Compassionate Use Narsoplimab for Severe, Refractory Transplant Associated Thrombotic Microangiopathy in Children.

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA directed therapy with eculizumab, a C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to complement C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the effector enzyme of the lectin pathway, MASP-2, has been studied in adults with TA-TMA as first line therapy with a response rate of 61%. While there are limited data of narsoplimab use as a second line agent in children, we hypothesized, that proximal complement pathway proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children.

METHODS: In this single center study, children were enrolled on single-patient, IRB approved compassionate use protocols for narsoplimab treatment. Clinical complement labs were obtained at the discretion of the treating physician, though all patients were also offered participation in a companion biomarker study. Research blood was sampled at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first dose of narsoplimab. Single ELISA kits were used to measure markers of complement activation per manufacturing instructions.

RESULTS: Five children with rTA-TMA received narsoplimab; 3 were in multi-organ failure and 2 had worsening multi-organ dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS, n=3), viral infections (n=3), and steroid refractory stage 4 lower gut, overall grade 4 acute graft versus host disease (GVHD, n=3). Two infants with concurrent SOS and no acute GVHD had resolution of organ dysfunction; 1 also developed transfusion independence (complete response) and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence, but had no improvement in organ manifestations (partial response), and two patients treated late in the disease course had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to give additional research blood. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with a subsequent decline in Ba, Bb, C3a, and C5a and increase in C3 in both clinical and research lab testing. Otherwise, there was not a clear pattern of other complement markers including MASP-2 levels after therapy.

DISCUSSION: In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefitted from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid refractory acute GVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful to monitor lectin pathway activation and inhibition.