Anaphylaxis to Cyclophosphamide Metabolites during Lymphodepletion for CAR-T Therapy
Transplantation and Cellular Therapy
; 29(2 Supplement):S160, 2023.
Article
in English
| EMBASE | ID: covidwho-2313851
ABSTRACT
Background:
Cyclophosphamide (Cy) is used in hematopoietic stem cell transplant (HSCT) preparative regimens and lymphodepletion for chimeric antigen receptor T-cell (CAR-T) therapy. We describe a case of cyclophosphamide hypersensitivity in a pediatric patient during CAR-T therapy. Case description A 13 year old boy was diagnosed with very high risk ALL in 2015 and had 2 isolated CNS relapses treated with intensified chemotherapy (chemo) and cranial radiation (1st relapse) and Blinatumomab with intrathecal (IT) chemo followed by sibling donor HSCT (2nd relapse). At age 19, and 18 months after HSCT, he had a 3rd CNS relapse treated with IT chemo and referral for CAR-T therapy. At our center, leukapheresis and CAR-T production (Novartis) were performed. Later, during lymphodepletion with fludarabine (Flu) and Cy, physiologic replacement hydrocortisone (HC) was briefly held to prevent interference with CAR-T function. After 3 days of Flu/Cy, he developed fever and hypotension requiring inotropic support. Hypotension and fever resolved with stress dose HC and antibiotics and was attributed to culture-negative sepsis and adrenal crisis. CAR-T infusion was subsequently delayed by skin GVHD requiring glucocorticoids and COVID-19 infection treated with convalescent plasma and nirmatrelvir/ritonavir. Physiologic HC replacement was continued when he was re-admitted for CAR-T therapy, but he again developed fever, diffuse erythema and shock in hours following the first dose of Cy necessitating stress dose HC, antibiotics, inotropes, and mechanical ventilation. Negative blood cultures and ongoing physiologic HC replacement suggested an alternative explanation for shock. Case reports of anaphylaxis to Cy metabolites implicated Cy as the causative agent so it was discontinued. After recovery, CAR-T cells were infused without complications. In the following weeks, he had no evidence of recurrent leukemia but was persistently pancytopenic. A sibling donor stem cell boost was proposed but the patient accepted only palliative care. He had several opportunistic infections before succumbing to E. coli sepsis. Discussion(s) The first episode of shock was initially attributed to adrenal crisis and sepsis, although no organism was identified. The second episode appeared anaphylactic in timing and clinical presentation with adequate HC replacement and negative cultures, suggesting Type I hypersensitivity. The patient previously received Cy uneventfully before HSCT, suggesting that the donor-derived immune system was the source of new Cy hypersensitivity. Onset of anaphylaxis within hours rather than minutes after Cy administration supports hypersensitivity to Cy metabolites rather than to the drug itself. This case highlights the importance of consideration of sensitivity to Cy metabolites as well as acquired donor-specific allergy even when alternative explanations are likely.Copyright © 2023 American Society for Transplantation and Cellular Therapy
adolescent; adrenal insufficiency; adverse drug reaction; allergy; anaphylaxis; antibiotic sensitivity; artificial ventilation; bacterium culture; blood culture; cancer patient; cancer recurrence; case report; cell function; central nervous system; chemotherapy; child; chimeric antigen receptor T-cell; chimeric antigen receptor T-cell immunotherapy; clinical article; complication; conference abstract; coronavirus disease 2019; drug combination; drug therapy; erythema; Escherichia coli; fever; graft versus host reaction; hematopoietic stem cell; human; human cell; hypersensitivity; hypotension; immune system; inotropism; leukapheresis; leukemia; male; nonhuman; opportunistic infection; palliative therapy; pancytopenia; patient referral; pediatric patient; physiological stress; relapse; sepsis; sibling donor; side effect; skull irradiation; surgery; systemic inflammatory response syndrome; T lymphocyte; antibiotic agent; blinatumomab; convalescent plasma; cyclophosphamide; endogenous compound; fludarabine; glucocorticoid; hydrocortisone; inotropic agent; lymphocyte antigen receptor; nirmatrelvir plus ritonavir; unclassified drug
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Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Transplantation and Cellular Therapy
Year:
2023
Document Type:
Article
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