Novel Therapies Do Not Increase Second Cancers in CLL

Authored by Brian Koffman, MDCM (retired), MSEd

Bottom Line:

Unlike chemoimmunotherapy, new oral therapies and monoclonal antibodies don’t increase the risk of other cancers versus active surveillance in CLL patients.

Who Performed the Research and Where Was it Presented:

Dr. Helen Ma of Long Beach Health System, University of California, Irvine, Long Beach, CA, USA, and colleagues presented the results in a poster session at the American Society for Hematology (ASH) Annual Meeting 2024.

Background:

Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) is a cancer of the immune system. All CLL / SLL patients are immunocompromised to some lesser or greater extent based on their disease status and treatment history. As a result, they are at higher risk for infections and other cancers (OC). This trial examines how the choice of frontline treatment contributes to the higher incidence of second malignancies. Chemoimmunotherapy (CIT) was by far the most commonly used option until the approval of oral targeted therapies of the first Bruton tyrosine kinase inhibitors (BTKi) in 2016 and venetoclax, the only commercially available BCL2 inhibitors in 2019. They are now the standard of care for initial therapy, often combined with anti-CD20 monoclonal antibodies (rituximab and obinutuzumab). This change in practice patterns allows one to study the impact of the different frontline therapeutic approaches.

Methods: 

Using the Department of US Veteran Affairs Central Cancer Registry (VACCR), a retrospective analysis was conducted of CLL / SLL patients during or after 2016 who were also diagnosed with a new other cancer, excluding nonmelanoma skin cancers.

Frontline treatment with either chemoimmunotherapy, monoclonal antibodies alone, or targeted therapies was compared to patients on active surveillance or “watch and wait.” Patients were followed until the date of OC, death, or last follow-up.

Results:

• 5,244 patients with CLL / SLL were included in the study
• The average follow-up was 3.19 years.
• The median age at diagnosis of CLL / SLL was 71.7 years
• Most patients were white (78%) and male (97%), which reflects the veteran population analyzed.
• 3,460 (66%) patients were managed with active surveillance
• 1,784 (34%) patients required frontline treatment:
  • 1,318 (25%) received targeted therapy:
    • ibrutinib (776, 59%)
    • acalabrutinib (246, 19%)
    • zanubrutinib (129, 10%)
    • venetoclax (164, 12%)
    • combination of ibrutinib and venetoclax on a clinical trial (3, <1%).
  • 329 (6%) chemoimmunotherapy
  • 137 (3%) monoclonal antibodies alone.
  • 505 (10%) patients were diagnosed with OC; therefore, 4,739 (90%) patients did not develop OC during the follow-up period after diagnosis of CLL / SLL. The following OC were observed:
    • lung (120, 24%),
    • prostate (105, 21%)
    • gastrointestinal tract (72, 14%)
    • hematologic malignancies (68, 13%)
    • melanoma (45, 9%)
    • kidney and bladder (43, 9%)
    • head and neck (16, 3%)
    • other/unknown (36, 7%)
  • As expected, more patients with OC had a history of tobacco use compared to those diagnosed with CLL / SLL without OC (70% vs 54%)
  • Surprisingly, fewer patients with OC had a history of alcohol use (60% vs 67%).
• When adjusting for other risk factors (age of diagnosis, tobacco and alcohol use), patients treated with chemoimmunotherapy had a significantly higher risk of OC compared to those on observation (OR 2.4)
• Patients treated with targeted therapies or monoclonal antibodies alone did not have a higher risk of OC (OR 1.1 and OR 1.4, respectively) than those on active surveillance.
• More patients with OC died compared to those without OC, 219/505 (43%) vs. 1,261/4,739 (27%), respectively, reminding us that with improved CLL / SLL treatments, more and more patients are dying for other reasons rather than the disease itself progressing.

Conclusions:

It is reassuring to know that modern therapies not only improve survival for those with CLL / SLL, but they do so without increasing the already higher risk of second cancers.

Links and Resources:

Listen to Dr. Koffman’s monologue below.

The ASH 2024 abstract can be read at First-Line Treatment Choice and Risk of Other Malignancies in US Veterans Diagnosed with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.