1125 - Frequent monitoring in chronic lymphocytic leukemia clinical trials: what is the true value?

Background: Industry-initiated clinical trial protocols on new precision therapeutics designed for chronic lymphocytic leukemia (CLL) require not only frequent admissions and blood analyses but also repeated computerized tomography (CT) examinations. The value of such intense monitoring has not been systematically analyzed and is in bright contrast to recommendations issued by the iwCLL guidelines.

Methods: This retrospective analysis included patients who participated in industry-initiated clinical trials. Descriptive analyses were performed on number of admissions, blood tests and CT examinations where the patients served as their own controls, i.e., were analyzed twice, once as specified in the study protocol and once hypothetically according to iwCLL guidelines. Time to response (TTR) and time to progression (TTP) as well as objective response rate (ORR) was also compared.

Results: Forty-two patients with CLL who participated in 7 pharma conducted phase 2 or 3 clinical trials at one single center between February 2013 and December 2020 were included in the study. The median age at study start was 73 years (range 52-87) and 43% received their study medication as first-line therapy. The most common regimen was zanubrutinib monotherapy (38%) followed by ibrutinib monotherapy (24%) and rituximab-bendamustine (12%). The median follow-up time was 38 months (range 2-108). The median numbers of outpatient visits per protocol and hypothetically according to iwCLL guidelines were 18 (range 3-34) and 10 (range 1-18), respectively (p < 0.0001). The corresponding median number of blood tests were 29,5 (range 3-73) and 18 (range 1-45), respectively (p < 0.0001).
The median number of CT examinations performed during treatment and follow-up according to study protocols were 10 (range 2-17) with an estimated median total radiation dose of 100 mSv (range 16 to 136-187), compared to zero CT examinations according to iwCLL guidelines (p < 0.0001). ORR was 90% per protocol and 93% when analyzed according to iwCLL guidelines (not significant). The median TTR and TTP were not significantly different per protocol vs per iwCLL guidelines: 5.62 months vs 4.57 months, respectively, for TTR (Fig 1), and not reached for TTP (Fig 2).

Conclusion: We conclude that participation in a clinical trial results in a considerable number of extra admissions and examinations for patients. The value of such intense monitoring appears to be limited since there was no significant difference in time to response or progression between the excessive monitoring as per protocol and the more restricted hypothetically reconstructed monitoring as per iwCLL guidelines. The cumulative radiation dose from CT examinations was, in many patients, higher than recommended in recent national radiation protection guidelines, especially if conducted early in the disease course. Harmonization of the monitoring requirements, especially regarding CT examinations, between CLL clinical trial protocols and iwCLL guidelines, is warranted.