Researchers in Denmark have discovered that people undergoing chemotherapy have a dramatically increased risk of developing leukaemia if they have specific gene mutations.
People undergoing chemotherapy for lymphoma and other types of cancer risk a seldom but very dangerous side-effect: leukaemia.
New research shows that this specific and often deadly side-effect can be especially linked to mutations in the genes of the DNA repair pathway, which increase the risk of developing leukaemia 10-fold.
The discovery has prompted doctors at Rigshospitalet to screen people with lymphoma for mutations in the repair genes to give them the best possible treatment.
“We have set this up as a standard examination so we can determine in advance whether the patients’ stem cells in the bone marrow are good enough to withstand high-dose chemotherapy treatment or whether the treatment will increase their risk of developing leukaemia. We have examined how patients’ lungs and heart function for many years, and now stem cell analysis can now be an additional part of the preliminary examination before giving high-dose chemotherapy,” explains a researcher behind the new study, Simon Husby, MD, PhD, Department of Haematology, Rigshopitalet, Copenhagen.
The research results have been published in the international high-ranking scientific journals Leukemia and Blood.
Reviewed all lymphoma patients in Denmark for 10 years
The researchers reviewed all people with lymphoma in Denmark treated with high-dose chemotherapy from 2000 to 2012.
Doctors freeze stem cells from people undergoing high-dose chemotherapy and then transplant them back into the bone marrow after treatment ends.
Simon Husby and colleagues examined stem cells from 565 patients with lymphoma and linked this to their subsequent trajectories.
The results showed that chemotherapy was more likely to be associated with leukaemia among people with mutations in the genes of the DNA repair pathway than those without these mutations.
Roughly 10% of the patients had these mutations. Of these, at least one third developed chemotherapy-related leukaemia versus only 2–3% of the patients without the mutations.
“This result means that we can quite accurately predict who may develop the deadly side-effect of leukaemia following chemotherapy,” says Simon Husby.
Chemotherapy does not destroy the mutated cells
According to Simon Husby, the reason mutations in the genes of the DNA repair pathway are associated with an increased risk of developing chemotherapy-related leukaemia is that chemotherapy does not destroy the stem cells with these specific mutations.
The body usually assesses whether cells are so damaged that they are beyond repair and sends them to be destroyed.
However, when the genes of the DNA repair pathway have mutated, the cells are enabled to grow indefinitely. Thus, the bone marrow will fill up with these defective cancer-prone cells.
Once 4–5% of the bone marrow comprises this type of mutated cells, the patient has a very high risk of incurable leukaemia.
“The problem is that chemotherapy does not destroy the mutated stem cells but readily destroys all the other stem cells in the bone marrow. Chemotherapy makes them accumulate even more mutations that further increase the risk of developing cancer,” explains Simon Husby.
Ensuring alternative treatment
The big question is what doctors should do with people with lymphoma who have a high risk of developing chemotherapy-related leukaemia.
Simon Husby says that the mutations in the genes of the DNA repair pathway do not directly disqualify people from chemotherapy but that the treating physician can seek alternatives if possible.
Simon Husby has received a grant for a research project for the next 2 years to investigate whether treatment with immunotherapy instead of chemotherapy improves survival.
Presumably also applies to other types of cancer
Doctor Husby explains that this is the first international study to examine how chemotherapy affects the risk of developing leukaemia among the patients from an entire country.
Some studies from selected treatment centres in the United States have shown similar results, but this trial is the first to include all patients from one country in the same analysis.
Simon Husby also says that the results probably apply not only to people with lymphoma but also to people with many other types of cancer, including breast cancer and gynaecological cancer, as a study in France found.
In the study in France, people with mutations in the genes of the DNA repair pathway had an increased risk of developing chemotherapy-related leukaemia.
“Investigating this problem is more relevant for some types of cancer than others. This is especially relevant for lymphoma since we often use high-dose chemotherapy because this is usually so effective and can cure many patients. However, some may develop leukaemia based on this, and we need to better identify these people so that we can provide an alternative for them,” says Simon Husby.
“Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study” has been published in Leukemia and “Clonal hematopoiesis evolves from pretreatment clones and stabilizes after end of chemotherapy in patients with MCL” has been published in Blood. In 2013, the Novo Nordisk Foundation awarded a 5-year clinical research grant to co-author Kirsten Grønbæk for the project Translational Epigenetics in Haematological Cancer. Kirsten Grønbæk is a lead figure in the Programme for Haematology supported by the Foundation since 2017 through the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen.
