Chronic Myeloid Leukemia In The Chronic Phase Research Articles

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Efficacy and safety of flumatinib in the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase: A real-world single-center retrospective study, with a focus on premature drug discontinuation

PurposeTo assess the real-world efficacy and safety of flumatinib as first-line and post-line treatments for chronic myeloid leukemia in the chronic phase (CML-CP). ResultsAmong 141 patients receiving flumatinib as first-line and post-line treatment, the 12-month major molecular response (MMR) rates were 69.4% and 67.6%, respectively. The median time to response was 6 and 10.5 months, respectively. In post-line treatment, the early molecular response (EMR) of flumatinib as second-line is significantly superior to that of third-line treatment (3-month EMR rate: 79.2% vs. 39.3%, P<0.001; 3-month MMR rate: 45.8% vs. 21.4%, P=0.033). Contrastively, patients who switched to flumatinib due to intolerance had significantly higher MMR rates at 3, 6, and 12 months compared to patients who switched due to inadequate response (60.6% vs. 24.2%, P=0.003; 66.7% vs. 36.0%, P=0.027; 84.2% vs. 50.0%, P=0.038). Premature drug discontinuation was observed in 28.4% of the patients. Grades 3–4 hematologic adverse events (AEs) were identified as independent risk factors for premature drug discontinuation. Patients who discontinued treatment and those who previously received only imatinib therapy had a poorer molecular response and failure-free survival. ConclusionsFlumatinib demonstrates favorable efficacy and safety. Treatment discontinuation can result in a poorer molecular response and long-term prognosis.

JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib.

Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML.

CFL1 is Implicated in Chronic Myeloid Leukemia Response during Imatinib Therapy.

Cofilin (CFL1) is one critical member of the actin deploy family (ADF). Overexpression of CFL1 is associated with aggressive features and poor prognosis in malignancies. We evaluated the expression of CFL1 in patients with chronic myeloid leukemia in the chronic phase (CML-CP), acute myelocytic leukemia (AML) and healthy controls. The role of CFL1 in imatinib therapy was also investigated using cell line. We found that the expression of CFL1 was lower in CML patients than that in healthy controls, and was significantly upregulated after imatinib therapy (p<0.05). CML patients with lower CFL1 achieved higher Major molecular response (MMR) rate after 6 months of imatinib therapy (p<0.05). Cofilin, P-cofilin and F-actin, especially branched F-actin were all upregulated after imatinib therapy. The lower CFL1 expression before treatment may predicts a better response to imatinib. Imatinib affects F-actin remodeling in CML patients by regulating CFL1 expression and activity.

ASC4KIDS: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Chronic Myeloid Leukemia in the Chronic Phase

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in the chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL (non-receptor tyrosine) kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the US Food and Drug Administration (FDA) with subsequent approvals worldwide for patients aged ≥18 years with Philadelphia chromosome-positive (Ph+) CML-CP treated with ≥2 prior TKIs in October 2021. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). This study aims to characterize the pharmacokinetics (PK), long-term safety profile, and antileukemic effects of asciminib in pediatric patients and identify a pediatric formulation dose that will lead to asciminib exposure comparable to 80 mg qd or 40 mg bid in adult patients. Methods This multicenter, open-label study (NCT04925479) includes patients aged 1 to &amp;lt;18 years with Ph+ CML-CP, without a BCR::ABL1 T315I mutation, treated with ≥1 prior TKI. For the pediatric formulation group, at least 15 patients will be included in each of the two age groups (1 to &amp;lt;12 years and 12 to &amp;lt;18 years), consisting of Part 1, 2 and 3. The study started with an exploratory adult formulation group of Adolescent patients (aged 14 to &amp;lt;18 years, body weight ≥40 kg) treated with the adult formulation dose (40 mg bid or 80 mg qd tablet) under fasting conditions. The primary endpoint includes PK parameters; secondary endpoints include: hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulations. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (a mini-tablet of 1.3 mg/kg with food) to assess safety, and to assess if the exposure in pediatric patients is comparable to exposure with the adult formulation over the first 28 days (patients either from pediatric or adult categories). After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort, 40 mg bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort, 80 mg qd regimen): 10 patients (5 from each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for the bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for the combined bid and qd regimen will be performed after all patients complete 52 weeks of treatment (total treatment period: 5 years [ Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of the study. There are 32 study sites open out of planned 35 study sites in 14 countries worldwide. The exploratory and the pediatric formulation groups recruited 4 patients and 9 patients, respectively, as of June 07, 2023, with a total of 13 patients in the study. The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

The Outcomes of Pregnancies in Japanese Patients with CML in the TKI Era; A Result of Nationwide Survey

Background The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved the survival of patients with chronic myeloid leukemia (CML). Although the median age at diagnosis of CML is around 55 years, CML affects all generations, rendering a substantial population of women of childbearing potential. Therefore, issues related to conception and pregnancy are becoming increasingly important, because TKIs have the potential risk of fetal abnormalities and spontaneous abortion. Planned pregnancy during treatment-free remission (TFR) is an ideal way to avoid exposure of the embryo and fetus to a TKI. However, in real-life situations, not all conceptions are planned, not all patients fulfill the eligibility criteria for TFR, and some cases develop CML during pregnancy. Information about pregnancy in patients with CML is still limited in the TKI era. Study Design and Methods We designed a retrospective observational study of female patients with CML in the chronic phase who experienced pregnancy. We conducted a nationwide survey to collect data associated with CML treatment, conception, and pregnancy outcomes. This study was approved by the institutional review boards of Aiiku Hospital and each hospital participating in the survey. This study is registered in the University Medical Information Network (UMIN000042762). Results We sent questionnaires to 463 hematological centers to ask whether they made a diagnosis of CML in female patients of childbearing age and we received replies from 206 centers (recovery rate: 44.5%). A total 853 female patients aged 45 years or younger were diagnosed as having CML between 2002 and 2020, and 78 patients became pregnant by December 2020. Information of 70 pregnancies in 49 patients was obatained for analysis. The median age at CML diagnosis was 26 (range, 9-40) years and the median age at pregnancy was 33 (range, 21-42) years. Times of pregnancy varied from once to five times, and times of childbirth ranged from zero to three times. There were three types of pregnancies: CML onset during pregnancy (n=9), unplanned pregnancy during treatment or stopping treatment with TKI (n=25), and planned pregnancy during TFR or treatment with interferon (IFN)-α (n=36). The median durations from CML diagnosis to first pregnancy were 4.1 years in patients with unplanned pregnancies and 9.1 years in patients with planned pregnancies. Nine pregnancies in patients with CML onset during pregnancy resulted in seven births and two elective abortions. Twenty-five unplanned pregnancies led to 14 births, eight elective abortions and three spontaneous abortions. In 36 planned pregnancies, there were 27 births, one stillbirth and seven spontaneous abortions, and one case was during pregnancy at the time of the search. Elective abortions were chosen in 10 pregnancies, possibly due to exposure of the embryo to a TKI (n=9) or due to not achieving MMR at the time of a positive pregnancy test (n=6). TFR was chosen in 31 pregnancies, resulting in 26 births and five spontaneous abortions. MMR or deeper response was sustained in 18 of 26 (69%) pregnancies with childbirth and 15 of 18 (83%) pregnancies with DMR at the time of a positive pregnancy test. Treatment with IFN-α was chosen in 23 pregnancies and resulted in 20 births and three spontaneous abortions. Among the 13 patients with MMR or a deeper response at the time of pregnancy, only one patient (7.7%) lost MMR during pregnancy. Treatment with IFN-α was commenced after loss of MMR was experienced during pregnancy with TFR in four cases, with MMR being regained in two cases and CCyR being sustained in the other two cases until delivery. Conclusions Although our analysis was based on a limited number of patients, TFR could be a reasonable option for patients who achieve DMR and desire childbearing. Treatment with IFN-α might be another option for pregnancy in patients who achieved MMR or a deeper response.

Real-World Effectiveness of Dasatinib Versus Imatinib in Newly Diagnosed Patients With Chronic Myeloid Leukemia

IntroductionLimited data exist comparing dasatinib with imatinib in clinical practice. This study assessed real-world outcomes associated with first-line (1L) dasatinib or imatinib treatment of chronic myeloid leukemia (CML). Patients and MethodsThis retrospective, observational, United States multisite cohort study analyzed electronic medical record data from adults with Philadelphia chromosome-positive (Ph+) CML in the chronic phase (CML-CP) after 1L dasatinib or imatinib between January 2014 and September 2018. Rates of and times to major molecular response (MMR) and deep molecular response (DMR) were assessed overall and in subgroups (low vs. intermediate/high risk, aged <65 vs. ≥65 years, low/normal vs. high body mass index [BMI]). ResultsThe dasatinib cohort (n = 309) experienced higher rates of MMR (n = 304, 79% vs. 65%, P < .001) and DMR (44% vs. 25%, P < .001) vs. the imatinib cohort with shorter median times to MMR (11.9 vs. 14.7 months, P < .001) and DMR (30.3 vs. 66.1 months, P < .001). Patients with intermediate-/high-risk disease and those aged <65 years had higher MMR and DMR rates and achieved response earlier with dasatinib (P < .01). Patients with low-risk disease treated with dasatinib had higher rates of DMR (60% vs. 32%, P = .01). Across BMI strata, rates of MMR and DMR were higher with dasatinib (P < .05). ConclusionsPatients with CML-CP treated with 1L dasatinib achieved higher rates of, with shorter times to, MMR and DMR versus 1L imatinib. These clinically meaningful improvements were observed across subgroups.

Atypical presentation of chronic myeloid leukemia with e13a2 BCR-ABL1 fusion transcript in a young male

Chronic myeloid leukemia (CML) is usually a disease of the elderly population characterized by a clonal hematopoietic progenitor cell disorder propelled by the product of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) chimeric gene, known as the Philadelphia chromosome. It occurs due to a balanced reciprocal translocation between the long arms of chromosomes 9 and 22, which codes for tyrosine kinase. The incidence of CML increases with age, and the median age of diagnosis in Western countries is 64 years. The most common finding at presentation is abdominal pain due to splenomegaly which is present in about half of the patients. We present a rare case of CML in the chronic phase where a young 23-year-old male presented with complaints of severe bilateral lower limb bone pain restricting mobility at the hip joint for 1 year. The upper end of the femur showed heterogeneous areas of bone infarct on the technetium 99 m-methylene diphosphonate bone scan. He was treated with imatinib mesylate, and he entered remission within 5 months of starting therapy. This case highlights the atypical presentation of the chronic phase of CML with the e13a2 BCR-ABL fusion transcript in a young patient and the complete recovery achieved with standard therapy.

The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With At Least 2 Tyrosine Kinase Inhibitors.

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.

Clinical management of second-generation tyrosine kinase inhibitor therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase, focusing on age and dose effects.

ABL1-tyrosine kinase inhibitors (TKIs) are an established treatment choice for patients with chronic myeloid leukemia in the chronic phase (CML-CP). However, effects of TKI dose modification have not been well investigated. In this study, we retrospectively analyzed 178 patients with newly diagnosed CML-CP who were treated with dasatinib or nilotinib, focusing on age and dose effects. Efficacy as measured by cumulative major molecular response (MMR) and molecular response 4.5 rates did not differ significantly between the younger group and elderly group. Elderly patients who started nilotinib at a reduced dose had similar or better efficacy outcomes (including cumulative MMR and continuation ratios) than other groups, and elderly patients who started dasatinib at a reduced dose had the lowest MMR ratio and longest MMR duration. Effects of dose modification based on age and TKI selection can be attributed to flexible management of TKI therapy in real-world practice, but further studies are required to validate the findings of this study.

Clinical Efficacy and Safety of Flumatinib in Newly Diagnosed Chronic Myelogenous Leukemia.

The present study aimed to investigate the efficacy and safety of flumatinib in patients newly diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP). A retrospective study was conducted using five patients newly diagnosed with CML-CP who received flumatinib (600 mg/day). Results of the present study demonstrated that all five patients with CML-CP that were treated with flumatinib achieved the optimal molecular response within three months. In addition, two patients experienced major molecular response (MMR), and one patient acquired undetectable molecular residual disease, which was maintained for more than one year. Moreover, one patient exhibited grade 3 hematological toxicity, two patients exhibited transient diarrhea, one patient exhibited vomiting and one patient exhibited a rash with pruritus. No second-generation tyrosine kinase inhibitor-specific adverse cardiovascular events occurred in any patients. In conclusion, flumatinib exhibits high efficacy and high early molecular response rate in patients newly diagnosed with CML-CP. The majority of patients obtained MMR within three months, and the adverse reactions experienced were mild and tolerable.

Imatinib-induced severe hematological toxicity: Prolonged myelosuppression resulting from extraordinary sensitivity in an old age

The advent of tyrosine kinase inhibitors (TKIs) has profoundly changed the therapeutic landscape of chronic myeloid leukemia (CML) in the chronic phase (CML-CP). Imatinib is the first-generation, and the first and as yet the most widely used TKI, and the recommended dose is 400 mg/day for treating CML-CP. Most patients tolerate this treatment well, and prolonged hematological toxicities have rarely been reported. In this manuscript, we report a newly diagnosed CML-CP patient who developed prolonged myelosuppression (lasting for more than three months) following only one week of imatinib at 400 mg/day as the solitary treatment. Imatinib was discontinued, and pancytopenia persisted, with a continuous decrease in hemoglobulin levels. After restoration of autologous hematopoiesis, reintroduction of imatinib at 100 mg/day resulted in recurrent myelosuppression, and subsequent treatment with imatinib at 50 mg/day achieved good hematological homeostasis. We hypothesized that extraordinary sensitivity resulted in severe and prolonged myelosuppression.

A scoring system to predict molecular responses in patients with chronic myeloid leukemia in the chronic phase receiving initial imatinib therapy

Objective: To develop a scoring system to predict molecular responses in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving initial imatinib therapy. Methods: Data from consecutive adults with newly diagnosed CML-CP treated by initial imatinib was interrogated and subjects were distributed randomly into training and validation cohort, in a ratio of 2∶1. Fine-gray models were applied in the training cohort to identify co-variates of predictive value for major molecular response (MMR) and MR4. A predictive system was built using significant co-variates. The predictive system was then tested in the validation cohort and the area under the receiver-operator characteristic curve (AUROC) was used to estimate accuracy of the predictive system. Results: 1 364 CML-CP subjects receiving initial imatinib were included in this study. Subjects were distributed randomly into training cohort (n=909) and validation cohort (n=455) . In the training cohort, the male gender, European Treatment and Outcome Study for CML (EUTOS) Long-Term Survival (ELTS) intermediate-risk, ELTS high-risk, high WBC (≥130×10(9)/L or 120×10(9)/L, MMR or MR4) and low HGB (<110 g/L) at diagnosis were significantly related with poor molecular responses and were given points based on their regression coefficients. For MMR, male gender, ELTS intermediate-risk and low HGB (<110 g/L) were given 1 point; ELTS high-risk and high WBC (≥130×10(9)/L) , 2 points. For MR4, male gender was given 1 point; ELTS intermediate-risk and low HGB (<110 g/L) were given 2 points; high WBC (≥120×10(9)/L) , 3 points; ELTS high-risk, 4 points. We divided all subjects into 3 risk subgroups according to the predictive system above. Cumulative incidence of achieving MMR and MR4 in 3 risk subgroups was significantly different in both training and validation cohort (all P values <0.001) . In the training and validation cohorts, the time-dependent AUROC ranges of MMR and MR4 predictive systems were 0.70-0.84 and 0.64-0.81, respectively. Conclusions: A scoring system combining gender, WBC, HGB level and ELTS risk was built to predict MMR and MR4 in CML-CP patients receiving initial imatinib therapy. This system had good discrimination and accuracy, which could help phsicians optimize the selsction of initial TKI-therapy.

Long-Term Molecular Testing and Clinical Response of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in the Chronic Phase: 5-Year Follow-up from SIMPLICITY, a Prospective, Observational Study

Introduction Tyrosine kinase inhibitors (TKIs) are commonly used as first-line therapy for the treatment of patients with chronic myeloid leukemia in the chronic phase (CML-CP). Molecular response is monitored regularly after initiating TKI therapy and less frequently after achieving BCR::ABL1 ≤ 0.1%. Although responses to TKIs have been extensively evaluated in clinical trials, utilization of molecular testing and clinical response associated with TKI therapy is not as well understood in real-world settings. SIMPLICITY (NCT01244750) is a prospective observational study assessing TKI use, molecular testing patterns, and clinical response in patients with CML-CP in routine clinical practice. Methods The SIMPLICITY study followed patients with CML-CP from routine clinical practice who received first-line treatment with the first-generation TKI imatinib (IM) or second-generation TKIs dasatinib (DAS) or nilotinib (NIL) in the USA and Europe. As this was an observational study, molecular testing was performed at the discretion of the treating team without directives from the study protocol. The cumulative proportion of US patients who underwent ≥ 1 molecular test as well as the rates of major molecular response (MMR; BCR::ABL1 ≤ 0.1%) and deep (4.5-log) molecular response (MR4.5; BCR::ABL1 < 0.0032%) were evaluated through 3 and 6 months, and yearly through 5 years, after starting TKI treatment. Patients were stratified by index TKI (IM or DAS/NIL). Descriptive statistics are presented. Results At data cutoff (January 28, 2020), a total of 810 prospective US patients were enrolled and included in this analysis, of whom 244 received IM and 566 received DAS/NIL. The median age (range) at diagnosis was 56 (18-91) years (IM, 58 [18-90] years; DAS/NIL, 55 [19-91] years). A total of 796 (98.3%) patients were followed through 3 months from the start of index TKI treatment, 792 (97.8%) through 6 months, 762 (94.1%) through 1 year, 704 (86.9%) through 2 years, 652 (80.5%) through 3 years, 590 (72.8%) through 4 years, and 538 (66.4%) through 5 years. Of those followed, the overall proportion of patients tested for molecular response ranged from 20.7% through 3 months to 92.2% through 5 years (Figure). The proportion of assessed patients who achieved MMR at least once increased over time; MMR was achieved in 15.8% of patients assessed through 3 months (IM, 11.1%; DAS/NIL, 17.1%), 35.0% through 6 months (IM, 28.7%; DAS/NIL, 36.8%), 58.2% through 1 year (IM, 51.6%; DAS/NIL, 60.5%), 77.4% through 2 years (IM, 72.9%; DAS/NIL, 79.2%), 86.6% through 3 years (IM, 84.8%; DAS/NIL, 87.3%), 92.5% through 4 years (IM, 90.6%; DAS/NIL, 93.4%), and 95.4% through 5 years (IM, 95.9%; DAS/NIL, 95.2%). The proportion of patients who achieved MR4.5 at least once also increased over time; MR4.5 was achieved in 6.1% of patients assessed through 3 months (IM, 2.8%; DAS/NIL, 7.0%), 15.9% through 6 months (IM, 9.2%; DAS/NIL, 17.9%), 32.5% through 1 year (IM, 23.4%; DAS/NIL, 35.6%), 50.2% through 2 years (IM, 41.3%; DAS/NIL, 53.6%), 63.8% through 3 years (IM, 54.9%; DAS/NIL, 67.4%), 73.8% through 4 years (IM, 67.9%; DAS/NIL, 76.3%), and 79.2% through 5 years (IM, 75.9%; DAS/NIL, 80.6%). Among all 810 enrolled patients, 473 (58.4%) and 393 (48.5%) achieved MMR and MR4.5, respectively, and remained in the study through 5 years. Mean (standard deviation) time from index TKI to best response in tested patients was 2.4 (0.5) months among patients assessed through 3 months and 24.4 (15.4) months among those assessed through 5 years. Conclusions At 5-year follow-up in US patients from the SIMPLICITY study, there was a consistent increase in the proportion of assessed patients who achieved MMR and MR4.5 over time for all patients treated with TKIs, with the caveat that patients who remained on treatment at each subsequent time point were more likely to respond. In general, a consistently higher proportion of patients treated with DAS/NIL achieved MR4.5 across the time points assessed compared with IM in this non-controlled study. Further studies evaluating molecular response to IM, DAS, NIL, and other TKIs beyond 5 years can help delineate further differences in outcomes and determine whether molecular testing frequency correlates with outcomes. Study support This study was funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes in Patients with Chronic Myeloid Leukemia in the Chronic Phase Randomized to Dasatinib or Imatinib after Suboptimal Responses to 3 Months of Imatinib Therapy: Final 5-Year Results from DASCERN

Introduction: Dasatinib has demonstrated superior responses versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP) (Cortes JCO 2016). Achievement of early molecular response (EMR; BCR::ABL1 ≤ 10% International Scale [IS]) at 3 months increases the probability of subsequent deep molecular response (DMR) and improves survival (Cortes JCO 2016, Hochhaus Leukemia 2016). However, ⅓ of pts treated with imatinib did not reach an EMR (Hughes Blood 2014); there are no standard treatment strategies for these pts. DASCERN (NCT01593254) is the first prospective, randomized, phase 2b trial to demonstrate the potential benefit of switching early to dasatinib in pts with no EMR after 3 months of initiating imatinib. At 12 months, pts randomized to dasatinib had significantly higher major molecular response (MMR) rates versus imatinib (29% vs 13%, primary endpoint) (Cortes Leukemia 2020). At 3 years, cumulative MMR rates were 67% and 40% with dasatinib and imatinib, respectively (Cortes EHA 2020 EP756). Switching to dasatinib did not increase the incidence of treatment-emergent adverse events (AEs). Here we report the results from the final 5-year analysis. Methods: Pts with complete hematologic response but no EMR at 3 months after initiating imatinib 400 mg were randomized 2:1 to an early switch to dasatinib (100 mg) or continue imatinib (≥ 400 mg). Pts who experienced subsequent failure with imatinib (per European LeukemiaNet 2013 recommendations at the time of the study) crossed over to dasatinib. The intent-to-treat (ITT) population included all pts randomized to each arm, irrespective of crossover status. Study endpoints included time to MMR and molecular response 4.5 (MR4.5; 4.5-log reduction in BCR::ABL1 levels; ≤ 0.0032% IS), progression-free survival (PFS), overall survival (OS), and safety. Results: At a median follow-up of 80 months (data cutoff, April 24, 2022), 174 and 86 pts with no EMR after imatinib were randomized to dasatinib and imatinib, respectively; 46 (53%) imatinib-randomized pts experienced subsequent imatinib failure and crossed over to dasatinib in a median of 9.5 months. Detailed baseline characteristics have been previously reported (Cortes EHA 2020 EP756). The median age was 37 years, and 73% of patients were Asian. All pts discontinued treatment, mainly due to study drug toxicity (26 [10%]), and other reasons (176 [68%], mostly study completion); 6 (2%) discontinued due to death. The MMR rate by 5 years in the ITT population was 77% and 44%, respectively, for pts in the dasatinib and imatinib arms. After accounting for crossover, cumulative MMR rates were 74% with dasatinib and 44% with imatinib; 65% of pts who crossed over from imatinib to dasatinib achieved MMR (Figure). Across the 5-year study period, more pts randomized to dasatinib than imatinib achieved MR4 and MR4.5 (MR4, 52% vs 31%; MR4.5, 36% vs 26%). Only 1/46 pts who later crossed over to dasatinib after imatinib failure achieved MR4.5. PFS in the ITT population was 94% in both treatment arms. PFS was numerically lower in pts who later crossed over to dasatinib after imatinib failure (90%). OS in the ITT population was similar between both arms (96% vs 95%). OS in pts who crossed over to dasatinib was 94%. Six additional deaths were reported since the 3-year follow-up. Any grade treatment-related AEs were experienced by 149 pts (87%) randomized to dasatinib, 69 (80%) randomized to imatinib, and 37 patients (80%) who crossed over to dasatinib. Treatment-related pleural effusion occurred in 31 pts (18%) randomized to dasatinib (n = 6 grade 3/4), 9 pts (20%) who crossed over to dasatinib after imatinib failure (n = 2 grade 3/4), and 0 pts who remained on imatinib (no crossover). Conclusions: At the final 5-year follow-up, sustained clinical benefit was observed from an early switch to dasatinib after suboptimal responses to 3 months of imatinib. MMR and DMR rates were higher in pts randomized to dasatinib versus imatinib. Overall, the safety profile was consistent with previous reports. These results complement the previous findings that switching to dasatinib promptly after a lack of EMR with imatinib increases the chance of achieving DMR, which may improve outcomes in pts with CML-CP. Therefore, this study further highlights the significance of achieving optimal responses early during treatment. Study support: Funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial

BackgroundBCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP).MethodsIn the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses.ResultsA total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia.ConclusionsOlverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation.Trial registration: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).

Variables associated with pulmonary hypertension screened by echocardiography in chronic myeloid leukemia patients on dasatinib therapy.

BackgroundPulmonary hypertension (PH) is a rare but life-threatening adverse event (AE) of dasatinib, but the associated variables are not clear. This study aimed to explore the variables associated with PH by echocardiography in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving dasatinib therapy.MethodsEchocardiography was performed to estimate the probability of PH and pulmonary artery systolic pressure (PASP). Binary logistic analysis and Fine–Gray hazard model were used to identify the variables associated with PH by using cross-sectional and longitudinal data.ResultsAmong the 243 patients in the cross-sectional dataset, with a median dasatinib therapy duration of 27 months, 30 (12.3%) were classified as having a high probability of PH. Increasing age (OR = 1.7, p = 0.002; OR = 1.5, p = 0.003) and pericardial effusion (OR = 4.3, p = 0.004; OR = 3.2, p = 0.014) were significantly associated with a high probability of PH and PASP ≥ 40 mmHg, respectively. Among the 161 patients in the longitudinal dataset, the 3-year cumulative incidences of a high probability of PH and PASP ≥ 40 mmHg were 9.3% and 22.1%, respectively. Pericardial effusion (HR = 3.8, p = 0.005) and cardiopulmonary comorbidities (HR = 3.2, p = 0.021) were significantly associated with a high probability of PH; increasing age (HR = 1.5, p < 0.001) and dasatinib as ≥ 3rd-line therapy (p = 0.032; 2nd-line vs. 1st-line, HR = 2.0, p = 0.200; ≥ 3rd-line vs. 1st-line, HR = 3.4, p = 0.047) were significantly associated with PASP ≥ 40 mmHg.ConclusionIncreasing age, pericardial effusion, cardiopulmonary comorbidities, and dasatinib as ≥ 3rd-line TKI therapy were associated with PH in the patients with CML-CP on dasatinib therapy.

Clinical Effect of Imatinib, Nilotinib, and Dasatinib on Chronic Myeloid Leukemia in Chronic Phase

The study was conducted to explore the effect of imatinib, nilotinib, and dasatinib in the treatment of chronic myeloid leukemia (CML) patients. Around 66 patients with CML in chronic phase were selected, subsequently the patients were subdivided into 3 groups with 22 patients in each group: Group A were treated with imatinib; Group B were treated with nilotinib; and Group C were treated with dasatinib. The study showed that, at 18 months of treatment, compared with group A, the molecular biology remission rates of group B and group C were significantly higher, p&lt;0.05; at 6 months and 18 months of treatment, compared with group A, the complete cytogenetic remission rates of group B and group C were significantly higher, p&lt;0.05; and compared with group A, the incidences of vomiting, headache and edema in groups B and C were significantly lower, p&lt;0.05. However, no significant different p&gt;0.05 were observed in the complete hematologic remission rates, and the incidences of neutropenia and thrombocytopenia among the three groups. In summary, nilotinib and dasatinib are effective in the treatment of patients with CML in the chronic phase, which is significantly better than imatinib treatment.

MiR-494 in Extracellular Vesicles as a Potent Biomarker of Chronic Myeloid Leukemia Treatment with Tyrosine Kinase Inhibitors

Extracellular vesicles (EVs) are nano-sized particles released from cells and transferring molecules (proteins, lipids and nucleic acids such as mRNA, tRNA and miRNA) to recipient cells. Surface antigens and components are important for the functions as cell-to-cell communication of EVs. Thus, EVs are useful biomarkers for various diseases including leukemias and other types of malignancies. We evaluated whether miRNAs in EVs released from chronic myelogenous leukemia (CML) cells could be used for diagnosis. Microarray analysis of miRNAs in EVs obtained from the culture supernatants of two CML cell lines showed that miR-494 and miR-373-5p were significantly decreased by tyrosine kinase inhibitor for BCR-ABL1. Validation analysis with Taqman-based qRT-PCR of whole serum obtained patients with CML in the chronic phase (n = 5) did not show a significant difference in miR-494 levels compared to the CML accelerated phase and blast crisis patients (n = 5). However, the levels of miR-494 were 2.9-fold higher in the accelerated phase or blast crisis than in the chronic phase (p &lt; 0.05). These results indicate that it is important to measure miR-494 using only EVs rather than whole serum. Our data suggest that EV-miR-494 is a useful biomarker of CML progression and evaluation of response to tyrosine kinase inhibitors.

Lower tumor burden is associated with better cognitive function in patients with chronic phase chronic myeloid leukemia

Cognitive function was assessed in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) therapy using the Montreal Cognitive Assessment (MoCA). Cross-sectional assessments of 100 newly diagnosed patients and 584 patients receiving TKI therapy for >1 year showed that 31 (31.0%) and 191 (32.7%) patients had mild cognitive impairment, respectively. In the multivariable analyses, higher percentages of blood blasts were associated with a worse MoCA score at diagnosis [β = −0.29, 95% confidence interval (−0.54, −0.03), p = .027]; deeper molecular response [versus < major molecular response, β = 0.74 (0.07, 1.40), p = .029], better MoCA score on TKI therapy. Increased MoCA scores were observed after 12 months of TKI therapy in 42 patients who were regularly followed up (p = .005). Lower tumor burden is associated with better cognitive function in CML-CP patients both at diagnosis and during TKI therapy.