Transcription of WNT Genes in Hematopoietic Niche's Mesenchymal Stem Cells in Multiple Myeloma Patients with Different Responses to Treatment.

Mesenchymal stromal cells (MSCs) are involved in bone tissue remodeling due to their ability to differentiate into osteoblasts and to influence osteoclasts' activity. Multiple myeloma (MM) is associated with bone resorption. During disease progression, MSCs acquire a tumor-associated phenotype, losing their osteogenic potential. The process is associated with impaired osteoblasts/osteoclasts balance. The WNT signaling pathway plays a major role in maintaining the balance. In MM, it functions in an aberrant way. It is not known yet whether the WNT pathway is restored in patients' bone narrow after treatment. The aim of the study was to compare the level of WNT family gene transcription in the bone marrow MSCs of healthy donors and MM patients before and after therapy. The study included healthy donors (n = 3), primary patients (n = 3) and patients with different response status to therapy (bortezomib-containing induction regimens) (n = 12). The transcription of the WNT and CTNNB1 (encoding ß-catenin) genes was accessed using qPCR. The mRNA quantity of ten WNT genes, as well as CTNNB1 mRNA encoding ß-catenin, a key mediator in canonical signaling, was evaluated. The observed differences between the groups of patients indicated that aberrant functioning of the WNT pathway was retained after treatment. The differences that we detected for WNT2B, WNT9B and CTNNB1 suggested their possible application as prognostic molecular markers.

Long-term outcomes of third-line therapy with tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia: A real-life experience.

Introduction: Tyrosine kinase inhibitor (TKI) therapy has greatly improved the prognosis of patients with chronic myeloid leukemia (CML), improving the survival expectancy of patients with chronic phase (CP) CML to that of the general population. However, despite these advances, nearly 50% of patients with CP CML experience failure to respond to frontline therapy, and most fail to respond to the subsequent second-line TKI. Treatment guidelines for patients failing second-line therapy are lacking. This study aimed to determine the efficacy of TKIs as third-line therapy in a "real-world" clinical practice setting and identify factors favorably influencing the long-term outcomes of therapy. Methods: We have retrospectively analyzed the medical records of 100 patients with CP CML. Results: The median age of the patients was 51 (range, 21-88) years, and 36% of the patients were men. The median duration of the third-line TKI therapy was 22 (range, 1- 147) months. Overall, the rate of achieving complete cytogenetic response (CCyR) was 35%. Among the four patient groups with different levels of responses at baseline, the best results were achieved in the groups with any CyR at the baseline of third-line therapy. Thus, СCyR was reached in all 15 and 8/ 16 (50%) patients with partial cytogenetic response (PCyR) or minimal or minor CyR (mmCyR), respectively, whereas CCyR was detected only in 12/69 (17%) patients without any CyR at baseline (p < 0.001). Univariate regression analysis revealed that the factors negatively associated with CCyR achievement in thirdline TKI therapy were the absence of any CyR on first- or second-line TKI therapy (p < 0.001), absence of CHR prior to third-line TKI (p = 0.003), and absence of any CyR prior to third-line TKI (p < 0.001). During the median observation time from treatment initiation to the last visit [56 (4-180) months], 27% of cases progressed into accelerated phase or blast phase CML, and 32% of patients died. Discussion: Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with CCyR on third-line than in the group without CCyR on third-line therapy. At the last visit, third-line TKI therapy was ongoing in 18% of patients, with a median time of treatment exposure of 58 (range, 6-140) months; 83% of these patients had stable and durable CCyR, suggesting that patients without CHR at baseline and without CCyR at least by 12 months on third-line TKI should be candidates for allogeneic stem cell transplantation, third-generation TKIs, or experimental therapies.

Withdrawal Syndrome After Tyrosine Kinase Inhibitor Discontinuation in Patients With Chronic Myeloid Leukemia in the Russian Prospective Study RU-SKI.

We aimed to characterize withdrawal syndrome (WS) and evaluate factors associated with its development in the prospective clinical study RU-SKI in patients with chronic myeloid leukemia with deep molecular response who discontinued tyrosine kinase inhibitor (TKI) therapy. In total, 98 adult patients with chronic myeloid leukemia chronic phase, TKI therapy ≥ 3 years, and deep molecular response (BCR-ABL ≤ 0.01%) ≥ 2 years were enrolled and observed without treatment. WS was defined as newly observed or worsening musculoskeletal pain after TKI cessation. WS symptoms were found in 41 (42%) of 98 patients with a median time of observation of 25 months (range, 12-42 months). WS grades 1 to 2 and grade 3 were observed in 39 (95%) and in 2 (5%) patients, respectively. The median duration of WS was 5 months (range, 1-25 months). WS was resolved in 37 (90%) patients. Anti-inflammatory therapy was used in 21 (51%) patients. Older age (P = .039) and longer TKI therapy (P = .001) were associated with WS. The 2-month landmark analysis found no association of WS development and the rate of molecular relapses. In total, 42% of the patients experienced WS after TKI therapy discontinuation in the RU-SKI study. Physicians should be warned about the possibility of WS development, and patients of older age and with longer TKI treatment need special attention.