Rationale for Frontline Ibrutinib +/- Rituximab in CLL

Ian W. Flinn, MD, PhD:The rationale for using ibrutinib and rituximab for this young patient with progressive and symptomatic CLL [chronic lymphocytic leukemia] comes from a series of trials, but most prominently the recent study that was presented in December at the ASH [American Society of Hematology Annual] Meeting & Exposition by Dr Tait Shanafelt. This study compared ibrutinib and rituximab in symptomatic patients who required treatment [with] fludarabine, Cytoxan, and Rituxan [FCR], which was the gold standard until this time.

In this study, we saw some really dramatic differences. We saw an improvement in progression-free survival for the patient population at large, but also, when we looked at the subgroups, we saw that virtually every subgroup that was tested—whether someone was old or they were young, whether they had a good performance status or a poor performance status, whether they had high-risk cytogenetics or not—benefited from treatment with ibrutinib and rituximab.

There’s 1 subgroup that probably bears a little bit more discussion, and that has to do with patients who have mutated immunoglobulin heavy chain. These are patients for whom we normally think of having good risk for their CLL. If we look at some of the long-term follow-up from studies, some of the studies conducted with fludarabine, Cytoxan, and Rituxan, or FCR, we see that a subgroup of those patients have a plateau in their survival curve as well as their progression-free survival curve. This would suggest that some patients treated with FCR with very good-risk CLL may never relapse and may go on for many, many years without needing therapy.

This is a controversial group of patients. When you treat someone with ibrutinib and rituximab, then you’re really committing them to therapy for a very long period of time, as long as they’re not having adverse events. And so some people have questioned this. But in this study, even in that mutated immunoglobin heavy chain group, those patients appeared to benefit from the ibrutinib and rituximab investigational treatment.

Personally, I use single-agent ibrutinib rather than ibrutinib and rituximab. This is based on a couple of other studies. One was the study from the Alliance [for Clinical Trials in Oncology] that compared bendamustine and rituximab with ibrutinib and with ibrutinib and rituximab. And in that study, researchers saw no difference between the ibrutinib group and the ibrutinib and rituximab group. Both groups did much, much better than the bendamustine-rituximab group in terms of progression-free survival.

And so from that it doesn’t really look like the addition of rituximab to ibrutinib adds much to ibrutinib alone. This is also supported by data from The University of Texas MD Anderson Cancer Center, where the addition of rituximab did not seem to improve outcomes for patients who were treated with ibrutinib. So ibrutinib alone did just as well as ibrutinib with rituximab. For that reason, I tend to treat my patients with just single-agent ibrutinib instead of the combination of ibrutinib with rituximab.

Transcript edited for clarity.

Case:A 62-Year—Old Male WithIgVH-Unmutated CLL

• A 62-year-old male presented to PCP with complaints of extreme fatigue and night sweats
• PE: Enlarged mobile lymph nodes bilaterally (~1.5 cm), no palpable spleen or liver
• Laboratory findings:
  • WBC; 100 X 10⁹/L
  • Lymphocytes; 82 X 10⁹/L
  • Hb; 11.2 g/dL
  • Platelets; 190 X 10⁹/L
  • ANC; 1,950/mm³
  • LDH 150 U/L
• Cytogenetic; del(11q),IgVH-unmutated
• β2M, 2.9 mg/L
• Referred to community oncology who diagnosed patient with chronic lymphocytic leukemia
• Patient was started on ibrutinib + rituximab (IR)
• Rai Stage I