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Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor
Sureda, A., Chabannon, C., Masszi, T., Pohlreich, D., Scheid, C., Thieblemont, C., Wahlin, B. E., Sakellari, I., Russell, N., Janikova, A., et al
Bone marrow transplantation. 2019
Abstract
Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.
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Results from a multicenter, noninterventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor
Morris, C., Chabannon, C., Masszi, T., Russell, N., Nahi, H., Kobbe, G., Krejci, M., Auner, H. W., Pohlreich, D., Hayden, P., et al
Bone marrow transplantation. 2019
Abstract
Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of hematopoietic stem cells (HSCs) for collection and subsequent autologous hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM). This international, multicenter, noninterventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF + plerixafor (G-CSF + P) versus G-CSF-; G-CSF + P versus G-CSF + chemotherapy (G-CSF + C); and G-CSF + P + C versus G-CSF + C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF + P versus G-CSF cohorts, 129 versus 129 in the G-CSF + P versus G-CSF + C cohorts, and 117 versus 117 in the G-CSF + P + C versus G-CSF + C cohorts were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded prespecified boundaries; noninferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF + P remains an option for the mobilization of HSCs in poor mobilizers with MM with no substantial differences in PFS, OS, and CIR in comparison with other regimens.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial
Beelen, D. W., Trenschel, R., Stelljes, M., Groth, C., Masszi, T., Remenyi, P., Wagner-Drouet, E. M., Hauptrock, B., Dreger, P., Luft, T., et al
The Lancet. Haematology. 2019
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Editor's Choice
Abstract
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 <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m(2) treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0.8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m(2) intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1.3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15.4 months (IQR 8.8-23.6) for patients treated with treosulfan and 17.4 months (6.3-23.4) for those treated with busulfan. 2-year event-free survival was 64.0% (95% CI 56.0-70.9) in the treosulfan group and 50.4% (42.8-57.5) in the busulfan group (HR 0.65 [95% CI 0.47-0.90]; p<0.0001 for non-inferiority, p=0.0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING medac GmbH.
PICO Summary
Population
Patients with acute myeloid leukaemia in first or consecutive complete haematological remission or myelodysplastic syndrome considered at an increased risk for standard myeloablative preparative regimens based on age (>/=50 years), an HSCT-specific comorbidity index of more than 2, or both. (n=460)
Intervention
Intravenous 10 g/m(2) treosulfan daily for 3 days followed by intravenous fludarabine daily for 5 days (n=221)
Comparison
0.8 mg/kg busulfan at 6-h intervals on days -4 and -3, followed by 30 mg/m(2) intravenous fludarabine daily for 5 days (n=240)
Outcome
Median follow-up was 15.4 months for patients treated with treosulfan and 17.4 months for those treated with busulfan. 2-year event-free survival was 64.0% in the treosulfan group and 50.4% in the busulfan group. The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (15% patients in the treosulfan group vs 15% in the busulfan group) and gastrointestinal disorders (11% patients vs 16% patients). Serious adverse events were reported for 8% of patients in the treosulfan group and 7% of patients in the busulfan group. Causes of deaths were generally transplantation-related.
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Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Gonzalez-Barca, E., Boumendil, A., Blaise, D., Trneny, M., Masszi, T., Finel, H., Michieli, M. G., Bittenbring, J. T., Gritti, G., Snowden, J. A., et al
Bone marrow transplantation. 2019
Abstract
Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.
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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
Gagelmann, N., Eikema, D. J., Iacobelli, S., Koster, L., Nahi, H., Stoppa, A. M., Masszi, T., Caillot, D., Lenhoff, S., Udvardy, M., et al
Haematologica. 2018
Abstract
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 upfront single (n = 3391) or tandem transplantation (n = 353) between 2005 and 2014 with available data on extramedullary in-volvement 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%) while the majority of 3062 (81.8%) patients had no extramedullary disease. More patients with extramedul-lary organ involvement had multiple involved sites (≥2;) (p < 0.001). In patients with single sites compared to patients without the disease, upfront transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: p = 0.86, and extramedullary organ: p = 0.88). In single paraskeletal involvement, this translated less clearly into 3-year overall survival (p = 0.07) while single organ involvement was significantly worse (p = 0.001). Multiple organ sites were associated with worse outcome (p < 0.001 and p = 0.01). First line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (p = 0.13, respectively).
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Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: An analysis by the Acute Leukemia Working Party of the EBMT
Giebel, S., Labopin, M., Potter, M., Poire, X., Sengeloev, H., Socie, G., Huynh, A., Afanasyev, B. V., Schanz, U., Ringden, O., et al
European journal of cancer (Oxford, England : 1990). 2018;96:73-81
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs). METHODS We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014. RESULTS In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)-based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01). CONCLUSION In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL.
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Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT
Czerw, T., Labopin, M., Giebel, S., Socie, G., Volin, L., Fegueux, N., Masszi, T., Blaise, D., Chaganti, S., Cornelissen, J. J., et al
Cancer. 2018
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Editor's Choice
Abstract
BACKGROUND Mobilized peripheral blood stem cells are currently the predominant source of grafts for allogeneic transplantation (allogeneic peripheral blood stem cell transplantation [allo-PBSCT]), although, in comparison with bone marrow, their use is associated with an increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the incidence of cGVHD include the addition of anti-thymocyte globulin (ATG) to the pretransplant conditioning regimen. METHODS The goal of this retrospective study was to analyze the effect of ATG on allo-PBSCT outcomes for adults with Philadelphia-negative acute lymphoblastic leukemia (Ph-neg ALL). The primary endpoint was survival free from relapse, grade 3 to 4 acute graft-versus-host disease (aGVHD), and cGVHD (ie, graft-versus-host disease-free/relapse-free survival [GRFS]). Nine-hundred twenty-four patients who underwent unmanipulated allo-PBSCT in their first complete remission between 2007 and 2016 were included. ATG was used in 97 of the 494 transplants from matched sibling donors (20%) and in 307 of the 430 transplants from human leukocyte antigen-matched (8 of 8 loci) unrelated donors (71%). RESULTS The use of ATG was an independent factor for an improved chance of GRFS (hazard ratio [HR], 0.70; P = .0009). Furthermore, it was associated with a reduced risk of both grade 2 to 4 (HR, 0.66; P = .005) and grade 3 to 4 aGVHD (HR, 0.58; P = .03). Similarly, its addition reduced the incidence of both total (HR, 0.45; P < 10(-5) ) and extensive cGVHD (HR, 0.30; P < 10(-5) ) as well as nonrelapse mortality (HR, 0.58; P = .01). No significant effect was found with respect to leukemia-free or overall survival. However, an increased risk of relapse was noted for those who received ATG (HR, 1.40; P = .04). CONCLUSIONS Patients with Ph-neg ALL treated with allo-PBSCT benefit from the use of ATG in terms of improved GRFS. Its use may, therefore, be considered in this setting. Cancer 2018. (c) 2018 American Cancer Society.
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High dose chemotherapy and autologous stem cell transplantation in nodular lymphocyte-predominant Hodgkin lymphoma: A retrospective study by the European society for blood and marrow transplantation-lymphoma working party
Akhtar, S., Montoto, S., Boumendil, A., Finel, H., Masszi, T., Jindra, P., Nemet, D., Fuhrmann, S., Beguin, Y., Castagna, L., et al
American Journal of Hematology. 2017
Abstract
Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P=.049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant. Copyright © 2017 Wiley Periodicals, Inc.
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Early Versus Delayed Autologous Stem Cell Transplantation and Interferon Maintenance in Multiple Myeloma: Single-Center Experience of 18 Years
Remenyi, P., Varga, G., Mikala, G., Reti, M., Gopcsa, L., Batai, A., Csukly, Z., Lengyel, L., Torbagyi, E., Barta, A., et al
Transplantation Proceedings. 2016;48(1):177-84
Abstract
BACKGROUND Autologous stem cell transplantation (ASCT) has become the mainstay of 1st-line treatment in younger patients with multiple myeloma (MM), but statistical confirmation of its superiority over other therapies, especially in the era of novel agents, is still lacking. METHODS We reviewed the results of all 548 myeloma ASCTs performed in our institute over the past 18 years. RESULTS More than one-half of the patients had access to novel agents before their transplantations. Although the age of the transplanted patients increased significantly over the years, treatment-related mortality (TRM) was remarkably low, especially in 1st-line transplanted patients (100-day TRM, 0.3%). The median overall survival (OS) of the entire cohort was 98.4 months. Patients transplanted within 12 months from the start of their therapy had significantly better responses than those having delayed ASCT (complete response rate, 58.1% vs 46.8%; P = .016) and significant post-ASCT progression-free survival (PFS) benefit (30.2 [26.1-34.3] mo vs 23.3 [16.8-29.8] mo; P = .036), but we found no significant overall survival difference. The results were similar in patients treated with or without novel agents before ASCT. During a period of time, interferon maintenance was our standard approach to post-ASCT maintenance. Our analysis showed not only a significant PFS advantage with interferon, but also a highly significant overall survival benefit (150.4 [105.1-195.8] mo vs 86.1 [72.5-99.7] mo; P = .003). CONCLUSIONS Our findings demonstrate that delayed ASCT can be feasible in selected patients. Copyright © 2016 Elsevier Inc. All rights reserved.