Which Path to Take in Frontline Therapy for CLL?

Experts reflect on core decisions inherent in selecting frontline therapy for patients with CLL, specifically regarding the use of BTK inhibitors, BCL2 inhibitors, anti-CD20 agents, and chemoimmunotherapy.

John C. Byrd, MD: There are 3 things that need to be taken into consideration. No. 1, what’s the patient appropriate for? If a patient is on warfarin, they shouldn’t go on a BTK [Bruton tyrosine kinase] inhibitor as first-line therapy. That would be a person we’d always treat with a venetoclax-containing regimen. Somebody with renal insufficiency is going to be more suited on to BTK inhibitor. A lot of things come down to patient preference and wanting to be on a chronic therapy, a pill that you might stay on for an extended period, possibly your whole life vs a time-dependent therapy. You may receive therapy for a year or multiple months and then go off and have a break. Depending upon the patients and how things are presented and their risk factors, you come to a decision. There’s no decision that’s right for every patient. It’s individual matching their risk factors for toxicity, the benefit from therapy, and their personal wishes in terms of how they want their disease controlled for CLL [chronic lymphocytic leukemia]. That’s the neat thing in both of these options. We see that patients have their disease very well controlled and have a good outcome with their disease.

Anna Schuh, MD, PhD: The question of whether the addition of an anti-CD20 antibody makes a difference to the BTK inhibitor remains an open question. There’re been a series of studies comparing ibrutinib with ibrutinib and rituximab in patients with comorbidities. The iLLUMINATE study also looked at fit patients the ECOG study, and the curves were essentially overlapping. There doesn’t seem to be a difference whether you give rituximab alongside ibrutinib. It slightly increases the MRD [minimal residual disease] rate, especially when it’s obinutuzumab and not rituximab, but I’d argue that’s just a window dressing. There are people who wouldn’t say that, and it does remain an open question. The recent results from ELEVATE TN, where there was a 3-way comparison: acalabrutinib, acalabrutinib-obinutuzumab, and chlorambucil-obinutuzumab. That study was not powered to identify a difference between acalabrutinib and acalabrutinib-obinutuzumab, although the curves are separating and they would suggest that there’s an advantage, a slight advantage of giving obinutuzumab in addition to acalabrutinib. That’s not what the NICE [National Institute for Health and Care Excellence] decision in the United Kingdom was. The NICE decided to approve acalabrutinib as a monotherapy because of the additional cost associated with giving obinutuzumab, the chair time, and the insignificant adverse effects and infusion reactions, in particular in patients who already have underlying cardiac problems; we can’t ignore them. On the basis of all the relevant evidence, I’d still say that monotherapy over BTK inhibitor is adequate, and we don’t need to add anti-CD20.

John C. Byrd, MD: We’re excited in the field of CLL that chemotherapy immunotherapy has about 6 nails in the coffin—5½, we’ll say. We’re having the discussion about chemotherapy-immunotherapy, who have IGVH-mutated CLL who were under the age 70 with a good performance status, where you can give this therapy and they’ll have a prolonged remission. They probably are cured, and that’s the only group in the up-front setting that chemotherapy-immunotherapy is appropriate for. Some patients who go to CAR [chimeric antigen receptor] T cells who have very refractory disease or receive cellular therapies, where you’re giving chemotherapy-immunotherapy as a preparative regimen for a cellular therapy; it’s appropriate. Outside those settings, there’s not a role for chemotherapy immunotherapy in CLL. Chemotherapy brings a lot of long-term toxicity, particularly in patients you expect to live a long time. We have more data that patients with CLL are having extended survival. In general, I’d say there’s very little role for chemotherapy-immunotherapy in CLL anymore.


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