Clinical outcomes of second-generation tyrosine kinase inhibitors versus imatinib in older patients with CML.

Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first-line treatment in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second-generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML-CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18-64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow-up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR-ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5-year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5-year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first-line treatment is an effective option for both younger and older CML-CP patients with or without comorbidities. This trial was registered at UMIN-CTR as 00003581.

[Observational study of chronic myeloid leukemia Chinese patients who discontinued tyrosine kinase inhibitors in the real-world].

Objective: This study aimed to observe whether the treatment-free remission (TFR) of second-generation tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) is better than imatinib (IM) . Methods: The clinical data of 274 CML patients who discontinued treatment and with complete clinical data were retrospectively studied from June 2013 to March 2021. Using both univariate and multivariate Cox proportional hazards regression models, risk factors influencing TFR outcomes after drug withdrawal in CML patients were assessed. Results: A total of 274 patients were enrolled, 140 patients were women (51.1%) , with a median age of 48 (9-84) years at the time of TKI discontinuation. Prior to TKI discontinuation, 172 (62.8%) patients were treated with IM, and 102 (37.2%) had received second-generation TKI treatment, including 73 patients who had shifted from IM to a second-generation TKI and 29 patients who used second-generation TKI as the first-line treatment. The rationale for converting to a second-generation TKI are as follows: 37 patients aimed deep molecular response (DMR) to achieve TFR, seven patients changed due to IM intolerance, and 29 patients changed because of failure to achieve the optimal treatment response. The use of the last type of TKI included 96 patients (94.1%) with nilotinib, three patients (2.9%) with dasatinib, and two patients (2%) with flumatinib, including one patient who changed to IM due to second-generation TKI intolerance. No statistical differences were found in the median age at diagnosis and TKI discontinuation, sex, Sokal score, IFN treatment before TKI, median time of TKI treatment to achieve DMR, and the reasons for TKI discontinuation between the second TKI and IM (P>0.05) .The median cumulative treatment time of TKI (71.5 months vs 88 months, P<0.001) , the last TKI median treatment time (60 months vs 88 months, P<0.001) , and the median duration of DMR (58 months vs 66 months, P=0.002) were significantly shorter in the second-generation TKI compared with IM. In the median follow-up of 22 (6-118) months after TKI discontinuation, 88 patients (32.1%) had lost their MMR at a median of 6 (1-91) months; of the 53 patients (60.2%) who lost MMR within 6 months, the overall TFR rate was 67.9%, and the cumulative TFR rates at 12 and 24 months were 70.5% and 67.5%, respectively. Withdrawal syndrome occurred in 26 patients (9.5%) . For patients who restarted TKI treatment, 72 patients (83.7%) achieved DMR again at a median treatment of 4 (1 to 18) months. The univariate analysis showed that the TFR rate of patients treated with second-generation TKI was significantly higher than those who were treated with IM (77.5% vs 62.2%, P=0.041) . A further subgroup analysis found that the TFR rate of the second-generation TKI patients was significantly higher than those treated with IM (80.8% vs 62.2%, P=0.026) . No significant difference was found in the second-generation TKI used as the first line treatment compared with those who were treated with IM (69.0% vs 62.2%, P=0.599) . The multivariate analysis results showed that second-generation TKI treatment was an independent prognostic factor affecting TFR in patients who discontinued TKI (RR=1.827, 95%CI 1.015-3.288, P=0.044) . Conclusion: In the clinical setting, more CML patients rapidly achieved TFR using second-generation TKI than IM treatment.

Pretransplantation use of the second-generation tyrosine kinase inhibitors has no negative impact on the HCT outcome.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) was a standard therapy in chronic phase (CP) chronic myeloid leukemia (CML). As a result of the effective therapy with tyrosine kinase inhibitors (TKI), HCT was shifted to defined clinical situations. We present the results of observational prospective analysis of 28 CML patients undergoing HCT after exposure to, at least, two lines of TKI (including dasatinib and/or nilotinib), with respect to response, overall survival (OS), treatment toxicity, graft versus host disease (GVHD), and progression/relapse incidence. RESULTS: All the patients but one engrafted with median time 19 days. OS for patients in CP1 and CP2/accelerated phase (AcP) were 92.9 and 85.7 %, respectively. Six patients allotransplanted in blast crisis (BC) CML died early after HCT. Eighteen patients achieved deep molecular remission (MR(4.5) or MR(4.0)). Relapse incidence was 29.6 %. Median time to progression (TTP) differs significantly depending on the CML phase prior to HCT, the best response achieved after HCT and development of chronic GvHD. NRM yielded the values 7.1, 12.5, and 50 % in CP1, CP2/AcP, and BC, respectively. Fatal outcome, due to veno-occlusive disease (VOD), was observed in two (7 %) patients. In five (17.9 %) patients, mild or moderate VOD was observed with no negative impact of preceding therapy with TKI2. Acute GvHD was diagnosed in 25.9 % of patients, while chronic GvHD developed in 42.9 % of individuals. CONCLUSION: Pretransplantation therapy with TKI2 in CP CML is safe and reasonable. In BC, the optimal approach before HCT is to reduce the leukemic burden and achieve subsequent CP.

Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors.

BACKGROUND AND OBJECTIVES: Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the response, and to analyze the effect of second-generation TKI on their outcome. PATIENTS AND METHODS: The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed. RESULTS: ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n=4), dasatinib (n=2), interferon (n=1) or hematopoietic stem cell transplantation (n=2). CONCLUSION: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients.