Major Molecular Response Rates Research Articles

Impact of Comorbidities on Response Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with First-Line Dasatinib Versus Imatinib: Exploratory Post Hoc Analysis of DASISION

Impact of Comorbidities on Response Outcomes in Patients with Chronic Myeloid Leukemia in Chronic Phase Treated with First-Line Dasatinib Versus Imatinib: Exploratory Post Hoc Analysis of DASISION

Efficacy and Safety of Front-Line Nilotinib Treatment and Discontinuation in Older Patients (≥65 years) with Chronic Myeloid Leukemia in Chronic Phase Who Have Achieved MR4.5: Results from ENESTfreedom

Efficacy and Safety of Front-Line Nilotinib Treatment and Discontinuation in Older Patients (≥65 years) with Chronic Myeloid Leukemia in Chronic Phase Who Have Achieved MR4.5: Results from ENESTfreedom

Safety and Efficacy Profile of Asciminib As Treatment in Chronic Myeloid Leukemia Patients after Several Tyrosine-Kinase Inhibitors Failure

Introduction: Asciminib is a new BCR-ABL1 inhibitor that differs from previous tyrosine kinase inhibitors (TKIs) in that it does not bind to the ATP-binding site of the kinase. Data from different clinical trials has shown an adequate safety and efficacy profile in chronic myeloid leukemia (CML) patients failing previous TKIs. However, no findings have been communicated in real life experience. The aim of our study is to present first results of asciminib in CML patients failing previous TKIs under the current compassionate use program. Methods: We retrospectively collected data from 31 patients treated with asciminib in 25 centers under compassionate use program. Data collecting was performed between October 2018 and June 2020. Patients baseline characteristics are shown in table 1. Most patients were heavily pretreated with 28 patients receiving 3 or more TKIs previous to asciminib. Eleven patients (35.5%) had been treated with ponatinib at some point throughout the disease. Twelve patients showed BCR-ABL1 mutations (only 1 case with T315I mutation). Switch to asciminib was due to intolerance in 22 patients and due to resistance in the remaining 9. Median dose of asciminib was 80mg per day (40mg every 12 hours). Treatment responses were evaluated according to European Leukemia Net recommendations. Data compilation and analysis were performed with REDCap Software and IBM SPSS (Version 25.0). Results: Median time on asciminib for the entire cohort was 35 weeks. Regarding toxicities, 13 patients (42%) experienced mild extra-hematological side effects (grade 1-2) being the most frequent fatigue (19%), joint pain (16%) and nausea (9%). Four patients (12,9%) showed severe (grade 3-4) extra-hematological events: fatigue, hepatotoxicity, hypertension and pericardial effusion (1 patient each). Three patients (9,7%) suffered from grade 4 thrombocytopenia, 2 of them associating grade 4 neutropenia. All toxicities according to previous TKIs adverse effects as well as cross-intolerance data is shown in table 2. Dose reduction had to be carried out in 9 patients (29%), 7 of those with temporary treatment interruptions; most owing to hematological adverse effects. In terms of efficacy (Graph 1), probability of reaching or at least maintaining previous response was 100%, 61.3% and 35.5% for complete hematological response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR), respectively. Regarding probabilities to improve previous responses, rates of CCyR and MMR were, respectively, 22,2% (2/9) and 22,2% (2/9) for resistant patients and 44% (4/9) and 62,5%. (10/16) for intolerant group. Amid the 11 patients previously treated with ponatinib, 3 patients (27,3%) showed improvement of response achieving at least MMR, 2 of them from the TKI-intolerant group and 1 from the TKI-resistant group. The median follow-up time was 40 weeks, after which 27 patients (87.1%) continued with asciminib. Treatment cessation happened in 2 patients due to progression to blastic phase and in 2 patients due to lack of efficacy. No patients discontinued due to side effects. Conclusion: The data presented, similar to that known from clinical trials, supports the use of asciminib in routine clinical practice in CML patients failing to previous TKIs. Disclosures Garcia-Gutiérrez: Novartis: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding; Incyte: Consultancy, Other: Travel, Accommodation, Expenses, Research Funding.

Asciminib, a First-in-Class STAMP Inhibitor, Provides Durable Molecular Response in Patients (pts) with Chronic Myeloid Leukemia (CML) Harboring the T315I Mutation: Primary Efficacy and Safety Results from a Phase 1 Trial

Asciminib, a First-in-Class STAMP Inhibitor, Provides Durable Molecular Response in Patients (pts) with Chronic Myeloid Leukemia (CML) Harboring the T315I Mutation: Primary Efficacy and Safety Results from a Phase 1 Trial

The Comparison of Frontline Lower-Dose Dasatinib 50 Mg/Day to Standard-Dose Dasatinib 100 Mg/Day in Newly Diagnosed Chronic Myeloid Leukemia: A Propensity Score Analysis

The Comparison of Frontline Lower-Dose Dasatinib 50 Mg/Day to Standard-Dose Dasatinib 100 Mg/Day in Newly Diagnosed Chronic Myeloid Leukemia: A Propensity Score Analysis

Bosutinib (BOS) Versus Imatinib for Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukemia (CML): Final 5-Year Results from the Bfore Trial

Bosutinib (BOS) Versus Imatinib for Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukemia (CML): Final 5-Year Results from the Bfore Trial

CML-023: Relationship Between High Body Mass Index (BMI) and Treatment Outcomes in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Dasatinib or Imatinib: Retrospective Analysis of the Phase 3 DASISION Trial

Context In the treatment of CML-CP, early molecular responses to tyrosine kinase inhibitors (TKIs) are associated with improved long-term outcomes, and major molecular response (MMR) at 18 months is an important goal. Obesity may elevate the risk of CML (Strom 2009), and high BMI at diagnosis can delay time to response and reduce MMR rate in patients treated with first-line imatinib (Breccia 2013). In the phase 3 DASISION study ( NCT00481247 ), dasatinib was associated with earlier, more durable, and deeper responses than imatinib (Cortes 2016). Objective Investigate the relationship between BMI and response to first-line TKIs. Design DASISION was an open-label multinational study assessing dasatinib versus imatinib for newly diagnosed CML-CP. Patients were randomized to 100mg dasatinib or 400mg imatinib once daily. In this exploratory analysis, patients were stratified according to high (≥25kg/m2) or normal BMI ( Results Collectively, 259 patients received dasatinib (high BMI, n=109; normal BMI, n=147; unknown, n=3) and 260 received imatinib (high BMI, n=107; normal BMI, n=147; unknown, n=6). Baseline characteristics were balanced within BMI subgroups. High BMI subgroup: significant improvements for dasatinib versus imatinib in median time to MMR (9.2 vs 27.6 months; P Conclusions Improved outcomes were seen in patients with high BMI treated with dasatinib versus imatinib; however, these differences were not seen with normal BMI. These findings need further validation to ascertain the role of BMI in predicting treatment responses in patients with CML-CP. Funding BMS. Previous presentation ASH 2019, HOPA 2020.

CML-277: Efficacy of Bosutinib in Imatinib-Resistant vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Context Bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Objective To evaluate the efficacy of bosutinib in patients with Ph+ CP CML according to subgroups of resistance (imatinib vs. dasatinib/nilotinib) or intolerance to prior tyrosine kinase inhibitors (TKIs). Design BYOND ( NCT02228382 ) is an ongoing, phase 4, single-arm, open-label study. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Setting Multicenter study in Europe and North America. Patients Patients with CML resistant/intolerant to prior TKIs. Interventions Bosutinib 500 mg QD (starting dose). Main outcome measures Cumulative response rates. Results Of 156 patients with Ph+ CP CML who received bosutinib, 52 had resistance only to imatinib, 31 had resistance to dasatinib and/or nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration was 24.1, 8.9, and 25.3 months, and median dose intensity was 360, 431, and 292 mg/day. At the data cut-off, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment. The main reason for discontinuation was adverse events: 19.2%, 25.8%, and 28.8% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. Corresponding discontinuations due to insufficient response occurred in 3.8%, 16.1%, and 1.4% of patients. No patient experienced on-treatment transformation to advanced phase CML. In patients without baseline complete cytogenetic response (CCyR), CCyR rates by 1 year were 65.0%, 50.0%, and 72.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. In patients without baseline major molecular response (MMR), cumulative MMR rates by 1 year were 55.6%, 28.6%, and 80.6% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. Deaths occurred in 3, 3, and 4 imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively. Conclusions Response rates were similar between imatinib-resistant and TKI-intolerant patients. Despite the fact that dasatinib/nilotinib-resistant patients were more heavily pretreated and had a shorter treatment duration, responses were also seen in patients with resistance to these second-generation TKIs. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Study Sponsor Pfizer.

Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.

Induction and maintenance for chronic myeloid leukemia-chronic phase: A novel treatment strategy.

e19526 Background: Imatinib remains the standard of care for CML-CP in many countries because of its affordability and safety with long term use. Given that upfront Nilotinib has higher rates of major molecular response and early deep responses predict long term responses, we hypothesized that upfront Nilotinib as induction followed by Imatinib maintenance may help to capitalize on the efficacy of Nilotinib without sacrificing the safety and efficacy of Imatinib. Methods: CML CP patients were divided into 3 groups at the time of diagnosis. Group 1 received Imatinib 400mg OD upfront, Group 2 and 3 received Nilotinib 300 mg BD for 1st 3 and 6 months respectively then switched over to Imatinib 400 OD. Quantitative real time PCR for BCR-ABL (RQ PCR for BCR-ABL) was done at 3, 6,12, 18, 24, 30, and 36 months to assess response. 3 early molecular responses were defined for analysis. EMR 1 was defined as Bcr-abl RQPCR < 10% at 3 months, EMR 2 as < 1% at 6 months and EMR 3 as < 0.1% at 6 months. Results: Patients on Nilotinib induction had deeper responses than patients on Imatinib at 3 and 6 months. However, subsequent molecular responses were similar in all 3 groups. The rates of Early Molecular responses were significantly better in the Nilotinib group compared to the Imatinib group. Significantly lesser patients in Group 1 had EMR 1 compared to Groups 2 and 3 [80.49% vs 100% vs 95.56%, p value 0.001]. Results were similar for EMR 2 and 3 [EMR 2: 34.15% vs 42.11% vs 60%, p value 0.017, EMR 3: 25.71% vs 25.53% vs 44.44%, p value Group 1 vs Group 3: 0.030]. TKI failure/progression rates were significantly better amongst patients who achieved EMR vs those who did not achieve EMR for EMR 2 and 3 but not EMR 1. For EMR 2, 42.68% who did not achieve EMR eventually had TKI failure compared to 18.03% of those who achieved EMR (p value 0.002). Similarly, 32.95% who failed to achieve EMR 3 progressed vs 11.9% of those who achieved EMR 3 (p value 0.011). 3 patients in group 1 and 1 patient in group 2 developed T315I mutation while none did in Group 3. Conclusions: The early advantage achieved with Nilotinib Induction was not sustained after switching to Imatinib maintenance. Nevertheless, target responses were still achieved and similar failure rates were present in all 3 groups. Patients who attained an EMR < 1 % at 3 months or < 0.1% at 6 months tend to have higher EFS and lower rates of TKI failure/progression irrespective of the treatment arm.

Relationship between molecular response and quality of life with bosutinib or imatinib for chronic myeloid leukemia

Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p < 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved MR5, emotional well-being and leukemia-specific domains showed the greatest improvement, with medium differences in effect sizes, whereas social well-being and physical well-being had the weakest relationship with MR.

Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

Long‐term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE)

SummaryIn the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice‐daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once‐daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months’ follow‐up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR‐ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5) were achieved within 48 months by more radotinib‐treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib‐treated patients (71% and 44%, respectively). Estimated overall and progression‐free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment‐free remission may be attainable.

Clinical efficacy and safety of imatinib treatment in children and adolescents with chronic myeloid leukemia

Chronic myeloid leukemia (CML) is relatively rare in childhood and few studies have reported the clinical use of imatinib (IM) in pediatric CML. In this study, we evaluated the efficacy and tolerability of IM in children and adolescents with CML.We investigated 21 patients under 18 years of age with newly diagnosed CML and treated with IM in Children's Hospital of Chongqing Medical University between May 2014 and February 2018. The disease was staged according to the European LeukemiaNet criteria and the IM dose was determined based on the disease stage. Cumulative responses and survival probabilities were estimated according to the Kaplan–Meier method.The estimated complete hematologic response rate of chronic phase-chronic myeloid leukemia (CML-CP) was 89.5% at 3 months. The complete cytogenetic response rates increased with time, reaching 47.4%, 73.7%, and 80.3% at 6, 12, and 24 months, respectively. The cumulative major molecular response rates were 42.1% and 76.3% at 12 and 24 months, respectively. With a median follow-up time of 33.8 months (range, 3.2–61.7 months), the estimated 2-year overall survival (OS) rate for CML was 95.2% (95% confidence interval [CI], 70.7%–99.3%). None of the CML-CP patients progressed to the accelerated phase or had a blast crisis. The 2-year OS and progression-free survival rates for the CML-CP cohort were both 100%, while the estimated 2-year event-free survival rate was 68% (95% CI, 42.1%–84.2%). None of the patients in this group had treatment-related deaths or IM discontinuation due to drug toxicities, and only 1 patient had a grade III–IV nonhematologic adverse event. Overall, anemia was the most common adverse effect and 42.9% of patients had a decrease in bone mineral density.IM was effective and the adverse effects were well-tolerated throughout the follow-up period in Chinese CML patients under 18 years of age.

Outcome of Imatinib Treatment in Yemeni Patients With Chronic Myeloid Leukemia and the Influence of Nonadherence to Treatment and Duration of Previous Hydroxyurea Therapy

BackgroundIn a developing country like Yemen, data are limited regarding the outcome of imatinib treatment of chronic myeloid leukemia and the effect of nonadherence to imatinib treatment and previous duration of hydroxyurea treatment. Patients and MethodsA longitudinal cohort study, which included 164 Yemeni patients, was performed. Data regarding the disease characteristics, adherence to treatment (the medication possession ratio) and outcome were analyzed. ResultsAfter a median follow-up of 60 months and a median duration of imatinib treatment of 46 months, 79 (48.2%) patients were adherent to treatment. In adherent patients, the overall survival and progression-free survival (PFS) were 78 (98.7%) and 73 patients (92.4%), respectively and major molecular response (MMR) rates at 12 months and at 46 months were 32 (41.0%) and 45 patients (57.0%), respectively, compared with 67 (78.8%), 51 (60%), 5 (6.9%), and 2 patients (2.4%), respectively, in nonadherent patients (P < .001 for all parameters). Nonadherence to imatinib treatment and duration of hydroxyurea treatment of more than 12 months before starting imatinib were found to adversely affect PFS in univariate (hazard ratio [HR], 7.5 and 9.7, respectively and P < .001 for both) and multivariate (HR, 5.6 and 9.3; P = .001 and P < .001, respectively) analysis. High risk Sokal score was found to adversely affect PFS in univariate analysis (HR of high to low risk, 2.8; P < .022) but not in multivariate analysis. ConclusionYemeni patients who were adherent to imatinib therapy achieved response rates similar to that of international standards. Nonadherence to imatinib treatment and previous duration of hydroxyurea treatment for more than 12 months, as a proxy of long interval between diagnosis and starting imatinib treatment, reduced the optimal response to imatinib therapy.

Marrow fibrosis is an independent predictor of hematological toxicity of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia

Hematological toxicity is a common adverse effect of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML). We retrospectively investigated the incidence of hematological toxicity after TKI administration in 143 CML patients and parameters associated with hematological toxicity. Severe hematological toxicity (grade 3–4) existed in 26 (18.2%) patients. Marrow fibrosis (MF), age, Sokal score, and spleen enlargement were associated with severe hematological toxicity. Further multivariate analysis showed that only MF was an independent predictor. Complete cytogenetic response(CCyR) rates and major molecular response (MMR) rates with grade 3–4 hematological toxicity were 42.3% and 26.9%, respectively, significantly lower than patients with grade 1–2 and without hematological toxicity (p = .032 for CCyR and p = .044 for MMR). Similar results were observed regarding progression-free survival (PFS) and overall survival (OS) (p = .011 for PFS and p = .037 for OS). This study indicated that MF was an independent predictor of severe hematological toxicity of TKIs.

Comprehensive analyses of safety and efficacy toward individualizing imatinib dosage in patients with chronic myeloid leukemia.

Safety and efficacy outcomes of imatinib treatment were evaluated using extensive clinical data collected from a total of 1003 patients with newly diagnosed chronic myeloid leukemia in chronic phase between 2001 and 2018. By 12months of imatinib treatment at a fixed dose of 400mg/day, 45.4% of patients experienced at least one type of dose-limiting toxicities (DLTs). The DLTs that frequently occurred first were thrombocytopenia (40.0%), neutropenia/leukopenia (14.3%) and dermatological reactions (12.1%). Patients with lighter body weight (≤ 64kg) and older age (> 43years) experienced a markedly higher occurrence of first DLTs by 12months than heavier and younger patients (57.9% vs. 30.1%, p < 0.001). On the other hand, 38.9% of patients achieved major molecular response (MMR) at 12months at the fixed dose. Female patients achieved a greater rate of MMR than male patients (45.6% vs. 35.5%, p = 0.028). In conclusion, patients with light weight and old age are more vulnerable to DLTs, whereas female patients gain more efficacy benefit at the fixed dose. The authors suggest that the initial dose of imatinib should be reduced to 300mg/day or lower for patients vulnerable to DLTs to diminish the risk of DLTs without compromising the achievement of MMR.

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia

AbstractChronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome–positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.

Fertility and disease outcomes in patients with chronic myeloid leukemia

目的报道服用酪氨酸激酶抑制剂（TKI）的男性慢性髓性白血病（CML）患者配偶和女性妊娠期诊断CML患者的生育和疾病结局。方法将1998年7月至2018年2月确诊并服用TKI治疗的男性CML患者及2009年10月至2018年2月期间妊娠期诊断CML的女性患者纳入研究。采用收集病历资料、问卷调查和门诊及电话随访方式收集患者疾病和生育相关信息。结果共收集服用TKI期间配偶妊娠的49例男性CML患者数据，其配偶初次受孕前，男性患者服用伊马替尼34例、尼洛替尼9例、达沙替尼6例，配偶受孕时，患者中位年龄为32（25～48）岁，TKI治疗时间为36（0.2～198）个月，除1例在仅获得完全血液学反应状态下为备孕而停药1年患者发生疾病进展外，其余48例男性患者均处于疾病稳定状态。所有男性患者的配偶共妊娠61次，生产55例婴儿，早产1例、生产低体重儿2例，其中1例合并尿道下裂，出生后行手术修复，其余均为足月健康婴儿。共收集18例女性妊娠期诊断CML的患者数据，2例自然流产，2例人工流产，14例分娩健康婴儿，未见先天畸形，确诊CML至开始TKI（伊马替尼15例，尼洛替尼3例）治疗时间为4（0.3～16）个月，中位随访45（7～114）个月，5年完全分子学反应、主要分子学反应、分子学反应4.5（MR4.5）获得率分别为88.9％、85.3％和35.1％，5年无失败生存、无进展生存和总生存率分别为64.2％、90.9％和90.9％，所有婴儿均正常发育。结论男性CML患者服用TKI对生育结局无不良影响，应避免盲目停药备孕。TKI时代，女性妊娠合并CML患者生育和疾病结局良好。

Phase 2 Study of Bosutinib in Japanese Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Phase 2 Study of Bosutinib in Japanese Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia