Chronic Lymphocytic Leukemia: Sequencing Agents

William G. Wierda, MD, PhD:Sequencing options and sequencing are very important these days. It’s because this disease is a chronic disease. Patients usually move through the various treatment options over a number of years, and new options become available all the time. So the characteristics of a relapsed population do change over time. Earlier on, several years ago, most of the relapsed patients had been treated with chemoimmunotherapy and were relapsing from their chemoimmunotherapy, and they were needing a salvage treatment with that treatment history.

Now we’re talking about an era of using ibrutinib in the frontline setting and not using chemoimmunotherapy. So our patients who are failing standard first-line therapy will transition into a population that’s ibrutinib refractory or BTK [Bruton tyrosine kinase] inhibitor refractory and chemoimmunotherapy naїve. They won’t have seen chemoimmunotherapy. So the population of patients changes based on what agents are available and what we start with. We are transitioning into an era in which standard first-line therapy will be a BTK inhibitor. Most patients who are failing BTK inhibitor or who are intolerant to a BTK inhibitor will be chemoimmunotherapy naïve. We have other nonchemotherapy options, and so for next treatment after BTK inhibitor, there will be nonchemotherapy options that we are reaching to, and we probably won’t still be reaching to chemoimmunotherapy. That includes a BCL2 small-molecule inhibitor, which is venetoclax, and then the PI3 [phosphatidylinositol 3] kinase inhibitors.

And sequencing of these treatments is really driven by what’s available to treat the patients with and approved in a particular setting and what patients have had previously. So again, if we’re in an era in which frontline therapy is a BTK-based inhibitor, patients who are failing BTK inhibitors will move on to treatment with a BCL2 small-molecule inhibitor most likely and then subsequently most likely to a PI3-kinase inhibitor. That sequence is driven by tolerability and toxicities that we see between BCL2 small-molecule inhibitor versus the PI3 kinase inhibitor.

There’s another trial that we were expecting to see at ASH [the American Society of Hematology Annual Meeting & Exposition] that was not presented. That is, a trial that’s referred to as the CLL14 trial. That’s a trial that was done by the German CLL Study Group. That trial compared chlorambucil plus obinutuzumab versus venetoclax plus obinutuzumab. So that was a standard chemoimmunotherapy regimen of chlorambucil-based treatment versus venetoclax and obinutuzumab, which is a nonchemoimmunotherapy, non-BTK inhibitor-based treatment. And that trial has reportedly been a positive trial and shown improvement in outcomes for patients who received venetoclax-obinutuzumab in the frontline setting. When that trial is reviewed by the FDA, we expect that trial to lead to the approval of venetoclax in the frontline setting.

And so at that point we will be talking about these 2 different treatment options in the frontline setting, ibrutinib versus venetoclax plus obinutuzumab. That will be a big discussion about what are patient characteristics that drive selection of ibrutinib over venetoclax-based therapy. Both of those treatment options are effective in patients who have 17p deletion. So 17p deletion in that setting becomes less important. If you’re considering those options, then it would be if you were considering a chemoimmunotherapy option.

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