Oncology

Chronic Lymphocytic Leukemia

Advertisment

Relapse After Venetoclax Plus Obinutuzumab in Chronic Lymphocytic Leukemia

patient care perspectives by Ian W. Flinn, MD, PhD

Overview

Venetoclax-plus-obinutuzumab combination therapy can provide patients with chronic lymphocytic leukemia (CLL) with an option for fixed-duration treatment in the front line. Treating patients who relapse after receiving this regimen involves a consideration of several disease-related factors.

Expert Commentary

Ian W. Flinn, MD, PhD

Director, Lymphoma Research
Sarah Cannon Research Institute
Tennessee Oncology
Nashville, TN

For patients who progress after being treated with venetoclax-plus-obinutuzumab therapy, I would check their cytogenetics and their next-generation sequencing at the time of next treatment.

Ian W. Flinn, MD, PhD

We conducted one of the early studies with the BCL-2 inhibitor venetoclax plus the anti-CD20 monoclonal antibody obinutuzumab for CLL, and I have many patients from that early trial who remain in remission to this day. Data from the CLL14 trial of frontline venetoclax plus obinutuzumab showed that progression-free survival was shorter in patients with TP53 aberrations. Now, while one would expect the progression-free survival to be shorter in this patient group, it was even shorter than what we would see with a Bruton tyrosine kinase (BTK) inhibitor–based approach in such a population. So, in cases of TP53 aberration, I tend to steer more toward a BTK inhibitor, and I usually start with acalabrutinib. 

For patients who progress after being treated with venetoclax-plus-obinutuzumab therapy, I would check their cytogenetics and their next-generation sequencing at the time of next treatment. In general, if someone had a very durable remission with venetoclax plus obinutuzumab and then relapsed, I would consider recommending that we go with the same regimen again, assuming that they had not acquired mutations in TP53 or other abnormalities. There may be variability among clinicians about what constitutes a short remission after venetoclax plus obinutuzumab, but I would say that less than 2 years is short; in that case, I would most likely not recommend repeating the same regimen at that time.

It is important to note, however, that venetoclax-based treatment and the sequencing of therapies in relapse continue to be an active area of investigation in CLL. It is possible that the duration of exposure to venetoclax needs to be optimized, and various approaches are being studied. In the relapsed/refractory setting, patients in the MURANO trial were randomized to 6 cycles of venetoclax plus rituximab followed by 2 years of venetoclax or to 6 months of standard-of-care bendamustine plus rituximab. In the frontline setting, the MAJIC trial (NCT05057494) will compare venetoclax plus obinutuzumab with acalabrutinib plus venetoclax, the latter of which is an all-oral regimen, and the duration of therapy in both arms will be guided by next-generation sequencing–based minimal residual disease testing.

At one time, there were concerns that deep remissions might not be possible in relapse after venetoclax-based therapy; however, we now know that patients can achieve durable remissions after venetoclax-based therapy and can be successfully retreated with venetoclax plus obinutuzumab or switched to a BTK inhibitor.

References

Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060. doi:10.1200/JCO.21.01181

ClinicalTrials.gov. A study of acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (MAJIC). Updated January 19, 2022. Accessed February 16, 2022. https://clinicaltrials.gov/ct2/show/NCT05057494

Davids MS, Fischer K, Robrecht S, et al. ReVenG: a phase 2 study of venetoclax plus obinutuzumab retreatment in patients with relapsed chronic lymphocytic leukemia [abstract 2634]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402. doi:10.1016/S1470-2045(21)00455-1

Davids MS, Mato AR, Hum J, et al. MAJIC: a phase 3 prospective, multicenter, randomized, open-label trial of acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma [abstract 1553]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Flinn IW, Gribben JG, Dyer MJS, et al. Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019;133(26):2765-2775. doi:10.1182/blood-2019-01-896290

Greil R, Fraser G, Leber B, et al. Efficacy and safety of ibrutinib in relapsed/refractory chronic lymphocytic leukemia patients previously treated with venetoclax in the MURANO study. HemaSphere. 2019;3(suppl 1):527. doi:10.1097/01.HS9.0000562928.03733.42

Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020;135(25):2266-2270. doi:10.1182/blood.2020004782

Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-3596. doi:10.1158/1078-0432.CCR-19-3815

Moreno C. Standard treatment approaches for relapsed/refractory chronic lymphocytic leukemia after frontline chemoimmunotherapy. Hematology Am Soc Hematol Educ Program. 2020;2020(1):33-40. doi:10.1182/hematology.2020000086

Roeker LE, Mato AR. Approaches for relapsed CLL after chemotherapy-free frontline regimens. Hematology Am Soc Hematol Educ Program. 2020;2020(1):10-17. doi:10.1182/hematology.2020000168

Seymour JF, Kipps TJ, Eichhorst BF, et al. Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):355. doi:10.1182/blood-2019-123930

Ian W. Flinn, MD, PhD

Chief Scientific Officer
OneOncology
Greco-Hainsworth Tennessee Oncology Centers for Research
Nashville, TN

Advertisment