Further Improving the Management of CLL

William G. Wierda, MD, PhD:This patient received ibrutinib in the frontline setting. They had a nice response. The RESONATE-2 trial was the clinical trial that led to approval of ibrutinib in the frontline setting. Most of those patients are responding to treatment and are able to continue on treatment and have continued disease control. So we don’t even know what the median progression-free survival from that trial is for a frontline treatment with ibrutinib, but it is several years.

In several years, if this patient progresses and needs an alternative treatment, right now the standard treatment option for a patient who is in such a setting would be venetoclax plus rituximab. Venetoclax plus rituximab was FDA approved based on a clinical trial referred to as the MURANO trial. That was a randomized trial of BR [bendamustine plus rituximab] versus venetoclax plus rituximab and showed an improvement in progression-free and overall survival for patients who received the venetoclax plus rituximab. And so that treatment, venetoclax and rituximab, would be my next recommendation for this patient when this patient progresses on ibrutinib.

There is another treatment option. The other treatment option is a PI3 kinase inhibitor—based treatment, idelalisib plus rituximab or duvelisib monotherapy. The toxicity profile and adverse events that you see with venetoclax-based treatment is different from what you see with a PI3 kinase–based inhibitor. PI3 kinase inhibitor treatment works in patients who have a 17p deletion, so that is an option, including for those patients whom we would consider high risk. But venetoclax-based therapy would be my next choice for this patient if they progressed.

Standards of treatment are really evolving very rapidly, and it’s been fortunate to work in CLL [chronic lymphocytic leukemia] and developing CLL treatments. Because over the recent years, we’ve had a number of agents that have been developed and are very, very active and effective in treating the disease. And we have long remissions and responses that we see with these nonchemotherapy options. So patients are doing exceptionally well. In fact, I think for a 78-year-old patient like this one, their life expectancy probably isn’t altered by the diagnosis of CLL. They will need treatment for their CLL, but their life probably isn’t shortened by the diagnosis of CLL because we have ibrutinib, we have venetoclax, we have the PI3 kinase inhibitors. So there is great reason for these patients to be optimistic about all the progress and advances that we are making.

We are very excited about our new clinical trials that we are working on, in particular combinations of these small-molecule inhibitors. Because with the combinations, we’re seeing very deep remissions with a fixed duration of treatment in which patients can be treated for a year or 2, get a deep remission, and then can come off treatment. So in the combination studies, we’re talking more and our trial design is a fixed duration of treatment and a remission period off treatment, which should be several years. And so we’re sort of transitioning back into this period of getting patients in remission and getting them off treatment, even with the small-molecule inhibitor therapies.

Now there are patients who develop resistance, and that is an area of unmet need. So there are drugs being developed for patients who are particularly ibrutinib refractory, reversible inhibitors of BTK [Bruton tyrosine kinase]. We still see Richter transformation, which is a transformation to an aggressive lymphoma that still is a difficult entity to treat, and we need more treatment options for those patients who develop Richter transformation. So our work is not done. We have new problems and challenges with resistance and figuring out resistance, but it’s been a very gratifying time to work in CLL research in terms of developing these new drugs and currently in terms of our trials that are ongoing with combinations.

Transcript edited for clarity.

An Elderly Woman With CLL

• A 78-year—old female presented with symptoms of fatigue and loss of appetite for the past six months
• PMH: recurrent bronchitis during past 12 months, treated with antibiotics
• PE: vital signs WNL, right cervical lymphadenopathy, spleen palpable 5 cm below costal margin, otherwise well-appearing
• Laboratory findings:
  • WBC, 53,000; 76% lymphocytes
  • Hb; 10.4 g/dL
  • Platelets; 150 X 10⁹/L
  • ANC; 180/mm³
• Flow cytometry; CD5+, CD19+, CD23+
• Cytogenetics, FISH: trisomy 12; IgVH mutated
• β2M, 3.6 mg/L
• BM biopsy; diffuse infiltration by CLL
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with ibrutinib and achieved a complete response to therapy after 4 months