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.