Although toxicity and resistance have restricted ibrutinib’s application, the drug has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Patients with detectable MRD who had previously been treated with ibrutinib in either the frontline or relapsed/refractory settings were eligible for this research, which took a “add on” approach. Following the addition of umbralisib and ublituximab (U2) to ibrutinib, patients were treated until they reached undetectable minimal residual disease (U-MRD), after which they entered a treatment-free observation period (TFO). Patients who had measurable MRD (flow cytometry, 1 cell in 10-4 cutoff for U-MRD) and had received ibrutinib for at least 6 months in any line of therapy were considered for inclusion. The addition of U2 to Ibrutinib was accompanied by serial assessments of minimal residual disease. Patients started TFO once U-MRD was attained or if a total of 24 cycles had been given. This research was conducted with the rate of U-MRD as its primary endpoint. The secondary goals were to prevent adverse events and maintain therapeutic benefits following treatment cessation. Around 28 individuals signed up. However, only 27 could be assessed for efficacy. Patients had been using ibrutinib for a mean of 21 months (range 7-67) prior to enrollment. To date, 14 patients (52%) have been deemed U-MRD compliant with the methodology, and 78.0% have undergone at least 1 U-MRD assessment. After a median of 6.4 months on triplet treatment, 17 patients (63%) have entered TFO. At 12 months, 95% of patients were expected to be progression-free. Hypertension accounted for 7% of all adverse events, diarrhea for 4%, and elevated ALT/AST for 4%. This triplet strategy includes a time-limited, MRD-driven treatment with ibrutinib, plus the inclusion of U2. The therapy was successful and well-tolerated. Long-term follow-up of patients treated with TFO has shown that the effect lasts.