Thompson, James E.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase–CML. The primary goal of TKI therapy in patients with chronic phase–CML is to prevent disease progression to accelerated phase–CML or blast phase–CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase–CML.

Background: First-line therapies for chronic-phase (CP) CML include the tyrosine kinase inhibitors(TKIs) dasatinib, nilotinib, bosutinib or imatinib, while ponatinib and asciminib are indicated only in later lines. There are typically high response rates to first-line therapy in CP-CML, with responses to second- and third-line therapy lower and highly dependent on the specific TKI. Our goal in this study is to evaluate the role of ponatinib in the treatment of patients with CML using data from routine clinical practice. Study design and methods: Data will come from the H. Jean Khoury Cure CML Consortium (HJKC3) CML registry, a North American multi-site research database. Participating sites include the HJKC3 members (curecml.org). Patient inclusion criteria include a diagnosis CML in chronic phase, receiving second line therapy after initial therapy with a second generation TKI (dasatinib, nilotinib, or bosutinib) or receiving third or later line TKI therapy for CML. Participating patients provide consent to collect their data both retrospectively and prospectively for 1 year. Clinical data, including toxicities and complications of TKI therapy, are abstracted from the electronic health record. Participating patients are invited to complete a questionnaire to assess health-related quality of life. Data are managed using REDCap, a secure web application. Study Objectives: The primary objective is to compare the outcome of patients treated with ponatinib vs. other TKIs as second or later line therapy. Secondary objectives are to evaluate patient-reported outcomes (PRO) for CML treated with second or later line therapy and to determine if there are any patient or disease characteristics that can predict outcomes. Statistical plan for clinical outcomes: Descriptive statistics will be used to compare baseline demographic characteristics. Categorical variables will be compared using the Chi-square test. Continuous variables will be compared using ANOVA. Overall survival will be calculated from the time of diagnosis to death from any cause and patients will be censored if they were alive at the last follow-up. Survival probabilities will be computed using the Kaplan-Meier method and compared with the log-ranktest. Cox regression analyses will be used to determine significant factors that influence survival, and hazard ratios with 95% confidence intervals will be presented. Event free survival (EFS) and transformation free survival (TFS) will be calculated for patients. For EFS, loss of complete hematologic remission, loss of major cytogenetic response, progression to accelerated or blast phase, or death from any cause at any time will be considered an event. For TFS, transformation to accelerated or blast phase while on therapy or death on study will be considered an event. Statistical plan for PRO: Different PRO domains will be analyzed separately (for example, depression separate from fatigue, etc.). Descriptive statistics for each PRO measure will be reported and compared to previously published studies. Differences by treatment type will be evaluated.

Background and significance: There are typically high response rates to first line TKI therapies in chronic phase chronic myeloid leukemia (CP-CML). However, responses in later lines (second line and beyond) are diminished and highly dependent on the specific tyrosine kinase inhibitors (TKIs) used. Asciminib received FDA approval in October 2021 for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) CML-CP who were previously treated with two or more TKIs, and in patients with Ph+ CML-CP with the T315I mutation. Our goal in this study is to evaluate the role of asciminib therapy for patients with CML beyond clinical studies, in routine clinical practice. Study Design and methods: Data for this study will be abstracted from the HJKC3 (H. Jean Khoury Cure CML Consortium) CML registry project (HJKC3-0005); the HJKC3 CML Registry is a collaborative academic multi-site registry. Patients will be consented to allow collection of both retrospective and prospective data for the HJKC3 CML Registry. The data forms and surveys will be built and managed through the Research Electronic Data Capture (REDCap), a secure web application managed by the Clinical & Translational Science Institute. Participating sites include members of the HJKC3 (curecml.org). This study will be an opportunity to evaluate asciminib usage in ‘real-world’ academic practices across the United States. This observational study will include cohorts of patients diagnosed with CP-CML previously treated with two or more tyrosine kinase inhibitors and/or receiving asciminib and/or those with a T315I mutation, not currently enrolled in a randomized controlled trial. The HJKC3 CML Registry intends to collect clinical and patient reported outcome (PRO) data. After obtaining patient consent, patients will be invited to complete PRO assessments. The study will attempt to collect PRO data regardless of disease or treatment status. PRO assessments will be primarily administered online, though study staff will offer alternatives (e.g., phone) for participants without internet access. Study subjects will be emailed a link to access a secure platform hosted by one of the study sites, Medical College of Wisconsin (MCW), using the REDCap platform. Study Objectives: The primary objective of the study is to describe characteristics of patients who were previously treated with two or more TKIs and treated with asciminib or with any other TKIs. The secondary objectives are to describe the clinical outcomes and PRO of those patients. Exploratory objectives include description of characteristics, treatment outcome and PRO for patients with T315I mutation. Statistical plan: The sample size of approximately 225 participants during the 5-year recruitment period is based on the available clinical expertise and ongoing recruitment data in the HJKC3 CML registry in lieu of statistical power analysis. We estimate that 150 patients in the HJKC3 CML registry will be treated with other TKI and 75 treated with asciminib. Among a total of 225 patients, we estimate that 75 patients with the T315I mutation will be enrolled in the registry. No formal statistical inference will be drawn to compare the outcomes between these two groups. Bayesian predictive probability (PP) will be utilized for the exploratory analysis of Major Molecular Response (MMR). Survival probabilities will be computed using the Kaplan-Meier method, and the p-values from the log-rank test will be provided. Different PRO domains of the patient's symptoms and functioning will be analyzed separately (e.g., depression separate from fatigue, separate from GI symptoms, etc.) since combining them into a summary score may dilute the effects of the individual (and not necessarily related) components and mask actual change. The main objective for the analyses of PRO data from the registry is to describe any differences by treatment type in patients treated with asciminib and other TKIs.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Abstract The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%–100%] and specificity was estimated at 100% (95% CI: 81.5%–100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS. Cancer Res; 73(1); 265–75. ©2012 AACR.