Reducing toxicity in the treatment of lymphoma

While prognosis for lymphoma patients has improved significantly in recent years due to modern treatments, diagnostics and imaging techniques, short-term and late effects of treatment continue to have a detrimental impact on their health. This project set out to investigate three different strategies for reducing the toxicity of treatment for lymphoma: i) drug substitution in Hodgkin lymphoma, (ii) a radiotherapy-free approach to treating primary mediastinal large B-cell lymphoma (PMBL), and (iii) chemotherapy-free treatment of post-transplant lymphoproliferative disorder (PTLD). These strategies are commonly used in clinical practice but have not been tested in prospective, randomised clinical trials.

Retrospective, observational, multicentre study designs were chosen to evaluate the above approaches to reducing the toxicity of treatment. To assess the impact of chemotherapy on stem cell genomic health, an analysis of mutation burden and mutational signatures was performed in haematopoietic stem and progenitor cells (HSPC) of previously treated Hodgkin lymphoma patients.

The key findings were that replacing procarbazine with dacarbazine in Hodgkin lymphoma treatment maintains an excellent 36-month progression-free survival (PFS) of 92.4%. The substitution also confers several toxicity benefits. Additionally, patients treated with dacarbazine-containing regimens had a far lower excess mutation burden in HSPC. This project showed for the first time that procarbazine is linked to the SBS25 mutational signature.

R-DA-EPOCH (Rituximab with dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubixin) is highly effective treatment for PMBL (3-year PFS 92.8%). However, in this real-world study 31% of patients received consolidative radiotherapy, while in the landmark Phase II trial radiotherapy was omitted(Dunleavy et al., 2013). In PTLD, our data suggest that a risk-stratified approach with first-line Rituximab monotherapy is effective and safe in real-world practice as well as in clinical trials.

In conclusion, the real-world data suggest that the strategies I have studied are effective in reducing toxicities of lymphoma treatment. Choice of chemotherapy regimen may also impact on HSPC genomic health.