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Treosulfan Compared with Reduced-Intensity Busulfan Improves Allogeneic Hematopoietic Cell Transplantation Outcomes of Older Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients: Final Analysis of a Prospective Randomized Trial
Beelen, D. W., Stelljes, M., Reményi, P., Wagner-Drouet, E. M., Dreger, P., Bethge, W., Ciceri, F., Stölzel, F., Junghanß, C., Labussiere-Wallet, H., et al
American journal of hematology. 2022
Abstract
The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant non-inferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer term follow-up are presented. Patients presenting HCT-specific comorbidity index > 2 or aged ≥ 50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m(2) IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2 to 66.1) vs 49.7% (95% CI, 43.3 to 55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49 to 0.84), P = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-months-OS rate 66.8% vs 56.3%; HR 0.64 (95% CI, 0.48 to 0.87), P = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients. This article is protected by copyright. All rights reserved.
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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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Busulfan or thiotepa based conditioning in myelofibrosis: a phase II multicenter randomized study from the GITMO group
Patriarca, F., Masciulli, A., Bacigalupo, A., Bregante, S., Pavoni, C., Finazzi, M. C., Bosi, A., Russo, D., Narni, F., Messina, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
We are reporting a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS). Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n=25), matched unrelated (n=25) or single allele mismatched unrelated (n=10). With a median follow-up of 22 months (range 1-68), the following outcomes at 2 years after HSCT in the FB vs. the FT arm were as follows: PFS 43% vs 55%, (P=.28), overall survival (OS) 54% vs. 70% (P=.17), relapse/progression 36% vs 24% (P=.24), non-relapse mortality (NRM) 21% in both arms (P=.99) and graft failure 14% vs. 10% (P=.96). A better PFS was observed in patients with intermediate-1 DIPSS score (P=.03). Neutrophil and platelet engraftment was significantly influenced by prior splenectomy [HR 2.28 (95% CI, 1.16-4.51) P=.02] and splenomegaly at transplant [HR 0.51 (95% CI, 0.27-0.94) P=.03]. In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.
PICO Summary
Population
Patients with myelofibrosis
Intervention
Fludarabine in combination with busulfan (FB) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT)
Comparison
Fludarabine in combination with thiotepa (FT), as conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT)
Outcome
At 2 years after HSCT in the FB vs. the FT arm were as follows: PFS 43% vs 55%, (P=.28), overall survival (OS) 54% vs. 70% (P=.17), relapse/progression 36% vs 24% (P=.24), non-relapse mortality (NRM) 21% in both arms (P=.99) and graft failure 14% vs. 10% (P=.96). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.
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Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas
Cortelazzo, S., Tarella, C., Gianni, A. M., Ladetto, M., Barbui, A. M., Rossi, A., Gritti, G., Corradini, P., Di Nicola, M., Patti, C., et al
Journal of Clinical Oncology. 2016;34(33):4015-4022
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Abstract
Purpose The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P < .001) and more infectious complications ( P < .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.