Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies

Abstract

We evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m 2 i.v. Â 4 days and melphalan 140 mg/m 2 i.v. Â 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities. Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission. The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation.

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

“…The late effects of either TBI or Bu were different: TBI appeared to be associated with more late complications such as growth abnormalities, osteoarticular complications, cataract, secondary malignancies and cognitive issues than BU. 26,31,32 On the other hand, Bu seemed to be responsible of more early toxicity with more venoocclusive disease, hemorrhagic cystitis and interstitial pneumonia than TBI and to be responsible of more irreversible alopecia. 22,25,33 We may postulate that the availability of IV-Bu associated to dose adjustment either to body weight or to individual pharmacokinetics study improve the results for both relapse incidence and-may be-early and late toxicities.…”

“…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. However, we have to continue our efforts and research in order to improve global results, that is, disease control and both acute and late side effect.…”

Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies

“…20 Attempts to improve outcome by augmenting RIC with TBI at 900 cGy have shown that the regimen, although well tolerated in children, was too toxic in older patients and the study had to be discontinued. 21 Intensity-modulated radiation therapy has opened a new era in radiation oncology. By delivering therapy from multiple directions using segmented or modulated beamlets, one can design radiation doses to fit the unique shape of the radiation target, optimizing radiation delivery to complex volumes and regions of the body.…”

Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome

“…Sierra et al [2][3][4] have analyzed patients with primary leukemia allografted from unrelated donors in relapse (n ¼ 94) or with primary induction failure (n ¼ 14) and have compared the outcome with 66 patients grafted in remission. In multivariate analysis, cell dose and remission status had a significant impact on leukemia-free survival; for patients grafted in relapse the overall 10-year survival was 18%, but if marrow blasts were less than 30% at the time of transplant survival was close to 40%.…”