Combined Treatment with Ibrutinib and Anti-CD38 Monoclonal Antibody Daratumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia with TP53 Aberrations: Results of the Filo Phase II Study IDA53

Background: Despite significant improvement with BTK inhibitors, long-term disease control of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with TP53 abnormalities remains challenging.

CD38 expression is an independent adverse prognostic factor in CLL. This has been related to the involvement of CD38 in CLL cells migration, proliferation, tissue invasion and BCR signaling (Vaisiti 2015; Matas-Cespedes 2016). Daratumumab is the first in class anti-CD38 monoclonal antibody approved in multiple myeloma in both relapse and frontline settings. Preclinical studies have shown daratumumab to induce significant effect on viability and migration of patient-derived CLL cells (Matas-Céspedes et al, 2016). Moreover, the combination of daratumumab and ibrutinib demonstrated synergistic effect on both in vitro CLL cells killing and in vivo tumor burden reduction and survival prolongation in a CLL xenograft model (Manna et al, 2019).

We therefore hypothesized that daratumumab would improve ibrutinib efficacy in R/R CLL patients with TP53 aberrations.

Methods: This phase 2 trial enrolled patients with R/R CLL and TP53 abnormalities regardless of cell surface CD38 expression. Treatment consisted of ibrutinib (420 mg/d) alone for one month then combined to intravenous daratumumab (16 mg/kg/d) administered weekly for 8 weeks, every other week for the subsequent 4 months then monthly until intolerance or disease progression. The primary endpoint was the complete response (CR) rate according to iwCLL criteria after 12 months (M12) of combined therapy. We estimated a 20% CR rate at M12 to be the target threshold for treatment efficacy and 7% the minimum acceptable. We planned to recruit 44 patients.

Results: Between December 2018 and May 2022, 29 patients have been enrolled. The study prematurely closed due to drop in patient accrual and failure to achieve the primary endpoint. Median age was 69 years [45-86] and sex ratio M/F was 18/11. Median number of previous lines was 1 [1-4]. Four patients (14%) had bulky adenopathy. Median lymphocytosis was 55 G/L (4.5-385). Median hemoglobin level and platelet count were 13.2 g/dL (8.1-17.3) and 127 G/L (37-188) respectively. All patients had TP53 disruption with 17p deletion in 16 cases (55%), TP53 mutations in 26 (93%), both in 14 (48%). Five had 11q deletion (18.5%). IGHV was unmutated in 16 patients (62%) and 2 additional patients had subset#2 stereotyped BCR. Eighteen patients had complex karyotype (72%) of whom 9 (36%) had very complex karyotype. Elevated b2microglobulin was present in 19 patients (73%). CD38 expression ranged from 0 to 87%.

At data cutoff (18 JUL 2022), 21 patients have reached M12 and 15 are still on treatment. Fourteen patients went off study of whom 6 before M12. Reasons of discontinuation were progressive disease (PD) in 4 patients (at month 4, 13, 19 and 25) of whom 2 Richter transformation (RT), related adverse event (AE) in 3 (grade 3 infusion related reaction (IRR), recurrent cutaneous carcinoma, atrial fibrillation), COVID-19 in 3, pandemic context in 1, death of unknown cause in 1, and consent withdrawal in 2 patients. Five patients died (1 RT, 3 COVID-19, 1 unknown cause). AEs and serious AEs (SAE) were reported in 29 and 19 patients, respectively. Grade ≥3 AEs were hematological (n=9), infections (n=7), metabolism disorder (n=5), IRR, renal deficiency, myalgia, urologic disorder, death of unknown cause (all n=1). Grade 1-2 AEs reported in ≥ 10% of patients included gastrointestinal disorder (n=16), metabolism disorder (n=10), cardiovascular disorder (n=7), cutaneous neoplasms (n=6), ENT infections (n=5), COVID 19 (n=5), bleedings (n=4) and skin disorders (n=3). No tumor lysis syndrome occurred. At M12, one patient achieved CR, 20 patients achieved PR. Overall response and CR rate were 78% and 3.7% in intend-to-treat calculation, and 95% and 4.5% in per protocol calculation, respectively. With a median FU of 20.2 months, median progression free and overall survival were 27.1 [95%CI 23.4-NR] and 33.5 [95%CI 27.1-NR] months, respectively. Although not significant, there was a trend toward shorter PFS in CD38+ patients that daratumumab did not reverse.

Conclusions: Daratumumab was safely combined with ibrutinib without unexpected toxicity in CLL. However, this combination did not provide any clear improvement of complete response rate in this very high-risk CLL population, as compared with ibrutinib alone.

Ysebaert:Abbvie, Astra-Zeneca, Janssen, Roche, Beigene, BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guieze:Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Delmer:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Abbvie: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Takeda: Honoraria.

daratumumab in chronic lymphocytic leukemia clinical trial ClinicalTrials.gov Identifier: NCT03734198