Frontline CLL Treatment With Fixed-Duration Regimens

Catherine C. Coombs, MD: Fixed-duration therapy is attractive for several reasons. It’s desirable from a patient standpoint to not have to be on therapy indefinitely, and there are cost benefits given that you don’t have to pay that monthly co-payment every month. You pay it for only 12 months, for example. As an added benefit, should you have any toxicity from the regimen, there is a defined end point, and many of the agents that are given indefinitely can have toxicities that can persist over time. A fixed-duration regimen can give a patient a reprieve from many toxicities that may occur while on therapy. It also helps with well-being. Taking chemotherapy every day reminds one of the fact that they have cancer, so it can also restore a degree of normalcy to the patient’s life to have a break.

Resistance mutations are known to develop. In earlier trials of venetoclax, about half of patients if not more developed resistance to the drug usually at 2 to 3 years. Subsequent studies have shown that the main mechanism of resistance is acquired mutations in BCL2. What we know is that these mutations occur with prolonged exposure, and it’s feasible that limiting the exposure to these drugs may limit the development of these resistance mutations. This needs to be further studied by longer-term follow-up of these fixed-duration regimens.

The venetoclax-obinutuzumab regimen certainly is beneficial when compared with the chlorambucil-obinutuzumab regimen with respect to progression-free survival [PFS]. The difference between the ways that the regimen performs is the most notable for patients with unmutated IGHV. They have a very high advantage with respect to progression-free survival when comparing how they do with chlorambucil-obinutuzumab regimen. Other high-risk markers still perform well with the regimen, but it does appear that patients with TP53 mutations or deletions may not have the same level of benefit as patients without those mutations. They still respond, but the degree of patients that attain that MRD [minimal residual disease] negative is lower than the overall population.

Venetoclax-obinutuzumab is different from the predecessor regimen that was used in the relapsed/refractory setting from the MURANO study of venetoclax-rituximab. The old way of doing venetoclax was you would ramp up and then add the CD20 afterward. Venetoclax-obinutuzumab in contrast has a 3-week lead-in of obinutuzumab, which is important to know. The 1 problem with this is that you can see obinutuzumab-infusion reactions, but the benefit outweighs that risk. Debulking can occur in those first 3 weeks, and patients who would otherwise have been at a higher risk for tumor lysis syndrome can actually have their risk downgraded because of that 3-week lead-in prior to the venetoclax subsequently starting.

Venetoclax-obinutuzumab is initiated most successfully and safely when it’s done with an experienced provider and team. At my own institution, we have a multidisciplinary team of myself, an excellent oncology-dedicated pharmacist, a nurse practitioner, and a nurse. This helps with patient safety to have an experienced team. It is important that there are good instructions on the manufacturer’s web page on how to initiate this drug safely. The key is stratifying the patient from the tumor lysis risk standpoint. The main tenants of that are knowing what their largest lymph node diameter is, which is from cross-sectional imaging and knowing what their absolute lymphocyte count is. You also need to know their renal function because even a patient of medium risk for tumor lysis, who has suboptimal kidney function, may be a patient who would be better served by initiating venetoclax in the hospital setting.

A decent portion of patients can get this—the venetoclax-initiated outpatient—after having their tumor lysis risk downgraded from the obinutuzumab. But you need to look at the numbers on the day of the venetoclax start to help determine that. Often the white blood cell count can come down with just that brief lead-in, which would then lead to a downgrading of the tumor lysis risk and potential outpatient initiation. The patient initially may have need inpatient had you started with the venetoclax by itself.

Transcript Edited for Clarity