Diagnosed Chronic-phase Chronic Myeloid Leukemia Research Articles

Asciminib: the next-generation bullet for first-line treatment of chronic myeloid leukemia

The standard of care for chronic myeloid leukemia (CML) involves tyrosine kinase inhibitors (TKIs), which suppress tyrosine kinase activity of BCR::ABL1. Hochhaus etal. reported that asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, showed superior efficacy and favorable safety compared with TKIs in the phase 3 ASC4FIRST trial in patients with newly diagnosed chronic-phase CML.1.

Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

BackgroundPatients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).MethodsIn a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.ResultsA total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, −5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).ConclusionsIn this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Retraction: Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era.

Retraction: Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study

BackgroundThere are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. Patients and MethodsData from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. Results2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). ConclusionNilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

18 months follow-up of deep molecular response 4.5 (MR4.5) with nilotinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a prospective, multi-center study in China.

Early stable deep molecular response (DMR) to nilotinib is associated with goal of treatment-free remission (TFR) in patients with chronic-phase chronic myeloid leukemia (CML-CP). It is important to early distinguish between patients who can achieve a DMR and those who are fit for TFR. We performed a multicenter study to explore the early cumulative MR4.5 rate at 18 months with nilotinib in patients with newly diagnosed CML-CP (ND-CML-CP) in China. Of the 29 institutes, 106 patients with ND-CML-CP received nilotinib (300 mg BID). The cumulative MR4.5 rate of nilotinib treatment at 18 months was 69.8% (74/106). The cumulative MMR and MR4.0 rates for nilotinib at 18 months were 94.3% (100/106) and 84.9% (90/106), respectively. Patients with an ultra-early molecular response (u-EMR) at 6 weeks were not significantly different in obtaining DMR or MMR by 24 months compared with those without u-EMR (p = 0.7584 and p = 0.9543, respectively). Our study demonstrated that nilotinib treatment in patients with ND-CML-CP contributed to obtain high early MR4.5.

Flumatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: An Open-Label, Multi-Center Study

Background Tyrosine kinase inhibitors (TKIs) ushered in the era of targeted therapy for chronic myeloid leukemia(CML), which greatly improved the prognosis of patients with CML. Flumatinib is a second-generation tyrosine kinase inhibitor (TKI), which is currently approved for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in China. And some current clinical trials revealed that flumatinib has been shown to be a more potent inhibitor of BCR::ABL than imatinib. Methods In this open label, single-arm, multicenter study, 127 patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML) treated with flumatinib were enrolled. The primary endpoint of this study was early molecular response (EMR) rates at 3 months. The secondary were the rates of complete cytogenic response (CCyR), major molecular response (MMR) at 3, 6, 12 months and treatment-related adverse events (AEs). The trial is registered with ClinicalTrials.gov NCT04591197. Results From October 2020 to December 2022, a total of 158 patients with CP-CML were assessed for eligibility, of whom 127 were followed up for more than 3 months. 79(62%) patients were men and 48 (38%) were women. The median age was 47 years (range, 19-82 years), The median time from diagnosis to treatment was 6 days (0-176 days) and the median follow-up was 9.7 months (range 3.1-26.6 months). Of evaluable 127 patients, EMR was achieved by 85% (95% confidence interval [CI], 77.6%-90.7%) of patients at 3 months. After the initiation of flumatinib treatment, the incidence of MMR at 3, 6, and 12 months was 24%, 59%, and 73%, respectively. Patients receiving flumatinib had higher rates of CCyR at 6 months and MMR 12 months than the data from DASISION (dasatinib) and ENESTnd (nilotinib) therapy (85% vs 73% vs 67% and 73% vs 46% vs 44%). Progression-free survival (PFS) rate at 1-year was 97.2%. Diarrhea (34%) were the most commonly reported adverse events. Most treatment-related adverse events were grade 1/2. None of the patients discontinued or died due to AEs. Conclusion Flumatinib as first-line therapy in patients with newly diagnosed CP-CML was not inferior to nilotinib and dasatinib and well tolerated.

Loss of Function of SETD2 Tumor Suppressor in Chronic Myeloid Leukemia (CML) Progenitors Fosters Genomic Instability and Enhances Clonogenic Potential

BACKGROUND AND AIMS - Genomic instability is a hallmark of chronic myeloid leukemia (CML) cells since the chronic phase (CP) of the disease, and results in BCR::ABL1 mutations and/or additional genetic and genomic aberrations that may drive resistance to tyrosine kinase inhibitors (TKIs) and progression to blast crisis (BC). Genomic instability is also a feature of CML stem and progenitor cells and may contribute to their persistence. The SETD2 tumor suppressor codes for a protein that trimethylates histone H3 at lysine 36 (H3K36me3). In solid tumors, SETD2 loss of function has been shown to impair H3K36me3-mediated recruitment of DNA damage response components. We have recently reported that non genomic loss of function of SETD2 is a feature of BC CML and results from premature proteasome-mediated degradation of the SETD2 protein triggered by Aurora kinase A phosphorylation and MDM2 ubiquitination. In the present study, we aimed to assess SETD2/H3K36me3 status in CD34+ progenitors of CP CML patients (pts) and whether SETD2/H3K36me3 deficiency may play a role in genomic instability in CML models. METHODS - Western blotting (WB) was used to assess SETD2 protein expression and H3K36me3 as a surrogate marker of SETD2 function in the CD34+ cell fraction isolated from the bone marrow of 20 newly diagnosed CP CML pts and from a pool of healthy donors (HD). SETD2 forced expression in CD34+ progenitors from newly diagnosed CP CML pts and in the SETD2-deficient KCL22 cell line was performed by nucleofection. SETD2 knock-down in the SETD2-proficient LAMA84 cell line was performed by RNAi. Clonogenic capacity was evaluated by clonogenic assays. Chromatin immunoprecipitation sequencing (ChIP-seq) for H3K36me3 was performed on an Illumina HiSeq2000 with a min 50 million 150-bp single-end reads per replicate. High resolution karyotyping wias perfomed with Cytoscan HD arrays. DNA damage and DNA repair activation were assessed in primary samples and cell lines by WB and immunofluorescence (IF) using antibodies specific for phospho-H2AX, mismatch repair (MMR) and homologous recombination repair (HR) proteins. RESULTS - WB demonstrated a marked down-modulation of SETD2 expression, paralleled by H3K36me3 deficiency, in the CD34+ cells of all newly diagnosed CP CML pts as compared to the total mononuclear fraction and to CD34+ cells from HDs. To investigate whether SETD2 loss affects the activation and proficiency of HR and MMR, we used chronic exposure to UV rays or a single exposure to hydrogen peroxide (1mM for 30 and 60 min). Both induced DNA damage in SETD2 siRNA-depleted LAMA84 cells. Compared to parental cells, cells silenced for SETD2 failed to activate the ATM-dependent repair pathway. Moreover, we found that ATM inactivation prevents H2AX foci formation, associated with a loss of RAD51 and RAD54 (HR) and MSH6 (MMR) repair foci. To confirm the hypothesis that SETD2 is a tumor suppressor implicated in maintaining genomic stability in CML, we transfected SETD2-deficient KCL22 cells with an ectopic SETD2 plasmid. SETD2 forced expression was able to restore DNA damage response, as demonstrated by WB and IF detection of ATM, p95 and H2AX phosphorylation, BRCA1, BRCA2 and CtIP expression and finally RAD51 and RAD54 localization on HR repair foci observed after UV or hydrogen peroxide exposure. High-resolution karyotyping after DNA damage showed increased rate of DNA breakpoints in SETD2-deficient cells, preferentially occuring at loci where H3K36me3 marks were lost as assessed by ChiP-seq. In line with the effects observed in cell line models, forced expression of SETD2 in CD34+ cells from 5 CP CML pts was found to restore proliferation control, since a &amp;gt;50% reduction in clonogenic potential was observed after nucleofection. CONCLUSIONS - Our findings demonstrate that SETD2 is a bona fide tumor suppressor in CML progenitors and establish a functional link between SETD2 loss of function and genomic instability. SETD2 inactivation may thus play a pivotal role in the harmful cascade of events that may foster drug resistance and ultimately lead to disease progression. Since SETD2 loss of function in CML is mediated by post-translation mechanisms, hence is reversible, therapeutic strategies aimed at interfering with these mechanisms may restore proliferation control and interrupt this cascade. Supported by AIRC IG 2019 (23001) and by Italian Ministry of Health, “Bando Ricerca Finalizzata 2016”, project GR-2016-02364880.

Molecular response in newly diagnosed chronic-phase chronic myeloid leukemia: prediction modeling and pathway analysis.

Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase III randomized trial (clinicaltrials gov. Identifier: NCT00471497), dichotomizing cases into good responders (BCR::ABL1 ≤10% on the International Scale by 3 and 6 months and ≤0.1% by 12 months) and poor responders (failure to meet these criteria). Predictive models based on gene expression demonstrated the best performance (area under the curve =0.76, standard deviation =0.07). All of the top 20 pathways overexpressed in good responders involved immune regulation, a finding validated in an independent data set. This study emphasizes the importance of pretreatment adaptive immune response in treatment efficacy and suggests biological pathways that can be targeted to improve response.

Efficacy and Safety of Bosutinib Vs Imatinib By Charlson Comorbidity Index in Newly Diagnosed Patients with Chronic Myeloid Leukemia

Introduction: The efficacy and safety of bosutinib (BOS) vs imatinib (IMA) in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) was assessed in the phase 3 BFORE trial (NCT02130557) after 5 years of follow-up (Brümmendorfet al., J Clin Oncol, 2022). Here we analyze the impact of comorbidities on efficacy and safety, reporting the results by Charlson Comorbidity Index (CCI) score. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive BOS or IMA (starting dose: 400 mg QD). Outcomes were assessed after 5 years (240 weeks) of follow-up (database lock: June 12, 2020) according to the CCI score without the age component (mCCI). Patients were grouped by mCCI scores of 2 (BOS, n=195; IMA, n=196 [2 untreated]) and >2 (BOS, n=73; IMA, n=72 [1 untreated]). Efficacy was assessed in all randomized patients (intent-to-treat population) and safety in patients who received >1 dose of study medication (safety population). Results: In patients with mCCI 2 and >2, the median treatment duration was 55.1 and 53.4 months with BOS vs 55.0 and 55.1 months with IMA; respective median (range) dose intensity was 396.4 (39−583) and 367.2 (74−573) mg/day with BOS vs 400.0 (240−765) and 400.0 (189−754) mg/day with IMA. Permanent treatment discontinuations in patients with mCCI 2 and >2, respectively, were reported in 36.4% and 50.7% of patients with BOS vs 45.4% and 32.4% of patients with IMA. The most common primary reasons for permanent discontinuation were adverse events (AEs) in the BOS arm (BOS: mCCI 2, 21.0%; mCCI >2, 35.6%; IMA: mCCI 2, 13.9%; mCCI >2, 8.5%) and lack of efficacy (suboptimal response, treatment failure, or disease progression) in the IMA arm (BOS: mCCI 2, 6.7%; mCCI >2, 2.7%; IMA: mCCI 2, 20.6%; mCCI >2, 9.9%). In both treatment arms, the majority of permanent discontinuations due to AEs occurred in year 1 (BOS: mCCI 2, 11.3%; mCCI >2, 20.5%; IMA: mCCI 2, 7.7%; mCCI >2, 5.6%). Among patients with mCCI 2 and >2, respectively, the proportion who achieved an early molecular response (BCR::ABL1 ≤10% at 3 months) was 79.4% and 83.8% with BOS vs 56.5% and 71.0% with IMA (Table 1). Cumulative response rates according to mCCI score and treatment arm are shown in the Table 1. There were 14 deaths during the study period in both the BOS- (mCCI 2, n=7; mCCI >2, n=7) and IMA (mCCI 2, n=9; mCCI >2, n=5) arms; 3 and 4 deaths, respectively, were assessed by investigators as CML-related (all in patients with mCCI 2). Treatment-emergent AEs (TEAEs) occurred in ≥98.5% of patients in each treatment arm and across CCI subgroups. In patient with CCI 2 and >2, respectively, the most common (≥30% in either subgroup) TEAEs with BOS were diarrhea (79.5% and 63.0%), thrombocytopenia (37.4% and 31.5%), nausea (35.9% and 41.1%), increased alanine aminotransferase ([ALT] 34.4% and 31.5%), and fatigue (17.9% and 30.1%). Most common TEAEs with IMA were diarrhea (37.1% and 49.3%), nausea (41.2% and 45.1%), muscle spasms (33.0% and 23.9%), and anemia (17.5% and 36.6%). Among patients with CCI 2 and >2, respectively, grade 3/4 TEAEs were observed in 69.2% and 84.9% with BOS vs 55.2% and 62.0% with IMA. The most frequently reported grade 3/4 TEAEs are shown in Table 2. TEAEs resulting in death in the BOS arm (n=3) were acute cardiac failure, myocardial ischemia, and renal failure (all in patients with CCI >2). TEAEs leading to death in the IMA arm (n=4) were sepsis and CML in patients with CCI 2, and pneumonia and cerebrovascular accident in patients with CCI >2. Conclusions: After 5 years of follow-up in the BFORE study, a substantial proportion of patients across mCCI scores achieved molecular responses with BOS or IMA. In the BOS arm, there was a trend toward a higher rate (>10% difference) of MR4 in patients with CCI 2 vs CCI >2, with a similar proportion of patients achieving MMR and MR4.5 in both subgroups. Molecular response rates by 60 months were higher with BOS vs IMA in patients with CCI 2 and similar in patients with CCI >2. Safety data were consistent with the known safety profiles of BOS and IMA. Discontinuations due to AEs were higher (>10% difference) in patients with CCI >2 in the bosutinib arm and similar across CCI groups in the imatinib arm. However, in both treatment arms, there were no relevant differences in the frequency of TEAEs across the most commonly occurring AEs between patients with CCI 2 and CCI >2. These results support the use of 400 mg once daily BOS in patients with newly diagnosed CP CML irrespective of baseline comorbidities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bosutinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia: final 3-year follow-up results of a phase 2 study

Bosutinib has been evaluated for treatment of chronic-phase chronic myeloid leukemia (CP-CML) in several clinical studies, including in Japan. This open-label, single-arm, phase 2 study evaluated the efficacy and safety of bosutinib at a starting dose of 400 mg once daily in Japanese patients (n = 60) with newly diagnosed CP-CML. The minimum follow-up period was 3 years and median duration of treatment was 35.9 months. At study completion, 60% of patients were still on treatment. Cumulative rates of major molecular response (MMR), molecular response4 (MR4), and MR4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively. No patient who achieved MMR or MR4 had a confirmed loss of response. No patient experienced on-treatment transformation to accelerated/blast phase or died within 28 days of the last bosutinib dose. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% (grade ≥ 3: 81.7%) of patients. The most common TEAEs were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). No new safety signals emerged during the follow-up period. Bosutinib continues to demonstrate a favorable benefit/risk profile and is an important treatment option for Japanese patients with newly diagnosed CP-CML. Optimal management of TEAEs during initial treatment with bosutinib should be prioritized.Trial Registration: ClinicalTrials.gov ID: NCT03128411.

P717: BOSUTINIB IN NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA: GASTROINTESTINAL, LIVER, EFFUSION AND RENAL SAFETY CHARACTERIZATION IN THE BFORE TRIAL

Background: Bosutinib is approved for the treatment of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Efficacy and safety of bosutinib vs imatinib in patients with newly diagnosed CP CML was assessed in the phase 3 BFORE trial (NCT02130557). Aims: The safety profile of bosutinib after 5 years follow-up, with a focus on gastrointestinal, liver, effusion and renal treatment-emergent adverse events (TEAEs), was characterized. Methods: Patients who received ≥1 dose of bosutinib (n=268) or imatinib (n=265) 400 mg/day in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. This analysis is based on the final database lock: June 12, 2020. Results: Median duration of treatment was 55 months for patients receiving bosutinib or imatinib; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of bosutinib- vs imatinib-treated patients. The most common newly occurring TEAEs (any grade) after 12 months were increased lipase (9.0%) with bosutinib, and diarrhea (8.3%) with imatinib. In bosutinib- vs imatinib-treated patients, 25.4% vs 14.3% had AEs leading to permanent treatment discontinuation; the majority discontinued in year 1 (14.2% vs 10.6%). The most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; year 1, 4.5%) with bosutinib vs thrombocytopenia (overall, 1.5%; year 1, 1.5%) with imatinib. Gastrointestinal, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of bosutinib- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) imatinib-treated patients. One grade 5 renal TEAE occurred in the bosutinib arm and was not considered related to treatment. Cumulative rates per treatment year are shown in the Table. The most common gastrointestinal TEAEs were diarrhea (bosutinib vs imatinib: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with bosutinib, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with imatinib. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). Gastrointestinal, liver, effusion and renal TEAEs infrequently led to treatment discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Image:Summary/Conclusion: The safety profiles of bosutinib and imatinib in BFORE were distinct, with no new safety signals identified after 5 years of follow-up. The onset of TEAEs occurred primarily during year 1 (e.g., gastrointestinal and liver), with an increased incidence of some TEAEs (e.g., effusion and renal) in later years. Discontinuations due to AEs generally occurred early into treatment, with low rates of discontinuation due to gastrointestinal, liver, effusion and renal AEs. These long-term safety results further support the use of first-line bosutinib as a standard of care in patients with CP CML.

Efficacy and Safety of Bosutinib in Japanese Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: Final 3-Year Results of a Phase 2 Study

Efficacy and Safety of Bosutinib in Japanese Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: Final 3-Year Results of a Phase 2 Study

BILATERAL CHYLOTHORAX AND ANASARCA CAUSED BY DASATINIB IN A PATIENT WITH CHRONIC MYELOGENOUS LEUKEMIA

TOPIC: Disorders of the Pleura TYPE: Medical Student/Resident Case Reports INTRODUCTION: Dasatinib is one of the tyrosine kinase inhibitors that is used in the treatment for Philadelphia positive Chronic Myeloid Leukemia (CML). Pleural effusion can occur in 10% of patients on dasatinib, but chylothorax was rarely reported as a side effect of dasatinib (1,2). CASE PRESENTATION: A 52 year-old male with medical history of CML presented with shortness of breath over the past 4months. Patient was diagnosed with CML 10 years ago. Initially he was started on imatinib which he did not tolerate secondary to headache and he was switched to dasatinib 100mg daily which he tolerated for 5 years. Bone marrow biopsy showed complete cytogenetic remission in 6-months and he achieved major molecular remission. Physical exam was remarkable for reduced air entry to both lungs, abdominal ascites, and lower extremities pitting edema up to the groins. Basic labs were within normal limits. Chest X-ray showed bilateral pleural effusions and confluent bibasilar infiltrates. Computed topography of the chest showed large bilateral effusions with passive atelectasis in the lower lobes (figure-1A and 1B). CT scan of the abdomen and pelvis showed diffuse body edema in the lower abdomen extending to both lower extremities. Large right hydrocele and moderate left hydrocele were also noticed (figure-1C). Imaging guided thoracentesis was performed on the right side and 1900 ml of milky fluid was drained. Pleural fluid analysis showed total protein of 4.6 g/dL (serum total protein:7.3 g/dL), glucose of 97 mg/dL (serum glucose: 84 mg/dL), elevated lactate dehydrogenase (116 U/L), elevated triglyceride (485 mg/dL), and elevated cholesterol (83 mg/dL). Based on that, Diagnosis of chylothorax was made and dasatinib was discontinued. Patient was started on short course of diuretics and oral prednisone. After one month of dasatinib discontinuation, patients SOB improved significantly. Abdominal and lower extremities swelling has improved too. Repeated CXR showed improved bilateral pleural effusion (figure-1D). We kept patient off dasatinib with monthly check of BCR/ABL by PCR with plan to restart dasatinib at 50 mg daily or switching to another treatment if he relapses. DISCUSSION: Pleural effusion is a known side effect of dasatinib and few reports of unilateral chylothorax have been reported. Bilateral chylothorax and anasarca are very rare side effects of dasatinib. In most of the cases, discontinuation of dasatinib can improve symptoms. In a previous case report, 63 year-old female presented with right sided dasatinib induced chylothorax which totally resolved after switching dasatinib to nilotinib (2). In another case report, the 71 year-old patient presented with dasatinib induced chylothorax that initially resolved and then recurred after re-initiation of dasatininb (3). CONCLUSIONS: Bilateral chylothorax after dasatinib is very rare. Most cases resolve completely with dasatinib discontinuation. REFERENCE #1: Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. doi: 10.1056/NEJMoa1002315. Epub 2010 Jun 5. PMID: 20525995. REFERENCE #2: Al-Abcha A, Iftikhar MH, Abu Rous F, et al. Chylothorax: complication attributed to dasatinib use. BMJ Case Rep. 2019 Dec 16;12(12):e231653. doi: 10.1136/bcr-2019-231653. PMID: 31848139; PMCID: PMC6936595. REFERENCE #3: Chen B, Wu Z, Wang Q, et al. Dasatinib-induced chylothorax: report of a case and review of the literature. Invest New Drugs. 2020 Oct;38(5):1627-1632. doi: 10.1007/s10637-020-00932-3. Epub 2020 Apr 4. PMID: 32248338. DISCLOSURES: No relevant relationships by hamed daw, source=Web Response No relevant relationships by Christopher Haddad, source=Web Response No relevant relationships by Tariq Kewan, source=Web Response No relevant relationships by Talha Saleem, source=Web Response

Debating Frontline Therapy in Chronic Myeloid Leukemia

The development of tyrosine kinase inhibitors (TKIs) in the early 2000s revolutionized the therapeutic landscape for chronic phase (CP) chronic myeloid leukemia (CML). Interferon alpha was previously the standard treatment for patients with CP CML prior to the development of TKIs; however, survival was dismal, with a median of 5-6 years (1). With the advent of TKI therapy, the estimated 10-year overall survival increased from less than 20% to more than 80% (2). When optimal therapy is instituted with appropriate monitoring, patients with CP CML now live close to normal life spans (3, 4). Imatinib, the first of these revolutionary medications, was approved by the FDA for the treatment of CML after failure of interferon-alpha therapy in 2001 and for newly diagnosed CP CML patients in 2003. Shortly thereafter, following preclinical and clinical data demonstrating increased potency against the BCR-ABL target, frontline approvals for the second-generation TKIs (dasatinib, nilotinib, and bosutinib) soon followed based on the results of their respective clinical trials (DASISION, ENEST and BFORE) (5–7). Each of these trials compared the efficacy of imatinib 400 mg daily with the corresponding second-generation TKI. Notably, no significant survival difference has been demonstrated between imatinib and any of the second-generation inhibitors. Accordingly, the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) practice guidelines recommend choosing a therapeutic agent based on risk scoring, age, and comorbidities (8, 9). Thus, the optimal frontline treatment of CP CML has become the subject of debate. A recently published meta-analysis sought to answer this question by comparing the safety and efficacy of imatinib versus dasatinib, nilotinib, bosutinib and ponatinib for initial treatment of CP CML (10). Second- and third-generation TKIs demonstrated superior clinical outcomes but also increased toxicity. The authors concluded that the choice of frontline therapy should depend on patients’ age and comorbidities. They suggested that patients without comorbidities should receive second-generation TKIs as initial therapy and that imatinib should be the preferred initial therapy for older patients or those with comorbidities. Notably, third-generation TKI (ponatinib) has not been approved nor is recommended as the frontline treatment of CP AML. Herein, we will review this recently published work and present the arguments for and against the use of second-generation TKIs as initial therapy for CP CML.

Optimizing Dose of Bosutinib to Minimize Adverse Events While Maintaining Efficacy in Patients with Newly Diagnosed Chronic Myelogenous Leukemia

Introduction: Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor that has demonstrated efficacy and a manageable safety profile in adult patients with chronic phase (CP) chronic myeloid leukemia (CML). A previous clinical trial (BELA), using a starting dose of 500 mg/day bosutinib, failed to meet its primary efficacy endpoint, primarily because of early discontinuation due to adverse events. Therefore, a new trial, BFORE, was recently conducted using a reduced starting dose of 400 mg/day. This analysis integrated results of these phase 3 trials in order to quantitatively assess the impact of reducing the starting bosutinib dose from 500 mg/day to 400 mg/day on safety and efficacy outcomes in adults with newly diagnosed CP CML.Methods: Oral bosutinib (400 or 500 mg/day) was administered to patients with newly diagnosed CP CML in 2 completed phase 3 trials. Patients with evaluable pharmacokinetic (PK) and pharmacodynamic data were included in the analysis. Bosutinib exposures were derived from a two-compartment PK model with first-order absorption and an absorption lag time. Exposure-response (E-R) analysis was conducted for the primary efficacy endpoint of major molecular response (MMR) assessed at 48 weeks using logistic regression. Safety endpoints were analyzed using ordered logistic regression to identify correlations between bosutinib exposures and ordered adverse event (AE) severity grades. Based on the incidence and clinical relevance of the AEs following treatment with bosutinib, 8 prespecified safety outcomes were included: diarrhea, nausea, vomiting, rash, elevated alanine and aspartate aminotransferase (ALT and AST), thrombocytopenia, and neutropenia. AEs were assessed at the first occurrence of the highest AE grade within the first year of treatment for each patient.Results: A total of 512 patients were included in the E-R analysis of MMR. The rate of MMR at 48 weeks for the bosutinib arm was 47.2% for a starting dose of 400 mg/day (BFORE) and 38.0% for a starting dose of 500 mg/day (BELA), suggesting that a lower dose did not compromise efficacy. Since the endpoint was defined at 48 weeks, time on treatment was included to account for the lack of MMR responses due to earlier trial discontinuation; hence the E-R analysis was only able to predict MMR at 48 weeks. Trough bosutinib plasma concentrations and time on bosutinib treatment were significant predictors (both P <0.05) of the probability of achieving MMR, with days on treatment having a larger impact than plasma concentrations (Figure 1, Table 1).The incidence of AEs associated with permanent discontinuation from bosutinib treatment was 14.2% for a starting dose of 400 mg/day (BFORE) and 21.0% for a starting dose of 500 mg/day (BELA). An E-R relationship between bosutinib exposures and time to event was identified for incidence of grade>0 diarrhea, nausea, and vomiting. Higher bosutinib exposure increased the probability of moving from one grade to the next higher one, while increased time to event decreased the probability of moving up from one grade to the next. For incidence of grade>0 rash, elevated ALT, and elevated AST, patients had a higher probability of an AE grade with increasing bosutinib exposures. In contrast, the incidence of grade>0 thrombocytopenia and neutropenia decreased with increasing bosutinib exposures.Conclusions: Both bosutinib exposure and time on bosutinib treatment were significant predictors of MMR, but time on treatment appeared to play a larger role in efficacy. This suggests that staying on treatment may be more important than receiving a higher dose of bosutinib. The incidence of AEs appeared to correlate with bosutinib exposure; higher bosutinib exposure was associated with a greater probability of an AE earlier on treatment for diarrhea, nausea, and vomiting, and at any time on treatment for rash, elevated ALT, and elevated AST. When comparing the 2 bosutinib starting doses, the incidence of AEs associated with permanent discontinuation suggests that the lower dose of bosutinib used in the BFORE trial (400 mg/day) did not compromise efficacy but decreased the probability of patients discontinuing due to AEs. [Display omitted] DisclosuresGarrett:Pfizer: Employment. Knight:Pfizer: Employment. Cortes:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding. Deininger:Celgene: Research Funding; Gilead: Research Funding; ARIAD: Consultancy; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy.

The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia

Objective Bosutinib, nilotinib and dasatinib are approved for the treatment of patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). In the absence of head-to-head comparisons between second-generation tyrosine kinase inhibitors (TKIs), the objective of this study was to indirectly compare the efficacy of bosutinib with nilotinib and dasatinib in first-line (1L) CP-CML. Methods Cross-trial heterogeneity in terms of patient baseline characteristics and imatinib dose escalation are difficult to adjust for in network meta-analyses and anchored matching-adjusted indirect treatment comparisons (MAICs). Therefore, an unanchored MAIC was performed using patient level data from bosutinib (BFORE trial) and published aggregated data from nilotinib (ENESTnd) and dasatinib (DASISION) trials. After matching, cytogenetic and molecular responses, and disease progression, after a minimum follow-up of 24 months were compared between nilotinib versus bosutinb and dasatinib versus bosutinib. Results The comparison of nilotinib versus bosutinib resulted in no statistically significant differences for MMR at and by 24 months, MR4 by 24 months, MR4.5 at and by 24 months, CCyR by 24 months, and disease progression, however, a decreased odds of MR4 at 24 months in favor of bosutinib versus nilotinib was observed. The comparison of dasatinib versus bosutinib by 24 months resulted in no statistically significant differences for MMR, disease progression, and CCyR, however a decreased odds of MR4.5 in favor of bosutinib versus dasatinib was observed. Conclusions Overall, in these analyses bosutinib demonstrates equivalent efficacy to nilotinib and dasatinib in the treatment of patients with newly diagnosed CP-CML.

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): 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

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