Targeted next generation sequencing gene panel in the medical management of chronic lymphocytic leukemia Brief INAHTAhta

Aim

This report aimed to assess the clinical benefit of a targeted next generation sequencing (NGS) gene panel in the management of chronic lymphocytic leukemia in routine care. The objective was to identify the relevant molecular alterations to be tested in chronic lymphocytic leukemia and to define the role of targeted NGS in detecting these alterations.

Conclusions and results

The analysis of the collected data has shown that targeted NGS:

• has a superior threshold for detecting mutations compared to Sanger sequencing, enabling the detection of subclonal mutations, which have the same clinical impact as clonal mutations;
• demonstrates the importance of testing for resistance mutations to improve prognosis and to adapt targeted therapies.

Recommendations

The French National Authority for Health (HAS) has recommended that the National Health Insurance reimburse targeted next generation sequencing gene panel testing in the following cases:

• TP53 and IGHV mutation testing before initiating first line treatment in all patients with symptomatic chronic lymphocytic leukemia;
• TP53 mutation testing before treatment modification for all patients with symptomatic relapse;
• TP53, BTK and PLCG2 mutation testing before treatment modification in patients with symptomatic relapse after receiving Bruton’s tyrosine kinase inhibitors;
• TP53 and BCL2 mutation testing before treatment modification in patients with symptomatic relapse after receiving BCL2 inhibitors;
• TP53, BTK, PLCG2 and BCL2 mutation testing before any change of treatment line in patients with symptomatic relapse after receiving Bruton’s tyrosine kinase inhibitors and BCL2 inhibitors.

Methods

The evaluation method was based on: (1) a critical analysis of systematic reviews, meta-analyses, and clinical practice guidelines identified through  a systematic search and selected based on explicit criteria; (2) the identification of (a) clinically relevant evidence of molecular alterations, assessed using the OncoKB and TOPOGRAPH classification systems, and (b) approvals from the French National Authority for Health Transparency Committee, or when unavailable, compassionate use decisions given by the French National Agency for Medicines and Health Products Safety for relevant targeted therapies; and (3)  consultation with an expert; and (4) stakeholders’ consultation (healthcare professionals, patient and user organizations), as well as the opinion of public health institutions.

Further research/reviews required

The French National Authority for Health notes that the composition of the targeted next generation sequencing gene panel may evolve following favorable assessments of new gene alterations. These evaluations will be conducted in a dynamic manner in response to advances in scientific knowledge such as the identification of new relevant evidence and/or the publication of new approvals by French National Authority for Health Transparency Committee, and where applicable, compassionate use decisions by the French National Agency for Medicines and Health Products Safety.