New Score Predicts When Patients With CLL Should Start Treatment

Nancy A. Melville

April 14, 2020

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early stage disease and are managed with active surveillance, but there is much uncertainty over when to start treatment. A simple prognostic model, based on the sum of three routine tests, can now help with this decision, say researchers.

The new score is effective in predicting the amount of time a patient with CLL will likely have before requiring treatment, the team notes. "Other prognostic scores that are available mostly aim at predicting overall survival of patients who are in need of therapy," first author Adalgisa Condoluci, MD, Department of Hematology, Institute of Oncology Research, Bellinzona, Switzerland, told Medscape Medical News.

"This is the first validated prognostic score for this population of early stage asymptomatic CLL specifically tailored at forecasting the need for treatment, which is the most relevant turning point of patients' lives and physicians' attitudes in early stage CLL."

The study was published this week in the journal Blood.

Importantly, CLL only progresses in a minority of patients, but not knowing which ones means uncertainty for the majority, note the authors. About one third of patients never require treatment, another third will not need treatment for many years, but the remaining third require therapy within the earliest months or years.

International guideline recommendations of a "watch and wait" strategy apply to as many as 70% to 80% of patients diagnosed with the disease.

This new tool should be a welcome addition in the management of patients with CLL, said Seema A. Bhat, MD, an assistant professor in the Division of Hematology at The Ohio State University, Columbus, who was approached for comment.

"In my opinion, it will improve clinical decision making both for the clinicians and patients," she told Medscape Medical News.

"It may offer a better idea to patients when they might expect treatment to start and hence they can plan their life accordingly," she added. The new score will "help to alleviate some of the inherent anxiety associated with watch-and-wait."

However, Bhat also noted that further validation with more rigorous clinical trials will be necessary.

"This simple prognostic tool has potential to translate to our clinical practice and be adapted by clinicians quickly," she said.

"However, this is a retrospective observational study and a prospective trial is warranted that will further validate this tool for early stage asymptomatic patients with CLL. A comparison to the CLL International Prognostic Index (CLL-IPI) scoring system in a randomized trial may also be justified," she added

Developing the New Score

For their study, the team evaluated data from 11 international cohorts of patients with early-stage CLL. They identified a total of 4933 patients and assessed 19 baseline biomarkers within 1 month of initial presentation, including clinical characteristics, laboratory values, cytogenetic abnormalities and gene mutations.

The combined scores of the three key covariates of unmutated immunoglobulin heavy chain (IGHV) genes, an absolute lymphocyte count
>15 x109/L, and the presence of palpable lymph nodes consistently and independently predict patients' likelihood of needing treatment within 1 and 5 years of diagnosis.

From this finding, the new scoring system was developed, allocating one point for the presence of each variable, with a score of 0 points considered low risk, 1 point an intermediate risk, and 2-3 points high risk.

The study showed the cumulative risk for need of treatment among those with a low-risk score was <0.1% at 1 year and 8.4% after 5 years of observation.

For an intermediate risk score, the respective risks for need for treatment at 1 and 5 years were 2.1% and 28.4%, and for high-risk patients the risks were 14.1% at 1 year and 61.2% at 5 years.

Validation of the system showed that about 30% of patients were categorized as low risk, about 35% were intermediate risk, and 35% were high risk.

"Patients scoring as high risk should be followed more closely than low- and intermediate-risk patients due to the likelihood of requiring treatment sooner," Condoluci said.

Condoluci noted that the three variables work in distinctive ways to help predict time to first treatment in CLL.

"IGHV mutation status is a molecular feature that has already been demonstrated to be an indicator of aggressiveness of the disease and in broad terms reflects the leukemia propensity to respond to proliferation signals provided by the microenvironment surrounding the tumor," she explained.

"The absolute lymphocyte count obtained with a simple blood cell count and the presence of palpable lymph nodes (>1 cm diameter) at the baseline clinical assessment give an idea of the how much the leukemia has already accumulated and the tumor burden," she added

IGHV Status Routinely Utilized

Whereas other risk assessment scores may involve the assessment of multiple molecular variables, the new model requires only that of IGHV mutation status, which is widely available and standardized.

"IGHV status has been recognized by the current guidelines as a predictive biomarker for treatment tailoring," Condoluci said. "Our results further support the indication for testing IGHV mutations in CLL patients."

"Moreover, since IGHV status never changes during the course of disease, it might be evaluated at the time of first diagnosis to provide an estimate of time to first treatment [for] the patient and [for] the treating physician," she added.

Risk Assessment Could Be Key in Early Treatment

Condoluci noted that previous research has already shown that there is no survival benefit in starting therapies in CLL before a patient's white blood cell counts and symptoms reach a certain threshold.

Therefore, the prognostic tool, in predicting symptom onset, could be particularly valuable if there is development of novel agents that provide a survival benefit to at-risk patients before their symptoms and white blood cell counts increase, she commented.

"In this scenario, upfront identification of high-risk patients is warranted."

The study was supported by various grants, including those from the Swiss Cancer League, the European Research Council (ERC) Swiss National Science Foundation,  The Leukemia & Lymphoma Society, the Italian Ministry of Health, and the Swedish Cancer Society. Condoluci has disclosed no relevant financial relationships. Several  coauthors report receiving honoraria from various pharmaceutical companies, as  detailed in the published study. Bhat has disclosed no relevant financial relationships.

Blood. Published online April 8, 2020. Abstract

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