Сhronic lymphocytic leukemia treatment: a single-centre experience
Olga B. Kalashnikova, Natalia B. Mikhailova, Elena V. Kondakova, Maria O. Ivanova, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contact: Dr. Olga B. Kalashnikova
Chronic lymphocytic leukemia (CLL) is the most common variant of adult leukemia, characterized by the accumulation of mature lymphocytes expressing CD19, CD23, CD20, CD5 markers. Approximately 40% of patients have a slow-progression course of CLL, with a life expectancy close to that of the general population. The presence of such group of patients justifies the waiting observation before the appearance of indications for therapy. Standard fludarabine-containing treatment regimens give good results in the first line of therapy with the median progression-free survival of 6.4 years (30.9%-12.8 years), but recurrence of the disease is inevitable for most patients. The results of chemoimmunotherapy (CIT) in the second and subsequent lines are not as successful, especially for patients with adverse prognosis (del17p/mutTP53, U-CLL, early relapse less than 24 months). Introduction of new targeted drugs allowed to improve the overall (OS) and progression-free survival (PFS) significantly in this category of patients. Purpose of the present work was to analyze the experience of therapy CLL patients in First State Pavlov Medical University.
Materials and methods
972 patients are available for the analysis of OS: 455 men, 517 women; median age is 65 years (23-94). The median period of observation was 64 months (0-367). Median OS – 80 months (6.7 years); 5-years-OS – 63%; 10-years-OS – 29%. 20% of patients had indications for therapy initiation at the time of diagnosis. Stage estimation at the moment of diagnosis is available in 798 patients (CLL – 783, LML – 15). Stage 0 was detected in 327 patients (42%) for CLL according to the Rai stage-system; therapy during the observation period was started in 58 patients (18%), median time before therapy initiation was 52 months (0.0-332). Stages I-II – 379 people (48%), of these, 244 (64%) needed treatment, the median time before therapy initiation was 11 months (0.0-227). Stages III-IV – 77 patients (10%), 72 (93.5%) of them started treatment, the median time before therapy initiation 4 months (0.0-65.4 months). Cytogenetic testing was performed in 220 patients (24.7%). Isolated del17p/mutTP53 (14%) was detected in 31 patients, complex karyotype in 16 (7%), complex karyotype with del17p/mutTP53 in 8 (4%), 2 aberrations, including del17p/mutTP53 in 23 (10%). The mutational status of IGHV was studied in 49 patients: M-CLL – 18 (37%); U-CLL – 31 (63%). Therapy was provided to 386 out of 798 patients available for analysis (48%). Of these, 64 (17%) died and 322 (83%) were alive. The median follow-up period was 78 months (ca. 6.5 years). 219 patients received only one line of therapy; 81 patients, 2 lines; 40, 3 lines; 46 patients, 4 lines.
The most effective first-line treatment options were Ibrutinib (ORR, 100%) and fludarabine-containing regimens (ORR, 81%). All patients receiving Ibrutinib as the first line remained without signs of disease progression; 51 out of 96 patients who received 4 to 6 courses of fludarabine-containing regimens remain without therapy so far. In the group of patients who received more than 1 line of therapy, the median time to progression was 20 months.
The efficiency of further lines of the therapy was much lower: ORR in the 2nd and the following lines of therapy in standard CIT regimens was steadily decreasing to 64% in the second line, and to <25% in the fourth one. Only ibrutinib showed good efficacy with ORR=85% in the 2nd and up to 50% in the fourth line of therapy. Out of 52 patients treated with ibrutinib, 45 (86.5%) are still alive, and 42 of them still continue the therapy. The median follow-up upon the therapy was 31 months (0-62), OS is 82%, PFS is 77%.
Standard CIT modes are not effective enough in patients with relapsed and refractory CLL. Ibrutinib demonstrates a sufficiently high efficacy in this category of patients. A more thorough approach to identifying a high-risk group is needed to select the most appropriate therapeutic option.
Chronic lymphocytic leukemia, IGHV mutation status, del17p/mutTP53, ibrutinib.