Part 3: Considerations for Venetoclax-Based Therapy in Frontline CLL

Sameer A. Parikh, MBBS

Assistant Professor of Medicine and Oncology

Mayo Clinic

Rochester, MN

CASE

• A 71-year-old woman reported symptoms of weight loss and increasing fatigue.
• Medical history: hypertension, medically controlled
• Physical examination: axillary lymphadenopathy, spleen palpable about 4 cm below costal margin; appears ill, does only limited daily activity
• Laboratory results:
  • White blood cell count: 47,000/mm3; 76% lymphocytes
  • Hemoglobin: 8.7 g/dL
  • Platelet count: 115,000/mm³
  • Absolute neutrophil count: 3600/mm³
  • Lactate dehydrogenase: 250 U/L
  • β₂-Microglobulin: 4.3 μg/L
• Flow cytometry: CD5+, CD20+, CD23+
• Fluorescence in situ hybridization (FISH): deletion 11q (del[11q])
• Molecular analysis: IGHV unmutated
• Bone marrow biopsy: diffuse infiltration by chronic lymphocytic leukemia (CLL), 90%-95%

Editor’s Note: This article is based on an earlier event. As such, more recent updates to the chronic lymphocytic leukemia landscape may not be reflected.

Targeted Oncology^TM: Can you describe the clinical trial data leading to the approval of fixed-duration therapy with venetoclax?

PARIKH: The CLL14 trial [NCT02242942] looked at fixed-duration venetoclax [Venclexta] and obinutuzumab [Gazyva] for 12 cycles compared with chlorambucil/obinutuzumab.¹ I’d emphasize that venetoclax was given for a year and everyone stopped treatment at that time point. Patients with del(17p) were included in this study.

With about 14 months of median follow-up, you can see that patients who got venetoclax and obinutuzumab did far better compared with those who got chlorambucil and obinutuzumab, which is not surprising. This led to the approval of venetoclax and obinutuzumab in the frontline setting.²

What genomic features would you consider to be adverse prognostic factors for the use of venetoclax?

As you start dissecting [these data], you will note that patients with unmutated IGHV status who were treated with venetoclax and obinutuzumab continued to [progress] faster compared with those with the mutated IGHV status, suggesting that this probably isn’t as good of a combination in patients with unmutated IGHV. Longer follow-up is necessary to see if this is truly because of unmutated IGHV or other factors that are at play. This is a cross-trial comparison.

In our practice, if we have a patient who has a TP53 mutation, we typically would not consider the addition of venetoclax and obinutuzumab. We would start off with single-agent BTK [Bruton tyrosine kinase] inhibitor therapy or consider adding a BTK inhibitor to an anti-CD20 agent as opposed to fixed-duration venetoclax and obinutuzumab therapy.

How does venetoclax affect minimal residual disease (MRD)?

The rate of undetectable MRD in the peripheral blood and bone marrow...is significantly better with venetoclax and obinutuzumab compared with chlorambucil and obinutuzumab, at 76% [versus 35%, respectively] undetectable in the peripheral blood. If you recall with ibrutinib and obinutuzumab in the ILLUMINATE study, it was about 35%, so it is much higher with the use of venetoclax and obinutuzumab. PFS [progression-free survival] by undetectable MRD status with the combination of venetoclax and obinutuzumab [is improved] compared with positive MRD at the end of treatment.

The PFS curve that is going down with venetoclax/obinutuzumab and positive MRD status doesn’t mean that patients should continue with venetoclax. That is a question in the context of a clinical trial, but this is generally thought of as a prognostic marker that patients will progress sooner compared with if they are MRD negative.

Another interesting piece is that patients who got chlorambucil/obinutuzumab [and achieved MRD-negative status] do almost as well as those with MRD-negative status on venetoclax/obinutuzumab. That was far better compared with even venetoclax and obinutuzumab [and MRD-positive status]. This just goes to show that if you are able to get a person into MRD-negative status, they are likely to do much better regardless of what kind of treatment you give them. Of course, you have to figure out if this patient will get there at 12 months or not, and the odds of that patient getting to MRD negativity are much higher with venetoclax and obinutuzumab.

What are the adverse event (AE) concerns with venetoclax?

The risk of tumor lysis with venetoclax [means clinicians must admit] patients for in-patient care for the first few doses of therapy if they are at high risk. The other important AEs include neutropenia.

CASE (continued)

• The patient was started on ibrutinib (Imbruvica) 420 mg daily.

Now that this patient has started BTK therapy, what will you be looking for?

In our experience, muscle aches and cramps are one of the more common AEs that lead to discontinuation of therapy. We’ve tried reducing the dose, a steroid dose, or something like that to help with the myalgias. Unfortunately, it can lead to stopping treatment in a few patients.

An AE that is unique to acalabrutinib [Calquence] is headache. Your patients will complain of a headache the first few weeks. I would typically tell them that it is responsive to caffeine or Tylenol. That’s a unique AE of acalabrutinib that doesn’t typically happen with ibrutinib.

If a patient is on 81 mg of aspirin, then I’m not too concerned about bleeding. I will get started with regular full-dose ibrutinib or acalabrutinib, but I will make sure that I check in with the patient at a week or 2 after the start of treatment to educate them about bruises on the upper extremities [and other areas], in which case I will bring down the dose of ibrutinib or acalabrutinib if it becomes excessive.

In my practice, [I might] administer FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)] to a young patient who can tolerate it with a mutated IGHV, a low risk, and a FISH-negative TP53. You put all of these things together, which is the ideal patient for FCR, and you may give that patient 3 or 4 cycles of FCR. If they are in MRD-negative remission, you don’t have to give the last 2 cycles of FCR.

When I give that option to a patient with a potential for 10-plus years of remission with about a 3% to 5% chance of MDS [myelodysplastic syndrome], I then give them the option of 1 year of venetoclax and obinutuzumab. Even if it’s a 55-year-old patient, most would choose venetoclax and obinutuzumab. Nobody wants that risk of MDS at 3% to 5% years after they get FCR. It’s becoming increasingly difficult to find patients who would be willing to get any kind of chemoimmunotherapy.

_References:

_{1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281}

_{2. FDA approves venetoclax for CLL and SLL. FDA. Updated May 19, 2019. Accessed September 29, 2020. https://bit.ly/3ijwf9n}