Therapeutic Approach for CLL Progression

Matthew S. Davids, MD, MMSc:If this patient starts on an ibrutinib-based regimen, I would expect the patient derive at least a few years of benefit from it. However, we don’t think that ibrutinib is going to be a curative option for patients like this. And so, eventually, they are likely to progress. At that point, we have a couple of different options we can consider, and we have some datasets to guide us in this respect.

One of them is some retrospective data that have recently been assembled by Anthony Mato and colleagues suggesting that a drug, venetoclax—which targets BCL2, a completely different mechanism from ibrutinib—may be effective for this group. And at least in this retrospective series, the patients tended to have more durable responses than switching to other drugs like idelalisib, which is hitting a similar pathway as ibrutinib.

We now also have some prospective data to guide us from a phase II study that was conducted by Jones and colleagues, treating patients who are progressing on ibrutinib with venetoclax. And about two-thirds of patients achieved response with good durability in that group. So, typically for a patient progressing on ibrutinib now, if they’re a candidate for venetoclax, that would usually be the drug I would turn to next unless they had certain comorbidities. For example, renal dysfunction can make it challenging to start venetoclax due to a risk of tumor lysis syndrome. And in that type of patient, I think idelalisib potentially with rituximab is a good option for that patient.

In terms of how we’re sequencing the novel agents now in CLL, we’ve been mainly using chemoimmunotherapy as frontline treatment in most cases. And I would say, in general, what I’ve seen is that ibrutinib has been used most commonly as the first agent in time of relapse.

Now this is all evolving as ibrutinib is moving up into the frontline treatment regimens for more and more patients. And then the question becomes, what do you use after that? And at this point, it seems like venetoclax is becoming the next drug that most people are reaching for. I think what’s going to be interesting in the field is that venetoclax is also moving up into the upfront setting. For example, an ongoing study called CLL14 is randomizing patients to venetoclax with obinutuzumab as a frontline regimen versus chlorambucil/obinutuzumab.

And if that study is positive, then that’s going to have major implications in terms of the sequencing of these different drugs. And then furthermore, regimens that combine all 3 of the major antibody regimens—obinutuzumab, ibrutinib, and venetoclax—if those are all given in the frontline setting, I think it’s a very exciting opportunity to get very nice responses. But the question becomes, what do you treat those patients with if and when they relapse? And I think that’s a major unanswered question for the field right now.

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