Master Arjun (name changed), a 5-year-old boy presented with fever, fatigue, chest discomfort, weight loss & loss of appetite had consulted Dr Mahadev Swamy, a leading Hemato-Oncologist based at Goa, for further clinical examination as referred by a General Physician from a community hospital. Basic workup on blood sample revealed suspected acute leukemia, which was confirmed on Bone marrow examination. The diagnosis was further refined, by flow-cytometry findings which revealed T-cell acute lymphoblastic leukaemia (T-ALL)
That is where the couple learnt that their son was afflicted with a blood disorder called Thalassemia, that it was a hereditary disorder and that as part of treatment, he would require periodic blood transfusions. From what little they understood about the disease they hoped against hope that their young daughter would be spared. However, by the time Sumit needed regular transfusions, Tanya also was diagnosed with the same condition and thus a nightmare began for the parents of having to care for two ailing children. A couple of years later when the going became tough with frequent trips to the hospital in Jhansi for transfusion for both the kids and the mounting medical expenses, the young couple became desperate for some guidance to save their children.
Post clinical examination, his bone marrow sample was sent for genetic testing to MedGenome Labs Ltd, Bangalore to assess the gene mutations. The results showed presence of mutation in NOTCH1 gene. Based on the report, Arjun was started on BFM-2009 chemotherapy which is a standard protocol.
Post induction chemotherapy, minimal residual disease (MRD) analysis was done both by flowcytometry and next generation sequencing (NGS, for NOTCH1), to assess the efficacy of the treatment. Minimal residual disease (MRD) is a concept used to assess the residual number of cancer cells in the body after cancer treatment. In case of childhood T-cell acute lymphoblastic leukemia (T-ALL), risk stratification of an individual is mainly based on minimal residual disease (MRD) quantification. Oncogenic mutation profiles can improve the discrimination of MRD-defined risk categories.
During the second phase of testing (follow-up), the NOTCH1 gene mutation was not detected on NGS. No other clinically relevant mutations were detected in Arjun’s sample. In view of Flow cytometry-MRD showing complete remission along with absence of baseline mutation, Arjun was continued on same chemotherapy regimen and there was no need of intensification to high risk chemotherapy.
NGS based comprehensive molecular profiling at baseline and subsequent follow-up with the spectrum of mutations would help to assess the risk for relapse. Mutation profile of an individual is an independent predictor of response to chemotherapy. The NGS technology has a very high sensitivity to detect samples with mutation loads as low as even 1%. When combined with MRD analysis, it identifies a significant subgroup of patients with a low risk of relapse.
Summary
- Base line genetic testing helped in detection of clinically relevant variants in NOTCH1 gene. Based on this result the patient was started with low risk chemotherapy.
- Post induction chemotherapy, mutation in NOTCH1 gene was not detected, which nullified the need for therapy intensification.
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