Desidustat for Pure Red Cell Aplasia in CKD Patients on Biosimilar Erythropoietin Preparations: A Case Series

Introduction

Erythropoietin (EPO) supplementation for anemia due to CKD rarely causes pure red cell aplasia (PRCA) by stimulating the formation of anti-EPO antibodies neutralizing all erythropoiesis-stimulating agents (ESAs), including endogenous EPO.¹ Most cases are associated with generic epoetin-α and manifest 2 to 63 months after initiation. Treatment involves ESA discontinuation and introduction of immunosuppressive agents like cyclosporine or corticosteroids.^1,2

The understanding that hypoxia stimulates endogenous EPO production through the hypoxia-inducible transcription factors (HIF) pathway is currently being explored. Inhibition of this pathway stimulates endogenous EPO production, even without hypoxia.³

Desidustat is an orally administered HIF-prolyl hydroxylase inhibitor, which stabilizes HIF and leads to endogenous EPO production and erythropoiesis. Desidustat was approved in India in March 2022.^4-6 Animal studies showed desidustat’s mechanism of improving EPO resistance by promoting EPO synthesis and decreasing hepcidin levels by HIF stabilization.

Case Series

We report 14 patients treated with desidustat for CKD with EPO-induced PRCA between May 2022 and May 2024. All patients were receiving generic EPO, IV iron, and vitamin D3. The treating nephrologist made the decision on dialysis adequacy or transfusion.

Diagnostic criteria for PRCA were based on KDIGO clinical practice guidelines for management of anemia of CKD, 2012. Anti-EPO antibody assay was performed in only one patient due to a lack of readily available laboratory support. Parvovirus infection and functional iron deficiency were ruled out with anti-Parvovirus IgM serology, and transferrin saturation and serum ferritin, respectively. Patients with fever and elevated CRP were excluded. Thymoma was ruled out in all patients by imaging.

The clinical profile of the patients has been listed in Table 1a-b. The median age was 61 (range: 51-69) years, 13 were males, and 13 were on hemodialysis. Fourteen patients were on thrice-weekly hemodialysis, and one had CKD stage III. Serum EPO level, measured in four patients, was low. Anti-EPO antibody assay was performed in only one patient due to a lack of readily available laboratory support.

The median duration from EPO initiation and PRCA diagnosis was 10 (range: 4-38) months. The median hemoglobin at diagnosis of PRCA was 5.7 (range: 3.2-8.6) g/dL. Median mean corpuscular volume (MCV) was 83.4 (range: 76-93) fL. Median reticulocyte percentage was 0.2% (range 0.07-0.29%). Median erythroid colony percentage in bone marrow aspirate was 2.44% (range: 1-6%).

The treatment details have been included in Table 2. Thirteen patients received multiple transfusions; the median number of transfusions was nine (range: 1-40). Four patients had received immunosuppressant therapy. The median duration of immunosuppressant therapy was 6 months (range: 1-11 months). In the remaining 10 patients, desidustat was the first-line therapy for PRCA.

Desidustat was initiated at a 100 mg dose thrice weekly in nine patients and 100 mg daily in the remaining five. After 1-3 months, the 100 mg thrice weekly was increased to 100 mg daily in two patients and to 150 mg thrice weekly in the another two.

Response was defined as attaining transfusion independence (Hb > 8 g/dL) for 6 months consecutively after initiation of therapy.

Two patients were lost to follow -up. Of the remaining 12, nine (64%) responded to desidustat, after a median duration of 4 (range: 3-8) months. Three remained transfusion-dependent. Median hemoglobin in responders at last follow-up was 12.5 g% (range: 8.5-13.6 g%). One patient developed clinical depression while on therapy; however, it is unclear whether this was related to desidustat. No other major adverse effects were observed. All 12 patients were last followed up between January and May 2024.

Discussion

There is limited published literature on successful management strategies for EPO-induced PRCA in CKD beyond immunosuppressants. Many of these are case reports, mostly on roxadustat, another HIF-PH inhibitor, and less frequently desidustat.^S1-S4 These case reports also show a response with a median of 3 months.

Ours is by far the largest case series demonstrating the effectiveness of desidustat for EPO-induced PRCA. The limitations of our study include its retrospective nature, the lack of anti-EPO antibody data, the absence of EPO level testing in all patients, and the failure to exclude other EPO resistance factors, such as secondary hyperparathyroidism and the effects of Angiotensin Converting Enzyme (ACE) inhibitors (ACEI) or angiotensin receptor blockers (ARB). Our results indicate that desidustat can be potentially repurposed to reverse EPO refractoriness with better tolerability. Further randomized controlled trials are warranted.