Sequencing After Frontline BTK Inhibition in CLL

Matthew S. Davids, MD, MMSc:Increasingly BTK [Bruton tyrosine kinase] inhibitors like ibrutinib are being used as frontline treatments for CLL [chronic lymphocytic leukemia]. And the question naturally arises, what do we do next if patients begin to progress either on ibrutinib or if they’ve stopped ibrutinib, if the disease relapses. Typically, when we get patients on this course of novel agent-based therapy, we tend to move to another novel agent. So we wouldn’t necessarily go to a chemoimmunotherapy approach in a patient who has progressed on ibrutinib. Mainly, that’s because we don’t really have much data to support that approach. There’s no reason to think that chemoimmunotherapy wouldn’t work for that patient. But often these patients have done well on ibrutinib for a few years. They’re older and maybe have more comorbidities so it’s desirable to move away from chemoimmunotherapy in the relapsed setting.

Furthermore, we have some recent data from the phase III MURANO study suggesting that patients who are treated with venetoclax, the BCL2 inhibitor, with rituximab, have a markedly superior progression-free and overall survival compared with patients with relapsed CLL who are treated with BR [bendamustine/rituximab]. So this is certainly evidence suggesting that a novel agent-based approach is helpful in the relapsed setting in comparison with chemoimmunotherapy, with the caveat that on that MURANO study there were very few patients who had progressed on ibrutinib.

We do have some data from a study which was specifically for patients progressing on ibrutinib who then went on to venetoclax monotherapy. There were about 90 patients on that trial, and about two-thirds had a nice response to venetoclax. So based on those data I feel comfortable recommending venetoclax, usually with rituximab, as the next line of therapy after patients who have progressed on frontline ibrutinib.

Now there are some patients who may not be great candidates for venetoclax. These are patients sometimes who may have significant renal dysfunction where you’re worried about risk of tumor lysis syndrome. There are also some logistical challenges of starting venetoclax to reduce this risk of tumor lysis syndrome.

In patients where there are difficulties initiating venetoclax or there isn’t a great renal function, these are patients where a PI3 kinase inhibitor can be a great option. We have a couple of different PI3 kinase inhibitors that are approved for relapsed CLL now. We have idelalisib, which has been approved for several years and is usually given in combination with rituximab. And then we have duvelisib, which was just approved in September of 2018, which provides an all oral option for patients who need a PI3 kinase inhibitor.

So I think for patients who have either progressed on both ibrutinib and venetoclax, or for patients who have progression on ibrutinib but for some reason are not a good candidate for venetoclax, these PI3 kinase inhibitor drugs are also a good option.

Transcript edited for clarity.

Case:A 74-Year-Old Male WithIgVH-Unmutated CLL

• A 74-year-old male presented to PCP with complaints of extreme fatigue, weakness, and weight loss of ~15lbs over the last 3 months.
• PMH: Mild hypertension managed by statin
• PE: BP 135/85, enlarged lymph nodes (~6cm), palpable spleen approx. 7cm below costal margin
• Laboratory findings:
  • WBC; 100 X 10⁹/L
  • Lymphocytes; 82 X 10⁹/L
  • Hb; 15.1 g/dL
  • Platelets; 125 X 10⁹/L
  • ANC; 1,800/mm³
  • LDH 250 u/L
• β2M, 4.3 mg/L
• FISH; normal
• Molecular analysis;IgVH-,TP53wild-type
• ECOG PS 1
• Rai Stage II