Ignite Creation Date:
2024-05-06 @ 6:52 PM
Last Modification Date:
2024-10-26 @ 2:56 PM
Study NCT ID:
NCT05811845
Status:
RECRUITING
Last Update Posted:
2024-06-14
First Post:
2023-03-31
Brief Title:
Mercaptopurine Therapeutic Drug Monitoring to Optimize the Maintenance Phase of Childhood ALL
Sponsor:
IRCCS Burlo Garofolo
Organization:
IRCCS Burlo Garofolo
Study Overview
Official Title:
Optimizing the Maintenance Phase of Childhood Acute Lymphoblastic Leukemia AIEOP Protocol Through Mercaptopurine Therapeutic Drug Monitoring and Proactive Strategies for Adherence
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Acute lymphoblastic leukemia ALL is the most common hematological malignancy in children 18 years The success of pediatric ALL therapy is remarkable but important challenges still need to be faced including cure rates in specific patients subsets eg adolescents and relapsed patients and short- and long-term chemotherapy-related toxicities The therapeutic scheme of the Associazione Italiana Emato-oncologia pediatrica AIEOP ALL protocols consists in a more intensive and toxic earlier phase to induce and consolidate remission about 6 months followed by a prolonged period of immunosuppression achieved by self- or parent-administered daily mercaptopurine MP and weekly methotrexate MTX per os It is now well established that the length of the maintenance phase up to 24 months after diagnosis is as necessary as the early remission induction for sustained event-free survival EFS Both MP and MTX can lead to potentially serious complications including potentially life-threatening myelosuppression and infections To exert its therapeutic effect MP requires an intracellular enzymatic conversion into active thionucleotides TGN and is thus susceptible to intra- and inter-individual variations in efficacy and toxicity Patients carrying variants in TPMT and NUTD15 genes are at risk of adverse effects when treated with standard MP doses these patients are identifiable by pre-emptive genotyping Recent studies demonstrated that an adequate and constant MP exposure during maintenance is associated with higher therapeutic success Prescribed MP doses are often changed by physicians to target a white blood cell count WBC range of 20-30 109L during maintenance In the AIEOP ALL 2009 protocol patients with lower mean TGN exposure during maintenance showed a trend towards a higher risk of relapse compared to others Similarly patients with higher intra-individual variability in TGN over time showed a trend towards a worse outcome Daily compliance to prescribed MP over time is a challenging issue for patients and may result in less effective therapy The high intra-individual variability in exposure due to the frequent dose adjustments and the potential lack of patients adherence to oral MP therapy over time might contribute to the risk of relapse The aim of this study is to assess through therapeutic drug monitoring of MP if patients exposure during maintenance is adequate and constant
Detailed Description:
Acute lymphoblastic leukemia ALL is the most common hematological malignancy in children 18 years The success of pediatric ALL therapy is remarkable 5 years survival 90 However important challenges still need to be faced including cure rates in specific patients subsets eg adolescents and relapsed patients 5 years survival 60-70 and 40-50 respectively and short- and long-term chemotherapy-related toxicities The therapeutic scheme of the Associazione Italiana Emato-oncologia pediatrica AIEOP ALL protocols consists in a more intensive and toxic earlier phase to induce and consolidate remission 6 months followed by a prolonged period of immunosuppression achieved by self- or parent-administered daily mercaptopurine MP and weekly methotrexate MTX per os It is now well established that the length of the maintenance phase up to 24 months after diagnosis is as necessary as the early remission induction for sustained event-free survival EFS Ideally the combination of antimetabolites MP and MTX is safe enough to provide the required antileukemic effects with minimal adverse events However both drugs can lead to potentially serious complications including potentially life-threatening myelosuppression and infections To exert its therapeutic effect MP requires an intracellular enzymatic conversion into active thionucleotides TGN and is thus susceptible to intra- and inter-individual variations in efficacy and toxicity In particular patients carrying variants in TPMT and NUTD15 genes are at risk of adverse effects when treated with standard MP doses these patients are identifiable by pre-emptive genotyping and pharmacogenetic-based dose adjustment guidelines are already available Recent studies of the Childrens Oncology Group COG and of the Nordic Society of Pediatric Hematology and Oncology NOPHO demonstrated that an adequate and constant MP exposure during maintenance is associated with higher therapeutic success Prescribed MP doses are often changed by physicians to target a white blood cell count WBC range of 20-30 109L during maintenance In the AIEOP ALL 2009 protocol patients with lower mean TGN exposure during maintenance below median cut-off of 27244 pmol10x108 RBC showed a trend towards a higher risk of relapse compared to others 115 vs 55 respectively Similarly patients with higher intra-individual variability in TGN over time above the 75th percentile of the coefficient of variation CV showed a trend towards a worse outcome 103 vs 48 These preliminary data were obtained in 265 ALL patients age median interquartile range 482 303-853 years 585 male follow up from maintenance beginning 1338 1377-4162 days 27 relapsed TGN measured in 391 blood samples of 209 patients Daily compliance to prescribed MP over time is a challenging issue for patients and may result in less effective therapy indeed the recent use of an electronic device - the medication bottle cap opening MEMS- revealed that patients self-reported MP intake overestimates true intake in particular in some sociodemographic groups Adherence is generally poorer in adolescents compared to younger children likely because drug administration may no more be under strict parents supervision this lower compliance can in part contribute to the survival disparity observed between the two age groups Thus the high intra-individual variability in exposure due to the frequent dose adjustments and the potential lack of patients adherence to oral MP therapy over time might contribute to the risk of relapse
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None