Stopping Tyrosine Kinase Inhibitors in Affecting Treatment-Free Remission in Patients With Chronic Phase Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how stopping tyrosine kinase inhibitors will affect treatment-free remission in patients with chronic myeloid leukemia in chronic phase. When the level of disease is very low, it's called molecular remission. TKIs are a type of medication that help keep this level low. However, after being in molecular remission for a specific amount of time, it may not be necessary to take tyrosine kinase inhibitors. It is not yet known whether stopping tyrosine kinase inhibitors will help patients with chronic myeloid leukemia in chronic phase continue or re-achieve molecular remission.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the 2-year treatment free remission (TFR) rate of children, adolescents, and young adults with chronic myeloid leukemia - chronic phase (CML-CP) following discontinuation tyrosine kinase inhibitor (TKI). II. To estimate the re-induction rate and maintenance of molecular remission (BCR-ABL1 =< 0.1%) at 1 year after restarting TKI for children, adolescents, and young adults. SECONDARY OBJECTIVE: I. To describe clinical factors and laboratory correlates affecting the persistence of major molecular remission (MMR) and re-initiation of treatment after stopping TKI (e.g. patient demographics, duration and level of prior molecular remission, duration and type of TKI, clinical presentation at diagnosis and immune studies). EXPLORATORY OBJECTIVES: I. To describe change in height standard deviation score over time in patients who are able to discontinue their TKI. II. To describe the long-term health outcomes including but not limited to gonadal function, endocrine function, and bone metabolism in patients who are able to discontinue TKI as well as those that need to restart TKIs. III. To describe differences in patient-reported health status after stopping TKIs, including those who need to resume TKI after stopping. IV. To describe the incidence and characteristics of TKI withdrawal syndrome in children. V. To evaluate changes in neurocognitive outcomes of patients enrolled on this study using a patient-completed, performance-based, computerized measure of neuropsychological functioning and a parent-report/self-report questionnaire. OUTLINE: Patients stop taking TKI medication within 10 days after enrollment. Patients undergo peripheral blood collection to monitor loss of MMR every 4 weeks in year 1, every 6 weeks in year 2, and every 12 weeks in year 3. Patients who lose their molecular remission may restart TKI medication and are monitored every 4 weeks in year 1, every 6 weeks in year 2, and every 12 weeks in year 3. After completion of study treatment, patients are followed up annually.

Official Title
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Stopping Tyrosine Kinase Inhibitors (TKI) to Assess Treatment-Free Remission (TFR) in Pediatric Chronic Myeloid Leukemia - Chronic Phase (CML-CP)

Conditions
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Chronic Phase Chronic Myeloid Leukemia, BCR-ABL1 Positive

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Other: Drug Withdrawn
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Tyrosine Kinase Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have been diagnosed with CML-CP at < 18 years of age. Patient must have histologic verification of CML-CP at original diagnosis Patient must be in molecular remission (MR) with a BCR-ABL1 level of =< 0.01% BCR-ABL1 as measured using the International Scale (IS) by RQ-PCR for >= 2 consecutive years at the time of enrollment Please note: The lab evaluating disease status and molecular response for this study must be College of American Pathology (CAP) and/or Clinical Laboratory Improvement Amendments (CLIA) certified (United States [US] only), sites in other countries must be certified by their accredited authorities. All labs must use the International Scale guidelines with a sensitivity of detection assay =< 0.01% BCR-ABL1 and be able to report results in =< 2 weeks Patient must have received any TKI for a minimum of 3 consecutive years at time of enrollment Patient agrees to discontinue TKI therapy REGULATORY REQUIREMENTS All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met ELIGIBILITY FOR PATIENT-REPORTED OUTCOMES (PROs): Age >= 8 years at the time of enrollment Ability to understand English or Spanish Cognitive ability to complete instruments according to the primary team ELIGIBILITY FOR AAML18P1 NEUROCOGNITIVE STUDY: Patient must be 5 years or older at the time of enrollment English-, French- or Spanish-speaking No known history of neurodevelopmental disorder prior to diagnosis of CML (e.g., Down syndrome, Fragile X, William syndrome, mental retardation) No significant visual or motor impairment that would prevent computer use or recognition of visual test stimuli Exclusion Criteria: Known T3151 mutation Additional clonal chromosomal abnormalities in Philadelphia chromosome (Ph) positive (+) cells at any time prior to enrollment that include major route abnormalities (second Ph, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype or abnormalities of 3q26.2 History of accelerated phase or blast crisis CML Female patients who are pregnant Lactating females are not eligible unless they have agreed not to breastfeed their infants Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Basic Science (stop taking TKI, biospecimen collection)<br>Patients stop taking TKI medication within 10 days after enrollment. Patients undergo peripheral blood collection to monitor loss of MMR every 4 weeks in year 1, every 6 weeks in year 2, and every 12 weeks in year 3. Patients who lose their molecular remission may restart TKI medication and are monitored every 4 weeks in year 1, every 6 weeks in year 2, and every 12 weeks in year 3. | Procedure: Biospecimen Collection<br>* Undergo blood collection<br>* Other names: Specimen Collection;Other: Drug Withdrawn<br>* Stop taking TKI medication<br>* Other names: Discontinued;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Tyrosine Kinase Inhibitor<br>* Re-start TKI medication<br>* Other names: TK Inhibitors;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-free remission (TFR) | The Kaplan Meier method will be used to estimate 2-year TFR along with a 95% confidence interval. | From date of TKI discontinuation to the date of the first event (molecular recurrence, hematologic relapse, cytogenetic relapse, re-initiation of TKI therapy, second malignant neoplasm, or death) or censoring, assessed up to 2 years | 
| Major molecular remission (MMR/MR3) | For patients re-initiating tyrosine kinase inhibitor (TKI) therapy, the cumulative incidence of major molecular remission will be calculated from the time of re-initiating TKI therapy treating deaths prior to achieving major molecular remission as competing events. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical factors and laboratory correlates affecting persistence of MMR | Clinical factors and laboratory correlates (e.g. duration and level of prior molecular remission, risk score, duration and type of TKI, disease scoring system and immune studies etc.) affecting persistence of MMR and re-initiation of treatment after stopping TKI will be assessed by Cox proportional hazard regression models. | Up to 36 months |