From the Journals

Updated CLL guidelines incorporate a decade of advances



Updated clinical guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL) include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.

The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.

Major changes or additions include:

Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.

“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.

IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.

Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.

Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.

The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.

Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.

Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.

“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.

Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.

MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.

Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.

“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.

They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.

The authors reported having no financial disclosures related to the guidelines.

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