How I treat CLL and MCL: From ‘watch and wait’ to BCL2 and BTK inhibitors, CAR T-cell therapy, and transplant

Blood & Cancer

Treatments for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) have advanced in recent years, with more new developments on the horizon.

James Gerson, MD, of the University of Pennsylvania, Philadelphia, reviewed some of these advances and future directions while describing how he would treat three patients. Host David H. Henry, MD, posed the following cases for consideration.

Case 1

In a 75-year-old male with no comorbid illness, routine blood work revealed a WBC count of 15,000/mcL. The manual differential showed mature lymphocytes and smudge cells. The patient has no constitutional symptoms, but there is suspicion of CLL. What to do?

• An incidental finding of elevated WBC is the most common presentation for CLL, Dr. Gerson noted.
• Flow cytometry is how most diagnoses are made. If the patient’s blood sample is CD5+ and CD20+, in the vast majority of cases, the patient has CLL.
• The main alternative diagnosis is MCL, so Dr. Gerson recommends checking for cyclin-D1 overexpression and translocation (11;14), which would be present in MCL.
• Dr. Gerson also recommends fluorescence in situ hybridization (FISH), cytogenetics, and next-generation sequencing to assist with prognostication.
• When the exam is normal and the patient is asymptomatic, no imaging is required.
• For this patient, treatment should be deferred until disease progression.

Case 2

A 75-year-old, fit male has a WBC of 25,000/mcL, noted after the patient reported not feeling well, having a distended abdomen, night sweats, and weight loss. Blood work shows a hemoglobin level of 10.5 g/dL and a platelet count of 130 x 103/mcL. What to do?

• Because this patient is symptomatic, treatment is indicated, Dr. Gerson said.
• However, because of the pandemic, Dr. Gerson would likely delay therapy, perhaps until after COVID-19 vaccination.
• To assess risk, Dr. Gerson would perform immunohistochemistry, FISH, and next-generation sequencing in this patient.
• Patients with 17p deletion have high-risk disease, those with TP53 missense or nonsense mutations have even higher-risk disease, and patients with both a deletion and a mutation are “at excessively high risk,” Dr. Gerson said.
• He favors giving a BTK inhibitor to patients with TP53 mutation/17p deletion because of results from the CLL14 trial (N Engl J Med 2019; 380:2225-36. https://bit.ly/38pVHbf).
• However, because of the “small signal” in the trial, Dr. Gerson said plenty of his colleagues use a BTK inhibitor interchangeably with a BCL2 inhibitor and anti-CD20 therapy (e.g., venetoclax and obinutuzumab).
• Dr. Gerson said ibrutinib and acalabrutinib have similar efficacy, according to unpublished results of the ELEVATE-RR trial (https://bit.ly/38onIjy).
• Both drugs inhibit platelets, and there appears to be a higher risk of atrial fibrillation with ibrutinib.

Case 3

A 75-year-old, fit male has an elevated WBC, noted after complaints of bone pain, weight loss, night sweats, and enlarged lymph nodes. There is suspicion of MCL. What to do?

• MCL is a complicated disease and “incredibly” heterogeneous in clinical and pathological behavior, Dr. Gerson noted.
• The classic finding in MCL is cyclin-D1 overexpression caused by (11;14) translocation, but there are atypical translocations as well.
• The approach to first-line treatment of MCL varies and may include cytarabine-based induction, bendamustine plus rituximab, or rituximab alone.
• Brexucabtagene autoleucel, a chimeric antigen receptor T-cell therapy, is changing the landscape of treatment for relapsed/refractory MCL, Dr. Gerson said, as this treatment may offer a cure.
• Investigational therapies for MCL include the BTK inhibitor pirtobrutinib (LOXO-305) and hematopoietic stem cell transplant.
• Pirtobrutinib is under investigation in patients with MCL, CLL, and other indolent lymphomas that have progressed on or are intolerant to first-line therapy (Lancet. 2021 Mar 6;397[10277]:892-901. https://bit.ly/3rvRv1h).

Show notes written by Ronak Mistry, DO, a resident at Pennsylvania Hospital, Philadelphia.

Disclosures

Dr. Gerson disclosed relationships with Loxo Oncology, Genentech, Pharmacyclics, and TG Therapeutics. Dr. Henry has no relevant disclosures.

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