Nitin Jain, MD, on First-Line Treatment With Pirtobrutinib-Based Regimen in CLL

Patients with CLL these days have many therapy options in the frontline setting. Patients with CLL are generally treated with a continuous BTK inhibitor or a combination of venetoclax plus obinutuzumab, which is a time limited therapy. In this abstract which we're presenting at the ASH meeting, we report a combination of pirtobrutinib, venetoclax, and obinutuzumab three drugs together as a time limited approach for patients with CLL. Previously, we have shown that combining ibrutinib plus venetoclax two oral drugs together led to high rates of undetectable MRD remission in the bone marrow. We argued that a third generation non-covalent BTK inhibitor and if we move it upfront in the first line setting in a time limited approach, and also add obinutuzumab, an approved antibody for patients with CLL. So combining three drugs together will be highly active and will likely lead to high rates of MRD remission. In this study conducted at MD Anderson Cancer Center, we updated 80 patients now with CLL, and these are the patients who met IWCLL treatment criteria and this was their first treatment. Patients received starting on day one with pirtobrutinib and obinutuzumab and starting in month two they started with venetoclax. Obinutuzumab was given for six cycles, as is the standard course of treatment and pirtobrutinib and venetoclax will continue until a total of cycle 13. So about one year of the combination therapy and we did bone marrow assessments for MRD assessment at the end of cycle seven and the end of cycle 13, and also did peripheral blood assessment at the same time points. We also did MRD assessment by next generation sequencing assay with a sensitivity of 10 to the minus six. So we have treated now 80 patients and our median follow-up is about 11.9 months. What we have seen that, at the month seven, which is a six months of the combination, we had very high rates of MRD six remission, which means one in a 1,000,000, 10 to the minus six sensitivity, both in the blood and the bone marrow. And when we looked at the 41 patients, we have reached a one year mark. The blood MRD six remission upwards of 80% and the bone marrow was about 80% as well. So these are high rates of MRD six remission, which we are noticing in these patients. So far, none of the patients has progressed or died with a follow-up of just around one year and also the toxicity. The most common toxicity was myelosuppression, mainly neutropenia, which was seen in 60% of the patients. Four patients out of 80 had neutropenic fever, but overall I think the drug was relatively well tolerated and we were able to decrease the dose of the drugs in some of the patients who had neutropenia as a side effect. So this trial continues to accrue more patients we are following these patients for, and eventually we'll see how this duration of response pans out with this one year time limited therapy.