Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia from a Matched Donor versus an HLA-Identical Sibling: Is the Outcome Comparable? Results from the International BFM ALL SCT 2007 Study

Abstract

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 § 5% vs 61 § 4%; P = .287), overall survival (72 § 4% versus 68 § 4%; P = .235), cumulative incidence of relapse (24 § 4% versus 25 § 3%; P = .658) and nonrelapse mortality (10 § 3% versus 14 § 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?—A multicenter EBMT-PDWP study

“…Bu/Cy/Eto was the second most frequently used MAC. This combination was applied in the international Berlin-Frankfurt-Münster (iBFM/ BFM) clinical trials [1,40,41], particularly in infants (Interfant-99) [42,43], and elsewhere [2,[44][45][46][47]. Within the observation period of this study, the alternative alkylator, treosulfan, was increasingly used for children with malignancies; but no treosulfan-containing regimen reached a significant number of cases [48].…”

The impact of donor type on the outcome of pediatric patients with very high risk acute lymphoblastic leukemia. A study of the ALL SCT 2003 BFM-SG and 2007-BFM-International SG

“…4-year EFS and CIR were also similar in both groups. NRM was lower in the MSD-group in the BFM-2003 study but appeared similar between MSD and MD-groups in the I-BFM-2007 [ 5 , 6 ]. Because of these published results, we decided to merge MSD and MD transplanted patient sub-groups for analysis.…”

“…Nevertheless, all these studies demonstrated the need for developing new approaches in order to increase the cure rate and to decrease the relapse incidence. Our algorithm of risk-group allocation was based on a combination of both biological and clinical criteria at time of disease occurrence and MRD level at the end of induction and of consolidation courses, in first and second line therapy [ 2 , 6 , 29 ]. Obtaining a better disease control before HSCT represents the absolute challenge we have to face [ 30 , 31 ].…”

“…Different previously published papers reported the main outcome for patients transplanted from either MSD or MD within BFM ALL SCT 2003 study [ 5 ] and International-BFM ALL SCT 2007 [ 6 ], as well as for patients transplanted from alternative donor in both studies [ 7 ]. Papers from Peters et al and Balduzzi et al demonstrated the non-inferiority of transplantation from a “9 or 10 out of 10” allelic matched donor, either related or unrelated, over the transplantation from an HLA-identical sibling in terms of EFS, OS, and CIR.…”

CAR T cells vs allogeneic HSCT for poor-risk ALL

“…23,25,27,40,41 Further intensification of chemotherapy to decrease or eliminate MRD and HSCT itself are not without significant risk of morbidity and mortality. 3,22,28,42 Therefore, the possibility of durable remission without consolidative HSCT is one aim of an ongoing trial developed by the COG and Novartis. AALL1721/Cassiopeia (Clinical Trials.gov identifier: NCT03876769), a phase 2 single-arm trial of tisagenlecleucel in children and young adults with National Cancer Institute HR B-ALL and persistent MRD at EOC, is the first trial of CAR T-cell therapy in CR1.…”