Discontinuation Outcomes Mutational Analysis BTK PLCγ2 Genes in CLL Patients Treated Ibrutinib

Perspective

The highly effective Bruton tyrosine kinase (BTK) inhibitor, Ibrutinib is approved for the treatment of chronic lymphocytic leukemia (CLL) as initial therapy as well as relapsed disease.

Extensively pre-treated CLL patients demonstrate initial responses to Ibrutinib followed by drug resistance and disease progression in some cases. Disease progression on Ibrutinib can be progression of CLL, i.e., increasing leukemic cell counts or Richter transformation lymphoma (RT). Recent reports have analyzed probable causes of Ibrutinib resistance by sequencing BTK and PLCγ2 genes that allow interesting clinical correlation between disease progression and mutational analysis.

In the report from Ohio State [1] of a total of 308 patients who were on Ibrutinib, the cumulative discontinuation rate was 25% (76 out of 308 patients). Disease progression was observed in 31 out of 76 patients with rest discontinuing for other reasons. In the MD Anderson data of 127 patients, the discontinuation rate was 26% and the reason for discontinuation was disease progression (Richter transformation) in 7, CLL progression in 7, 3 patients went for stem cell transplantation, 2 patients discontinued for miscellaneous causes and 14 patients had adverse events or sudden death. Patients who discontinue Ibrutinib with a RT transformation have particularly poor prognosis with a median survival of only 3-4 months [2]. The outcome is slightly better in patients that have CLL progression on Ibrutinib [1,2]. Interestingly progression of CLL was seen later the course of Ibrutinib treatment than Richter’s transformation with a reported cumulative incidence of 4-6% while RT was observed earlier in the course of treatment with Ibrutinib with an incidence of 5-6% [1,2].

Maddocks, et al. [1] report sequencing data on BTK and PLCγ2 genes from CLL patients who progress on Ibrutinib. Both these genes are required for effective B-cell receptor signaling and mutations resulting in Ibrutinib resistance in patients have been previously described in both these genes [3]. The drug binds to the cysteine residue 481 (C481) and mutations have been reported that alter this residue as well as other residues of the BTK gene [3] (Figure 1). PLCγ2 gene mutations are gain of function mutations that also result in Ibrutinib resistance. The mutations in BTK and PLCγ2 genes are found in patients who experience a CLL progression (11 of 11 patients) on Ibrutinib and are in frequently seen in patients whose progression is a Richter transformation (RT, 2 of 9 patients) event (Figure 1). This appears logical as CLL progression is due to alteration of the target kinase, BTK so the drug is unable to block kinase activity and leukemic cells escape inhibition. In the case of Richter transformation, prior genomic analyses have reported that the resulting lymphoma is quite dissimilar to CLL at the genomic and transcriptional level [4]. Leukemic cells undergoing RT acquire a large number of additional novel driver events and signaling pathways that override the BTK inhibition which results in disease progression which is not necessarily associated with mutation in BTK gene itself. Maddocks, et al. report that in 2 of 9 Richter transformation patients BTK gene mutation was observed upon sequencing [1]. Interestingly these patients demonstrated a mixed pattern of progression with both RT and progressive CLL. It is plausible that in these cases the transformation is clonally related (BTK gene mutation present) to CLL in contrast to other RT transformations that are genetically distinct (clonally un-related, lack of BTK gene mutation).

    

    

    Figure 1:  Schematic with possible outcomes of disease progression in CLL patients on Ibrutnib therapy and their relationship to BTK and PLCγ2 mutations.