CLL: Rationale for Ibrutinib and Chemotherapy

Matthew S. Davids, MD, MMSc:As I mentioned, there’s an ongoing prospective phase III trial in the Alliance comparing bendamustine/rituximab with ibrutinib-based regimens for the frontline treatment of older patients with CLL. We’re going to be waiting a while until we get the results of those prospective data. And so, now what we have is a recent retrospective study that was presented at the ASH meeting by Robak and colleagues. They tried to compare across different trials looking at ibrutinib monotherapy and comparing that to older chemoimmunotherapy regimens from other trials.

And what they found was that, in general, the ibrutinib-based regimens were better tolerated in terms of the toxicity profiles and superior in terms of progression-free and overall survival. So, it’s certainly a very promising retrospective series of data. But certainly, we need to exercise caution when interpreting this because it’s a retrospective comparison, and although they tried to match the patient characteristics between the trials as much as possible, there are certain limitations to that type of approach.

So, I think it is certainly suggestive, as we have learned from other trials, that ibrutinib is an effective treatment option for frontline therapy. However, I think that we need to await the prospective data before we can definitively say that that’s the case. I would say that the Robak findings are consistent with my own clinical practice in treating patients up front with ibrutinib, with the 1 exception being that any time we’re looking at clinical trial-based data, we’re looking at a special group of patients who tend to be, in general, younger and fitter than the real-world population. And certainly, some of my real-world patients with other medical comorbidities, in particular cardiac issues or bleeding risk, have run into some difficulties with ibrutinib as a frontline treatment. And I think that may not be reflected as much in the trial data.

For the older population with comorbidities with CLL, I think chemotherapy-free options are very promising for the future of the disease. We already have some initial promising results from the ASH meeting in 2017 with combinations of ibrutinib and venetoclax, with or without the antibody obinutuzumab. And I do really think that that’s where the field is headed. Because for these elderly patients, the chemoimmunotherapy regimens, though effective, are often very toxic. And in particular, risk of infection can be life-threatening.

So, having these new regimens of novel agents with or without antibodies, I think, is going to be a major breakthrough for CLL patients, and in particular, that’s in terms of their intolerability. I think as we move forward into the future also, we’re hoping to develop more time limited regimens. Because right now, most of these novel agents have been developed as a continuous therapy. And so, I’m optimistic that by combining multiple agents, we’ll be able to develop these time-limited regimens, which will be both helpful in terms of the cost of the regimen, but also reducing toxicity and hopefully preserving efficacy.

Transcript edited for clarity.

• A 76-year-old male presented with symptoms of low-grade fever, (101.1^oF) chills, and weight loss. The patient feels severely fatigued and required extensive rest. He was recently hospitalized for pneumonia.
• PMH: Hypertension controlled on candesartan, diabetes managed with metformin
• PE: Pallor and is weak-appearing, vital signs WNL, enlarged mobile lymph nodes bilaterally (~2.0 cm), anterior cervical chain, no hepatosplenomegaly
• PS, ECOG 2
• Laboratory findings:
  • WBC; 18.5 X 10⁹/L, 65% lymphocytes
  • Lymphocytes; 86.2 X 10⁹/L
  • Hb; 12.2 g/dL
  • Platelets; 305 X 10⁹/L
  • ANC; 120/mm³
• Flow cytometry; CD5+, CD19+, CD23+, CD38-low,
• Cytogenetics, IgVH mutation status, unknown
• β2M, 2.6 mg/L
• BM biopsy; 50% lymphocytes
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with ibrutinib and achieved a complete response to therapy after 2 months