The treatment of patients with CLL who have del(11q) has been one of our major unmet needs. It remains a high-risk marker in CLL, even in the era of novel agents, although there is wide variability in 11q-deleted disease. It is unclear what drives this wide clinical variability, but there is a subset of patients with genomic instability and complex karyotype who have shorter remissions, even when receiving one of the novel therapies. These patients can be as sick as those with 17p deletion, while others with del(11q) resemble unmutated patients without a high-risk chromosome. Part of the reason for the variability in disease severity may be related to the presence or absence of mutations in the other ATM allele, which may sometimes be germline. We have recently reported that germline variants in ATM are associated with a higher risk of CLL and an increased likelihood of del(11q) or ATM mutation in the CLL cells. Much of the older literature on ATM mutations in CLL did not take into account whether the allele was germline or somatic. We think that germline alleles are significant in terms of decreasing ATM (ataxia telangiectasia, mutated) function, but they may differ from somatic mutations in their effect. Thus, we need studies controlling for these and other variables, such as germline ATM mutation vs somatic ATM mutation, ATM mutation vs del(11q), and (most likely) 11q deletions that include BIRC3 vs deletions that do not.

Genomic instability and complex karyotype may also contribute to the variability in severity of del(11q) in CLL. Most laboratories still do fluorescence in situ hybridization (FISH) analysis without a karyotype (because the karyotype requires stimulation). In that case, whether or not a patient has a complex karyotype is not known. Additionally, although somatic mutation panels are often available, most clinicians only obtain FISH. We do not see many patients who get somatic mutation panels, and such panels may or may not include ATM. Dedicated germline analysis of ATM for CLL is still too investigational.

An analysis combining data from several studies suggested that patients with del(11q) CLL do very well with ibrutinib, although longer follow-up is needed. A potential therapeutic approach in patients with del(11q) is the combination of B-cell receptor and poly ADP ribose polymerase (PARP) inhibition. The use of PARP inhibitors for solid tumors provides a proof of concept for this approach in that PARP inhibitors can be synergistic with other agents. Synergistic effects with ibrutinib and the PARP inhibitor olaparib were reported in an abstract presented at the 60th American Society of Hematology Annual Meeting & Exposition in 2018 by Álamo et al. It is unclear whether this will be investigated further, as the field is currently focused on the potential use of ibrutinib plus venetoclax. I would be enthusiastic about a study evaluating the combination of ibrutinib plus a PARP inhibitor, as we need to identify additional classes of active drugs in CLL. I do not think we would have difficulty accruing patients for such a study because many of them know that they are higher risk and therefore would likely be eager to participate.