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Study Finds Link Between Gene Mutations and Death from Infection in CLL

Study Finds Link Between Gene Mutations and Death from Infection in CLL
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Published on April 14, 2021

What Gene Mutations Can Tell Us About CLL Infection Outcomes

A study has found that patients with chronic lymphocytic leukemia (CLL) who have mutations in one or more of four genes — BRAF, FBXW7, NRAS or XPO1 — were more likely to die from contracting an infection than those without a mutation. Infection is the leading cause of death for patients with CLL, accounting for almost half.

The findings mean that testing for those mutations could be used to identify patients who are at a higher risk of dying and inform future treatment strategies, said study author Monica Else, an honorary senior scientific officer in the Division of Molecular Pathology at London’s Institute of Cancer Research.

“It also raises the intriguing possibility of a relationship between these genes and the origin of infections in leukemia,” she said in a press release. “It is very possible that infections play a role in the way CLL develops and if so, these mutations might be a part of that."

The study, which was published in the journal Leukemia, is the first to analyze the causes of death in CLL patients in detail, in particular infections.

Infections cause death in patients with CLL largely because of the patient’s impaired immune system. Chemo-immunotherapy such as FCR (fludarabine, cyclophosphamide and rituximab) can further weaken the immune system and make patients more susceptible to infections and secondary cancers. That is why patients with CLL are particularly vulnerable to COVID-19.

Clinical Trial Details

Researchers at the ICR and the University of Southampton analyzed the causes of death of patients enrolled in the LRF CLL4 trial, which compared conventional chlorambucil therapy to fludarabine (alone or with cyclophosphamide).

The LRF CLL4 trial collected data from 777 patients with CLL from 1999 to 2004. The average follow-up time was 13 years. The initial findings were published in The Lancet in 2007.

According to the new study, of the 600 patients who died of a known cause, 43% died of infection — either as a primary or secondary cause.

ICR and University of Southampton scientists compared blood samples from those who died of infection and those who died from other causes.

Of the 499 patients for whom gene mutation data were available, 73 (15%) carried one or more of these genes: BRAF (6%); FBXW7 (2%); NRAS (2%); and XPO1 (6%). Infection caused death in 69% of the patients who had a mutation in one or more of those genes, compared to 39% who didn’t have any of the four mutations.

The fatal infections were pneumonia (67%) and/or sepsis (38%) and/or opportunistic infections such as aspergillus (11%). (Aspergillus is a type of fungus. Health problems include allergic reactions, lung infections, and infections in other organs, according to the CDC.)

There were no differences between the two groups in terms of demographics, the stage of their CLL and treatment history. However, patients who died of infection were more likely than those who died of other causes to have received more than one line of treatment.

CLL and Gene Mutations

While more than 40 mutated driver genes have been identified in CLL, specialists tend to focus on deletion 13q, deletion 11q, trisomy 12 and deletion 17p (linked to TP53), according to Dr. Adam Kittai, a hematologist and CLL specialist at the Ohio State University Comprehensive Cancer Center in Columbus.

“Right now, in CLL, there aren't many mutations that are actionable or tested,” Dr. Kittai said in a recent Patient Power program. His center tests for 50 genes in patients with CLL. “What I mean by actionable is that a drug was developed that targets that mutation. We have other medications that work really well regardless of mutational status.”

Mutations in genes such as BRAF and XP01 occur less frequently in patients with CLL: 2% to 6% for FBXW7, about 3% for BRAF and less than 2% for XPO1. Because of this, their significance in CLL is unclear.

"If these mutations turn out to be important in the origin of infections, or in the way that CLL develops as a result of its interaction with infections, then it will be very exciting,” Else said in the ICR release.

Commenting on the findings in the press release, CLL4 Principal Investigator Dr. Daniel Catovsky, professor emeritus at the ICR, added: “Although our trial initially focused, successfully, on answering the question of which is the most effective cancer drug treatment for CLL, the results have now shed new light on the management of infection — a crucial question for patients, and all the more so now in the era of COVID-19."

~Megan Trusdell

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