High Cell Death Rates at Start of Ibrutinib Therapy Predict for Deeper Remissions in Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: The BTK inhibitor ibrutinib blocks B-cell receptor and other signaling pathways in CLL cells and has become a standard CLL therapy. Isotopic labeling with deuterated water (²H₂O) to measure the effects of ibrutinib on CLL cell proliferation and death directly in patients revealed that ibrutinib profoundly inhibits proliferation and induces high rates of leukemia cell death (registered at clinicaltrials.gov as NCT01752426; Burger et al., JCI Insight, 2017). Here, we report a long-term follow-up of this trial in which we analyzed long-term outcomes and correlated CLL cell birth and death rates with depth of response over time.

Methods: Thirty patients with previously untreated CLL/SLL enrolled in the study to receive continuous long-term ibrutinib monotherapy, after one month of labeling with deuterated water. For our analyses, we stratified patients in groups based on high or low CLL cell death rates in the peripheral blood (PB) or lymphatic tissues (lymph nodes, spleen), i.e. death rates above or below the median, assessed over the first months on therapy, as detailed in the original publication. Responses were assessed according to 2008 IWCLL guidelines, with the exception that lymphocytosis was not used as a sole criterion for progression. PB MRD was quantified by flow cytometry with a sensitivity 10^-4.

Results: The median age of the participants was 64 years (range, 48 - 78); 63.3% were male. Thirteen patients (43%) had advanced stage disease, 57% had unmutated IGHV genes, and 10% carried 17p deletion (del17p). Twenty-two patients (73%) completed 5 years of protocol treatment and subsequently continued treatment with commercial supply ibrutinib. The patients were followed for a median time of 107 months (range, 6 - 111). The reasons for eventual treatment discontinuation (n=21) were adverse events (n=8, 38%), progressive disease (n=4, 19%), change to another treatment (n=5, 24%), death (n=2, 7%) and other reasons (n=2, 7%). To date, nine patients are still receiving ibrutinib. Five patients (17%) achieved a complete remission, 24 (80%) achieved partial remission, and one patient (3%) had stable disease, resulting in an overall response rate of 97%. Median progression-free (PFS) and overall survival (OS) were not reached at a median follow-up of 107 months. Five-year PFS was 80.6%, and OS was 90%. PB MRD was measured in 18 patients after 5 years of ibrutinib (54 to 60 cycles); all patients had detectable MRD (median 11.8%, range, 0.06 - 47.30%). We found that CLL cell death rates in PB and tissues after treatment initiation inversely correlated with the level of PB MRD after 5 years (r=-0.5872, P=0.0104 and r=-0.4407, P=0.0672). MRD levels were significantly lower in patients with high CLL cell death rates in PB (7.03% ± 3.68% vs. 29.46% ± 5.53%, mean ± SEM, P=0.0056) and in tissues (9.73% ± 5.49% vs. 28.89% ± 4.42%, P=0.0155) as compared with patients with lower CLL cell death rates (Figure 1). Tissue CLL cell death rates were significantly higher in patients with IGHV-unmutated CLL compared to mutated (28.88% ± 2.75% vs. 13.16% ± 2.82%, P=0.0005), and MRD levels trended lower (IGHV-unmutated: 10.71% ± 5.39% vs. IGHV-mutated: 28.36% ± 6.02%, P=0.0878). No statistically significant correlation was found between CLL cell birth rate at baseline or after start of ibrutinib and MRD levels after 5 years of treatment.

Conclusion: CLL cell death rates during early treatment correlated with achieving lower MRD levels. We found that CLL cell death rates are higher in IGHV-unmutated patients suggesting a higher dependency of IGHV-unmutated clones on BCR signaling and, therefore, resulting in deeper responses.

Ferrajoli:Beigene: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Jain:Aprea Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; TransThera Sciences: Research Funding; Cellectis: Honoraria, Research Funding; Ipsen: Honoraria; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Mingsight: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Incyte Corporation: Research Funding; Beigene: Honoraria; Servier Pharmaceuticals LLC: Research Funding; Medisix: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Novalgen: Research Funding; Takeda: Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Cellectis: Honoraria, Research Funding; Dialectic Therapeutics: Research Funding; Loxo Oncology: Research Funding; MEI Pharma: Honoraria; Fate Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Thompson:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria. Wierda:Sunesis: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Janssen: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Pharmacyclics LLC: Research Funding; Xencor: Research Funding; Sanofi: Consultancy; Juno: Research Funding; Karyopharm: Research Funding; Kite, a Gilead Company: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Genzyme: Consultancy; GSK/Novartis: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Cyclacel: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; AbbVie: Research Funding. Burger:TG Therapeutics: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics LLC: Consultancy, Research Funding; Novartis: Consultancy.