High-Dose Total Body Irradiation and Myeloablative Conditioning before Allogeneic Hematopoietic Cell Transplantation: Time to Rethink?

Mohty, Mohamad; Malard, Florent; Savani, Bipin N.

doi:10.1016/j.bbmt.2014.09.010

Cited by 34 publications

(18 citation statements)

References 34 publications

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“…busulfan. 33,34 Decreased toxicity was not achieved at the expense of less antitumor efficacy. Our sequential conditioning regimen approach still exerts an antileukemic effect in patients with AML in primary treatment failure, 75% of whom achieved CR by day 30 after their transplant.…”

Section: Discussionmentioning

confidence: 99%

Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

et al. 2016

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T he prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m 2 /day) and cytosine arabinoside (1 g/m 2 /day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33-71) at 1 year and 38% (95% CI: 18-46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26-64) at 1 year and 29% (95% CI: 13-48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1-24) at 1 year and 12% (95% CI: 3-19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174. IntroductionThe prognosis of patients with acute myeloid leukemia (AML) in primary treatment failure remains very poor. Primary treatment failure or primary refractory AML is defined by failure to achieve a complete hematologic remission (CR) after one or two courses of induction chemotherapy.1,2 For these patients, the chance of achieving a CR with another standard or conventional treatment, including the use of intermediate-or high-dose cytosine arabinoside (Ara-C) alone or in combination with an ABSTRACT © Ferrata Storti Foundationanthracycline, fludarabine or gemtuzumab-ozogamicin, is 10-20% at best. The overall survival rate at 1 year is less than 20%, with a median survival of less than 6 months.3-5

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Section: Discussionmentioning

confidence: 99%

Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

et al. 2016

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“…[3][4][5][6] Among these, the impact of the conditioning intensity and TBI on aGVHD is still a matter of debate. 4,5,[7][8][9][10][11] To the best of our knowledge, the Center for International and Blood Marrow Transplant Research reported the largest study, which included over 5000 recipients who received a transplant between 1999 and 2005 to identify the risk factors for aGVHD. 5 They analyzed the impact of the type of conditioning in sibling donors and unrelated donors, and concluded that the conditioning intensity, TBI and graft source have a combined effect on the risk of aGVHD.…”

Section: Introductionmentioning

confidence: 99%

Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation

Nakasone

Fukuda²,

Kanda

et al. 2014

Bone Marrow Transplant

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The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P o 0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P o 0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P = 0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.

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“…Although NRM was higher in patients receiving Bu in univariate analysis, after adjustment for patient age, among others, there was no difference in NRM between the 2 conditioning regimens in multivariate analysis. Given TBI is a the major risk factor of longterm complications [21] and the favorable safety profile associated with the use of i.v. Bu [22], i.v.…”

Section: Discussionmentioning

confidence: 99%

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Intermediate- or High-Risk Acute Myeloid Leukemia in Complete Remission: A Study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Malard

Labopin

Stuhler

et al. 2017

Biology of Blood and Marrow Transplantation

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Post-transplant relapse is the leading cause of treatment failure in acute myeloid leukemia (AML) patients after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT). To improve their outcome, we evaluated the outcome of a sequential intermediate-intensity conditioning regimen combining fludarabine, cytosine arabinoside, amsacrine, cyclophosphamide, and either total body irradiation or busulfan (FLAMSA) in patients with intermediate or high-risk AML in first or second complete remission (CR). A total of 265 patients (median age, 55 years; range, 19 to 76) with AML who underwent allo-HSCT using a FLAMSA regimen were included. At the time of transplant, 216 (81.5%) were in CR1 and 49 (18.5%) in CR2. Cytogenetic was intermediate in 114 (43%) and poor in 42 (15.8%) patients, whereas 109 patients (41.1%) had a secondary AML. With a median follow-up of 46 months (range, 1 to 145), the Kaplan-Meier estimate of overall and leukemia-free survival at 2 years were 56.1% (95% CI, 49.7% to 62.6%) and 52.8% (95% CI, 46.4% to 59.2%), respectively. At 2 years, the cumulative incidences of relapse and nonrelapse mortality were 22.8% (95% CI, 17.6% to 28.4%) and 24.0% (95% CI, 18.8% to 29.5%), respectively. In multivariate analysis, patient age and cytogenetics were the only parameters with a significant impact on overall survival. These data suggest that the FLAMSA sequential intermediate conditioning regimen provides an efficient disease control in intermediate- and high-risk AML patients, including those in CR2 and with secondary AML.

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High-Dose Total Body Irradiation and Myeloablative Conditioning before Allogeneic Hematopoietic Cell Transplantation: Time to Rethink?

Cited by 34 publications

References 34 publications

Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Intermediate- or High-Risk Acute Myeloid Leukemia in Complete Remission: A Study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

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