Relapse is a major concern in T-cell Acute Lymphoblastic Leukaemia (T-ALL). While frontline chemotherapy is quite successful in achieving complete remission upfront, 30 to 50% of adult patients may face relapse in the mid-term, with poor survival rates. From the biological point of view, relapsed cells bear specific mutations that confer them higher resistance to anticancer drugs and, therefore, are able to expand after the initial treatment.

The question of where these cells come from has been a constant in the cancer genetics field for a long time. There is evidence supporting the idea that chemotherapy itself may induce mutations into cancer cells and help create the conditions for relapse. However, some relapses happen early, suggesting the mutated cells could be already in the primary tumour and just got selected by the treatment. A recent study, published at the specialised journal Hemasphere by Dr. Celia González-Gil and supervised by Dr. Eulàlia Genescà, offers new data pointing to a mixed answer to that old question, with a larger than expected proportion of relapses coming from the genetic diversity of the initial tumour.

The team took advantage of two trials from the PETHEMA group and analysed 74 paired samples from 37 relapsed adult patients – one taken at diagnosis and another taken at relapse – to look whether the genetic abnormalities found in relapsed cells were already in the non-treated tumour or, on the contrary, were the consequence of new post-treatment mutational events. Samples were analysed by using the most advanced genetic technologies like genome sequencing and single cell analysis.

Results showed that the answer was far more complex, and relapse may indeed happen in many ways. On one hand, researchers identified patients with cells bearing mutations in the N/KRAS genes, right at diagnostics, that were resistant to frontline treatment like methotrexate or prednisone. These cells represent a “resistance profile”, can survive the treatment and are an already known relapse indicator.

A second profile was identified, the “relapse profile”, counting with alterations in several genes, including NT5C2. Mutations in this gene in relapse cells were linked to resistance to maintenance treatment, usually administered 6 months after diagnosis. These mutated cells were not routinely detected at diagnosis and, therefore, were first considered secondary mutational events at relapse. However, by using ultra-sensitive single cell analysis, the team could find tiny populations of these cells in samples taken at diagnosis, meaning that they could really be part of the tumour’s initial genetic diversity.

While these results might support the idea that many relapsed cells are already present at diagnostic (60% of the cases in the PETHEMA cohort), with methods’ sensitivity making the difference, researchers acknowledge that around 40% of the cases don’t fit any profile, strengthening the idea that, in fact, different relapse mechanisms exist.

Understanding relapse is paramount to better adjust the treatments in a personalised way. As researchers proved in this study, tumour diversity at diagnosis has a huge impact on relapse probability in the short to mid-term. The use of advanced methodologies in the clinical setting will allow the precise profiling of patients and choose the right treatment from the beginning.

The current research has been funded by the Spanish Association Against Cancer (AECC), ISCIII, co-funded by the European Union ERDF/ESF program and grants from the Spanish and Catalan Governments and Leukemia Stiftung. No generative AI tools have been used in this news piece.

Reference Article: González-Gil, C., Lopes, T., Morgades, M., Fuster-Tormo, F., Montesinos, P., Medina, C.R., Hermosín, L., González-Martínez, T., Queipo, M.-P., González-Campos, J., Martínez-Sánchez, P., Díaz-Beya, M., Coll, R., Maluquer, C., Zamora, L., Artola, T., Vall-Llovera, F., Tormo, M., Torrent, A., Martínez-Laperche, C., Gil-Cortés, C., Barba, P., Cervera, M., Ribera, J., Fernández-Delgado, M., Ayala, R., Cladera, A., Mateos, M.C., Vidal, M.J., Feliu, J., Torres, A., Azaceta, G., Calasanz, M.J., Bigas, A., Esteller, M., Orfao, A., Ribera, J.M. and Genescà, E. (2025), Genetic evolution and relapse-associated mutations in adult T-cell acute lymphoblastic leukemia patients treated in PETHEMA trials. HemaSphere, 9: e70148. https://doi.org/10.1002/hem3.70148