“Double-Refractory” CLL: Progressive Disease after Therapy With Both a BTK Inhibitor and a BCL2 Inhibitor 

Mr. L is a 69-year-old man with CLL, previously treated with fludarabine, cyclophosphamide, and rituximab (FCR), ibrutinib, and most recently venetoclax plus rituximab. He has been observed since that time. His prognostic markers are notable for unmutated IGHV genes, presence of 11q deletion by FISH, and a positive TP53 mutation.   

During routine follow-up Mr. L is noted to have increasing adenopathy on exam (3 cm right cervical node and bilateral 2 cm axillary nodes), as well as a spleen palpable approximately 2 cm below the left costal margin on deep inspiration. Upon further discussion, you learn that he has lost about 10% of his body weight over the past 6 months despite no changes to his diet or activity level.  Laboratory evaluation shows ongoing increase in white blood cell count (currently 73 x 10⁹/L) and new cytopenias (hemoglobin of 9.8 g/dL and platelet count of 112 x 10⁹/L). There is no evidence of hemolysis or nutritional deficiency on additional laboratory evaluation. Lactate dehydrogenase (LDH) is within normal limits.  

Restaging CT scans and bone marrow biopsy confirm diffuse adenopathy throughout the neck, chest, abdomen, and pelvis. The marrow demonstrates 90% involvement by CLL.   

Mr. L returns today to discuss next steps in his care now that he has demonstrated progression after prior therapy with chemo-immunotherapy, BTK inhibitor, and BCL2 inhibitor plus monoclonal anti-CD20 antibody. You review with him the clinical trials currently available at your institution, as well as currently recommended regimens per NCCN guidelines¹, including duvelisib, idelalisib with or without rituximab, pirtobrutinib, ibrutinib plus venetoclax, alemtuzumab with or without rituximab, high-dose methylprednisolone with or without anti-CD20 monoclonal antibody, and lenalidomide with or without rituximab. He asks about CAR T-cell therapy because he heard about it in one of his patient support groups; as this is only available at certain centers via clinical trials, he does not feel this is the best option for him. Ultimately, he decides he would like to proceed with pirtobrutinib-based therapy.   

Discussion

Any patient with CLL progressing after treatment with both a BTK inhibitor (BTKi) and having received BCL2 inhibitor (BCL2i)-based therapy, particularly those with high-risk features like Mr. L, should be presented with clinical trial options when available. This “double-refractory” scenario in patients with CLL is a space where much ongoing research is needed to improve patient outcomes.   

Pirtobrutinib is a novel BTKi that can work even in patients who have developed resistance mutations to earlier-generation BTK inhibitors. It is currently approved in mantle cell lymphoma and, despite being on the NCCN guidelines, does not have a current FDA approval for use in CLL.   

The data to support use of pirtobrutinib in CLL is based on the phase 1/2 BRUIN study, which evaluated the use of pirtobrutinib in 317 patients with relapsed/refractory CLL/SLL, 247 of whom had previously received a BTKi. Of those 247 patients with prior BTKi exposure, 100 patients had also previously received BCL2i-based therapy such as venetoclax. Overall response rate (ORR) in patients with relapsed CLL and prior BTKi exposure was 73.3% (95% CI: 67.3%-78.7%), including 4 complete responses, 176 partial responses, and 1 nodular partial response. The ORR increased to 82.2% if partial response with lymphocytosis was included. In a subgroup analysis, patients with a PLCG2 mutation (n = 18) did appear to have a slightly lower overalL response rate of 56%.² The analysis of patients with prior exposure to both BTKi and a BCL2i such as venetoclax, like in the case of Mr. L, the ORR was 70% (79% if partial response with lymphocytosis was included).   

At median follow-up of 19.4 months, the median progression-free survival was 19.6 months (95% CI: 16.9-22.1). When limited to the patients who had received both prior BTKi and a BCL-2i like Mr. L, the median PFS was 16.8 months (95% CI: 13.2-18.7). Those patients who received only a BTKi experienced a median PFS of 22.1 months (95% CI: 19.6-27.4). Interestingly, for those patients who were extremely heavily treated, having received BTK, BCL-2, and PI3K inhibitors, as well as chemoimmunotherapy, the median PFS was still longer than 1 year, at 13.8 months (95% CI: 10.3-NE). Investigators reported that the median PFS for patients with 17p deletions or TP53 mutations was 16.9 months, and those patients with wild-type IGHV had a median PFS of 18.7 months.² The most common adverse effects associated with pirtobrutinib were infections (71%), bleeding (42.6%), and neutropenia (32.5%), with grade 3 or higher infections occurring in 28.1% and neutropenia in 26.8% of patients. Treatment-related lymphocytosis was found to occur early in the first cycle of treatment.2 Other common AEs of interest in BTKi occurred at relatively low rates with pirtobrutinib, including hypertension (14.2%), atrial fibrillation or flutter (3.8%), and major hemorrhage (2.2%). The authors report a low discontinuation rate of 2.8%, but it should be kept in mind that this is a heavily pretreated population without many other viable options.   

Overall, pirtobrutinib represents a reasonable therapeutic option for Mr. L, although it is important to recognize that long-lasting remissions of relapsed/refractory CLL after prior exposure to both BTKi and BCL2i remain elusive, and more research is needed in this space.    

References

1. National Comprehensive Cancer Network. NCCN Guidelines Version 1.2024: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Accessed November 21, 2023. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf  
2. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389:33-44.