DISCUSSION
We report a unique case of infantile T-ALL, treated initially per COG protocol AALL0631, and complete remission was not achieved, who subsequently achieved remission following an individualized therapy based on AALL0434.
T-ALL is an aggressive disease with a slower pattern of disease response compared to B-cell ALL7. T-ALL prognosis is heavily based on MRD response after a second cycle of chemotherapy. It has been found in UK ALL trials that increased doses of asparaginase improve rates of successful treatment1. Initially the pediatric oncology group (POG) trial 9404 had found that the addition of high dose methotrexate (HD-MTX) to T-ALL treatment protocols increased survival8. However, results from COG trial AALL0434 found that HD-MTX had lower 5 year disease free survival (DFS) and overall survival (OS) when compared to Capizzi methotrexate (85.3% and 89.4% respectively versus 91.5% and 93.7%9,10). The inclusion of nelarabine resulted in significant improvement, with a 4 year DFS of 92.2% +/- 2.8% for Capizzi methotrexate with nelarabine compared to 78% +/- 3.7% for HD-MTX without nelarabine9,10. Analysis of 4year DFS for T-ALL patients who received Capizzi methotrexate with nelarabine found 92.2% +/- 2.8% compared to Capizzi methotrexate without nelarabine of 89.8% +/- 3%10. Nelarabine is cytotoxic to T-lymphoblasts through accumulation of ara-GTP which is found in high levels in T-cells, and has been found to have a 55% response rate with relapsed/refractory T-ALL1,11. This led us to choose Capizzi methotrexate and nelarabine for our patient’s individualized therapy, after which she was found to be MRD negative, allowing for progression to SCT.
Nelarabine can result in neurological toxicity, which typically occurs within the first 12 days of infusion; toxicity is cumulative with subsequent dosing12. In one study, neurological events were noted in 72% of patients with 50% occurring in children, with a median age of 10-years-old, and 85% in adults, with a median age of 48-years-old12. Most neurological symptoms were reversible and included malaise, somnolence, confusion, ataxia, muscle weakness, and peripheral neuropathy8,12. Our patient had no identifiable neurological toxicity associated with her nelarabine infusion; however, identifying neurologic toxicity in an infant is difficult, and is a clear limitation of our assessment of the patient’s tolerance of this regimen.
A diverse spectrum of genetic and epigenetic mutations of immature thymocytes comprise T-ALL, with several well documented, targetable pathways including Notch, JAK/STAT, P13K/Akt/mTOR, and MAPK1. However, how best to decipher these genetic changes to improve our understanding behind the pathogenesis of T-ALL is understudied. In addition, how to utilize this information for further treatment options remains unclear.
Foundation One identified a LMO2 overexpression, which is found in ~9% of patients with T-ALL1. LMO2 overexpression results in an effect similar to that of a T-cell receptor translocation in T-ALL, and is a common driver of T-cell malignancies, but has not previously been reported in infantile T-ALL2. Our patient also had a unique CSF3Rmutation which is associated with promotion of neutrophil differentiation through granulocyte colony-stimulation factor binding13,14. CSF3R mutation has been identified in chronic neutrophilic leukemia and atypical chronic myeloid leukemia15. There is little information available regarding this genetic mutation in T-ALL. The use of GCSF during Induction Intensification was taken into context with our patients CSF3R mutation, as this is a variant of unknown significance it was determined that keeping GCSF in her treatment did not present significant risk of changing the effect of GCSF of her neutrophils.
This case highlights the specialized management, outcome, and unique genomic findings in a rare diagnosis of infantile T-ALL. Future research should focus on reporting rare infantile T-ALL leukemia cases to help guide management and successful remissions for these patients.