Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05811910 |
| Other study ID # |
58/22 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 30, 2021 |
| Est. completion date |
December 31, 2023 |
Study information
| Verified date |
March 2023 |
| Source |
IRCCS Burlo Garofolo |
| Contact |
Marco Rabusin, MD |
| Phone |
+39 0403785111 |
| Email |
marco.rabusin[@]burlo.trieste.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Therapeutic success in childhood ALL reaches an outstanding success that currently relies
upon risk stratification of patients with appropriate modulation of chemotherapy intensity
based on underlying blasts' biological and molecular characteristics, and depth of initial
treatment response. ALL polychemotherapeutic approaches share similar therapeutic scheme,
with more intensive and toxic earlier phases (about 6 months) followed by a prolonged
immunosuppressive regimen for maintenance (about 18 months). Protocols comprise
glucocorticoids, antimetabolites, asparaginase, alkylating agents, antimitotic drugs
antibiotics and, in case of Philadelphia positive ALL, anti-tyrosine kinase inhibitors
combined together at different dosages and timing according to the patient's class of risk.
ALL chemotherapeutic agents can damage nearly all organs. Some adverse reactions are
extensions of the drugs' desired pharmacological effects on bone marrow and affect almost all
children. Other adverse effects occur unpredictably in a smaller fraction of patients who,
for unknown reasons, are more susceptible. Concerns about chemotherapy-related toxicities
generated a significant need of finding predictive markers for the a priori identification of
at-risk patients. Pharmacogenomics markers can be useful tools in clinics for tailoring
therapy intensity on patients' genetic profile and in basic research for better understanding
mechanistic and regulatory pathways of the biological functions associated with ALL treatment
toxicities. Several genome wide association studies explored the landscape of ALL
treatment-associated toxicities, discovering the contribution of important variants. Among
these, TPMT single nucleotide polymorphisms (SNPs) have a well-recognized role in
thiopurine-induced myelotoxicity. SNP rs924607 (C>T) in the promoter region of the gene
encoding for the centrosomal protein 72 (CEP72) was associated with increased risk and
severity of vincristine-related peripheral neuropathy. The aim of this study is to perform a
GWAS in ALL children to provide insight into genetic loci affecting the occurrence of severe
(grade III-V) vincristine-related peripheral neuropathy during induction therapy in the AIEOP
protocols.
Description:
Acute lymphoblastic leukemia (ALL) is the most common haematological cancer in children.
Therapeutic success in childhood ALL reaches an outstanding success (5-years survival of
about 85-90%), that currently relies upon risk stratification of patients with appropriate
modulation of chemotherapy intensity based on underlying blasts' biological and molecular
characteristics, and depth of initial treatment response. Although with some difference,
worldwide ALL polychemotherapeutic approaches share the same therapeutic scheme, with more
intensive and toxic earlier phases (to induce and consolidate remission, about 6 months),
followed by a prolonged immunosuppressive regimen for maintenance (about 18 months). In
particular, protocols comprise mostly glucocorticoids, antimetabolites, asparaginase,
alkylating agents, antimitotic drugs antibiotics and, in case of Philadelphia positive ALL,
anti-tyrosine kinase inhibitors combined together at different dosages and timing according
to the patient's class of risk. ALL chemotherapeutic agents can damage nearly all organs.
Some adverse reactions such as the hematological toxicities and their consequences (such as
infections) are extensions of the drugs' desired pharmacological effects on bone marrow, and
affect almost all children. Other adverse effects occur unpredictably in a smaller fraction
of patients who, for unknown reasons, are more susceptible. High dose antimetabolites and DNA
damaging drugs may cause a direct injury in healthy proliferating tissues, resulting in
mucositis (about 40% of ALL patients). Corticosteroids may cause bone toxicities (such as
osteoporosis, 5-70%), endocrinopathies (such as insulin resistance, hyperglycemia and
prediabetes, 10-20%) and central nervous system toxicities (10-15%). Vincristine treatment is
associated to peripheral motor or sensory neuropathy development (5-15%).8 Methotrexate
crystals can precipitate in kidneys, inducing nephrotoxicity (about 3%).9 Asparaginase can
lead to hypersensitivity reactions (30-70%) and pancreatitis (2-18%). Additional acute
toxicities such as venous thromboembolism are rarer but still might contribute to the
incidence of treatment related deaths. Concerns about chemotherapy-related toxicities have
generated a significant need of finding predictive markers for the a priori identification of
at-risk patients. In particular, pharmacogenomics markers can be useful tools both in clinics
for tailoring therapy intensity on patients' genetic profile and in basic research for better
understanding the mechanistic and regulatory pathways of the biological functions associated
with ALL treatment toxicities. Several genome wide association studies (GWAS) -performed
mainly by US/Canadian Children's Oncology Group (COG) ALL protocols- had explored and
investigated the landscape of ALL treatment-associated toxicities, discovering the
contribution of important variants. Among these, TPMT single nucleotide polymorphisms (SNPs)
have a well-recognized role in thiopurine-induced myelotoxicity ad genotype-based guidelines
are already available. SNP rs924607 (C>T) in the promoter region of the gene encoding for the
centrosomal protein 72 (CEP72) was found to be associated with increased risk and severity of
vincristine-related peripheral neuropathy. To author's knowledge, this is the only variant
whose clinical validation is currently ongoing in a perspective clinical trial (Saint Jude
Children Research Hospital (SJCRH) Total Therapy XVII, NCT03117751). The aim of this study is
to perform a GWAS in ALL children to provide insight into genetic loci affecting the
occurrence of severe (grade III-V) vincristine-related peripheral neuropathy during induction
therapy in the AIEOP protocols
