CLL14: Venetoclax and Obinutuzumab in Patients With Previously Untreated CLL

Video

An expert on chronic lymphocytic leukemia reviews the CLL14 trial, evaluating venetoclax plus obinutuzumab in patients with previously untreated CLL.

Case: A 72-Year-Old Woman with Newly Diagnosed Chronic Lymphocytic Leukemia (CLL)

  • Patient KM is a 72 y/o woman.
    • PMH: Hypertension (well controlled on medication)
    • SMH: Does not smoke; drinks occasional glass of wine in social setting; Walks with friends 2-3 times weekly.

Clinical Presentation:

  • In October 2022, KM visited her PCP for her annual checkup. She reported having persistent fatigue and recent occurrences of night sweats.

Clinical Workup and Diagnosis:

  • WBC: 186,000; 80% lymphocytes
  • Hgb, 9.4 g/dL
  • Platelets, 85 x 109/L
  • ECOG PS 0
  • Elevated serum beta-2-microglobulin
  • Flow cytometry, CD5+, CD20+, CD23+
  • TP53 mutation status – unmutated; IGHV mutation status – unmutated
  • Bone marrow biopsy confirms diagnosis of chronic lymphocytic leukemia (CLL)

Current Treatment:

  • After discussions with her family and clinical team, KM was initiated on fixed duration of venetoclax + obinutuzumab.
    • KM was started on obinutuzumab at 100 mg IV Day 1, followed by 900 mg IV on Day 2, then 1000 mg IV on Days 8 and 15 of Cycle 1; Currently infused with 1000 mg IV on Day 1 of remaining cycles.
    • She was initiated on a ramp-up dosing schedule of venetoclax starting on C1D22 and currently taking the recommended dose of 400 mg PO daily.

Transcript:

John Allan, MD: The CLL14 [trial] is a landmark study that has changed how we treat patients with CLL [chronic lymphocytic leukemia]. It has now matured with a 5-year median follow-up of patients. We have really good data and are starting to get longer-term data. This was recently presented at EHA [European Hematology Association annual meeting] of 2022 by Othman Al-Sawaf, [MD,]who was the lead for the German CLL study group for this study. What we’ve seen is that the median progression-free survival [PFS] still has not been met. We see at 5 years about 64% of patients are still progression free. The benefit is that they are off therapy.

CLL14 treated patients for 1 year, and then all patients stopped treatment regardless of some MRD [minimal residual disease] or response, and stopped therapy at that point in time. And 5 years later, 64% of patients are progression free. I think the overall survival [OS] is measured still in the 80%-plus range. What we are seeing is that patients are having excellent outcomes, which has established this regimen basically as a standard of care for our patients with CLL.

What we’re starting to note though is that with long-term follow-up, after stopping treatment, patients with higher-risk disease are starting to separate themselves and are progressing sooner, particularly patients with IGHV unmutated disease, which is relevant for the patient in this case. The median PFS for patients with an unmutated IGHV has been met right around or a bit over 5 years. The median PFS for patients with TP53 disruption is met right around 4 years. In patients without those features, the median PFSs haven’t been met, and the 5-year PFS rates are in the 70%-plus range, if not higher, which is very consistent with what we see with continuous therapy BTK [Bruton tyrosine kinase] inhibitors.

So while this patient, because she has an unmutated IGHV, may expect to have a remission of 5 to 6 years, somewhere in that range, half of the patients are still going to have a remission longer than that. There is a great benefit that this patient will be off of therapy for those 4 to 5 years, sparing toxicities and financial issues. And there are good data that suggest we may be able to regain responses with venetoclax retreatments, and good data that even if we don’t use venetoclax at that relapse, there will be good salvage options using a BTK inhibitor. We’ve never shown a detriment to OS in these patient subgroups as of yet. While the PFS seems less than those patients without these high-risk features after a fixed-duration [venetoclax] approach, the outcome is still so much better than what we’ve ever experienced before. With 5, 6 years in remission before needing treatment and being off of therapy with high-risk disease features, it is still a very valid treatment approach. And some may argue it would still be the best approach for these patients as you try to eliminate these clones and get to an MRD-negative state, and potentially prevent resistance and some of these other things from arising.

Transcript edited for clarity.

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