Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, CLL, Diseases, Therapies, Lymphoid Malignancies, Minimal Residual Disease
Methods: CLL pts (n=35) who had residual disease (by clinical or molecular assessment) after primary induction treatment were enrolled on a prospective phase 2 trial (NCT02649387). MRD assessed in blood (PB)/bone marrow (BM), was determined by 8-color flowcytometry (1x10-4) and defined as ≥1 CLL cell per 10,000 leukocytes or ≥0.01%. Patient were eligible if they had detectable residual (non-progressive) disease within 1 year of completing induction and no prior ibrutinib (or other BTKi) treatment. Ibrutinib 420mg PO QD was given on days 1-28 of a 28-day cycle for up to 36 cycles. Clinical (iwCLL 2008 response criteria) and molecule response MRD (on PB) was done at baseline and then every 3 cycles while on treatment. BM-MRD evaluation was conducted only if PB-MRD was negative (on two separate timepoints 3 months apart). Monitoring of the PB-MRD was continued for 24 months after completing time-limited maintenance with ibrutinib. Cumulative toxicity was assessed using the CTCAE v4.0 and iwCLL criteria.
Results: Patient characteristics are summarized in Table 1. In 34 out of 35 (97%) patients, obinutuzumab alone was used as induction therapy. The median follow up is 38.6 months (range 0.9-73.2) and the median number of maintenance cycles completed is 34 (range 1-36). Of the 33 patients assessed for PB-MRD, 8 (24.2%) pts became MRD- on at one assessment. Five patients had BM-MRD assessment with 1 (2.8%) converting to MRD-. The median time to achievement of MRD- was 4.4 months (range 2.7-34.7). We noted that single agent ibrutinib was unable to deliver stringent MRD-negativity (defined as achievement of MRD- status both in PB and BM sustained over 2 consecutive evaluations at least 3 months apart).To assess if pre-maintenance response could impact MRD post-treatment; we note that out of the 8 pts that achieved MRD-, 2 (25%) started with CR and 6 (75%) with nPR/PR at registration. Deepening of response was noted in 5 pts (14.3%) after a median of 14 cycles [3 (8.6%) pts improved nPR to CR and 1(2.9%) went from nPR to CRi and 1 (2.9%) went from a CRi to a CR]. Nine patients proceeded to subsequent treatment with the median time to next treatment (mTTNT) of 32.5 m (range: 12.1 – 61.0). One patient died due to a failure to thrive and acute kidney injury on dialysis and six pts have progressed. The median PFS for the entire cohort was 41.1 m (95% CI: 39.8 – NE). The most commonly reported adverse events (AEs) (seen in >10% pts) regardless of attributions were thrombocytopenia (24 pts; 68.6%), anemia (12 pts; 34.3%), neutropenia (9 pts; 25.7%), lymphopenia (9 pts; 25.7%), hypertension (9 pts; 25.7%), leucopenia (6 pts; 17.1%), fatigue (5 pts; 14.3%), headache (4 pts; 11.4%), and skin infections (4 pts; 11.4%). Atrial fibrillation (AFib) was noted in 3 pts (8.6%).
Conclusion: We conclude that BTK targeting with ibrutinib alone although able to clear PB-MRD (24.2%), had limited efficacy to eradicate BM-MRD (2.8%) demonstrating a differential impact in these two disease compartments. While the rate of complete MRD eradication was not necessarily high (when compared to recent data with BTKi/BCL2i combination regimens) MRD-kinetics over time demonstrated progressive decrease in disease burden and response improvement with maintenance treatment. The sequential single agent treatment approach was well tolerated, and the time-limited therapy aimed at minimizing cumulative toxicity seemed to be effective in lowering rate of Afib (compared to historical control ~16%). This data warrants further investigation of time-limited maintenance therapy with newer, more favorably tolerated BTKi and/or Bcl2i post induction treatment(s) to optimize response vs. cumulative toxicity. Further evaluation of sequential time-limited treatments in CLL is warranted.
Disclosures: Ailawadhi: GSK, Sanofi, BMS, Takeda, Beigene, Pharmacyclics, Amgen, Janssen: Consultancy.
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