Publications by authors named "Nico Gagelmann"

17 Publications

  • Page 1 of 1

The role of novel agents for consolidation after autologous transplantation in newly diagnosed multiple myeloma: a systematic review.

Ann Hematol 2021 Feb 29;100(2):405-419. Epub 2020 Oct 29.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Despite the increasing inclusion of novel agents within the multiple myeloma (MM) treatment sequence, their role for posttransplant consolidation therapy remains unclear. We systematically reviewed studies evaluating the efficacy of novel agent consolidation. We identified 11 citations on 12 prospective comparative studies, and 5 citations were single-arm or comparative studies with preliminary results. Nine different regimens were evaluated in 5905 patients. Risk assessment yielded serious risk of bias and heterogeneity across study designs was high. Irrespective of the regimen, deepened responses after consolidation were seen and improvements were more pronounced with multi-agent consolidation. Bortezomib, thalidomide, and dexamethasone improved long-term survival versus duplet consolidation, including in patients with high-risk cytogenetics. The addition of daratumumab to triplet regimens yielded modestly improved responses with significantly increased rates of minimal residual disease negativity but survival results were limited by short follow-up. In high-risk MM, responses were not different, whereas progression-free survival appeared to be improved with consolidation therapy, challenging the association of response and overall outcome in this subgroup. Our findings highlight the necessity of longer follow-up and consistent reporting to ensure comparability of studies to enable better evidence assessment and to identify patients benefitting from consolidation therapy.
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http://dx.doi.org/10.1007/s00277-020-04316-8DOI Listing
February 2021

Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia.

Biol Blood Marrow Transplant 2020 Oct 9. Epub 2020 Oct 9.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.007DOI Listing
October 2020

Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP-EBMT.

Bone Marrow Transplant 2021 Jan 24;56(1):210-217. Epub 2020 Jul 24.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

We analyzed newly diagnosed multiple myeloma patients with del(17p) and/or t(4;14) undergoing either upfront single autologous (auto), tandem autologous (auto-auto) or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation. 623 patients underwent either auto (n = 446), auto-auto (n = 105), or auto-allo (n = 72) between 2000 and 2015. 46% of patients had t(4;14), 45% had del(17p) while 9% were reported having both abnormalities. Five-year overall survival (OS) was 51% (95% confidence interval [CI], 45-58%) for single auto, 60% (95% CI, 49-72%) for auto-auto, and 67% (95% CI, 53-80%) for auto-allo (p = 0.187). Five-year progression-free survival (PFS) was 17% (95% CI, 12-22%), 33% (95% CI, 22-43%), and 34% (95% CI, 21-38%; p = 0.048). Five-year relapse rate was 82, 63, and 56%, while non-relapse mortality was 1, 4, and 10%. In multivariable analysis, in t(4;14) with single auto as reference, auto-auto (hazard ratio [HR], 0.44; p = 0.007) and auto-allo (HR, 0.45; p = 0.018) were associated with better PFS. In terms of t(4;14) and OS, auto-auto appeared to improve outcome compared with single auto (HR, 0.49; p = 0.096). In del(17p), outcome in PFS was similar between single auto and auto-auto, while auto-allo appeared to improve PFS (HR, 0.65; p = 0.097). No significant difference in OS was identified between the groups in patients with del(17p).
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http://dx.doi.org/10.1038/s41409-020-01007-wDOI Listing
January 2021

Development of CAR-T cell therapies for multiple myeloma.

Leukemia 2020 09 22;34(9):2317-2332. Epub 2020 Jun 22.

Department of Stem Cell Transplantation with Research Department Cell and Gene Therapy University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Currently available data on chimeric antigen receptor (CAR)-T cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated multiple myeloma (MM) patients. The CAR-T field in MM is rapidly evolving with >50 currently ongoing clinical trials across all phases, different CAR-T design, or targets. Most of the CAR-T trials are performed in China and the United States, while European centers organize or participate in only a small fraction of current clinical investigations. Autologous CAR-T cell therapy against B cell maturation antigen shows the best evidence of efficacy so far but main issues remain to be addressed: duration of response, longer follow-up, prolonged cytopenia, patients who may benefit the most such as those with extramedullary disease, outcome prediction, and the integration of CAR-T cell therapy within the MM treatment paradigm. Other promising targets are, i.a.,: CD38, SLAMF7/CS1, or GPRC5D. Although no product has been approved to date, cost and production time for autologous products are expected to be the main obstacles for broad use, for which reason allogeneic CAR-T cells are currently explored. However, the inherent risk of graft-versus-host disease requires additional modification which still need to be validated. This review aims to present the current status of CAR-T cell therapy in MM with an overview on current targets, designs, and stages of CAR-T cell development. Main challenges to CAR-T cell therapy will be highlighted as well as strategies to structurally improve the CAR-T cell product, and thereby its efficacy and safety. The need for comparability of the most promising therapies will be emphasized to balance risks and benefits in an evidence-based but personalized approach to further improve outcome of patients with MM.
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http://dx.doi.org/10.1038/s41375-020-0930-xDOI Listing
September 2020

Double Counting of Patients in Meta-analyses of Observational Studies-Reply.

JAMA Oncol 2020 05;6(5):787-788

Department of Stem Cell Transplantation, Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1001/jamaoncol.2020.0173DOI Listing
May 2020

B cell maturation antigen-specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta-analysis.

Eur J Haematol 2020 Apr 20;104(4):318-327. Epub 2020 Jan 20.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in clinical studies for relapsed/refractory multiple myeloma (RRMM). We performed a systematic literature review to summarize the current body of evidence on the role of anti-BCMA CAR T cells for RRMM.

Objectives And Methods: Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included using a conventional meta-analysis. Main efficacy outcomes were response, relapse, and survival. Safety outcomes were cytokine release syndrome (CRS) and neurotoxicity.

Results: Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% confidence interval [CI], 74%-88%) and complete response of 36% (24%-50%). Higher CAR cell doses were associated with higher response rates. The pooled relapse rate of responders was 45% (27%-64%), and median progression-free survival was 10 months. Present extramedullary disease did not show worse outcome. Severe CRS grades 3-4 and neurotoxicity occurred in 15% (10%-23%) and 18% (10%-31%).

Conclusion: Anti-BCMA CAR T cells showed high response rates, even in patients with present extramedullary disease, while relapse occurred in half of the patients who achieved a response. Larger studies with longer follow-up especially evaluating the association of response and survival are needed.
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http://dx.doi.org/10.1111/ejh.13380DOI Listing
April 2020

Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide Therapy vs Other Donor Transplantations in Adults With Hematologic Cancers: A Systematic Review and Meta-analysis.

JAMA Oncol 2019 Oct 17. Epub 2019 Oct 17.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Use of haploidentical (HAPLO) stem cell transplantation with posttransplant cyclophosphamide is rapidly increasing in adults with hematologic cancers. However, its specific role compared with other transplant strategies has yet to be identified.

Objective: To synthesize the existing evidence regarding outcomes of stem cell transplantations comparing HAPLO stem cell transplantation and posttransplant cyclophosphamide therapy with transplantations from matched related donors (MRDs), matched unrelated donors (MUDs), or mismatched unrelated donors (MMUDs).

Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting abstracts were searched for the key words haploidentical and cyclophosphamide from inception through March 1, 2019.

Study Selection: Studies comparing HAPLO stem cell transplantation and posttransplant cyclophosphamide therapy with transplantations from other donors in adults with hematologic cancers were eligible for meta-analysis.

Data Extraction And Synthesis: Pooled odds ratios (ORs) and 95% CIs were calculated using a random-effects model.

Main Outcomes And Measures: Main outcomes were all-cause mortality, nonrelapse mortality, and relapse.

Results: A total of 30 studies including 22 974 participants were analyzed. HAPLO stem cell transplantation with posttransplant cyclophosphamide therapy was associated with increased all-cause mortality compared with MRDs (OR, 1.17; 95% CI, 1.05-1.30), similar all-cause mortality compared with MUDs (OR, 1.06; 95% CI, 0.96-1.18), and reduced all-cause mortality compared with MMUDs (OR, 0.75; 95% CI, 0.61-0.92). Regarding nonrelapse mortality, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with worse outcomes compared with MRDs (OR, 1.20; 95% CI, 1.04-1.40) but better outcomes compared with MUDs (OR, 0.75; 95% CI, 0.61-0.92) and MMUDs (OR, 0.51; 95% CI, 0.25-1.02). In terms of relapse, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with similar outcome compared with MRDs (OR, 1.01; 95% CI, 0.86-1.17) and MMUDs (OR, 1.06; 95% CI, 0.77-1.47) but showed increased relapse compared with MUDs (OR, 1.20; 95% CI, 1.03-1.40).

Conclusions And Relevance: Results of this meta-analysis suggest that MRDs, if available, remain the optimal donors regarding mortality and HAPLO stem cell transplantation with posttransplant cyclophosphamide may be preferred over MMUDs. Prospective comparisons with MUDs are needed.
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http://dx.doi.org/10.1001/jamaoncol.2019.3541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802371PMC
October 2019

Allogeneic stem cell transplantation in patients with myelofibrosis harboring the MPL mutation.

Eur J Haematol 2019 Dec 16;103(6):552-557. Epub 2019 Sep 16.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Primary and post-ET/PV myelofibrosis are myeloproliferative neoplasms harboring in most cases driving mutations in JAK2, CALR or MPL, and a variable number of additional mutations in other genes. Molecular analysis represents a powerful tool to guide prognosis and clinical management. Only about 10% of patients with myelofibrosis harbor alterations in MPL gene. No data are available about the transplantation outcome in the specific MPL-mutated group.

Patients: We collected the data of 18 myelofibrosis patients(primary: 14; post-ET: 4) transplanted in 4 EBMT centers (Hamburg, Paris, Essen, and Hannover) between 2005 and 2016.

Results: Before the transplant, we explored the molecular profile by NGS and reported the frequency of mutations occurring in a panel of genes including JAK2, MPL, CALR, U2AF1, SRSF2, SF3B1, ASXL1, IDH1, IDH2, CBL, DNMT3A, TET2, EZH2, TP53, IKZF1, NRAS, KRAS, FLT3, SH2B3, and RUNX1. The 1-year transplant-related mortality was 16.5%, 5-years overall survival and 5-y relapse-free survival 83.5%. The only relapse occurred in a patient who harbored mutations in both ASXL1 and EZH2 genes.

Conclusion: These retrospective data suggest that MPL-mutated myelofibrosis patients have a favorable outcome after allogeneic transplantation with very low rate of disease relapse (5.5%) in comparison with the available historical controls regarding myelofibrosis in all.
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http://dx.doi.org/10.1111/ejh.13318DOI Listing
December 2019

Tandem Autologous Stem Cell Transplantation Improves Outcomes in Newly Diagnosed Multiple Myeloma with Extramedullary Disease and High-Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2019 11 6;25(11):2134-2142. Epub 2019 Jul 6.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous-allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; P = .02 and P = .03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.004DOI Listing
November 2019

Comparison of Dynamic International Prognostic Scoring System and MYelofibrosis SECondary to PV and ET Prognostic Model for Prediction of Outcome in Polycythemia Vera and Essential Thrombocythemia Myelofibrosis after Allogeneic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 06 28;25(6):e204-e208. Epub 2019 Mar 28.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
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http://dx.doi.org/10.1016/j.bbmt.2019.03.024DOI Listing
June 2019

Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation.

Blood 2019 05 13;133(20):2233-2242. Epub 2019 Feb 13.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Allogeneic hematopoietic stem cell transplantation is curative in myelofibrosis, and current prognostic scoring systems aim to select patients for transplantation. Here, we aimed to develop a prognostic score to determine prognosis after transplantation itself, using clinical, molecular, and transplant-specific information from a total of 361 patients with myelofibrosis. Of these, 205 patients were used as a training cohort to create a clinical-molecular myelofibrosis transplant scoring system (MTSS), which was then externally validated in a cohort of 156 patients. Multivariable analysis on survival identified age at least 57 years, Karnofsky performance status lower than 90%, platelet count lower than 150 × 10/L, leukocyte count higher than 25 × 10/L before transplantation, HLA-mismatched unrelated donor, mutation, and non-/ driver mutation genotype being independent predictors of outcome. The uncorrected concordance index for the final survival model was 0.723, and bias-corrected indices were similar. Risk factors were incorporated into a 4-level MTSS: low (score, 0-2), intermediate (score, 3-4), high (score, 5), and very high (score, >5). The 5-year survival according to risk groups in the validation cohort was 83% (95% confidence interval [CI], 71%-95%), 64% (95% CI, 53%-75%), 37% (95% CI, 17%-57%), and 22% (95% CI, 4%-39%), respectively ( < .001). Increasing score was predictive of nonrelapse mortality ( < .001) and remained applicable to primary (0.718) and post-essential thrombocythemia (ET)/polycythemia vera (PV) myelofibrosis (0.701) improving prognostic ability in comparison with all currently available disease-specific systems. In conclusion, this MTSS predicts outcome of patients with primary and post-ET/PV myelofibrosis undergoing allogeneic stem cell transplantation.
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http://dx.doi.org/10.1182/blood-2018-12-890889DOI Listing
May 2019

Optimized EBMT transplant-specific risk score in myelodysplastic syndromes after allogeneic stem-cell transplantation.

Haematologica 2019 05 17;104(5):929-936. Epub 2019 Jan 17.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany

The aim of this study was to develop and validate a clinical and transplant-specific prognostic score using data from a large cohort of patients with myelodysplastic syndromes reported to the European Society for Blood and Marrow Transplantation registry. A Cox model was fitted to detect clinical and transplant-related variables prognostic of outcome. Then, cross-validation was performed to evaluate the validity and consistency of the model. Seven independent risk factors for survival were identified: age ≥50 years, matched unrelated donor, Karnofsky Performance Status <90%, very poor cytogenetics or monosomal karyotype, positive cytomegalovirus status of the recipient, blood blasts >1%, and platelet count ≤50 × 10/L prior to transplantation. Incorporating these factors into a four-level risk score yielded hazard ratios for death, with low-risk (score of 0-1) as reference, of 2.02 (95% CI: 1.41-2.90) for the intermediate-risk group (score of 2-3), 3.49 (95% CI: 2.45-4.97) for the high-risk group (score of 4-5), and 5.90 (95% CI: 4.01-8.67) for the very high-risk group (score of >5). The score was predictive of survival, relapse-free survival, relapse, and non-relapse mortality (<0.001, respectively). Cross-validation yielded significant and reproducible improvement in prognostic ability with C-statistics being 0.609 (95% CI: 0.588-0.629) 0.555 for the registry and 0.579 for the Center for Blood and Marrow Transplant Research registry. Prediction was even further augmented after applying a nomogram using age and platelets as continuous variables showing C-statistics of 0.628 (95% CI: 0.616-0.637). In conclusion, compared to existing prognostic systems, this proposed transplant-specific risk score offers improved performance with respect to post-transplant risk stratification in myelodysplastic syndromes.
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http://dx.doi.org/10.3324/haematol.2018.200808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518902PMC
May 2019

Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis.

Biol Blood Marrow Transplant 2018 10 16;24(10):2101-2109. Epub 2018 May 16.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Over the past 25 years, several randomized controlled trials have investigated the efficacy of different antiviral agents for cytomegalovirus (CMV) prophylaxis in allogeneic hematopoietic cell transplantation. We performed a systematic literature review, conventional meta-analysis, and network meta-analysis using a random-effects model and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) as effect estimates. Fifteen randomized controlled trials were identified, including 7 different antiviral agents: acyclovir, ganciclovir, maribavir, brincidofovir, letermovir, valacyclovir, and vaccine. Twelve trials used placebo as comparator while 3 trials compared different antiviral agents. We found evidence for CMV disease and infection being significantly reduced by antiviral prophylaxis, with an RR of .66 (95% CI, .48 to .90) and .63 (95% CI, .50 to .79). Across the network, ganciclovir showed the best relative efficacy for CMV disease while letermovir provided first rank of being the best option for CMV infection. The risk for death was not significantly influenced by antiviral prophylaxis in the meta-analysis, with an RR of .92 (95% CI, .78 to 1.08), as well as in the network meta-analysis. In terms of safety, letermovir was at least similar in comparison with placebo and most agents while both letermovir and acyclovir showed significantly reduced risk for serious adverse events compared with ganciclovir, with RRs of .55 (95% CI, .30 to 1.00) for letermovir and .63 (95% CI, .42 to .93) for acyclovir. With a probability of 81%, letermovir appears to be the best option in terms of safety. Future randomized head-to-head comparisons are needed to evaluate the definite efficacy and safety of different prophylactic strategies.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.017DOI Listing
October 2018

Long-Term Results of Prophylactic Donor Lymphocyte Infusions for Patients with Multiple Myeloma after Allogeneic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2018 07 21;24(7):1399-1405. Epub 2018 Apr 21.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The major reason for treatment failure after allografting in multiple myeloma (MM) is relapse. Donor lymphocyte infusions (DLIs) are considered a valuable post-transplant strategy mainly for relapsed patients but using them to prevent relapse in MM has been reported rarely. In the present study, we examined the efficacy of prophylactic DLIs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in myeloma patients with a long-term follow-up of more than 5 years. A total of 61 patients with MM who did not relapse or develop disease progression after allo-HSCT were treated with prophylactic DLI in an escalating fashion (overall 132 DLI procedures) to deepen remission status and prevent relapse. Overall response rate to DLI was 77%. Thirty-three patients (54%) upgraded their remission status, 41 patients (67%) achieved or maintained complete remission, and 26% achieved a molecular remission. Incidence of acute graft-versus-host disease (GVHD) grade II to IV was 33% and no DLI-related mortality was noted. After a median follow-up of 68.7 months from first DLI the estimated 8-year progression-free survival (PFS), and overall survival (OS) in a landmark analysis was 43% (95% confidence interval [CI], 28% to 57%) and 67% (95% CI, 53% to 82%), respectively, with best outcome for patients who acquired molecular remission (8-year PFS was 62% and 8-year OS was 83%). Prophylactic escalating DLI in a selected cohort of MM patients to prevent relapse after allograft resulted in a low incidence of severe GVHD and encouraging long-term results, especially if molecular remission is achieved.
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http://dx.doi.org/10.1016/j.bbmt.2018.04.018DOI Listing
July 2018

Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT.

Haematologica 2018 05 1;103(5):890-897. Epub 2018 Feb 1.

Department of Stem Cell Transplantation, University Medical Center Hamburg- Eppendorf, Hamburg, Germany

We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; <0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: =0.86, and extramedullary organ: =0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (=0.07) while single organ involvement was significantly worse (=0.001). Multiple organ sites were associated with worse outcome (<0.001 and =0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (=0.13 for both).
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http://dx.doi.org/10.3324/haematol.2017.178434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927971PMC
May 2018

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis.

Biol Blood Marrow Transplant 2017 Dec 30;23(12):2184-2191. Epub 2017 Aug 30.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Since 2000, various phase III randomized controlled trials (RCTs) have investigated the efficacy of rabbit antithymocyte globulin (ATG) in patients following allogeneic stem cell transplantation (allo-SCT). Comparisons of different ATG formulations are lacking, however. Our aim was to synthesize all published efficacy evidence to enable a comparison of all available formulations of rabbit ATG in the allo-SCT setting. We performed a systematic literature review to identify all available phase III RCT evidence. We searched the Cochrane Library, MEDLINE, MEDLINE In-Process, and the website www.ClinicalTrials.gov. In addition, a trial presented at the Annual Meeting of the American Society of Hematology 2016 was added to include the most recent evidence. We identified a total of 6 RCTs, including 2 formulations: anti-T lymphocyte globulin (ATLG; Grafalon, Neovii Biotech, Lexington, MA) and polyclonal globulin immunized with human thymocytes (Thymoglobulin [Thymo]; Genzyme-Sanofi, Cambridge, MA). The evidence was synthesized using a conventional network meta-analysis (NMA). The best treatment for preventing graft-versus-host disease (GVHD) was ATLG, which had a more favorable hazard ratio (HR) compared with standard treatment (chronic GVHD: HR, .42; 95% confidence interval [CI], .31 to .56; acute GVHD grade II-IV: HR, .54; 95% CI, .39 to .73; acute GVHD grade III-IV: HR, .50; 95% CI, .29 to .86), whereas both ATLG and Thymo were at least similarly effective in terms of transplantation-related mortality (TRM) (ATLG: HR, .90; 95% CI, .61 to 1.32; Thymo: HR, .90; 95% CI, .56 to 1.44). Thymo tended to be the better treatment option regarding overall survival (OS) (HR, .86; 95% CI, .59 to 1.26). Our NMA provides the first report of the relative efficacy of all available rabbit ATG formulations in patients undergoing allo-SCT. Until additional data from randomized head-to-head comparisons are available, based on the present analysis, ATLG seems to be the best option to prevent chronic and acute GVHD. Both formulations show similar efficacy in terms of TRM, whereas Thymo appears to be the better treatment option in terms of OS.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.027DOI Listing
December 2017

Infectious disease consultation for Staphylococcus aureus bacteremia - A systematic review and meta-analysis.

J Infect 2016 Jan 9;72(1):19-28. Epub 2015 Oct 9.

Paul Martini Sepsis Research Group, Department of Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Center for Clinical Studies, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. Electronic address:

Objective: Mortality and morbidity of Staphylococcus aureus bacteremia (SAB) still remains considerably high. We aimed to evaluate the impact of infectious disease consultation (IDC) on the management and outcomes of patients with SAB.

Methods: We systematically searched 3 publication databases from inception to 31st May 2015 and reference lists of identified primary studies.

Results: Our search returned 2874 reports, of which 18 fulfilled the inclusion criteria, accounting for 5337 patients. Overall 30-day mortality was 19.95% [95% CI 14.37-27.02] with a significant difference in favour of the IDC group (12.39% vs 26.07%) with a relative risk (RR) of 0.53 [95% CI 0.43-0.65]. 90-day mortality and relapse risk for SAB were also reduced significantly with RRs of 0.77 [95% CI 0.64-0.92] and 0.62 [95% CI 0.39-0.99], respectively. Both, the appropriateness of antistaphylococcal agent and treatment duration was improved by IDC (RR 1.14 [95% CI 1.08-1.20] and 1.85 [95% CI 1.39-2.46], respectively). Follow-up blood cultures and echocardiography were performed more frequently following IDC (RR 1.35 [95% CI 1.25-1.46] and 1.98 [95% CI 1.66-2.37], respectively).

Conclusions: Evidence-based clinical management enforced by IDC may improve outcome of patients with SAB. Well-designed cluster-randomized controlled trials are needed to confirm this finding from observational studies.
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http://dx.doi.org/10.1016/j.jinf.2015.09.037DOI Listing
January 2016