HLA-identical haematopoietic stem cell transplantation for acute leukaemia in children: less relapse with higher biologically effective dose of TBI

Abstract

To examine relapse, survival and transplant-related complications in relationship to disease-and pre-treatment-related characteristics, we evaluated 132 children, who consecutively received an allogeneic HLA-identical SCT for acute leukaemia in our centre: ALL in first remission (n ¼ 24), ALL in second remission (n ¼ 53) and AML in first remission (n ¼ 55). The source of the stem cells was bone marrow in all but three cases. Most patients (89%) were pre-treated with cyclophosphamide and an age-related dose of TBI. Initially, GVHD prophylaxis consisted of long-course MTX only (n ¼ 24), later shortcourse MTX and CsA (n ¼ 102) was given. All patients were nursed in strictly protective isolation and received total gut decontamination to suppress their potentially pathogenic enteric microflora. The 5-year probability of overall survival was 63, 53 and 74% for ALL1, ALL2 and AML1, respectively (median follow-up: 10.6 years). The overall transplant-related mortality was 6%. The incidence of acute GVHD was 17%; 6% was grades II-IV. A higher total biologically effective TBI dose (BED) resulted in a decreased relapse frequency (P ¼ 0.034) and increased overall survival. AML patients with acute GVHD got no relapse (P ¼ 0.02); this was not the case in ALL patients. Fractionated TBI regimens with higher BED should be evaluated in prospective studies.

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

“…STBI and hyperfractionated schedules with higher biological effective dose values than 9.9 Gy administered in three fractions were associated with a lower risk of relapse, concurring with other reports. 33,34 Lung dose did not impact upon OS or relapse in multivariate analyses. Even though shielding generally limits it to 75-80% of the total dose so as to reduce the risk of interstitial pneumonia and transplant-related mortality, in some series the ensuing reduced dose to rib BM was linked to a higher incidence of relapse.…”

Impact on long-term OS of conditioning regimen in allogeneic BMT for children with AML in first CR: TBI+CY versus BU+CY: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

“…Even though fractioned TBI seems to give superior results regarding relapse and OS rates while limiting adverse effects on the other tissues comparing to single-dose TBI, the huge concerns regarding secondary malignancies and growth, hormonal and metabolic disorders still remain crucial, particularly in pediatric population with expected long-time survival. 26,28,34 Some alternative regimens have been used and reported but failed to strongly demonstrate advantage because of a too small cohort or a higher number of early relapse and regimen-related deaths. 29,32,[35][36][37] Much progress was done in the HSCT field from 1990s: improvement in HLA typing, improvement of supportive care, more available immunosuppressive drugs, improvement in laboratory cellular therapy settings, better understanding and monitoring of minimal residual disease.…”

“…Immunosuppressive effect was required to ensure engraftment. 4,27,28 Historically, combination of CY (Cy 120 mg/kg) and TBI was the most used conditioning regimen. 25,28,29 Radiation-free regimen had been proven effective for eradication of leukemia and sufficiently immunosuppressive for engraftment in HLA-matched sibling transplantation.…”

“…4,27,28 Historically, combination of CY (Cy 120 mg/kg) and TBI was the most used conditioning regimen. 25,28,29 Radiation-free regimen had been proven effective for eradication of leukemia and sufficiently immunosuppressive for engraftment in HLA-matched sibling transplantation. Because of higher incidence of treatmentrelated mortality with CY at the dose of 200 mg/kg in adult patients, it was reduced to 120 mg/kg in the 80 s. 30 However, Michel et al 5 demonstrated both the feasibility and the better efficacy of Bu-Cy200 in pediatric population.…”

Hematopoietic stem cell transplantation for childhood malignancies of myeloid origin

“…The development of acute GVHD decreased relapse risk in AML in more than one trial supporting a GVL effect, although the correlation is not quite as strong as in chronic myeloid leukemia (CML). 6,7 The timing of relapse after initial therapy was criticalsurvival was 21% after early (o1 year) and 48% after late relapse. 8 Although not prospectively studied, a retrospective registry review reported similar outcomes in young children (o18 months) following HLA-matched sibling or unrelated donor transplantation in CR1 (3-year survival 54 and 49% respectively).…”