iPSC Neurons From Adult Survivors of Childhood Cancer Who Have Persistent Vincristine-Induced Neuropathy

St. Jude Children's Research Hospital

Status: Completed

Conditions: Lymphoma; Leukemia

Study type: Observational

Funder types: Other; NIH

Identifiers

NCT02564484

SJLPSC

R01CA036401 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This observational study is designed to establish induced pluripotent stem cells (iPSCs) from childhood cancer survivors who did or did not develop persistent treatment-induced peripheral neuropathy, from which to make human neurons for comparing their sensitivity to vincristine and other potentially neurotoxic drugs.

Investigators will assess the effects of inherited genome variations on treatment-induced peripheral neuropathy that persists in adults who were cured of childhood cancer. Cells from childhood cancer survivors who did or did not develop drug-induced neuropathy will be isolated and induced to become neurons. Cell sensitivity to anticancer agents will be tested in both groups and compared to determine if the survivors have genetic variants that correspond to those identified in companion genomic studies. This will assist in determining if gene variants increase the risk of treatment-induced neurotoxicity.

The investigators are interested in detecting changes of phenotype pre-post treatment in each group (cases, controls) respectively, as well in comparing the pre-post treatment phenotypic changes between the two groups (cases vs. controls).

Full description

Participants will be recruited from an existing protocol at St. Jude (SJLIFE, NCT00760656). Complete neuropathic evaluations are obtained as part of SJLIFE, and the information will be shared for use in the SJLPSC study. A one-time blood draw will be obtained, and peripheral blood mononuclear cells (PBMC's) will be isolated for eventual creation of induced pluripotent stem cells (iPSC) that will be differentiated into human neurons. These human neurons will allow the investigators to functionally validate and further interrogate CEP72 genetic variants or variants in other genes that are associated with persistent (or acute) vincristine neuropathy using a "state of the art" cellular model of human neurons. Furthermore, creating neurons from patients at the extremes (highly sensitive to vincristine-induced neuropathy and matched controls) allows the study of differences at baseline and after treatment with vincristine.

PRIMARY OBJECTIVE:

• To establish induced pluripotent stem cells (iPSCs) from childhood cancer survivors who did or did not develop persistent treatment-induced peripheral neuropathy, from which to make human neurons to assess their sensitivity to vincristine and determine whether neurons from patients who developed neuropathy are more sensitive to vincristine or other neurotoxic chemotherapy.

SECONDARY OBJECTIVE:

• To evaluate the iPSC neurons made from patients with persistent treatment-related neuropathy and iPSC neurons from patients who did not develop neuropathy from the same treatment, for phenotypic difference prior to and after exposure to vincristine or other potentially neurotoxic medications.

Enrollment: 137 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria - Neuropathy Patients:

• Adult survivor of childhood ALL
• Presence of any neuromotor, neurocortical, or neurocerebellar toxicity after vincristine treatment (either acute and/or persistent neuropathy)
• At least 50% of the persistent vincristine neuropathy cases will have the CEP72 promoter variant (rs924607) or a coding variant in CEP72 that is predicted to be damaging (CADD score >9). The balance of neuropathy cases will either have variants in other genes that are associated with vincristine neuropathy identified in the ongoing genome-wide association study (GWAS) of 1250 St. Jude Life ALL survivors, or have neuropathy in the absence of known genetic variants altering the risk of neuropathy.
• Patient understands the nature of the study and provides informed consent

Inclusion Criteria - Controls:

• Adult survivor of childhood diagnosis of ALL
• Absence of persistent neurotoxicity (grade 0) after completion of a standard vincristine-containing chemotherapy regimen (may or may not have experience acute neuropathy during treatment.
• Matched to a specified subject with neurotoxicity based on age (within 5 years), tumor type, chemotherapy regimen or total vincristine dosage, race and ethnicity.
• At least 50% of the controls will have the CEP72 promoter variant T/T genotype (at rs924607) or a coding variant in CEP72 that is predicted to be damaging (CADD score >9). The balance of controls will either have variants in other genes that are associated with vincristine neuropathy identified in the ongoing GWAS of 1250 St. Jude Life ALL survivors, or will not have a known genetic variant altering the risk of neuropathy.
• Patient understands the nature of the study and provides informed consent

Inclusion of Women and Minorities:

• Individuals of both genders, all races and ethnic groups are eligible for this protocol.

Exclusion Criteria - Both Cohorts:

• Treatment with other severely neurotoxic chemotherapy (i.e. cisplatin) prior to or concomitantly with vincristine. Carboplatin therapy is allowed
• Presence of peripheral neuropathy prior to vincristine therapy
• Poorly controlled or insulin-dependent diabetes or other condition likely to predispose to neurotoxicity
• Pregnant females
• Currently receiving treatment for cancer

Trial design

137 participants in 2 patient groups

Neuropathy

Description:

Adult survivors who developed persistent treatment-related neuropathy.

Control

Description:

Adult survivors who did not develop persistent treatment-related neuropathy.