Ibrutinib-resistant CLL: unwanted and unwonted!

In this issue of Blood, Ahn et al find intriguing clinical and molecular differences between early and late relapsing patients in a phase 2 trial of chronic lymphocytic leukemia (CLL) treated with ibrutinib.¹ 

The introduction of ibrutinib has changed the paradigm of CLL management. Treatment is moving away from cytotoxic chemotherapy and toward targeting biological pathways like B-cell receptor signaling and induction of apoptosis. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), has been approved for treatment of CLL that harbors mutations in TP53 or deletion of 17p for relapsed or refractory disease²  and also for first-line treatment.³ 

Resistance to ibrutinib, however, occurs in a subset of patients, particularly in heavily pretreated patients and in high-risk CLL.^4,5  Unfortunately, this resistance correlates with aggressive disease, either progressive CLL or Richter transformation, that is difficult to treat. It is therefore of prime importance to not only understand the molecular mechanism of resistance, but also to detect the emergence of resistant disease early or even preemptively, because affected patients will require biologically tailored alternative treatment strategies.

Ahn et al and others have commented on two distinct types of resistant disease that are of special interest (see figure).⁶  Although patient numbers are small, in the first group of patients, Richter transformation occurs within 12 to 18 months of treatment initiation and, at transformation, BTK and PLCG2 mutations are not common. In contrast, a second group of patients with later progression of CLL that is frequently associated with mutations of BTK and PLCG2. There may be a third group of patients with progression of CLL without BTK or PLCG2 mutations. However, the majority of patients who have CLL progression while receiving ibrutinib seem to harbor mutations in their CLL tumor cells in the targeted BTK, in phospholipase PLCG2, or both.⁴ 

The article by Ahn et al reports a phase 2 trial that included elderly patients with CLL and patients with CLL who harbored del(17p) and were treated with first-line ibrutinib. In that cohort, 15 (17.9%) of 84 patients progressed with a median follow-up of 34 months. Similar to previous studies, it is always the target cysteine residue C481 that is mutated in BTK. The variety of amino acid changes in this position point to the mode of action and specificity of ibrutinib: abrogation of the covalent binding to C481 with retention of the full-length functional BTK points to the importance of full (irreversible) inhibition vs incomplete (competitive) inhibition as a therapeutic mechanism.

In PLCG2, it is the autoinhibitory SH2 domain whose function is lost in resistant cells by deletion or mutation, leading to an induction of PLCG2 activity that is independent of BTK. Two of these amino acid changes resulted in a hyperactivated form of PLCG2 via the GTPase RAC.⁷  An unresolved issue is the oftentimes low allelic fraction of mutations of BTK and PLCG2 that has been observed in patients with resistant CLL.^1,8  Concurrent mutation of BTK and PLCG2 suggests either that the mutations are present in different subclones or that an additional activation of PLCG2 is advantageous for bypassing BTK inhibition. In addition, the sequence of events is not strictly defined because mutation of PLCG2 does not occur first in all patients.

However, the fact that BTK and PLCG2 are specifically mutated in ibrutinib-resistant CLL underlines the critical importance of the BCR pathway for survival of CLL cells, that BTK within CLL cells is the bona fide target of ibrutinib, that inhibition of the BCR pathway with its critical elements BTK and PLCG2 is the therapeutic principle, and that therapeutic success depends on inhibition of this pathway.

Ahn et al, along with others, noted that development of resistance to ibrutinib seems to be a selection process by cells harboring BTK and/or PLCG2 mutations that are present, at least in some cases, before initiation of ibrutinib treatment.⁹  If these unusual (unwonted) cells are only present or subsequently only increase in patients that do develop resistance—which remains to be tested—their detection could be used to instruct treatment decisions. In their analysis of consecutive samples, Ahn et al could show that under selection pressure with ibrutinib, CLL clones with a mutation of BTK grow faster than clones with a mutation of PLCG2, although this could be tested only in a small number of patients. In contrast, growth rates of clones with mutations of BTK in the same patient were identical. Thus, from a sensitive detection of the numbers of unwonted CLL cells harboring BTK or PLCG2 mutations before treatment, in theory the development of resistance could be predicted in patients prospectively.

Upon development of resistance against ibrutinib, salvage treatment with PI3K inhibitors (eg, idelalisib) or BCL2 inhibitors (eg, venetoclax¹⁰ ) lead to prolonged survival, whereas treatment of patients with Richter transformation remains largely ineffective.¹  Therefore, identification of this latter group of patients at or even before initiation of ibrutinib treatment is an urgent unmet need.

How can these findings inform clinical management? Unfortunately, the quality of response to ibrutinib seems to be no measure of the probability of relapse as a result of the emergence of resistance. Serum levels of CCL3 and CCL4 were tested by Ahn et al as prognostic factors but did not increase in all patients with disease progression. However, mutations of BTK and PLCG2 predated clinical progression. It could therefore be advantageous to monitor mutations of BTK and PLCG2 in CLL patients in a clinical setting to prevent development of resistant CLL.⁶  To target these unwonted cells that are pretherapeutically present and that harbor mutations of BTK or PLCG2, combinatorial treatment is possibly the best choice (eg, CLL2-GIVe trial of the German Chronic Lymphocytic Leukemia Study Group and Jones et al¹⁰ ). With the molecular mechanisms of resistance against the novel targeted therapies being described in detail, it becomes more and more clear that these therapies maybe best used when complementing each other. They are the likely route to highly effective treatment, with the ultimate goal of a cure for patients suffering from CLL.