Choosing First-Line CLL Therapy in a Patient With Del(17p), TP53

Treating high-risk chronic lymphocytic leukemia (CLL) requires careful consideration of a patient's genetic profile and comorbidities to select the most effective targeted regimen. Mazyar Shadman, MD, MPH, professor of the Clinical Research Division, medical director for Cellular Immunotherapy and the Bezos Family Immunotherapy Clinic, and Innovators Network Endowed Chair at the Fred Hutchinson Cancer Center, focused on first-line treatment options for a patient with a TP53 aberration during a virtual Case-Based Roundtable event. Shadman highlighted preferred NCCN regimens and noted that chemoimmunotherapy is no longer a recommended option for this high-risk patient population.

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CASE SUMMARY

• A 66-year-old White woman presented with fatigue and unintentional weight loss​.
• Medical history: Asymptomatic lymphocytosis identified in 2021; initially monitored; after 2 years, developed anemia, night sweats, and splenomegaly
  • Hyperlipidemia
  • Chronic kidney disease (stage III)​
• Medications:​ atorvastatin​, omeprazole​
• ECOG performance status: 1​
• Splenomegaly: 17 cm along the long axis
• Imaging:
  • CT scan: largest lymph node, 3.2 × 1.9 cm​; all other under 3 cm
  • PET scan: standardized uptake value (SUV), 3
• Laboratory results:
  • White blood cells (WBCs): 66.8 × 10⁹ cells/μL​
  • Absolute lymphocyte count (ANC): 55.1 × 10⁹ cells/μL​
  • Hemoglobin: 9.7 g/dL​
  • Platelet count: 175 × 10³/μL​
  • Lactate dehydrogenase: 240 U/L​
  • Serum creatinine: 1.4 mg/dL
• Fluorescence in situ hybridization: deletion 17p (del[17p])
• Molecular analysis: IGHV unmutated (VH1-69),​ TP53​ mutated, complex karyotype ​
• The patient is in the unfavorable risk category.

Targeted Oncology: Which factors do you look at when trying to decide on treatment for patients with CLL?

Mazyar Shadman, MD, MPH: In terms of picking the right treatment choice, we look at a number of factors. We look at patients’ age, performance status, and comorbidities. Some of these drugs, Bruton tyrosine kinase [BTK] inhibitors may come with some bleeding or cardiac risk. So in patients with major cardiac problems, we may want to have a cardio-oncologist on board. In patients with severe kidney problems, we may not want to use venetoclax [Venclexta] and basically using comorbidities as our variables that we consider in making a decision. We look at the genetic profile of disease, del(17p) or TP53 mutation; in short, any aberration in the TP53 gene, either in form of a deletion or mutation are important in making a clinical decision.¹

Complex karyotype, which is defined by having 3 or more abnormal chromosome findings on your conventional karyotype—and by some new definitions, maybe 5—is also considered to be an adverse factor in some settings. IGHV mutational status is important. Having an unmutated status could predict the duration of progression-free survival in fixed-duration therapies. In general, picking the right regimen is based on risk and benefit profile and patient preferences. In the relapse setting, of course, it's important to know what type of response patients had to prior lines of therapy and also what was the reason for treatment discontinuation.

Can you discuss the first-line treatment options for this patient with CLL, del(17p), and a TP53 mutation?

We treat [having] both as an aberrant TP53. In a way, it doesn't matter if there's a deletion or mutation, if they have a dysfunctional TP53 gene, they are considered in this category. What we don't see [in the NCCN guidelines] is chemoimmunotherapy.²

In terms of the preferred regimens that we have listed, we have the BCL-2 inhibitor–containing regimen, venetoclax [Venclexta] and obinutuzumab [Gazyva], and also venetoclax/acalabrutinib [Calquence]/obinutuzumab. For the covalent BTK inhibitor—based regimens, we have acalabrutinib plus/minus obinutuzumab, and then we have zanubrutinib [Brukinsa], and we don't see ibrutinib [Imbruvica]; that's now shifted to the other recommended regimens.

What do you think of the venetoclax combinations for this subset of CLL?

Venetoclax/obinutuzumab is not a [bad option], but the survival in someone with abnormal TP53 will be shorter than somebody without, so that's something to remember. Also, we have venetoclax plus acalabrutinib plus/minus obinutuzumab. I think if we decided to use this combination for a patient with del(17p), it only makes sense to use venetoclax/acalabrutinib plus obinutuzumab. There are no data for venetoclax and acalabrutinib without the antibody for patients with del(17p).

The AMPLIFY study [NCT03836261] did not include patients with del(17p), so that doublet is not relevant. The study that used venetoclax and acalabrutinib and obinutuzumab was the single-arm study at the Dana-Farber group did [NCT03580928]. I mentioned it because there's some confusion in the NCCN guidelines about that.

What other combination options are recommended by the NCCN?

BTK inhibitors are choices that make a lot of sense for high-risk patients, including this patient. We have data for both zanubrutinib and acalabrutinib. We have some other options with venetoclax and ibrutinib. This combination is not approved in the United States, and it's not expected to be approved in the United States based on some safety concerns from the GLOW trial [NCT03462719]. It is approved and is being used in Europe, Canada, and Australia. This combination will not be the first BTK inhibitor plus BCL-2 inhibitor that we'll have in the United States as an FDA-approved regimen. Ibrutinib was sent to the "Other recommended regimens" category because of the randomized studies that were done in the relapsed setting.

In terms of using high-dose methylprednisone and obinutuzumab, those are rarely used these days with the access to the novel drugs.

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_{DISCLOSURES: Shadman previously reported employment with Bristol Myers Squibb; a consulting or advisory role with AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeOne Medicines Ltd, Bristol Myers Squibb/Celgene, MorphoSys, Kite, a Gilead company, Fate therapeutics, Lilly, Genmab, Merck, Nurix, and ADC Therapeutics; and patents, royalties, or other intellectual property with Koi Biotherapeutics Stock options.}

_References:

_{1. Shadman M. Diagnosis and treatment of chronic lymphocytic leukemia: a review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma; version 1.2026. Accessed October 31, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf}