Table 1.

Strategies evaluated in the economic evaluation

Comparator	Current or future practice?	Pre-treatment genetic or genomic testing?	Ibrutinib used?	Notes
A	Current	Genetic testing	No	This strategy reflects current practice in hospitals that use genetic information to stratify patients by likely response to FCR treatment. Symptomatic patients first undergo genetic testing (FISH testing and Sanger sequencing) to identify those with TP53 mutations, with the two patient groups then following different clinical pathways. For patients without a TP53 mutation, first- and second-line treatment is either combination FCR or BR chemotherapy. Patients with refractory disease (or patients who have acquired a TP53 mutation following an earlier line of treatment) receive ofatumumab combination therapy, with a proportion also undergoing allogeneic transplantation. Patients with a TP53 mutation receive ofatumumab treatment, consolidated with allogeneic transplantation in a proportion of patients, followed by a second course of ofatumumab treatment if required
B	Current	Genetic testing	Yes	This strategy is similar to Comparator A, but refractory treatment for all patients is now ibrutinib. This is categorised as a current practice comparator as genetic testing is still used to stratify patients to first-line treatment
C	Current	None	No	This strategy reflects current practice in hospitals that do not use genetic information to stratify patients by likely response to FCR treatment. This pathway is the same as that for patients with no TP53 mutation in Comparator A, with the caveat that in Comparator C, patients cannot move from first-line to refractory treatment as there is no genetic testing (thus, the emergence of a high-risk genetic mutation cannot be identified)
Intervention 1	Future	Genomic testing	Yes	In this strategy, patients are stratified using genomic testing (targeted NGS) into likely FCR responders and non-responders. FCR responders follow a pathway similar to that for patients with TP53 mutations in Comparator B. Non-responders receive ibrutinib as first-line treatment until they no longer respond, then receive best supportive care
Intervention 2	Future	Genomic testing	Yes	In this strategy, patients are again stratified using genomic testing, with FCR responders following the same pathway as in Intervention 1. However, non-responders now receive first-line ofatumumab treatment and then refractory ibrutinib treatment

BR bendamustine and rituximab, FCR rituximab, cyclophosphamide and fludarabine, FISH fluorescent in situ hybridisation, NGS next-generation sequencing