Venetoclax Alone and In Combination: Overcoming Ibrutinib Resistance 

A 72-year-old man with CLL was initially treated with fludarabine, cyclophosphamide, and rituximab (FCR) in 2008. He relapsed in 2015 and has been receiving ibrutinib since then. He returns for follow-up reporting abdominal fullness and unintentional weight loss. Today’s labs reveal increased white blood cell count, and slightly increased LDH:     

1. WBC: 45 x 10,⁹/L; 85% lymphocytes on manual differential   
2. Hb: 13.9 g/dL 
3. Platelets: 274 x 10⁹/L 

LDH: 300 U/L 

Given the laboratory changes and new symptoms, you order a CT of the chest, abdomen, and pelvis to re-evaluate his disease status. Imaging demonstrates interval development of bulky adenopathy throughout the abdomen and pelvis in addition to interval development of splenomegaly (spleen 19 cm).   

How would you treat this patient’s disease progression?    
   
Decision-making: Important Data       

The BTK inhibitor ibrutinib has been shown to be highly effective in relapsed/refractory disease, regardless of the presence of genomic aberrations, for those patients who can tolerate it. Final results of the 2019 RESONATE trial reported an overall response rate of 91% and a median progression-free survival (PFS) of 44.1 months. Progressive disease (PD) and adverse events (AEs) were the two most common reasons for ibrutinib discontinuation, and they were experienced by 37% and 16%, respectively, of the patients receiving the therapy.1 Unfortunately, patients who discontinue ibrutinib due to PD have worse PFS than those who discontinue due to AEs in both relapsed and frontline settings.^2,3

Although venetoclax has been studied as a single agent, guidelines recommend administering venetoclax in combination with a monoclonal anti-CD20 antibody such as rituximab or obinutuzumab. In the relapsed setting, the MURANO trial demonstrated a median PFS of 53.6 months for patients with relapsed CLL receiving 2 years of venetoclax plus 6 cycles of rituximab (Ven-R).⁴ Key AEs with the Ven-R regimen included 57.7% incidence of grade 3-4 neutropenia, though only a 3.6% incidence of febrile neutropenia and 17.5% incidence of infections and infestations.⁵ An additional key AE of note with venetoclax-based regimens, tumor lysis syndrome (TLS), occurred in 6 of 194 patients receiving the MURANO Ven-R regimen.⁴

The CLL14 trial was published in 2019 and examined venetoclax in the frontline setting, paired with obinutuzumab instead of rituximab.⁶ Additionally, venetoclax was only administered for 1 year compared to the 2 years of venetoclax administered in the MURANO trial. In this regimen, patients received 3 weeks of obinutuzumab therapy before initiation of venetoclax weekly dose escalation, whereas in the MURANO study, rituximab was not added until after venetoclax weekly dose escalation was completed.⁵ In the CLL14 trial, tumor lysis syndrome was reported in 3 of 212 patients who received venetoclax plus obinutuzuamb, none of whom met criteria for clinical TLS by Howard criteria.⁶ The GAIA (CLL13) trial also evaluated varying venetoclax-based regimens in the frontline setting for CLL.⁷ In this study, venetoclax-based regimens containing obinutuzumab outperformed venetoclax plus rituximab with respect to PFS and percentage of patients with undetectable MRD at 15 months of therapy. Rates of grade 3 or 4 infections were relatively similar, but slightly higher for patients receiving venetoclax plus obinutuzumab compared to those receiving venetoclax plus rituximab (13.2% vs. 10.5%).    

Discussion   
   
Currently, the only on-label venetoclax-based regimen in the relapsed setting is venetoclax plus rituximab. This is also borne out in the NCCN guidelines. Therefore, venetoclax plus rituximab is a reasonable treatment recommendation for this patient.    
   
However, several frontline studies have demonstrated improved PFS and decreased rates TLS for patients who receive venetoclax plus obinutuzumab. Therefore, it is also reasonable to recommend venetoclax (for 2 years) plus obinutuzumab (for 6 cycles) in this setting if insurance will cover the treatment for the patient based on the data outlined above.    
   
An additional future direction for disease progression on ibrutinib will likely include the noncovalent BTK inhibitor pirtobrutinib, which has demonstrated efficacy in patients with resistance mutations associated with disease progression on ibrutinib. Studies are ongoing, and there is not currently an FDA approval for pirtobrutinib in CLL, but it has been approved in mantle cell lymphoma so pursuit of off-label use may be an option in select patients. CAR T-cell therapy is currently only available through clinical trials, most of which require prior exposure to both BTK inhibitors and venetoclax-based therapy.   
   
Overall, venetoclax-based regimens represent an effective next line of therapy in patients who experience disease progression while on ibrutinib, both in terms of PFS and uMRD. Key adverse events for which to monitor include neutropenia, infections, and TLS. One additional important consideration in this patient would be the known risk of disease flare with stopping ibrutinib in a patient who is already demonstrating signs of progressive disease on ibrutinib. This risk warrants consideration for a layered approach, such as continuing ibrutinib for the first several weeks as described by Hampel et al.⁸

References

1. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94:1353-1363. 
2. Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: Updated results of the E1912 trial. Blood. 2022;140:112-120.
3. Jain P, Thompson PA, Keating M, et al. Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib. Cancer. 2017;123:2268-2273. 
4. Seymour JF, Kipps TJ, Eichhorst BF, et al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022;140:839-850. 
5. Seymour JF, Kipps TJ, Eichhorst BF, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107-1120. 
6. Fischer K, Al-Sawar O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. 
7. Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388:1739-1754. 
8. Hampel PJ, Call TG, Ding W, et al. Addition of venetoclax at time of progression in ibrutinib-treated patients with chronic lymphocytic leukemia: Combination therapy to prevent ibrutinib flare. Am J Hematol. 2020;95:E57-E60.