Case 1: Prognostic Features and Chemoimmunotherapy Treatment Options

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William Wierda, MD, PhD:For diagnostic purposes, could you comment on bone marrow versus blood workup? What’s essential to have to make a diagnosis of CLL?

Adam Bagg, MD:In most instances, we get by with doing a peripheral blood analysis. As long as the patient has greater than 5x10⁹/L monoclonal B cells with an immunophenotype characteristic of CLL, that, in my opinion, is sufficient to make a diagnosis. In a patient with cytopenias, it might be important to do a marrow to ascertain the basis of the cytopenias. Is it due to extensive marrow involvement? Are there pure red cell aplasia and other considerations that might be contributing to the cytopenias? Certainly, bone marrow is useful in many cases. I’m not sure that it’s required in all cases. It depends on the complete blood count.

William Wierda, MD, PhD:In terms of the prognostic significance of these markers, maybe we’ll start with you, Nitin. Can you comment on the prognostic features for this patient and how they may relate to the outcomes for this patient?

Nitin Jain, MD:For this particular patient, given that the patient has deletion 11q, studies have shown this to be a high-risk prognostic marker for patients with CLL—with lower progression-free survival and overall survival, in the context of chemoimmunotherapy. Also, the patient has unmutatedVgene status. Again, this has been associated with a high-risk prognosis for decreased progression-free survival and overall survival compared with the mutatedVgene. With these 2 prognostic markers, which tend to go hand-in-hand, most of the time, deletion 11q and unmutatedVgene, I think this patient is certainly at high risk for disease progression. She has already shown signs of disease progression with anemia, and I think we should consider treatment for this patient.

William Wierda, MD, PhD:Based on what you just indicated, we should be talking to this patient about treatment. This is an older patient. This patient is in their 70s. We really have 2 different approaches to treating this patient. We can approach treatment in terms of chemoimmunotherapy and then we have the new small molecule inhibitors that we need to discuss. Maybe we could start out with the chemoimmunotherapy, since we have a lot of long-term data for chemoimmunotherapy. Maybe you can summarize, for us, the studies that have been done, that are relevant for the older population, with regard to chemoimmunotherapy regimens and the outcomes associated with these options.

Nitin Jain, MD:Sure. The study I wanted to highlight is the CLL10 trial, which is actually a trial for younger patients for CLL, generally less than 65 years of age. These patients were treatment naive, fit patients. Patients above age 65 were also treated in the study. In this particular trial, patients were randomized to receive either FCR (fludarabine/cyclophosphamide/rituximab) versus bendamustine/rituximab (BR). This was done by the German CLL Study Group. The primary endpoint was progression-free survival. The study showed that in older patients—approximately one-third of these patients—when they compared FCR versus BR, there was a similar progression-free survival. However, when they looked at the study, overall, the FCR arm had a superior progression-free survival. Above 65 years of age, the FCR regimen led to increased cytopenias, neutropenia, and infection risk. So, I think that study may tell us that if you have an older patient in whom you are thinking about chemoimmunotherapy, bendamustine/rituximab may be a reasonable alternative to FCR.

However, there is another trial, the CLL11 study, which was really designed for patients who were older or who had comorbidities. These patients were randomized to receive either chlorambucil, as a monotherapy or chlorambucil plus obinutuzumab or chlorambucil plus rituximab. The study showed that the arm with the chlorambucil plus obinutuzumab regimen was the most superior, in terms of progression-free survival and overall survival, compared with the other arms. This particular study led to the approval of this regimen, chlorambucil plus obinutuzumab, as the standard of care for frontline therapy for older patients with CLL. So, that’s another option that we have available.

William Wierda, MD, PhD:You reviewed a couple of chemoimmunotherapy regimen options for the patient. The choice between the options is driven more by…

Nitin Jain, MD:I think it’s driven more by the overall performance status of the patient’s comorbidities. Bendamustine/rituximab is likely going to be a more myelosuppressive regimen than chlorambucil plus obinutuzumab. So, if you have a patient who is maybe 65 to 70 years of age, who has a good performance status, and you are thinking about chemoimmunotherapy, I think BR may be a reasonable alternative. However, for a patient such as this patient, at 75 years of age, obinutuzumab/chlorambucil might be a better option.

William Wierda, MD, PhD:And the expected progression-free survival with chlorambucil/obinutuzumab, in this patient population, would be?

Nitin Jain, MD:In the CLL11 trial, the median progression-free survival of this patient population was 31 months, just over 2.5 years or so.

William Wierda, MD, PhD:In terms of relapse, with this type of treatment, with the patient characteristics that this particular patient has, maybe you can comment on the expectations for long-term outcomes for this patient?

Nitin Jain, MD:This patient has deletion 11q, as well as unmutatedVgene. Both of these have been shown to be high-risk prognostic markers with chemoimmunotherapy. What I mentioned, the 31 months of progression-free survival, would be applicable to an all-patient population, where you look at everyone, together. Because this patient is high risk, I would expect the median progression-free survival to certainly be less than that—probably on the order of 1 to 2 years. Certainly, I think that remains to be suboptimal, with the chemoimmunotherapy, but that’s what you could potentially achieve with chlorambucil/obinutuzumab.

William Wierda, MD, PhD:So, we would likely be talking to this patient, in a relatively short period of time, about relapse and retreatment?

Nitin Jain, MD:Yes.

Transcript edited for clarity.