What is the Role of PI3K Inhibitors in the Treatment of CLL?


Andrew Zelenetz, MD, offers guidance on how PI3Ki (phosphoinositide 3-kinase inhibitors) fit into the treatment landscape of chronic lymphocytic leukemia.

Andrew Zelenetz, MD: The big question is with the availability of multiple agents. We have multiple BTK [Bruton tyrosine kinase] inhibitors. We have venetoclax. We have a couple of additional—and what looked like effective—BCL2 inhibitors in clinical trials. We have noncovalent BTK inhibitors that have activity in patients who develop resistance to BTK and particularly with the 1641C mutation of BTK. We have a large number of drugs. The question then becomes, “Where do we fit the PI3 kinase inhibitors in the spectrum of truth?”

In my practice, if I don’t have a clinical trial available, I’ll start patients on a BTK inhibitor. Some patients will opt preferentially to be treated with a CLL14-like treatment with obinutuzumab and venetoclax because it’s time limited. If I start with venetoclax, I’ll typically go to a BTK inhibitor. If I start with a BTK inhibitor, I’ll try to maximize the duration of the benefit of the class of drug. In a case like this, with a patient who developed atrial fibrillation, I normally wouldn’t immediately switch. I would switch to a different BTK inhibitor, such as acalabrutinib or zanubrutinib, because of the lower risk of atrial fibrillation. If patients develop resistance and have a 1641C mutation, I don’t give up on the class of the drug. I switch to a noncovalent BTK inhibitor such as pirtobrutinib to try to maximize the duration of benefit from this class of drug.

The other thing we’ve seen, and we have emerging data, is that combinations of a venetoclax with a BTK inhibitor are highly effective and result in very high levels of undetectable minimal residual disease [MRD]. We’ve recently presented data on a 3-drug combination: obinutuzumab, zanubrutinib, and venetoclax. This was a response-adapted treatment. The median time to discontinuation of treatment because patients achieved undetectable minimal residual disease for a minimum of 2 months was only 10 months on therapy.

Many clinicians ask, “What’s the role of MRD monitoring in patients with chronic lymphocytic leukemia?” This isn’t a simple question because the role of MRD monitoring is tightly tied through the treatment that you’re giving. For instance, BTK inhibitors and PI3K inhibitors rarely, if ever, will resolve in undetectable minimal residual disease even as measured by 4- to 10-color flow, which have a sensitivity of 10-40. But if you’re talking about a next-generation immunosequencing assay, then we’re talking about an assay with a sensitivity of 1 in 105 or 1 in 106. In that setting, there’s no role for minimal residual disease testing with open-ended therapies like BTK inhibitors and PI3K inhibitors.

The emerging for MRD determination is in with combinations where we expect high rates of undetectable minimal residual disease and could potentially help guide the discontinuation of therapy. Right now, we’re not using MRD testing in that way. But in the not-too-distant future, you’re going to see emerging data that say, “If you’ve given 12 months of obinutuzumab and venetoclax, and you’re still MRD positive, particularly if you have TP53 mutation, then you probably should continue with treatment and not discontinue.” Some of the applications of MRD testing are just emerging. Certainly, in the setting of open-ended BTK or PI3K therapy, simply monitoring peripheral blood counts and physical exams are adequate to know whether patients are responding or have developed disease resistance.

This transcript has been edited with clarity.

Case: A 77-Year-Old Man With Chronic Lymphocytic Leukemia

Initial Presentation

  • A 77-year-old man presented to urgent care reporting worsening fatigue accompanied by persistent, unexplained fevers and night sweats over the past few weeks and unintentional 12-lb weight loss over the past 6 months
  • PMH: HTN, medically controlled; BPH; OA in spine and hips
  • PE: palpable cervical, axillary, and right-sided inguinal lymphadenopathy

Clinical Workup

  • Labs: WBC 49,000, lymphocyte 74%, ANC 3700/mm3, Hb 9.2 g/dL, PLT 90 x 109/L, LDH 240 U/L, B2M 4.1 mg/L
  • FC: CD 5+, CD23+, CD20+ monoclonal B-cell population; confirmed diagnosis of CLL

Hem/Onc Workup

  • Mutation testing: IGHV unmutated; FISH: positive for del(11q)
  • Rai stage IV; Binet stage C
  • ECOG PS 1


  • Started on treatment with ibrutinib 420 mg PO QD; his symptoms improved and he achieved partial response
  • 3 months into treatment he returned to urgent care reporting SOB, pain in his chest, confusion, and anxiety; he was convinced he was having a heart attack
    • Work-up revealed treatment-related atrial fibrillation
    • Situation was explained to the patient and he was offered medication and monitoring but preferred to change to a different medication out of concern for this happening again or worsening
    • Labs were repeated
  • Treatment was initiated with idelalisib 150 mg PO BID + rituximab
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