Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase / 中华血液学杂志

Objective: To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) . Methods: From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed. Results: A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved <CHR on the first-line TKI-therapy, the interval from diagnosis to switching to second-line TKI ≥18 months, AP or hematologic failure, or non-specific mutation of BCR-ABL kinase domain before second-line TKI therapy, developing severe hematologic toxicity during the second-line TKI therapy were variables associated with poor responses or outcomes on second-line TKI therapy. With a median follow-up of 6 (range, 3-129) months, the cumulative CHR, CCyR and MMR were 95.7%, 29.3%, and 18.6%, respectively in those receiving the third-line TKI therapy. The 2-year PFS and OS rates were 66.8% and 93.8%, respectively. The patients with an interval from diagnosis to starting TKI ≥6 months, achieving no cytogenetic response on the second-line TKI, the interval from diagnosis to starting second-line TKI ≥60 months, and progression to AP before the third-line TKI therapy had lower probabilities of responses and unfavorable outcomes. Conclusions: The efficacy of dasatinib and nilotinib as second- or third-line TKI-therapy were active in the CML patients with TKI-resistance. The best response achieved on previous TKI-therapy, the disease phase before switching TKI, and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.

Analysis of the efficacy and influencing factors of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia in the chronic phase and accelerated phase / 中华血液学杂志

Objective@#To explore the efficacy and prognosis of nilotinib or dasatinib as second- or third-line treatment in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) and accelerated phase (AP) .@*Methods@#From January 2008 to November 2018, the data of CML patients who failed first- or second-line tyrosine kinase inhibitor (TKI) -therapy received nilotinib or dasatinib as second-line and third-line therapy were retrospectively reviewed.@*Results@#A total of 226 patients receiving nilotinib or dastinib as second-line (n=183) and third-line (n=43) therapy were included in this study. With a median follow-up of 21 (range, 1-135) months, the cumulative rates of complete hematological response (CHR) , complete cytogenetic response (CCyR) and major molecular response (MMR) were 80.4%, 56.3%and 38.3%, respectively in those receiving TKI as second-line TKI therapy. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.7%and 93.1%, respectively. Multivariate analyses showed that Sokal high risk, female gender, the best response achieved <CHR on the first-line TKI-therapy, the interval from diagnosis to switching to second-line TKI ≥18 months, AP or hematologic failure, or non-specific mutation of BCR-ABL kinase domain before second-line TKI therapy, developing severe hematologic toxicity during the second-line TKI therapy were variables associated with poor responses or outcomes on second-line TKI therapy. With a median follow-up of 6 (range, 3-129) months, the cumulative CHR, CCyR and MMR were 95.7%, 29.3%, and 18.6%, respectively in those receiving the third-line TKI therapy. The 2-year PFS and OS rates were 66.8% and 93.8%, respectively. The patients with an interval from diagnosis to starting TKI ≥6 months, achieving no cytogenetic response on the second-line TKI, the interval from diagnosis to starting second-line TKI ≥60 months, and progression to AP before the third-line TKI therapy had lower probabilities of responses and unfavorable outcomes.@*Conclusions@#The efficacy of dasatinib and nilotinib as second- or third-line TKI-therapy were active in the CML patients with TKI-resistance. The best response achieved on previous TKI-therapy, the disease phase before switching TKI, and the severe hematologic toxicity developing on the current TKI-therapy were associated with the responses and outcomes.

Comparison of nilotinib vs imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase / 中华血液学杂志

Objective: To compare the cytogenetic and molecular responses, outcomes and severe hematologic toxicity of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) . Methods: Newly diagnosed CML-CP patients were consecutively recruited from January 2006 to December 2018 who received nilotinib and imatinib as first-line treatment. Clinical data were retrospectively analyzed. Results: A total of 524 patients were classified into 439 (83.8%) receiving imatinib and 85 (16.2%) receiving nilotinib. Comparing with imatinib group, patients in nilotinib group were much younger (P=0.019) and more with intermediate and high Sokal risks (P<0.001) , WBC ≥100×10(9)/L (P<0.001) , HGB<120 g/L (P<0.001) , blast cells in bone marrow (P=0.026) , splenomegaly (P<0.001) by physical examination at diagnosis, and longer interval from diagnosis to TKI treatment (P=0.003) . With a median TKI duration of 57 (range 3-153) months, the probabilities of complete cytogenetic response (CCyR) (P=0.011) , major molecular response (MMR) (P=0.001) and MR(4.5) (P=0.046) were much higher in nilotinib group than those in imatnib according to each risk group. There is no statistical significance on probabilities of failure free survival (FFS) , progression free survival (PFS) and overall survival (OS) at 6 years between the two groups. Multivariate analyses showed that imatinib was an adverse factor associated with achieving CCyR (OR=0.6, 95% CI 0.5-0.8, P=0.001) , MMR (OR=0.6, 95% CI 0.5-0.9, P=0.032) and MR(4.5) (OR=0.6, 95%CI 0.5-0.9, P=0.032) and poor FFS (OR=1.9, 95%CI 1.0-3.4, P=0.041) . In addition, Sokal score was an independent factor affecting cytogenetic and molecular responses, treatment failure, disease progression and survival. Male, WBC ≥100×10(9)/L or HGB<120 g/L at diagnosis were significantly associated with lower cytogenetic and molecular response rates and/or poor FFS. The severe hematologic adverse events were not associated with different TKIs. Conclusions: Nilotinib reaches to the faster and deeper cytogenetic and molecular responses and significantly improves FFS than imatinib in newly diagnosed patients with CML-CP.

Comparison of nilotinib vs imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase / 中华血液学杂志

Objective@#To compare the cytogenetic and molecular responses, outcomes and severe hematologic toxicity of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) .@*Methods@#Newly diagnosed CML-CP patients were consecutively recruited from January 2006 to December 2018 who received nilotinib and imatinib as first-line treatment. Clinical data were retrospectively analyzed.@*Results@#A total of 524 patients were classified into 439 (83.8%) receiving imatinib and 85 (16.2%) receiving nilotinib. Comparing with imatinib group, patients in nilotinib group were much younger (P=0.019) and more with intermediate and high Sokal risks (P<0.001) , WBC ≥100×109/L (P<0.001) , HGB<120 g/L (P<0.001) , blast cells in bone marrow (P=0.026) , splenomegaly (P<0.001) by physical examination at diagnosis, and longer interval from diagnosis to TKI treatment (P=0.003) . With a median TKI duration of 57 (range 3-153) months, the probabilities of complete cytogenetic response (CCyR) (P=0.011) , major molecular response (MMR) (P=0.001) and MR4.5 (P=0.046) were much higher in nilotinib group than those in imatnib according to each risk group. There is no statistical significance on probabilities of failure free survival (FFS) , progression free survival (PFS) and overall survival (OS) at 6 years between the two groups. Multivariate analyses showed that imatinib was an adverse factor associated with achieving CCyR (OR=0.6, 95% CI 0.5-0.8, P=0.001) , MMR (OR=0.6, 95% CI 0.5-0.9, P=0.032) and MR4.5 (OR=0.6, 95%CI 0.5-0.9, P=0.032) and poor FFS (OR=1.9, 95%CI 1.0-3.4, P=0.041) . In addition, Sokal score was an independent factor affecting cytogenetic and molecular responses, treatment failure, disease progression and survival. Male, WBC ≥100×109/L or HGB<120 g/L at diagnosis were significantly associated with lower cytogenetic and molecular response rates and/or poor FFS. The severe hematologic adverse events were not associated with different TKIs.@*Conclusions@#Nilotinib reaches to the faster and deeper cytogenetic and molecular responses and significantly improves FFS than imatinib in newly diagnosed patients with CML-CP.

Effect of stopping tyrosine kinase inhibitors during pregnancy on disease status and reproductive outcomes among patients with chronic myeloid leukemia / 中华血液学杂志

Objective: To explore the pregnancy outcome and disease status among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI) when they stopped TKI treatment during pregnancy. Methods: The clinical characteristics, reproductive outcomes and disease status of the patients who stopped TKI due to pregnancy between November 2004 to November 2017 were retrospectively collected. Results: A total of 14 CML patients in chronic phase (CML-CP), 12 patients were Sokal-low-risk. The median time of TKI treatment was 46.5 (15-123) months before the drug was stopped. The median age at the time of pregnancy was 29 (24-32) years. The median time of TKI exposure was 4 (0-9) weeks in 12 accidental pregnancies. Outcomes were available for 13 pregnancies, 9 cases (69.2%) delivered healthy babies, 1 case (7.7%) delivered polydactylia malformation baby, 3 cases (23.1%) had spontaneous abortion. The last one was still in pregnancy (no organ malformations were observed in color Doppler ultrasound). At the end of the follow up date, 10 children developed normal, the median age was 14 (0.7-65) months. Of the 14 patients who stopped TKI, 7 in complete molecular response (CMR), 3 in MR(4) (BCR-ABL(IS) <0.01%, ABL transcript >10 000), 2 in major molecular response (MMR), 2 in complete cytogenetic response (CCyR). The median time of TKI discontinuation during pregnancy was 33.5 (4-40) weeks. At the end of pregnancy, 4 cases were in CMR, 4 in MR(4), 1 in MMR and 4 in CCyR. No patients lost CCyR and complete hematologic remission. Conclusions: During the treatment of imatinib and Nilotinib, unplanned pregnancy may have a normal infant, but may lead to spontaneous abortion and congenital malformations. Female of CML-CP who had sustained and stable MMR at least 24 months and Sokal-low-risk had higher safety factor discontinued TKI during pregnancy, but still had a risk of increasing tumor load, so monitored the level of BCR-ABL of peripheral blood monthly during pregnancy is necessary.

Comorbidity profile and its impact on reported outcome in Chinese patients with chronic myeloid leukemia in chronic phase receiving tyrosine kinase-inhibitor therapy / 中华血液学杂志

Objectives: To explore the comorbidity profile and its impact on reported outcome of patients with chronic myeloid leukemia in chronic phase (CML-CP) receiving tyrosine kinase-inhibitor (TKI) therapy in China. Methods: From September 2015 to March 2016, anonymous questionnaires were distributed to adult CML patients who were receiving TKI treatment in China. The questionnaires included demographics, comorbidity(ies), TKI(s) therapy, annual out-of-pocket expense for TKIs, treatment responses, health-related quality of life (HRQoL) measured by the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), satisfaction with therapy, impact of TKI therapy on work and daily life. Results: Data from 1 108 respondents in CML-CP were analyzed, 701 (63.6%) were male, median age was 42 years (range, 18-88 years), 76.4% were currently on imatinib, median TKI-therapy-duration was 29 months (range, 3-178 months). Of them, 300 (27.1%) had ≥1 comorbidity(ies), including hypertension(30.3%), diabetes (21.0%), coronary heart disease (12.3%), gastro-intestinal disease (12.3%), liver disease (11.7%), kidney disease (8.3%), cerebrovascular disease (6.7%) and lung diseases (5.7%), thrombosis (1.3%), other benign diseases (15.3%) and other cancer (8.0%), and 74 (24.7%) had ≥2 comorbidities. Multivariate analyses showed the comorbidity profile of other benign diseases was significantly associated with lower HRQoL score and TKI therapy affecting work and daily life, but it did not significantly affect patients' satisfaction with TKI treatment. Female and no complete cytogenetic response (CCyR) were associated with lower HRQoL score, education level ≥bachelor degree and TKI-therapy duration ≥3 years were associated with higher HRQoL score. Switching between first and second generation TKIs and no CCyR were associated with dis-satisfaction or extreme dis-satisfaction with TKI therapy, free out-of-pocket expense for TKI was associated with better satisfaction. Age<60 years and no CCyR were associated with TKI therapy affecting work and daily life. Conclusions: The survey showed that 27.1% Chinese adult patients with CML-CP receiving TKI-therapy had comorbidity(ies). Different comorbidity profile had different impact on patients' HRQoL and different impact of TKI therapy on work and daily life.

Effect of stopping tyrosine kinase inhibitors during pregnancy on disease status and reproductive outcomes among patients with chronic myeloid leukemia / 中华血液学杂志

Objective@#To explore the pregnancy outcome and disease status among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI) when they stopped TKI treatment during pregnancy.@*Methods@#The clinical characteristics, reproductive outcomes and disease status of the patients who stopped TKI due to pregnancy between November 2004 to November 2017 were retrospectively collected.@*Results@#A total of 14 CML patients in chronic phase (CML-CP), 12 patients were Sokal-low-risk. The median time of TKI treatment was 46.5 (15-123) months before the drug was stopped. The median age at the time of pregnancy was 29 (24-32) years. The median time of TKI exposure was 4 (0-9) weeks in 12 accidental pregnancies. Outcomes were available for 13 pregnancies, 9 cases (69.2%) delivered healthy babies, 1 case (7.7%) delivered polydactylia malformation baby, 3 cases (23.1%) had spontaneous abortion. The last one was still in pregnancy (no organ malformations were observed in color Doppler ultrasound). At the end of the follow up date, 10 children developed normal, the median age was 14 (0.7-65) months. Of the 14 patients who stopped TKI, 7 in complete molecular response (CMR), 3 in MR4 (BCR-ABLIS <0.01%, ABL transcript >10 000), 2 in major molecular response (MMR), 2 in complete cytogenetic response (CCyR). The median time of TKI discontinuation during pregnancy was 33.5 (4-40) weeks. At the end of pregnancy, 4 cases were in CMR, 4 in MR4, 1 in MMR and 4 in CCyR. No patients lost CCyR and complete hematologic remission.@*Conclusions@#During the treatment of imatinib and Nilotinib, unplanned pregnancy may have a normal infant, but may lead to spontaneous abortion and congenital malformations. Female of CML-CP who had sustained and stable MMR at least 24 months and Sokal-low-risk had higher safety factor discontinued TKI during pregnancy, but still had a risk of increasing tumor load, so monitored the level of BCR-ABL of peripheral blood monthly during pregnancy is necessary.

Comorbidity profile and its impact on reported outcome in Chinese patients with chronic myeloid leukemia in chronic phase receiving tyrosine kinase-inhibitor therapy / 中华血液学杂志

Objectives@#To explore the comorbidity profile and its impact on reported outcome of patients with chronic myeloid leukemia in chronic phase (CML-CP) receiving tyrosine kinase-inhibitor (TKI) therapy in China.@*Methods@#From September 2015 to March 2016, anonymous questionnaires were distributed to adult CML patients who were receiving TKI treatment in China. The questionnaires included demographics, comorbidity(ies), TKI(s) therapy, annual out-of-pocket expense for TKIs, treatment responses, health-related quality of life (HRQoL) measured by the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), satisfaction with therapy, impact of TKI therapy on work and daily life.@*Results@#Data from 1 108 respondents in CML-CP were analyzed, 701 (63.6%) were male, median age was 42 years (range, 18-88 years), 76.4% were currently on imatinib, median TKI-therapy-duration was 29 months (range, 3-178 months). Of them, 300 (27.1%) had ≥1 comorbidity(ies), including hypertension(30.3%), diabetes (21.0%), coronary heart disease (12.3%), gastro-intestinal disease (12.3%), liver disease (11.7%), kidney disease (8.3%), cerebrovascular disease (6.7%) and lung diseases (5.7%), thrombosis (1.3%), other benign diseases (15.3%) and other cancer (8.0%), and 74 (24.7%) had ≥2 comorbidities. Multivariate analyses showed the comorbidity profile of other benign diseases was significantly associated with lower HRQoL score and TKI therapy affecting work and daily life, but it did not significantly affect patients' satisfaction with TKI treatment. Female and no complete cytogenetic response (CCyR) were associated with lower HRQoL score, education level ≥bachelor degree and TKI-therapy duration ≥3 years were associated with higher HRQoL score. Switching between first and second generation TKIs and no CCyR were associated with dis-satisfaction or extreme dis-satisfaction with TKI therapy, free out-of-pocket expense for TKI was associated with better satisfaction. Age<60 years and no CCyR were associated with TKI therapy affecting work and daily life.@*Conclusions@#The survey showed that 27.1% Chinese adult patients with CML-CP receiving TKI-therapy had comorbidity(ies). Different comorbidity profile had different impact on patients’ HRQoL and different impact of TKI therapy on work and daily life.

Analysis on tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia in the real world: experience from single center / 中华血液学杂志

Objective@#To explore status of tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) in the chronic phase (CP) in the real world, to analyze causes, factors and outcomes associated with TKI discontinuation and the possibility of pursuit treatment-free remission (TFR) in China.@*Methods@#From January 2013 to August 2016, data of CML-CP patients in Peking University People’s Hospital which were not enrolled in clinical trials were retrospectively collected and analyzed.@*Results@#Data of 662 CML-CP patients were collected. With a median follow-up after TKI-therapy of 26 months (range, 3-187 months) , 187 patients (28.2%) experienced TKI cessation of at least 2 weeks. Causes of TKI discontinuation included hematologic adverse events 57.8% (n=108) , non-hematologic adverse events 30.4% (n=57) , financial burden 25.1% (n=47) , and others 7.0% (n= 13) . Multivariate analyses showed female, ≥40 years, no co-morbidity, and interval from diagnosis to TKI initiation ≥6 months, TKI switch and patients from other hospitals were factors associated with TKI discontinuation because of hematologic adverse effects. Female and patients from other hospitals were factors associated with TKI discontinuation because of non-hematologic adverse effect. TKI switch, generic TKI used and patients from other hospitals were factors associated with TKI discontinuation because of financial toxicity. Patients TKI discontinuation because of hematologic, non-hematologic or financial toxicity achieved a lower complete cytogenetic response or complete molecular response (CMR) than those with uninterrupted TKI-therapy. Patients with TKI discontinuation because of hematologic or financial toxicity had a shorter progression-free survival than those with uninterrupted TKI-therapy. 5 of 7 patients who obtained sustained CMR and discontinued TKI-therapy experienced disease recurrence with a median duration of 3 months (range, 2-32 months) . In 39 patients from other hospitals who aimed to confirm their optimal response of sustained CMR in Peking University People’s Hospital, 21 (53.8%) were BCR-ABL positive.@*Conclusion@#In the real world in China, half of CML-CP patients who discontinued TKI-therapy were incurred to TKI-related hematologic adverse effect, and both a quarter of them, TKI-related non-hematologic toxicities and financial toxicity, respectively. Discontinued TKI-therapy due to hematologic adverse events or financial toxicity was associated with lower TKI-therapy response rates. Nowadays, based on the Chinese situation, it is too early to talk about TFR.