A Preliminary Assessment of HeterozygousCFHR3-CFHR1Deletion As a Permissive Mutation in Carfilzomib-Induced Atypical Hemolytic Uremic Syndrome
Authors: Portuguese Andrew Jay , Fiala Mark A , Wildes Tanya M. , Vij Ravi , Lipe Brea 
Published: November 2020

Carfilzomib is a critical chemotherapy medication used to treat patients with relapsed or refractory multiple myeloma. Unfortunately, drug-induced atypical hemolytic uremic syndrome (aHUS) has been established as a devastating and unpredictable side-effect of carfilzomib. Loss-of-function mutations in alternative complement pathway regulatory genes, such as complement factor H (CFH) and its related proteins (CFHRs), are the most frequently identified genetic abnormalities seen with aHUS. In our recently published work, two of three patients treated at the University of Rochester Medical Center for carfilzomib-induced aHUS were found to harbor the heterozygousCFHR3-CFHR1deletion, a genetic variant that is generally considered benign, implicating it in development of disease. We sought to further characterize the relationship between the heterozygousCFHR3-CFHR1deletion and development of carfilzomib-induced aHUS by conducting a case-control study.
We screened banked frozen peripheral blood mononuclear cell (PBMC) samples from subjects treated with carfilzomib-based regimens at Washington University. Criteria for aHUS case selection were defined as all of the following: elevated LDH, decreased haptoglobin or elevated total bilirubin, evidence of schistocytes on peripheral blood smear, de novo anemia and thrombocytopenia, acute kidney injury, no evidence of infectious diarrhea (if tested), and active carfilzomib treatment at the time of disease. To ensure that controls had adequate exposure to carfilzomib, controls were selected from subjects who received ≥20 treatment cycles. Additional control selection criteria included: age &gt;40 years, no evidence of hemolysis (LDH &lt;250 U/L, total bilirubin &lt;1.2 mg/dL), no de novo anemia or thrombocytopenia (hemoglobin &gt;9 g/dL and platelets &gt;100 x 109/L), and no chronic or acute kidney disease (creatinine &lt;1.5 mg/dL). Ultimately, three cases of aHUS and four controls were identified. Corresponding PBMC samples were submitted to the Molecular Otolaryngology and Renal Research Laboratories for multiplex ligation-dependent probe amplificationCFH-CFHR5genomic region testing.
We found that two of three case samples (4 of 6 total [67%], including the previously published cases), and two of four control samples (50%) harbored the heterozygousCFHR3-CFHR1mutation. No otherCFH-CFHR5genomic region mutations were detected. The frequency of heterozygousCFHR3-CFHR1deletion was not found to be significantly different between case and control groups. Given the large amount of carfilzomib exposure among the control group, this result suggests that the heterozygousCFHR3-CFHR1deletion is likely not a predisposing mutation in the development carfilzomib-induced aHUS. However, an adequately powered case-control study would be required to statistically rule-out the association.

Disclosures
Wildes: Seattle Genetics:Consultancy;Janssen:Research Funding;Carevive Systems:Consultancy.Lipe:Janssen:Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees.