Low-dose fractionated total body irradiation (TBI) adversely affects prognosis of patients with leukemia receiving an HLA-matched allogeneic bone marrow transplant from an unrelated donor (UD-BMT)

Abstract

Summary:The optimal total body irradiation (TBI) regimen for unrelated donor bone marrow transplant (UD-BMT) is unknown.In the present study we analyze the outcomes of two different TBI regimens used in our center for patients with leukemia undergoing an UD-BMT. Between January 1994 and August 2001, 99 consecutive UD-BMT patients entered this comparative study. The conditioning regimen consisted of cyclophosphamide, 120 mg/kg followed by TBI on days ؊3, ؊2 and ؊1. Forty-six patients received TBI 12 Gy (2 Gy, twice a day) in six fractions (HF-TBI) and 53 patients received TBI 9.90 Gy (3.30 Gy per day) fractionated over 3 days (F-TBI). End-points were transplanted-related mortality (TRM), leukemia relapse rate (LRR) and overall survival (OS). At median follow-up of 22 months (58 months for HF-TBI and 17 for F-TBI, respectively), 60 patients were alive (32 in HF-TBI sub-group and 28 in F-TBI one). The actuarial 5-year TRM was 31% for HF-TBI and 41% for F-TBI (P = 0.1), whereas the 5-year LRR was 13% for HF-TBI and 31% for F-TBI (P = 0.04). The actuarial 5-year OS was 68% for patients treated with HF-TBI and 51% for those treated with F-TBI (P = 0.02). At multivariate analysis F-TBI schedule emerged as an adverse predictor for OS (P = 0.04) and LRR (P = 0.03). These data indicate that a lower total dose of TBI appears significantly less effective in leukemia eradication and associated with worse overall survival when compared with a higher dose of radiation. Allogeneic hemopoietic stem cell transplant (HSCT) is an established treatment modality for a variety of congenital and acquired disorders of the hemopoietic system. 1 Being an HLA-genotypically identical sibling (SIB-HSCT) available for less than 30% of the potential transplant candidates, the use of alternative donors has been increasingly explored; 2 nowadays, HSCT from unrelated donors (UD-BMT) has become a steady approach and many patients have achieved complete immunologic tolerance and long survival. 3,4 However, compared with SIB-HSCT, transplant from unrelated donors is associated with a high incidence of graft-versus-host disease (GVHD), morbidity and mortality. [5][6] Total body irradiation (TBI) is included in the vast majority of conditioning regimens to be used in SIB and UD-BMT, although busulfan-based conditioning regimens have been extensively reported. 7 The aims of TBI are to destroy the host marrow to allow repopulation with donor marrow cells, to achieve immunosuppression in order to prevent graft rejection and to eradicate leukemia cell population. 8 TBI is generally delivered with a fractionated or hyperfractionated regimen in an attempt to increase the therapeutic ratio between disease cell killing and normal tissue toxicity. 9 Clinical studies have confirmed the therapeutic efficacy of once-a-day or multiple daily fractionated TBI regimens with lower risk of radiation-induced toxicity compared to single dose TBI. 8,10 However, the optimal regimen of TBI with regard to total dose, number and type of fractionation remains controversial. 11...

In haematopoietic SCT for acute leukemia TBI impacts on relapse but not survival: results of a multicentre observational study

“…19 Despite these premises and the good clinical outcomes, this schedule was associated with a higher leukemia relapse rate and a worse OS than 12 Gy (six fractions in 3 days) in unrelated transplant recipients. 19 In our allogeneic HSCT recipients, multivariate analysis showed probability of relapse was higher after conditioning with 9.9 Gy than with either of the two hyperfractionated schedules. Comparing results from Genoa and the present series is, however, difficult due to differences in disease and disease stage at transplant.…”

Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

“…11,31 Lowering the TBI dose to 9.9 Gy given along with cyclophosphamide appeared to be associated with a higher relapse rate while not reducing NRM. 45,46 However, relapse rates may be dependent on not only total TBI dose but also dose rate and fractionation schema. Along these lines, evidence of an improved benefit-risk ratio is provided by a recent series of unrelated donor transplantations after conditioning with single-exposure TBI of 5.5 Gy and cyclophosphamide.…”

In vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT

“…There was a trend for the rituximab group to be younger (P ¼ 0.03), with more lymphoproliferative disorders (P ¼ 0.02), treated in more recent years (P ¼ 0.0001). Patients were treated on our standard transplant protocols; these included a conventional conditioning regimen for most patients based on cyclophosphamide and TBI 11 or on a reduced intensity conditioning based on the combination of thiotepa and cyclophosphamide. 12 Most patients received unmanipulated BM as stem cell source, 71 vs 76% in rituximab group and in controls, respectively.…”