Managing Disease Recurrence in CLL


An overview of assessing risk of disease recurrence, steps taken to minimize recurrence, and when to consider second-line treatment for patients with 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.


John Allan, MD: Once you treat a patient and stop their therapy, the next big question is, how do you minimize the risk of disease recurrence? In this setting, it’s hard to minimize the risk of disease recurrence aside from assessing the baseline biologic molecular features of the CLL [chronic lymphocytic leukemia] going into the treatment. Because we’re using a fixed-duration approach and stopping treatment, there’s no way to minimize risk recurrence. But we assess for the risk of recurrence by these risk factors, and we can at least set the stage for expectations.

We’re stopping treatment, so we’re not modifying therapy, in terms of these patients. One way we do this, and 1 way I do this, is to utilize MRD [minimal residual disease] analysis. I’ll use either flow-based assays or next-generation sequencing assays. In patients who are MRD negative, there are lots of data—whether it’s combination fixed durations or venetoclax-obinutuzumab-based fixed durations—demonstrating that regardless of your risk, if you’re MRD negative, you’ll have phenomenal outcomes and better outcomes than patients with MRD-positive disease. Although it isn’t used in terms of managing a patient or making treatment decisions, it is very prognostic and can help set expectations for a patient. I use MRD at the end of the treatment to help understand how long a patient will be in remission. In patients who are MRD negative, 5-year outcomes were 64% for all comers. This starts to push up to 70%-plus, 80%-plus, or higher for patients who are MRD negative, particularly those with lower-risk disease. That’s 1 way I assess the risk of recurrence.

We’re now learning with venetoclax-obinutuzumab-based approaches that certain genetic features that we learned at ASH [American Society of Hematology Annual Meeting] 2022 will predict recurrence. One is the NOTCH1 mutation. Patients with NOTCH1 mutations seem to be recurring sooner rather than later. There’s another higher-risk disease feature, EGR2, which also can predict recurrence. Obviously, TP53disruption and unmutated IGHV predict recurrence sooner as well. For the first time, NOTCH1 and some of these other genetic mutations are identifying patients at risk for earlier recurrence. Does it impact overall survival? We don’t know. Does it impact re-treatment? We don’t know. But we set expectations differently for patients if they have these features. This is why it’s so important to understand our FISH [fluorescence in situ hybridization], have our FISH analysis, have our IGHV-mutational analysis, and have our next-generation-sequencing analysis—to put together the true risk of the patient. What are the molecular features driving the disease and the expectations for remissions once you stop treatment, particularly if you’re MRD negative?

Transcript edited for clarity.

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