“While the primary endpoint, the undetectable-MRD [complete response] rate, maybe looked a little low, we know undetectable MRD in the era of chemoimmunotherapy translates to better outcomes, and we’re seeing that data emerge with novel agents, including venetoclax,” said Dr Thompson. “Half of patients in the relapsed and refractory cohort and 67% of treatment-naive patients achieving undetectable MRD is a really promising thing about the combination.”

Most patients tolerated the treatment well, and Dr Rogers pointed out that the finite time course of the treatment helped patients put up with some inconvenient, but not dangerous, side effects. “We saw some diarrhea and stomach upset, but not horrible nausea, and most of the time it wasn’t bad enough that patients wanted supportive medication for it,” she said.

Unlike chemotherapy, this treatment did not cause any cognitive deficits. The most worrisome adverse events were hematological, and 94% of patients experienced neutropenia. Adverse events caused 3 patients to discontinue the study, and 1 patient eventually died of neutropenic infection.


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“When you are in the clinic talking to patients, it’s really appealing for certain patients to have time-limited therapy,” said Dr Thompson. However, she added, “there is the caveat with this study that patients were allowed to continue ibrutinib past cycle 14 at the discretion of the investigator.”

An obvious sticking point for triple therapy is the high cost. “This regimen is extremely expensive,” Dr Rogers acknowledged. “But you only take them for a year. If the remission lasts for several years, then it’s actually pretty cost-effective.” Further follow-up will determine how long the remission lasts, and that will help inform decision making about whether the treatment is worthwhile.

“I think the key question will be, ‘How do we select patients who are appropriate for this intensive triple-combo therapy vs which patients really need to achieve undetectable MRD?’” said Dr Thompson. “There are still patients who do well with a single agent.”

Younger, healthier patients, who can tolerate the intense treatment might see the appeal of taking the drugs for approximately 1 year only rather than staying on treatment indefinitely. Those who have high risk factors, such as deletion 17p or deletion 11q, which indicate a potentially faster growing cancer, might prefer the triple therapy.

Patients who are in their 80s or 90s, however, or those with disease characterized as low risk based on the genetic features of the cancer, might be better served with a single agent. “Those people will probably just take 1 drug so they don’t have too many side effects,” said Dr Rogers. “They might finish their natural lifespan only having taken 1 drug.”

References

  1. Rogers KA, Huang Y, Ruppert AS, et al. Phase II Study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. Published August 14, 2020; JCO2000491. doi:10.1200/JCO.20.00491
  1. ClinicalTrials.gov. Bcl-2 Inhibitor GDC-0199 in Combination With Obinutuzumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or Previously Untreated Chronic Lymphocytic Leukemia. NCT02427451.  https://clinicaltrials.gov/ct2/show/NCT02427451. Accessed September 4, 2020.