Narsoplimab for severe transplant-associated thrombotic microangiopathy

A 6-year-old female child was diagnosed with acquired aplastic anemia in December 2019. Cytogenetic studies showed 46XX karyotype, chromosomal breakage study was normal, paroxysmal nocturnal hemoglobinuria clone was absent and clinical exome did not show any genetic mutation for inherited bone marrow failure syndrome. She did not have any significant infection during the pre-transplant course, except for the SARS-CoV-2 infection in June 2020. As she had no matched sibling or matched unrelated donor, she received a haploidentical stem cell transplant in July 2020.

The conditioning regimen was Rabbit ATG from Day-9 to Day-7 (0.5 mg/kg for 1 day and 2 mg/kg for 2 days), Fludarabine 40 mg/m2 for 4 days (Day-6 to Day-3), Cyclophosphamide 14.5 mg/kg for 2 days (Day − 6 and Day-5) and single fraction TBI (400 cGy) on Day − 1. On the day of transplantation, she received a peripheral blood stem cell graft from the father with 10 million CD34+ cells/kg and 2.41 × 108 CD3+ T cells/kg. Post-transplant Cyclophosphamide (50 mg/kg) was given on Day+ 3 and Day+ 4 followed by Ciclosporin and Mycophenolate mofetil on Day+ 5 as graft-versus-host disease (GvHD) prophylaxis.

On Day+ 9, she developed high-grade fever with the onset of engraftment. Her ferritin was raised at 65000 ng/mL and her bone marrow had haemophagocytosis. Blood cultures were negative. On day+ 13, a diagnosis of Candida tropicalis-driven macrophage activation syndrome was established on blood PCR and radio imaging of the abdomen. She was treated with antifungals (caspofungin and posaconazole), intravenous immunoglobulin (1 g/kg for 5 days), and intravenous Methylprednisolone (2 mg/kg). She continued to have high-grade fever and ferritin peaked at 190,000 ng/ml on Day+ 13. Hence, one dose of intravenous Alemtuzumab (0.1 mg/kg) was administered following which her fever subsided.

The patient developed hypertension from Day+ 13 requiring three antihypertensive medications. On Day+ 14, she had loose motions with abdominal pain. Abdominal pain persisted with frequent loose motions and significant hematochezia. An ultrasound scan of the abdomen was suggestive of pan-colitis. Oral Budesonide was started for possible gut GvHD, and intravenous Methylprednisolone was continued considering the possibility of stage 4 gut GvHD. The patient had neutrophil engraftment on day+ 16 and the neutrophils continued to increase. However, hemoglobin and platelet count gradually decreased. TA-TMA was suspected because of anemia, thrombocytopenia, hypertension, gastrointestinal bleeding, decreased serum albumin, and raised lactate dehydrogenase. On Day+ 20, the blood smear showed 1 fragmented RBC per high power field, and on Day+ 37 fragmented RBCs peaked at 5 per high power field. Urine protein:creatinine ratio was 0.47 on Day+ 20, and the ratio peaked at 2.88 on Day+ 34. Serum haptoglobin level was very low (< 5 mg/dl), but the direct antiglobulin test was negative. Soluble C5b-9 assay is not available nationally and hence was not performed. ADAMTS-13 activity was normal. Based on the Overall-TMA criteria the diagnosis of TA-TMA was confirmed.

Ciclosporin was discontinued, and the patient was given Inj Defibrotide from Day+ 21. There was no evidence of pathogenic variation in TMA-associated genes on clinical exome. She continued to have laboratory and clinical parameters of TMA after 10 days of treatment with Defibrotide. Eculizumab, a terminal complement inhibitor was considered. Eculizumab is exorbitantly expensive and hence it was not possible to treat with Eculizumab. Narsoplimab was available through an expanded access program for compassionate use. Narsoplimab was therefore accessed and commenced at a dose of 4 mg/kg twice a week on Day+ 30.

The patient’s stool pattern changed from frequent small-volume stools to large-volume stools with ongoing hematochezia. Severe colitis with inflammatory thickening measuring 5.5 mm extending up to the caecum and base of the appendix was seen on an ultrasound scan. Since gut GvHD and TA-TMA are known to coexist, she was also started on a TNF-α inhibitor (Etanercept). She developed pneumatosis coli after two doses of Etanercept on Day+ 40 and Day+ 43, and hence Etanercept was stopped. She continued to have significant intestinal bleeding requiring 86 mls/kg of packed red cell transfusion for 7 days. Intestinal mucosa appeared friable on a serial ultrasound scan with a risk of perforation. Therefore, endoscopic biopsies were not attempted, and monitoring of intestines was done with serial ultrasonography.

Narsoplimab was increased from twice a week to thrice a week on Day+ 45 because of significant intestinal bleeding. Her lactate dehydrogenase improved dramatically after starting Narsoplimab and her haptoglobin normalized on Day+ 48 (Fig. 1a). Her hypertension improved and her antihypertensive requirement was reduced to a single antihypertensive medication from Day+ 59 (Fig. 1a). Her intestinal bleeding reduced from Day+ 50 and completely stopped on Day+ 82. Inj Methyprednisolone was gradually tapered from Day+ 72 and stopped on Day+ 92 because of improvement in gut symptoms. There were no schistocytes in the peripheral blood smear after Day+ 70. The patient received the last packed cell transfusion on Day+ 70 and the last platelet transfusion on Day+ 77 (Fig. 1c). Narsoplimab was reduced to twice a week regimen on Day+ 109, a once-a-week regimen on Day+ 133, and stopped on Day+ 195 (Fig. 1a).

Fig. 1figure 1

a Time course of clinical and laboratory markers of transplant-associated thrombotic microangiopathy is shown. Lactate dehydrogenase (LDH), haptoglobin, urine protein:creatinine ratio, schistocytes/hpf are plotted and events such as diarrhea, radiological colitis, and the number of anti-hypertensive medications and treatment of thrombotic microangiopathy with defibrotide and narsoplimab are shown. LDH is shown on the left y-axis and haptoglobin, urine protein:creatinine ratio, and schistocytes are shown on the right y-axis. b Lactate dehydrogenase (LDH) pre-narsoplimab and on treatment with narsoplimab are shown. A statistically significant difference in the LDH levels was observed on the unpaired t-test (p < 0.0001). c Hemoglobin and platelet trends during the early episode of TA-TMA are shown. The patient was red cell-dependent and platelet-dependent until day+ 70 and day+ 77 respectively. Abbreviations: ANC – absolute neutrophil count, LDH – lactate dehydrogenase, Hb – Hemoglobin, tww – twice a week, thw – thrice a week, onw – once a week, vol – volume

During this period, the patient had CMV reactivation on Day+ 59 with CMV copy numbers of 16,500/ml. She received Inj Foscarnet for 2 weeks, and CMV viremia resolved on Day+ 73. She had a herpes zoster skin infection on Day+ 111, which resolved with Acyclovir.

The patient developed liver GvHD from Day+ 217. Therefore, Tacrolimus was started from Day+ 217, and Ruxolitinib was added from Day+ 237. She had severe reticulocytopenia secondary to parvovirus infection on Day+ 246. Parvovirus infection was managed with immunoglobulin infusion. Concurrent with parvoviremia, she developed a second episode of TA-TMA manifested by circulating schistocytes, anemia, thrombocytopenia, low albumin, and an increase in lactate dehydrogenase and creatinine (Fig. 2). Urine protein:creatinine ratio increased to 0.89. Hence, Tacrolimus was stopped, steroids were started, and Ruxolitinib was continued. She was started on Narsoplimab from Day+ 254, initially twice a week for 3 weeks. Narsoplimab was escalated to thrice a week from Day+ 274 because of persistent TA-TMA, and then tapered to twice weekly from Day+ 290 and stopped on Day+ 357.

Fig. 2figure 2

Second episode of TMA occurred concurrently with parvoviremia. Six parameters are shown: albumin, creatinine, LDH, hemoglobin, platelets, and reticulocyte percent. Some of these parameters, especially haematological ones, are affected in parvoviremia and TMA. However, albumin, creatinine, and LDH are primarily affected in TMA. Normalization of albumin, creatinine, and LDH marked the resolution of TMA

Liver GvHD resolved with steroids and Ruxolitinib. The patient is alive and well and had no features of TA-TMA on the last follow-up of D + 650.

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