Risk Stratification at Relapse:
The study adapted Children’s Oncology Group (COG) definitions for risk-stratification: LR is defined as late B-ALL marrow relapse, end-block 1 MRD <0.1% and late Isolated Extra-Medullary (IEM) relapse, end-block 1 MRD < 0.1% ; Intermediate Risk (IR) defined as late B-ALL marrow, end-block 1 MRD ≥ 0.1% and late IEM, end-block 1 MRD ≥ 0.1% and High Risk patients defined as early B-ALL marrow relapse, early IEM relapse and T-Cell All relapse irrespective of timing and site. Late IEM relapse is defined as ≥ 18 months from diagnosis, while early IEM is < 18 months from diagnosis and early marrow relapse is defined as < 36 months from diagnosis and late marrow relapse as ≥ 36 months from diagnosis.
Second Line Therapy :
Second-line therapeutic strategy was determined through study-defined risk assessment, where in patients who were established to be resistant to the standard 4-drug regimen were reinduced with CCG regimen-A that involved HD-AraC (high dose cytosine arabinoside) with fludarabine or idarubicin in six-patents, while the other six-patients with CR1 duration of 18 months re-induced with the CCG regimen B that involved 4-drug induction regimen of PVDA. Patients treated with regimen-A were consolidated with teniposide / AraC, while patients on regimen-B were treated with HD-ARAC /asparaginase. Post-consolidation maintenance therapy continued for 120 weeks utilizing non-resistant drug pairs in both the regimens in patient who were not planned to undergo Hematopoietic Stem Cell transplantation. All patients were intended to received CNS directed radiation therapy: patients with CNS involvement received cranio-spinal radiation with 2400 cGy to the brain and 1200 cGy to the spine, while patients without CNS - disease at relapse received cranial radiation alone (1800 cGy).
In five-patients, UKALR3 regimen: dexamethasone, vincristine, mitoxantrone, peg-asparaginase and intrathecal methotrexate was administered; FLAG regimen with / or without idarubicin in five-patients; REZ-BFM regimen: dexamethasone, mercaptopurine, methotrexate, AraC and asparaginase in three-patients; St. Jude Total XIII B HR protocol in three-patients; while, two-patients were treated with other salvage protocols (one with ICE and one with COG 0232) and one-patient refused therapy.
Patient stratified as HR at relapse or patients stratified as IR or LR with resistance to first-line of salvage therapy were eligible for allogeneic HSCT, if a suitable donor was available. Amongst the 13 out of the 31 patients underwent HSCT, ten patients were stratified as HR, while three patients were stratified as IR at relapse. The source of donor were fully matched HLA (human leukocyte antigen)- identical siblings for all patients and the conditioning regimen used cyclophosphamide (CY) and Total Body Irradiation (TBI), while prophylaxis for Graft-Versus-Host-Disease (GVHD) included MTX (methotrexate) and CSA (cyclosporine).