Ototoxicity is a debilitating side effect of platinating agents with substantial inter-patient variability. We sought to evaluate the association of TPMT and COMT genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P=0.013) and craniospinal irradiation (P=0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wildtype mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.
Hematological toxicity (hematotoxicity) leading to peripheral cytopenias is a common long‐term adverse effect following the use of CD19‐chimeric antigen receptor (CD19‐CAR) T‐cell therapies. However, management remains unclear for patients whose cytopenias persist beyond 1 month after CAR T‐cell infusion. We present the case of a 21‐year old who received CD19‐CAR T‐cell therapy for relapse following a haploidentical transplant. He developed hematotoxicity and consequently multiple life‐threatening infections. We administered a CD34+ hematopoietic stem cell boost (HSCB) from his transplant donor, which led to hematopoietic recovery and resolution of his infections without any effect on the activity of CD19‐CAR T cells. CD34+ HSCB can be a safe and effective option to treat hematotoxicity following CD19‐CAR T‐cell therapy.
Background
EPP is a rare disorder of heme biosynthesis in which patients present with disabling photosensitivity. A subset of patients develop severe liver disease with progressive liver failure necessitating an OLT. A HCT can potentially cure EPP by replacing the native bone marrow, which is the primary site of heme synthesis. However, due to concerns for inherent risks of treatment‐related toxicities, the use of HCT has been reserved for patients undergoing an OLT to avoid disease recurrence in the hepatic graft. Data for HCT in EPP are lacking, particularly in the pediatric population.
Case (Methods/Results)
We present the case of a 12‐year‐old patient with EPP photosensitivity and cirrhosis, whom we successfully treated with pre‐emptive allogeneic HCT, significantly improving the patient's quality of life. We used a matched‐unrelated donor bone marrow–derived graft. Our patient achieved full donor peripheral blood chimerism and has not had any evidence of GVHD. In addition to resolution of photosensitivity, our patient had reversal of liver fibrosis which we feel was largely due to intervention at an early stage of compensated cirrhosis.
Conclusion
Our case highlights the successful application of a known RIC regimen to this rare disorder that was well tolerated with sustained donor engraftment. It also emphasizes the importance of timing for HCT in patients with EPP and liver fibrosis. HCT should be considered early in pediatric patients with EPP‐hepatopathy to prevent progression to liver failure and need for OLT with lifelong immunosuppression.
Hematological toxicity (hematotoxicity) is the most common long-term
adverse effect following the use of CD19-chimeric antigen receptor
(CD19-CAR) T-cell therapies. However, its management remains unclear. We
present the case of a 21-year-old who received CD19-CAR T-cell therapy
for relapse following a haploidentical transplant. He developed
hematotoxicity and consequently multiple life-threatening infections. We
administered a CD34+ hematopoietic stem cell boost (HSCB) from his
transplant donor that led to hematopoietic recovery and resolution of
his infections without any effect on the activity of CD19-CAR T cells.
CD34+ HSCB can be a safe and effective option to treat hematotoxicity
following CD19-CAR T-cell therapy.
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