Correlation between a 2-week change in platelet count and clinical outcomes after the initiation of ravulizumab treatment in adult patients with atypical hemolytic uremic syndrome: post-hoc analysis of the phase III trial.

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease with poor outcomes when untreated, in which ravulizumab or eculizumab are the standard of care where available. It has been proposed to regularly monitor platelet counts as an early response to ravulizumab or eculizumab. This study aimed to investigate the association between the early response to ravulizumab treatment and renal outcomes through 26 weeks in complement inhibitor-naïve adults with aHUS.

Methods: Adult patients with aHUS enrolled in the ALXN1210-aHUS-311 phase III study of ravulizumab were divided into two groups according to the achievement of complete thrombotic microangiopathy (TMA) response, i.e., platelet count and lactate dehydrogenase (LDH) normalization and ≥ 25% improvement in serum creatinine (sCr) from baseline, by 26 weeks and baseline characteristics were compared. Changes in hematologic parameters, platelet count and LDH, were compared between the two groups. Finally, we examined whether early hematologic improvement was associated with renal recovery (dialysis discontinuation or ≥ 25% improvement in sCr from baseline) through 26 weeks.

Results: Of 56 ravulizumab-treated patients, 30 achieved complete TMA response for 26 weeks, and 26 did not. Patients with complete TMA response showed rapid improvements in platelet counts. In patients without complete TMA response, delayed normalization of platelet counts was observed. By day 15, 93.3% (28/30) of patients with complete TMA response at 26 weeks and 26.9% (7/26) of patients without complete TMA response achieved platelet normalization. At 26 weeks, 62.5% (35/56) achieved renal recovery; however, 37.5% (21/56) did not. In patients with renal recovery, 85.7% (30/35) of patients had platelet count normalization by day 15; in patients without renal recovery, 23.8% (5/21) of patients had platelet count normalization (P < 0.0001). Receiver operator characteristic curve analysis showed a moderate association between platelet counts on day 8/15 and renal recovery within 26 weeks (day 8: area under the curve [AUC] = 0.7985; day 15: AUC = 0.8406).

Conclusions: Platelet count normalization occurred in 62.5% (35/56) by day 15 after ravulizumab initiation and was associated with renal recovery through 26 weeks in complement inhibitor-naïve adults with aHUS.

Trial Registration: This study was performed as a post-hoc analysis of the ALXN1210-aHUS-311 phase III clinical trial (NCT02949128, registered October 25, 2016).