Prognostic Assessment In Patients With Chronic Lymphocytic Leukemia (CLL) In Clinical Practice: A European Research Initiative On CLL (ERIC) Survey
Authors: Moreno Carol , Stilgenbauer Stephan , Montillo Marco , Tadeusz Robak , Kimby Eva , Rosenquist Richard , Oscier David 
Published: October 2019

Abstract

Background
Although recommendations for assessing prognosis in patients with CLL have been formulated (IWCLL, 2008; ESMO, 2013; NCCN, 2013), the actual use of prognostic and predictive markers in patients with CLL seen in daily practice is unknown.

Study objectives
To ascertain the use of prognostic and predictive markers in patients with CLL not included in trials.

Methods
Three-hundred and eighty-two members included in the ERIC database were invited to participate in a survey which included a comprehensive list of parameters potentially useful to evaluate patients with CLL at three different steps: 1. At diagnosis; 2. During clinical course; 3. Before therapy.

Results
One-hundred sixteen out of the 382 ERIC members (30%), mainly from academic institutions (91%), participated in the survey. Here we present a summary of this study which can be seen at its full length at www.ericll.org

Prognostic factors at diagnosis
The most frequently evaluated parameters (by > 80% of the participants) are: age, disease stage, ECOG, B-symptoms, WBC count, LDT, tumor bulk, DAT, LDH and B2M; CIRS is evaluated by 45% and only 7% measure sTK routinely. CD38 is assessed by virtually all investigators, but not ZAP-70 (58%) nor CD49d (24%). Imaging studies are frequently employed: ultrasonography (US) (51%), CT (21%). PET/CT is never investigated at diagnosis. FISH for 13q-, 11q-, 17p-, and +12 is required by > 70%. Among biomarkers, those more frequently used are IGHV mutational status (54%) and TP53 mutations (25%). As per the newly described gene mutations around 20% of the participants would like to determine mutations of NOTCH1, SF3B1, MYD88, and BIRC3 should they be available.

Prognostic factors over the course of the disease
Sixty percent of participants re-assess prognostic parameters over the course of the disease. Bone marrow (aspirate/biopsy), lymph node biopsy and imaging studies are performed in subjects with progressive disease. However, 72% of the participants never use PET/CT, which does not seem to be related to the technique availability since only 3% of the participants would use PET/CT if available.

Parameters studied before initiating treatment
Beside standard clinical parameters, other features frequently evaluated include ECOG (96%), DAT (77%), CIRS (66%) and bone marrow (45%). US, CT scans, and PET/CT are routinely (or occasionally) assessed by 45% (52%), 39% (42%), and 3% (42%) of the investigators, respectively. IGHV mutational status is repeated by a few participants (19%). 17p- and 11q- are studied by 79% and 68% of the investigators, respectively. Likewise, TP53 mutations are routinely (or occasionally) investigated by 40% (27%), NOTCH1 by 6% (13%), SF3B1 by 6% (12%), MYD88 by 4% (10%), and BIRC3 by 4% (9%).
Most (89%) investigators consider pre-treatment findings to select therapy, the clinical parameters frequently considered toward that end being age (80% of investigators), ECOG (43%) and CIRS (37%). Biologically, 17p- (79%) and TP53 mutations (40%) along with 11q- (48%) and 13q- (26%) are the most frequently investigated markers. Novel mutations are investigated by 9%-15% of participants and around 20% would use them if possible.

Conclusions
Although international recommendations are generally followed, the evaluation of patients with CLL at diagnosis includes in many cases parameters (e.g., 17p-, TP53 mutations) more useful as predictive (i.e., predicting response to therapy) than prognostic (i.e., predicting disease progression) factors, as well as ancillary studies (e.g., imaging studies) only recommended within clinical studies. In many instances prognostic markers are repeated over the course of the disease. Finally, treatment decisions are mainly based on clinical features and consolidated biomarkers (i.e., FISH cytogenetics, TP53 mutations). The results of this study need to be taken cautiously because of potential investigator-related biases and its relatively small sample size. However, it could be useful as a basis for refining, based on what is actually done in daily practice, recommendations about evaluation and prognostication of patients with CLL.

Disclosures:
Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.