Targeted therapy in chronic lymphocytic leukemia

Abstract: Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature B lymphocytes in blood, bone marrow and lymphoid tissues. Historically, patients with TP53 aberration and with refractoriness to chemoimmunotherapy had a dismal prognosis. During the past few years a paradigm shift has taken place in the treatment of CLL as new, targeted agents have been introduced. The aim of this thesis was to explore targeted agents in patients with advanced CLL. In the first study, the safety and efficacy of lenalidomide in combination with alemtuzumab was explored in a phase I-II trial. The rational was that lenalidomide has its major effects in lymph nodes and alemtuzumab in the bone marrow. Furthermore, the capacity of low-dose lenalidomide in maintaining immune functions in advanced-phase CLL patients during alemtuzumab treatment was evaluated. The combination showed an acceptable safety profile as well as clinical efficacy with an overall response rate (ORR) of 58%. Median response duration was 12 months. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and the maximum tolerated dose was 5 mg/day. Low-dose lenalidomide increased the frequency of proliferating CD8+ T cells but had no effect on the immune checkpoint marker, programmed cell death 1 (PD-1), on T cells. After combination treatment, granzyme B+ T cells increased. In conclusion, low-dose lenalidomide and alemtuzumab induced major changes in T cells, including increased proliferative activity and cytotoxic potential. In the second study, the safety and efficacy of ibrutinib in combination with alemtuzumab was explored in a phase I trial. The rational was that ibrutinib has its major effects in lymph nodes and alemtuzumab in the bone marrow. Further, the toxicity profiles differ. The treatment combination was efficient: 7 out of 8 patients responded to treatment and 7 achieved minimal residual disease negativity. Within 2 weeks, ibrutinib led to decreased proliferation of CLL cells and T cells. After 4 weeks of ibrutinib therapy, PD-1 expression was unchanged on T cells. Due to a high rate of opportunistic infections, the study was closed in advance and we recommend against the combination of ibrutinib and alemtuzumab. In the third study, the safety and efficacy of ibrutinib, when used in routine health care, was evaluated. Ninety-five consecutive patients, treated in a compassionate use program, were analyzed. At a median follow-up of 10 months, the ORR was 84%, the progression free survival (PFS) rate was 77% and the overall survival (OS) rate was 83%. PFS and OS were significantly inferior in patients with TP53 aberration. Atrial fibrillation occurred in 8% and Richter transformation (RT) occurred in 7% of patients. Half of the patients would not have met the inclusion criteria for the pivotal study of ibrutinib: this demonstrates the real-world representativity of the patients. The observed efficacy and toxicity of ibrutinib in the study were similar to that in pivotal studies. In the fourth study, a long-term follow-up of the patients in the compassionate use program for ibrutinib was carried out. At 30-month follow-up, the ORR rate was unchanged at 84%, the PFS rate was 52% and the OS rate was 63%. Fifty-one percent of patients remained on treatment. In contrast to the early (10-month) report, TP53 aberration had no negative survival impact. In multivariate analyses, OS was significantly associated with baseline comorbidities and PFS was associated with baseline comorbidities and number of prior therapies. Fifty-one percent of the patients had grade 3-4 infections and 13% had grade 3-5 opportunistic infections. Fifteen percent developed atrial fibrillation. RT occurred in 13%. Twenty-six percent of patients had dose reduction or temporary treatment breaks, which had no significant impact on the outcome. Four of 6 patients who had progressive disease while on ibrutinib were tested for mutation of Bruton’s tyrosine kinase. All of them carried the most common mutation leading to ibrutinib resistance. In conclusion, ibrutinib was effective and well tolerated for long-term use. The observed efficacy of ibrutinib was somewhat inferior to that of pivotal studies. The observed frequencies of treatment discontinuation and dose reductions were greater than in clinical studies.

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