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Predictors of Systemic Exposure to Oral 6MP During Maintenance in Adolescentsand Young Adults with Acute Lymphoblastic Leukemia

Award Number: R01CA248439
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY / ABSTRACT Patients diagnosed with cancer between the ages of 15-39y have not seen the same improvement in survival when compared with patients diagnosed as children (<15y). These patients have received special designation by the NCI as adolescents and young adults (AYA), accompanied by a mandate to address these outcome disparities. Acute lymphoblastic leukemia (ALL) epitomizes this phenomenon, where survival rates in AYA continue to lag behind children (5y overall survival: 1-14y: 86%; 15-21: 56%; 22-29: 42%; 30-39: 35%). Across pediatric-inspired and adult-style therapy regimens, ALL therapy includes a prolonged (~2y) maintenance phase of chemotherapy requiring daily oral 6-mercaptopurine (6MP). A large investigation recently confirmed that inadequate systemic exposure to 6MP is associated with an increased risk of relapse; to measure systemic 6MP exposure, this comprehensive approach assessed the levels of a 6MP metabolite (thioguanine nucleotide [TG]) incorporated into DNA (DNA-TG). Several AYA-specific factors likely contribute to systemic 6MP exposure and have not been examined systematically. These factors are likely related to both the AYA patient (6MP adherence) and healthcare (disease management, reflected by the provider-prescribed 6MP dose intensity [DI]), as well as the barriers and facilitators within these domains. We hypothesize that systemic exposure to 6MP will correlate with both 6MP adherence (in the patient domain) and disease management, as represented by provider- prescribed 6MP DI (in the healthcare domain). We will examine these associations between DNA-TG levels and both 6MP adherence and 6MP DI, adjusting for pharmacogenetics. We will then identify barriers/ facilitators to both 6MP adherence and disease management, using a mixed methods convergent parallel study design, both quantitatively determining the predictors of adherence and 6MP DI, and qualitatively describing the perspectives of both the patients and healthcare providers. We will conduct this study using a prospective cohort of AYA patients in ALL maintenance therapy across a national 14-site consortium of multiple types of facilities and oncology practices. For 6 months per patient, 6MP adherence will be monitored electronically and monthly DNA- TG levels will be followed (peripheral blood). Patient questionnaires will capture self-reported barriers and facilitators of adherence as well as sociodemographics; institution-level questionnaires will capture healthcare factors. Findings from this study have the potential to identify both patient-related and healthcare-related targets amenable to interventions with the potential to mitigate AYA outcome disparities in AYA patients with ALL. Furthermore, this study establishes the infrastructure to continue to follow this cohort for relapse, and conduct intervention(s) informed by this proposed trial within a novel AYA-focused consortium.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $184,052 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	4	3/11/2024	NON-COMPETING CONTINUATION	$151,098
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$32,954
														Subtotal = $184,052

Issue Date FY: 2023 ( Subtotal = $649,823 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	3	2/17/2023	NON-COMPETING CONTINUATION	$649,823
														Subtotal = $649,823

Issue Date FY: 2022 ( Subtotal = $681,026 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	001	2	5/25/2022	NON-COMPETING CONTINUATION	$68,105
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	2	2/18/2022	NON-COMPETING CONTINUATION	$612,921
														Subtotal = $681,026

Issue Date FY: 2021 ( Subtotal = $809,032 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	001	1	4/13/2021	NEW	$239,487
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Cause and Prevention Research	000	1	3/24/2021	NEW	$569,545
														Subtotal = $809,032

Grand Total All Awards = $2,323,933

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Predictors of Systemic Exposure to Oral 6MP During Maintenance in Adolescentsand Young Adults with Acute Lymphoblastic Leukemia

Award Number: R01CA248439

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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