Extended Follow up of a Phase 2 Study of Early Intervention with Lenalidomide in Patients with High-Risk Chronic Lymphocytic Leukemia

INTRODUCTION: Lenalidomide (LEN) is an effective therapy for chronic lymphocytic leukemia (CLL) and has immunomodulatory effects that were hypothesized to improve immune function in patients (pts) with untreated early stage CLL. A NCI/CTEP sponsored phase 2 study (NCT01351896) randomized asymptomatic pts with high-risk CLL to receive LEN either concurrent with or delayed from (3 months after 1st dose) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13). The primary endpoint was the proportion of pts who achieve an antibody response to the 2nd PCV13 vaccine and was not significantly different between groups (Thangavadivel et al., Clinical Cancer Research 2020). Despite this, many pts experienced effective CLL disease control with LEN. Here we report long-term results from this trial to examine the impact of LEN early treatment on CLL disease course, complicating infections (INF), and second neoplasms (SN).

METHODS: Pts ≥18 and <80 years-old who had CLL with a high-risk feature, defined as FISH positive for del(17)(p13.1) and/or del(11)(q22.3), complex karyotype (≥3 abnormalities), or unmutated IGHV status, no prior treatment, and no iwCLL 2008 criteria for treatment were eligible. LEN was started at 2.5mg daily and increased to 5mg as tolerated. Data on INF and SN was determined from study adverse events and graded (gr) using CTCAE v4.0 and 5.0. Overall survival (OS) and progression-free survival (PFS) were calculated from the start of LEN and discontinuation of LEN, and analyzed using the Kaplan-Meier method. Time to next therapy (TTNT) was calculated from start or discontinuation of LEN to the initiation of next therapy treating death without new therapy as a competing risk. Data cut for analysis was 6/12/2023.

RESULTS: A total of 49 pts were enrolled between 11/2011 and 7/2014. The median age was 59 (range 40–70) years, 69% were men, and 96% were Caucasian. In terms of CLL features, 94% (46/49) were IGHV unmutated, 47% (23/49) had complex karyotype, 14% (7/49) had del(17)(p13.1), and 31% (15/49) had del(11q)(q22.2). The median follow-up from LEN start was 4.6 (range 0.4-11.2) years and median time on LEN treatment was 3.7 (range 0.02-10.1) years with 2 pts remaining on LEN at 9.7 and 10.1 years.

The median PFS after starting LEN was 5.7 (95% CI: 3.2-6.4) years with an estimated 8-year PFS of 25.9% (95% CI: 13.9%-39.6%) (Figure). Eleven pts had progressive disease (PD) at the time of LEN discontinuation and their median time from first dose of LEN to PD was 3.7 (range 0.3-6.0) years. For those who discontinued without PD, the median PFS from discontinuation was 1.5 (95% CI: 0.6-2.6) years. For those who initiated a subsequent therapy, the median TTNT from starting LEN was 4.4 (range 0.3-9.1) years and from discontinuing LEN was 1.1 (range 0.1-7.8) years. There were 7 deaths, and the median OS was not reached with an estimated 8-year OS of 73.9% (95% CI: 51.6%-87.2%).

There were 217 episodes of INF that occurred in 88% (43/49) of pts. Patients experienced multiple INF: 24 (49%) pts had 1-3 INFs and 19 (39%) had ≥3 INFs with 5 of those having >10 INFs. The most frequent INFs were upper respiratory (n=71), sinus (n=37), skin and soft tissue (n=27), and lower respiratory (n=22) (Table). INFs were gr 1-2 in 95% of cases. Gr ≥3 INF were experienced by 18% (9/49) of patients with 10 events. There were 9 gr 3 INFs (lower respiratory tract n=4, kidney n=1, urinary tract n=1, appendix n=1, joint n=1, meninges n=1) and 1 gr 5 COVID-19 INF which occurred in a pt who discontinued LEN >2 years prior. The rate of gr ≥3 INF was 3.8 (95% CI: 1.8-7.0) per 100-person-years.

SN were experienced by 8 pts who had 19 SNs. The most common SN were non-melanoma skin cancers (n=15). Other SN were lung adenocarcinoma (n=2 in 1 pt), melanoma in situ (n=1), and squamous cell carcinoma in a parotid lymph node from a skin SCC (n=1). The rate SN was 7.2 (95% CI 4.3-11.3) per 100-person-years. There were no cases of acute leukemia.

CONCLUSIONS: In this population of pts with CLL with high-risk disease features predictive of need for earlier treatment, LEN resulted in a prolonged time to subsequent therapy, even in cases of LEN discontinuation. The incidence of gr ≥3 INFs and SN were as expected for this population supporting that LEN does not increase risk for these complications.