Comparison of Intensive Chemotherapy (CHT), Allogeneic (ALLO) or Autologous (AUTO) Stem Cell Transplantation (SCT) as Post-Remission Treatment for Children with Very High-Risk Acute Lymphoblastic Leukemia (VHR-ALL). Final Results of the PETHEMA ALL-93 Trial.
Authors: Ribera Josep-Maria , Ortega Juan-Jose , Oriol Albert , Bastida Pilar , Calvo Carlota , Perez-Hurtado Jose-María , González-Valentin Maria-Elvira , Martin-Reina Vicky , Molines Antonio , Ortega-Rivas Fernando , Queipo Maria-Pilar , Rivas Concepción , Egurbide Izaskun , Heras Inmaculada , Poderos Concepción , Martínez-Revuelta Eva , Guinea Jose-Maria , Potro Eloy del , Deben Guillermo 
Published: October 2019

Abstract
Results of therapy in children with VHR ALL are disappointing and he role of SCT is controversial. Few studies have compared ALLO or AUTO SCT with intensive chemotherapy in children with VHR-ALL.
This multicenter randomized trial compare three options of post remission therapy in children (0–18 yr) with VHR-ALL: intensive consolidation plus maintenance chemotherapy (CHT), ALLO or AUTO SCT. Inclusion criteria: one or more of the following: age 0–1 yr., WBC>300x109/L for B-lineage ALL (mature B-ALL excluded), or >100x109/L for T lineage-ALL, t(9;22) or BCR/ABL, t(4;11) or other 11q23 or MLL rearrangements, t(1;19) or slow response (>10% blast cells in BM study at day 14 of induction therapy) or resistance to other induction therapies. Treatment schedule: Induction: 5-drug (VCR, DNR, PDN, ASP, CPM); early intensification: 3 1-week cycles including HD-MTX, HD-ARAC and HD-ASP over 3 mo. Patients with an HLA-identical familiar donor were assigned to ALLO SCT and the remaining were randomized to AUTO SCT or to delayed intensification CHT (the same three cycles given in the post-remission period) followed by maintenance CHT (MP+MTX) up to 2-yr. in complete remission (CR).
Study period: 1993–2003, 119 pts, 106 evaluable (70 VHR de novo ALL, 36 with slow response to other induction therapies), 68% males, median age 8 yr. (range 3 mo-18). Early pre-B: 17 (16%), common+pre-B: 41 (39%), T: 48 (45%). Cytogenetics (81 [76%] valid cases after central review): normal: 38 (47%) t(9;22): 8 (10%), 11q23: 13 (16%), t(1;19): 2 (2%), other: 20 (25%). Response to therapy: Induction death 2 (3%), resistant disease 4 (6%) and CR 64/70 (91%) with baseline VHR features. Of 100 evaluable patients, 24 pts were assigned to ALLO SCT, 38 randomized to AUTO SCT and 38 to CHT. With a median follow-up of 6.5 yr (range 1.3-12.4), medians for DFS and OS were 2.5 yr and 3.6 yr, and 5-yr DFS and OS probabilities were 45±8% and 48±8%. Groups of ALLO, AUTO and CHT were comparable for the main clinicobiologic characteristics and the rate of response to therapy. Intention-to-treat analysis showed no differences in DFS and in OS for donor vs. no donor comparison as well as for comparison of AUTO vs. CHT in the whole series as well as wthin separate subgroups of patients (infants, patients with T-ALL, B-lineage ALL and patients with chromosomal rearrangements). The same results were observed when the analysis was performed on the basis of effectively treated pts (ALLO SCT performed in 74%, AUTO SCT in 66% and delayed intensification CHT in 74% of the pts). By multivariate analyses, slow response to induction therapy was associated with a lower CR, whereas T-cell phenotype was the only variable associated with a lower DFS and OS probabilities.
This study failed to prove that, when a family donor is available, allogeneic SCT produces a better outcome than autologous SCT or chemotherapy in children with VHR-ALL. Among children with VHR ALL slow response to therapy and T-cell phenotype are the main adverse prognostic factors