of death was tumour progression (85.1%). Non-relapse mortality was 3.1% [2.3-4.1; 95% CI] at 3 months and 5.2% [4.1-6.5; 95% CI] at one year after CAR-T. The most frequent causes of non-relapse mortality were cell-therapy-related toxicities including organ toxicities (6.4% of total deaths) and infections (4.4% of total deaths). Our data demonstrates good safety in the European real-world setting. [ABSTRACT FROM AUTHOR]

Elderly patients (EP) of 60 years and above with acute lymphoblastic leukemia (ALL) have a dismal prognosis, but pediatric-inspired chemotherapy and allogeneic stem cell transplantation (allo HCT) are used reluctantly due to limited data and historical reports of high treatment-related mortality in EP. We analyzed 130 adult ALL patients treated at our center between 2009 and 2019, of which 26 were EP (range 60–76 years). Induction with pediatric-inspired protocols was feasible in 65.2% of EP and resulted in complete remission in 86.7% compared to 88.0% in younger patients (YP) of less than 60 years. Early death occurred in 6.7% of EP. Three-year overall survival (OS) for Ph − B-ALL was significantly worse for EP (n = 16) than YP (n = 64) with 30.0% vs 78.1% (p ≤ 0.001). Forty-nine patients received allo HCT including 8 EP, for which improved 3-year OS of 87.5% was observed, whereas EP without allo HCT died after a median of 9.5 months. In Ph + B-ALL, 3-year OS did not differ between EP (60.0%, n = 7) and YP (70.8%, n = 19). Non-relapse mortality and infection rate were low in EP (14.3% and 12.5%, respectively). Our data indicate that selected EP can be treated effectively and safely with pediatric regimens and might benefit from intensified therapy including allo HCT. [ABSTRACT FROM AUTHOR]

Summary: Although second allogeneic haematopoietic cell transplantation (allo‐HCT2) is a therapeutic option for patients relapsing after first HCT (allo‐HCT1), there is limited data on allo‐HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo‐HCT2 as a salvage treatment for relapse following allo‐HCT1 between the 2000 and 2017. The median age at allo‐HCT2 was 34·6 years (range: 18–74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo‐HCT2. Acute graft‐versus‐host disease (GVHD) grade II–IV and III–IV occurred in 33% and 17% of the patients, respectively. The incidence of 2‐year total and extensive chronic GVHD was 38% and 19%, respectively. The 2‐ and 5‐year cumulative incidence of non‐relapse mortality, relapse incidence, leukaemia‐free survival, overall survival and GVHD‐free, relapse‐free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo‐HCT1 to relapse, conditioning for allo‐HCT1, Karnofsky score at allo‐HCT2 and donor type for allo‐HCT2. In conclusion, outcomes of allo‐HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence. [ABSTRACT FROM AUTHOR]

Selective digestive decontamination (SDD) with the oral, non-absorbable antimicrobial substances gentamicin, vancomycin and amphotericin B was optionally used at our institution to reduce the risk of gastrointestinal tract derived infections in multiple myeloma (MM) patients undergoing high-dose chemotherapy with subsequent autologous stem cell transplantation (HDCT/ASCT). The majority of patients received sulfamethoxazole-trimethoprim as pneumocystis pneumonia prophylaxis. From 203 patients receiving their first HDCT/ASCT between 2009 and 2015, we compared retrospectively 90 patients receiving SDD to 113 patients not receiving SDD. The administration of SDD was associated with a reduction of bacterial infections after HDCT/ASCT (overall: 8% versus 24%, p =.002; gram-negative pathogens: 1% versus 11%, p =.006) and less use of systemic antibiotics (62% versus 77%, p =.022). Omission of SDD was an independent risk factor for developing neutropenic fever and bloodstream infections. SDD could be an option to reduce bacterial infections in patients undergoing HDCT/ASCT that needs to be tested in prospective trials. [ABSTRACT FROM AUTHOR]

Atypical chronic myeloid leukaemia ( aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo- HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation ( EBMT) registry who underwent allo- HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen ( HLA)-identical siblings in 64% and matched unrelated ( MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo- HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality ( NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo- HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with severe thrombocytopenia are at risk for bleeding during insertion of central venous catheters (CVCs). Although most guidelines recommend preprocedural platelet (PLT) transfusions at a threshold of less than 50 × 109/L, there is only weak evidence supporting such recommendations. STUDY DESIGN AND METHODS: The current study aimed to establish a safe PLT transfusion trigger in patients with CVC placements. We performed a retrospective single-center analysis of 604 CVC insertions in 193 patients with acute leukemia receiving intensive chemotherapy or stem cell transplantation. RESULTS: A total of 48% of the patients had a bleeding risk during CVC insertions, mostly due to thrombocytopenia. The bleeding incidence was 32% with 96% Grade 1 and 4% Grade 2 bleedings requiring prolonged local compression. There were no Grade 3 to 4 bleedings. Hemoglobin levels were similar before and 24 and 48 hours after the CVC insertion in the bleeding and nonbleeding group and there was no difference in the red blood cell (p = 0.72) and PLT transfusion requirements (p = 0.057) after CVC insertion. In multivariate analysis, only patients with PLT counts of less than 20 × 109/L were at higher risk for bleeding before (p = 0.015) and after preprocedural PLT transfusions (p = 0.006) compared to patients with PLT counts of 100 × 109/L or more. CONCLUSION: CVC placements can safely be performed in patients with PLT counts of 20 × 109/L or more without preprocedural PLT transfusions. [ABSTRACT FROM AUTHOR]

To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte-colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety-two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim ( n = 46; 50%), or daily filgrastim ( n = 46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p = 0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p = 0.024). Pegfilgrastim-treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10) versus 0.5 transfusions (range, 0-9), p = 0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim ( p = 0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin's and non-Hodgkin's lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim. Methods: We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed. Results: Fourteen (26%) patients with Hodgkin's lymphoma and 40 (74%) patients with non-Hodgkin's lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 μg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38). Conclusion: Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In contrast to human leukocyte antigen (HLA) matching, ABO-blood group incompatibility plays a minor role in the success of allogeneic hematopoietic stem cell transplantation (HSCT). Incompatible ABH histo-blood group antigens, expressed on recipient endothelial cells (EC) and donor erythroid progenitor cells, may represent targets for graft-versus-host disease (GVHD) and host-versus-graft reactions, respectively. The aims of the current study were to investigate: (1) red blood cell (RBC) engraftment and (2) EC chimerism as a potential result of replacement of recipient EC by donor bone marrow (BM)-derived EC in a patient following major ABO-incompatible (A to O) and gender-mismatched HSCT, who died at day 350 of severe acute GVHD. Methods: Blood counts and anti-A/B isoagglutinin titers were analyzed repeatedly. Heart and BM specimens were obtained at autopsy. The expression of ABH histo-blood group antigens was examined by immunhistochemistry, X/Y chromosomes were detected by chromogen in situ hybridization (CISH). Results: RBC engraftment defined as appearance of 1% reticulocytes in the peripheral blood was delayed and correlated with anti-donor isoagglutinin titers. Circulating hematopoietic cells were exclusively of donor origin demonstrating full donor hematopoietic chimerism, whereas EC in heart and BM blood vessels were exclusively of the recipient type. Conclusions: Pure red cell aplasia (PRCA) after major ABO-incompatible HSCT was caused by anti-A/B isoagglutinins produced by recipient-type plasma cells. Using ABO and gender mismatch for discrimination, heart and BM blood vessels demonstrated no evidence for EC chimerism 11 months after ABO-incompatible HSCT. These findings suggest that EC replacement and chimerism do not represent major mechanisms responsible for tolerance induction after HSCT. [ABSTRACT FROM AUTHOR]

We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater highdose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P= .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. [ABSTRACT FROM AUTHOR]