To the Editor:
We describe the case of a 65-year-old male with advanced gastroesophageal junction adenocarcinoma on chemoimmunotherapy with PD-1/PDL-1 axis inhibition, a taxane, and ramucirumab, a monoclonal antibody that is a vascular endothelial growth factor receptor 2 antagonist. After more than 4 months on therapy, he developed hypertension, and nephrotic-range proteinuria. Renal function deteriorated with a drop in estimated glomerular filtration (eGFR) rate of 20 to 25 ml/min per 1.73 m2, reaching a nadir eGFR of 69 ml/min per 1.73 m2. He had a stable chronic anemia with negative hemolytic markers and no thrombocytopenia (Supplementary Table S1). Functional complement assay revealed a mildly elevated s-c5b9 (Supplementary Table S1), with negative complement genetic testing (Supplementary Table S2). Kidney biopsy was consistent with renal thrombotic microangiopathy (rTMA) (Figure 1). Ramucirumab was discontinued for 3 months. Proteinuria decreased, but failed to normalize. One month prior to reinitiation of ramucirumab, terminal complement pathway blockade with eculizumab, a C5 inhibitor, was started. Proteinuria subsequently resolved (Supplementary Figure S1) despite reinitiation of ramucirumab, initially at half dose, followed by full dose rechallenge. Eculizumab did not affect cancer response to therapy. After a 6-month eculizumab holiday, the patient’s proteinuria recurred, and eculizumab was reinitiated. The patient continued to require antihypertensive therapy while on C5 inhibition.
Figure 1.
Kidney biopsy findings. Glomeruli are nonproliferative and exhibit (a) segmental pseudothrombi, (b) segmental hyaline wire loop lesions, and glomerular basement membrane duplication (a–c). There is no significant glomerular or extraglomerular immunofluorescence staining (not shown). (d) Electron microscopy shows segmental cellular interposition and segmental subendothelial lucency with loss of fenestration and intracapillary hyaline deposits (scale = 6 μm).
We report, to the best of our knowledge, the first case of biopsy-proven rTMA temporally associated with VEGFi in which maintenance treatment with terminal complement blockade allowed for rechallenge with full dose ramucirumab. Importantly, the patient did have initial evidence of terminal complement pathway activation with an elevated s-c5b9. Rechallenge with bevacizumab post–C5 inhibition with eculizumab has been described.1 However, new onset rTMA with transition from bevacizumab to ramucirumab has been reported, indicating a potentially different risk profile between the 2 monoclonal antibodies.2,3 Notably, in our case, discontinuation of eculizumab resulted in relapse of the patient’s proteinuria, suggesting recurrent rTMA (Supplementary Table S1). With the patient’s mild renal dysfunction, rechallenge with VEGFi while on C5 inhibition was felt to be safe, though caution is warranted for patients with significant renal dysfunction. The role of terminal complement blockade in VEGFi-associated rTMA requires further study, given the importance of these targeted agents in cancer treatment across multiple tumor groups.
Disclosure
All the authors declared no competing interests.
Patient Consent
The authors declare that they have obtained consent from the patient discussed in the report.
Author Contributions
EBB, AJ, SMH, HY, and NL were mutually involved in the planning and outline of the manuscript. EBB and AJ cowrote the original manuscript and created the tables and figures. LB contributed the histopathologic data and figures to the manuscript. NL, HY, LB, and SMH reviewed and edited all the revisions of the manuscript.
Footnotes
Figure S1. Trend in serum creatinine and proteinuria over time. Eculizumab administration and rechallenge with ramucirumab are highlighted.
Table S1. Relevant renal-specific and hematologic biomarker results over time, including functional complement pathway testing. Additional complement markers including C4d and CBb were tested and within normal limits. Ancillary testing for etiologies of thrombotic microangiopathy including LDH, haptoglobin, methylmalonic acid, folate, and B12 levels were tested and were within normal limits.
Table S2. Results of Mayo complement genetic testing panel.
Supplementary Material
Figure S1. Trend in serum creatinine and proteinuria over time. Eculizumab administration and rechallenge with ramucirumab are highlighted. Table S1. Relevant renal-specific and hematologic biomarker results over time, including functional complement pathway testing. Additional complement markers including C4d and CBb were tested and within normal limits. Ancillary testing for etiologies of thrombotic microangiopathy including LDH, haptoglobin, methylmalonic acid, folate, and B12 levels were tested and were within normal limits. Table S2. Results of Mayo complement genetic testing panel.
References
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Supplementary Materials
Figure S1. Trend in serum creatinine and proteinuria over time. Eculizumab administration and rechallenge with ramucirumab are highlighted. Table S1. Relevant renal-specific and hematologic biomarker results over time, including functional complement pathway testing. Additional complement markers including C4d and CBb were tested and within normal limits. Ancillary testing for etiologies of thrombotic microangiopathy including LDH, haptoglobin, methylmalonic acid, folate, and B12 levels were tested and were within normal limits. Table S2. Results of Mayo complement genetic testing panel.