Expanding the Prognostic Toolkit

At present, there is no other prognostic score that looks specifically at patient outcomes for individuals initiating ibrutinib therapy. The CLL International Prognostic Index (CLL-IPI) is an existing model that can be used to stratify patients with CLL into 4 risk categories based on factors including age, clinical stage, serum β-2 microglobulin, and IGHV or TP53 mutational status. However, in an editorial published with the NIH study, Stephan Stilgenbauer, MD, of Saarland University and the University of Ulm in Germany, pointed out that the CLL-IPI model “was established in the chemoimmunotherapy context and was not based on targeted treatments” such as ibrutinib.2

In the NIH study, Dr Ahn and colleagues compared the 4-factor model with the CLL-IPI model in 531 patients for whom the necessary data points were available for both tools. The vast majority (88%) of the patients were assigned to the high- or very high-risk groups using the CLL-IPI, while the 4-factor model achieved comparatively more balanced risk stratification.1

Continue Reading

Notably, one-third of the patients who were captured in high-risk categories of the CLL-IPI were classified as low- or intermediate-risk in the 4-factor model. Patients in the high-risk CLL-IPI group were also found to have better PFS and OS compared with those in the high-risk 4-factor model group.

“With the CLL-IPI, we didn’t know whether it was predictive of outcomes for patients who are going on ibrutinib or other novel therapies,” said Jennifer A. Woyach, MD, who is an associate professor in the department of internal medicine at The Ohio State University Comprehensive Cancer Center-James in Columbus. “We have also known for a while that there are a number of factors that will predict which patients will do well on ibrutinib or those who will have shorter remission durations, but they were not things that are easily or widely available in clinical practice.”

The 4-factor prognostic score developed in the NIH study “includes factors that almost everybody is already doing as part of standard care,” Dr Woyach added. Bruce G. Raphael, MD, of NYU Langone Health, validated Dr Woyach’s observation, noting that all of the prognostic factors assessed in the model are known and acknowledged as important in standard CLL practice — particularly, TP53 mutation burden.

According to Dr Ahn, this 4-factor model has utility not only in the day-to-day management of patients, but also in clinical research. “Many trials that are ongoing in CLL are doing guesswork on what the patient population looks like for each trial,” Dr Ahn said. “By using this model, we can accurately capture how many patients are high-risk patients in a given trial, and that can be useful when interpreting data from these trials.”

Future Directions

The 4-factor model is promising in its present form, but will require further refinement, according to Dr Stilgenbauer. “With its expanding use, ibrutinib is more often being administered in the first-line setting. In this scenario, only approximately 10% of patients with CLL present with TP53 abnormality, and LDH and B2M are often not markedly elevated. Therefore, many of the patients started on BTK inhibitors today will fall into the low-risk category.”2

In addition, further validation of the model is needed for treatments other than ibrutinib. Ibrutinib is approved for all lines of therapy in CLL, but the current National Comprehensive Cancer Network (NCCN) guidelines also list other targeted agents, including acalabrutinib and venetoclax.3

The value of the model in the CLL setting is clear, specifically in terms of guiding treatment decisions. It separates patients who might do poorly from those who will do very poorly, and allows oncologists to realize that they probably should be putting those patients on protocol, Dr Raphael said. “[Oncologists] may not know exactly what to give them, but [they] know what not to give them — single-agent ibrutinib.”

Dr Woyach agreed with this assessment. “The model won’t necessarily alter existing treatment strategies, except in high-risk patients who may benefit from enrolling [in] a clinical trial rather than [receiving] standard-of-care ibrutinib,” she said. “In these patients, we should be thinking about newer strategies with combination therapies or alternative agents.”

Disclosure: Some of the authors of the original study disclosed financial relationships with the pharmaceutical industry and/or medical device industry. For a full list of disclosures, please refer to the original study.


  1. Ahn IE, Tian X, Ipe D, et al. Prediction of outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: development and validation of a four-factor prognostic model. J Clin Oncol. Published online October 7, 2020. doi:10.1200/jco.20.00979
  2. Stilgenbauer S. Four-factor score for outcome of ibrutinib treatment in chronic lymphocytic leukemia: prognostic model for risk group definition. J Clin Oncol. Published online October 13, 2020. doi:10.1200/jco.20.02685
  3. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia (Version 1.2021). Published September 28, 2020. Accessed November 10, 2020.