Early post-induction Augmented therapy improves outcome in children and adolescents with T-cell acute lymphoblastic leukemia

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all newly diagnosed ALL in children and adolescents and is associated with worse outcomes compared to pre-B ALL. We aimed to decrease T-ALL relapses by intensifying our regimen. Methods: Patients with T-ALL were treated using two different regimens; before September 2014, patients were treated per St. Jude Total XV protocol; subsequently, a major change was adopted by adding two intensive blocks: FLAG and Re-Intensification (fludarabine, dexamethasone, cytarabine, etoposide and asparaginase). Cranial radiation was limited to patients with WBC >=100k/µl at diagnosis and/or patients with CNS2/CNS3 status. Results: Between June 2005 and April 2020, a total of 100 patients (76 males) were treated and followed for a median of 70 months (range, 14-181 months). Median age at diagnosis was 9 years (range,0.5-17.8 years). Forty-eight patients were diagnosed after September 2014 and received the augmented regimen; their median follow up was 46 months (range,14-74 months). The 5-yr-EFS estimates for patients who received the augmented regimen vs. standard regimen were 87%±4.9% vs 67%±6.8% (p=0.03); and the 5-yr-OS estimates were 87%±5.1% vs. 71%±6.3% (p=0.06) respectively. Treatment related mortality (TRM) were reported in 2 patients treated using our standard regimen but none for patients who received the augmented regimen. Conclusions: We implemented a novel approach with early intensification added to a backbone of modified St. Jude Total-XV regimen for patients with T-ALL that resulted in improved outcome with no treatment related mortality.

Treatment-related mortality in children with acute lymphoblastic leukemia in a low-middle income country

Objective: To determine the proportion of treatment-related mortality (TRM) among mortalities of Pediatric Acute Lymphoblastic Leukemia (ALL), to identify probable causes and risk factors. Methods: An observational; retrospective, cohort study. Pediatric patients of ALL who expired during treatment were enrolled. Death due to relapse and deaths before treatment were excluded. Retrospective data was collected from ward record and analyzed in SPSS 16. Results: Total 247 patients of ALL expired while 144 patients were enrolled as per inclusion criteria. The proportion of TRM was 58.3%. Median age was 5 years. Male-to-female ratio was 1.3:1. Commonest cause of TRM was sepsis (n=126, 87.5%), followed by hemorrhagic complications (n=11, 7.6%), drug toxicity (n=4, 2.8%), tumor lysis syndrome (n=2, 1.4%) and thromboembolism (n=1, 0.7%). Significant factors associated with TRM were weight-for-age, immunophenotype, reason for admission and absolute neutrophil count. Conclusion: Treatment-related mortality though potentially avoidable is still a major cause of death among pediatric patients of ALL in low-middle income countries. Sepsis is the most common cause and infection prevention and control is vital in improving survival. Best supportive care must be made available for the patients on induction chemotherapy, with concomitant malnutrition, high-risk immunophenotype and profound neutropenia. Continuous...

Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol

Background The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70–85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. Methods The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. Results The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129). Conclusions The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - A multi-centric clinical study of GD-2008-ALL protocol

Background The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70%-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality(TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. Methods The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1,765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. Results The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2 %) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day33 positive group (n=7) was 28.6%, while in the MRD Day33 negative group (n=67) was 7.5% (p=0.129). Conclusions The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.