Successful Therapy Reduction in NCI Standard Risk (SR) Highly Favorable Subgroup of Childhood Acute Lymphoblastic Leukemia

Background: Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood; it is curable in 80-90% of patients. Current efforts focus on therapy guided by sensitive and specific methods of minimal residual disease (MRD) monitoring, tailoring the type and intensity of chemotherapeutic agents to improve cure rates, quality of life and decrease morbidity. We sought to study the outcome of low risk (LR) ALL treated per modified St Jude total XV Study.

Methods: We adopted the modified St Jude total XV study ,B-cell precursor patients with age between 1 and 10 years and presenting leukocyte count <50×10^9/L, leukemic cell DNA index ≥1.16, or TEL-AML1 fusion are classified to have low-risk ALL, provided that they do not have testicular or central-nervous-system (CNS-3) leukemia, hypodiploidy (<45 chromosomes), E2A-PBX1 fusion, or MLL rearrangement, and have a treatment response at day 15 by minimal residual disease (MRD) of <5% and at day 46 of remission-induction <0.01%. We further identified a subgroup of (LR) ALL; defined by presenting age between 2 and 6 years, leukocyte count of <10x 10^9/L and MRD of <0.01% at day 15 of remission induction as Very Low Risk ALL (VLR). Patients with St Jude Low Risk (LR) ALL were treated per St Jude total XV study with several modifications: On 2007; doxorubicin was omitted from reinduction II to lower the total cumulative dose of anthracycline to 80 mg/m2, pulses of dexamethasone and vincristine were stopped at week 72 of maintenance instead of 100. On 2012; for patients identified as VLR; pulses of vincristine /dexamethasone were stopped at week 52 and HDMTX given at week 10 and 12 of maintenance therapy was omitted, frequency of triple Intrathecal chemotherapy remained unchanged (13-18) for LR ALL based on CNS status.

Results: We reviewed 184 patients with (LR) between May 2006 to Feb 2018, (the median age at diagnosis, 7.3 years; range, 1.5-9.8). Eighty-two patients (45%) and 102 patients (55%) were treated as VLR and LR ALL respectively. The only significant difference in patients of two groups were age at diagnosis 2-6 years(VLR, 100%; LR, 46%; p<0.001), initial count <10x 10^9/L (VLR, 100%; LR, 65%; p<0.001) and MRD at day 15<0.01%(VLR, 100%; LR, 61%; p<0.001). At median follow up of (48 months; range, 17 to 157), in the subgroups of NCI standard risk defined above; as very low risk(VLR) ALL and low risk (LR) ALL, the 5-year EFS were 92%±3.4; 85%±4 (p=0.12), and the 5-year OS were 98%±1.7; 93%±3.3 (p=0.2) respectively.

Conclusion: Chemotherapy was substantially reduced safely in subgroup of children with low risk ALL who were selected on the basis of presenting age, leukocyte count and undetectable MRD levels early at day 15 and at day 46 of remission induction without jeopardizing the survival rate. Patients with St Jude LR ALL maintained outstanding outcomes despite reduction of chemotherapy.