Case Overview: A 73-Year-Old Woman With CLL

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EP: 1.Case Overview: A 73-Year-Old Woman With CLL

EP: 2.Frontline Management of Chronic Lymphocytic Leukemia

EP: 3.Second-Line Treatment Options for Relapsed CLL

EP: 4.Monitoring and Managing Adverse Effects of CLL Therapy

EP: 5.Ongoing Challenges and Unmet Needs in CLL

Jeff Sharman, MD: Hello. My name is Jeff Sharman. I’m the medical director of hematology research for The US Oncology Network at Willamette Valley Cancer Institute and Research Center, and I practice general oncology in Eugene, Oregon. I would like to share a case of a 73-year-old woman with relapsed chronic lymphocytic leukemia [CLL] today. Her initial diagnosis occurred at age 73, when she presented to her primary care provider for a routine checkup complaining of mild progressive fatigue, unintended weight-loss, and occasional night sweats for the past 3 months. She had a history of hypertension that was medically controlled. She had mild osteoarthritis. She had high-risk prediabetes, managed with metformin, diet, and exercise.

On the physical exam, she had palpable right-sided axillary and bilateral inguinal adenopathy. Work-up at that time revealed a white blood cell count of 51,000 per mm3: 78% of which were lymphocytes. She had an absolute neutrophil count of 3700 per mm3, hemoglobin of 8.9 g/dL, and platelets of 90,000 per mm3. Her LDH [lactate dehydrogenase] was within normal limits, and her ß-2 microglobulin was elevated. Her creatinine clearance was diminished at 31 mL/min. Flow cytometry revealed a B-lymphocyte population with coexpression of CD5 protein, CD23 protein, and CD20 protein. This monoclonal B-cell population was confirmed to be CLL. FISH [fluorescence in situ hybridization] was performed and tested positive for deletion of chromosome 17P. Her IGHV status was unmutated, and she had Reye syndrome stage IV disease on the basis of her thrombocytopenia, or Binet stage III disease. Her ECOG performance status was 1, but her Cumulative Illness Rating Scale was 7. She was started on treatment with 420 mg of ibrutinib [Imbruvica] once daily.

Her symptoms improved, and she achieved stable disease with resolution of her lymphadenopathy. Three years later, however, she complained of increasing fatigue, abdominal pain, and decreased appetite. Upon physical exam she had return of her palpable lymphadenopathy and splenomegaly and this time, her creatinine clearance was 40 mL/min. CT scan was performed and did reveal multiple lymph nodes, in excess, of 5 cm. At that time, treatment was initiated with idelalisib, 150 mg twice daily, as well as rituximab [Rituxan].

There are a number of interesting things to think about with this case. First of all, general impressions: What do I think about this patient? In many cases, we’re given case presentations of 76-year-olds who are otherwise perfectly healthy, except for their CLL. But in the real world, we see that medical comorbidities are quite common and significant. They influence how patients are going to be able to adhere with follow-up plans and how these diseases are going to impact their CLL treatment. Realistically, we all have to make treatment decisions—for these patients who have medical comorbidities—and select therapies that take that into account.

That’s really important. When we think about risk factor stratification, 1 test stands out above all others; that’s FISH. FISH stands for fluorescence in situ hybridization, and there are 5 main categories of responses. Patients can have deletion of chromosome 13q. They could have normal chromosome changes. They can have an extra copy of chromosome 12. They can have a deletion of 11q or 17p; 17p is really the works. These are patients who are going to be refractory or experience early relapse from any toxic therapy. I very much agree with her initial treatment selection of ibrutinib. Ibrutinib is 1 of the oldest BTK [Bruton tyrosine kinase] inhibitors and the 1 that’s got the longest track record. But even for patients started on ibrutinib, if they have deletion of 17p, they’re typically going to have a shorter overall disease control with ibrutinib than they would if they lacked the 17p. It’s really important for us to know this ahead of time.

Another molecular characteristic that’s underutilized is TP53 mutation. TP53 mutation is not acquired by way of FISH. It’s a test obtained by sequencing, and it behaves roughly as bad as 17p. When people have 17p, the TP53 gene is missing. Knowing both at a sequence level and as FISH testing, the status is of TP53 is really important. In this case, I don’t think it’s surprising that she had disease progression within just 3 years of starting ibrutinib. Typically, when patients with adverse molecular characteristics progress, they may have acquired a mutation in their BTK protein, and 1 of the interesting features, currently, is what we call cysteine 41 serum. That’s the binding site for the covalent BTK inhibitors. Ibrutinib, acalabrutinib [Calquence], and zanubrutinib [Brukinsa] all bind irreversibly to that site. If the cancer cells are able to put a mutation in that spot, the covalent inhibitors will no longer work.

Other mutations can arise, but they’re far and away the most common. It’s worthwhile to check, and it will become more worthwhile as additional drug therapies become available in the next few years.

This transcript has been edited for clarity.