Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series

Abstract

Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity. Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity. Onasemnogene abeparvovec (Zolgensma) is an adeno-associated virus vector-based survival motor neuron 1 gene (SMN1) therapy, approved in the US, Europe, Japan, Brazil, Israel, and Canada for the treatment of children with spinal muscular atrophy (SMA). This therapy helps patients with SMA produce adequate SMN protein. It is a one-time intravenous infusion, administered concomitantly with corticosteroid (followed by subsequent taper) to ameliorate CD8+ T-cell–mediated immunity against adeno-associated virus capsids in host liver cells. The most common adverse reactions associated with onasemnogene abeparvovec reported in clinical trials were elevated aminotransferases and vomiting.1Zolgensma (onasemnogene abeparvovec) prescribing information, 2019.www.fda.gov/media/126109/downloadDate accessed: August 25, 2020Google Scholar Warnings and precautions listed in the US prescribing information are acute serious liver injury, elevated aminotransferases, thrombocytopenia, and elevated troponin-I.1Zolgensma (onasemnogene abeparvovec) prescribing information, 2019.www.fda.gov/media/126109/downloadDate accessed: August 25, 2020Google Scholar Acute liver injury can occur, and serial monitoring of liver function, platelets, and troponin-I concentrations are recommended. Thrombotic microangiopathy (TMA) is characterized by arteriole and capillary endothelial pathology and microvascular thrombosis. TMA presents clinically as a syndrome of hemolytic anemia, thrombocytopenia, and acute kidney injury. TMA is rare, occurring in 1.0-3.3 cases/million/year,2Joly B.S. Zheng X.L. Veyradier A. Understanding thrombotic microangiopathies in children.Intensive Care Med. 2018; 44: 1536-1538Crossref PubMed Scopus (4) Google Scholar,3Dixon B.P. Gruppo R.A. Atypical hemolytic uremic syndrome.Pediatr Clin North Am. 2018; 65: 509-525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar and can result from either genetic or acquired etiologies, such as exposure to toxins or infections and adverse drug reactions,4Al-Nouri Z.L. Reese J.A. Terrell D.R. Vesely S.K. George J.N. Drug-induced thrombotic microangiopathy: a systematic review of published reports.Blood. 2015; 125: 616-618Crossref PubMed Scopus (167) Google Scholar resulting in dysregulation of the alternative pathway of complement. Some features of TMA overlap with thrombotic thrombocytopenic purpura. However, activation of the alternate complement pathway and resultant acute kidney injury differentiates TMA from thrombotic thrombocytopenic purpura. Drug-induced TMA has been reported in association with many pharmaceutical products, including vaccines, immunosuppressive agents, and antibiotics, as well as nonprescription substances, such as herbal or alternative therapies.4Al-Nouri Z.L. Reese J.A. Terrell D.R. Vesely S.K. George J.N. Drug-induced thrombotic microangiopathy: a systematic review of published reports.Blood. 2015; 125: 616-618Crossref PubMed Scopus (167) Google Scholar Although the actual mechanisms of TMA can vary, some reports have suggested etiologies that include direct toxic effects (sometimes dose- and duration-dependent) as well as immune-mediated reactions.4Al-Nouri Z.L. Reese J.A. Terrell D.R. Vesely S.K. George J.N. Drug-induced thrombotic microangiopathy: a systematic review of published reports.Blood. 2015; 125: 616-618Crossref PubMed Scopus (167) Google Scholar Neurologic, cardiovascular, and respiratory complications may occur. Treatment of TMA includes withdrawal of the trigger agent, when possible, and supportive care. Refractory or progressive cases also may require plasmapheresis, dialysis, or anticomplement monoclonal antibody therapy, such as eculizumab.5Kaplan B.S. Ruebner R.L. Spinale J.M. Copelovitch L. Current treatment of atypical hemolytic uremic syndrome.Intractable Rare Dis Res. 2014; 3: 34-45Crossref PubMed Google Scholar We report 3 children with new adverse reactions of TMA following onasemnogene abeparvovec infusion and discuss potential etiologies, with the aim to increase awareness to optimize early recognition and treatment of TMA in these children. Using data from the Novartis Global Safety Database, we conducted a search of all cases who were administered onasemnogene abeparvovec for SMA through July 1, 2020, using the search terms “haemolytic uraemic syndrome,” “microangiopathic haemolytic anaemia,” “thrombotic microangiopathy,” “thrombotic thrombocytopenic purpura,” “microangiopathy,” “acute kidney injury,” and “haemolytic anaemia” to identify any cases of TMA reported. This database includes safety information from the clinical trials, managed access programs, and postmarketing (commercial) settings. Three cases were identified and the corresponding child neurologist and pediatric nephrologist from each center were contacted to provide complementary data from the patient's medical record in a deidentified manner. All 3 children received prednisolone 1 day prior to and for a minimum of 30 days following treatment with 1.1 × 1014 vg/kg of onasemnogene abeparvovec (Table).TableOverview of thrombotic microangiopathy reports for SMA patients treated with onasemnogene abeparvovecVariablesCase 1Case 2Case 3CountryUSAustraliaUSSource of reportRESTOREMAPRESTOREDemographics5 mo, female12 mo, female14 mo, femalePatient weight at dosing6.5 kg12.1 kg8.7 kgTime to onset and first symptom following onasemnogene abeparvovec7 d; hypertension, decreased urine output8 d; vomiting, reduced oral intake and urine output7 d; vomiting, dehydrationNusinersen (most recent dose)NoYes (1 mo previously)Yes (4 mo previously)Laboratory evidence of TMA (baseline and following onasemnogene abeparvovec)HemoglobinBaseline: 10.3 g/dLNadir: 7 g/dL (day 7)Baseline: 11.4 g/dLNadir: 9.6 g/dL (day 10)Baseline: 12.5 g/dLNadir: 6.1 g/dL (day 13)PlateletBaseline: 503 k/μLNadir: 17 k/μLBaseline: 378 k/μLNadir: 11 k/μLBaseline: 506 k/μLNadir: 17 k/μLCreatinineBaseline: 0.1 mg/dLPeak: 0.7 mg/dLBaseline 0.28mg/dLPeak: 0.93 mg/dLBaseline: 0.1 mg/dLPeak: 0.3 mg/dLLDHPeak: 4208 U/LPeak: 2902 U/LPeak: 1677 ULUrinalysisProtein and bloodProtein and bloodProtein and bloodPT, PTT, and INRNormalNormalNormalVaccines within 1 mo of onasemnogene abeparvovecYes (influenza, Prevnar, and Haemophilus influenzae type B, given 6 days after therapyYes (10 days previously)NoConcurrent infectionsAspiration pneumonia 4 d before dosing; (Acinetobacter baumannii and Pasteurella)Second event of pneumonia 3 d after dosingNoUrinary tract infection 3 d after presentation (Escherichia coli)Acute complement pathway investigations (classic/alternative) at presentation of TMAComplement (C3)1.1 g/L (ref 0.9-1.8)Complement (C4)0.07 (ref 0.15-0.57)Bb fragment concentration3.8 mg/L (ref <2.2)Soluble C5b-90.9 mg/L (ref <0.3)CH50160 U eq/mL (ref >70)FH autoantibody <50 AU (ref <200 AU)Factor B32.3 mg/dL (ref 22-50)Factor H369 mg/L (ref 180-420)Factor I34 mg/L (ref 16-40)Complement (C3)0.62 g/L (ref 0.72-1.64)Complement (C4)0.05 g/L (ref 0.14-0.42)Complement (C3)57.8 mg/dL (ref 90-180)Complement (C4)0.13 g/L (ref 0.15-0.57),Bb fragment concentration2.8 mg/L (ref <2.2)Soluble C5b-90.95 mg/L (ref <0.3)CH50eq 134 U Eq/mL (ref >70)Alternative pathway functional assay 62% (ref 50%–130%)Hemolytic assay 0.6% (ref <3%)FH autoantibody <50 AU (ref <200)Factor B 30.7 mg/dL (22-50)Factor H 330 mg/L (ref 180-420)Factor I 35.5 mg/L (ref 18-44)TreatmentsPRBC and platelet transfusions, glucocorticoids, plasmapheresis, diuretic for fluid overload, antihypertensivesIV methylprednisolone, low-potassium diet, furosemide for fluid overload, antihypertensives, close clinical and laboratory monitoringPRBC transfusion, methylprednisolone followed by PO prednisolone, 25% albumin, furosemide, antihypertensives, eculizumab (single dose)Outcome (time from diagnosis)Recovered (2 wk) with persistent hypertensionRecovered (4 wk)Recovered (4 wk) with resolution of hypertension and nephrotic syndrome(3 mo)Investigations concerning potential predisposition factors (hereditary or acquired)Functional complement assay with low C4, and normal C3, CFH, I, neg CFHAb, CH50, high C3b-9 (SMAC)ADAMTS13 normalNo genetic testing completedStool and urine cultures negativeFunctional complement assays normal (C3, C4, CFH and I, neg anti-CFHAb, CD46)ADAMTS13 normalNo genetic testing completedStool and urine cultures negativeFunctional complement assay with low C3 and C4, and normal CFH, I, neg CFHAb, CH50ADAMTS13 normalACTN4 gene and Heterozygous missense variant p.G855R in FAT1 geneStool culture negative; urine culture + for E coliACTN4, alpha-actinin-4; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; CFHAb, anti-complement factor H autoantibody; FH, factor H; INR, international normalized ratio; IV, intravenous; LDH, lactate dehydrogenase; MAP, managed access program; PO, by mouth; PRBC, packed red blood cell; PT, prothrombin time; PTT, partial thromboplastin time; RESTORE, registry of patients with spinal muscular atrophy receiving disease-modifying therapies. Open table in a new tab ACTN4, alpha-actinin-4; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; CFHAb, anti-complement factor H autoantibody; FH, factor H; INR, international normalized ratio; IV, intravenous; LDH, lactate dehydrogenase; MAP, managed access program; PO, by mouth; PRBC, packed red blood cell; PT, prothrombin time; PTT, partial thromboplastin time; RESTORE, registry of patients with spinal muscular atrophy receiving disease-modifying therapies. A 5-month-old female patient was treated with onasemnogene abeparvovec while hospitalized and undergoing treatment for aspiration pneumonia. Four days before dosing, her sputum culture grew Proteus and Acinetobacter species. She had another episode of pneumonia 3 days after onasemnogene infusion. Seven days after onasemnogene infusion, she developed TMA with hemolytic anemia, hematuria, proteinuria, leukocytosis, thrombocytopenia, and severe hypertension. Renal ultrasound scan indicated diffuse increase in cortical echogenicity bilaterally. The features of TMA resolved within 2 weeks following plasmapheresis, except hypertension, which continues to persist 1 year later. Functional TMA panel indicated evidence of complement pathway activation with no autoantibodies or abnormal complement components. Genetic evaluation was not performed. A 12-month-old female patient was at her baseline with no active infections when she received onasemnogene abeparvovec. Six days following onasemnogene abeparvovec infusion, she developed twice-daily vomiting, although she tolerated oral corticosteroid dosing. Eight days postinfusion, she presented with reduced oral intake and urine output and was hypertensive. Laboratory tests showed hemolysis, thrombocytopenia, transaminitis, and acute kidney injury with microscopic hematuria and significant albuminuria. Renal ultrasound scan indicated increased echotexture and reduced corticomedullary differentiation. Echocardiogram indicated mild pericardial effusion. However, by day 12 after infusion, she began to improve with supportive care, and complete resolution occurred within 4 weeks. A 14-month-old female patient with a family history of chronic kidney disease of unknown etiology in 2 second-degree relatives received onasemnogene abeparvovec while in her usual state of health without active infection. She developed intermittent vomiting 1 day after infusion, which persisted, although she tolerated oral corticosteroid dosing with the use of ondansetron as needed. One week following onasemnogene abeparvovec infusion, she presented with dehydration, thrombocytopenia, hemolytic anemia, hypoalbuminemia, and acute kidney injury. Complement (C3) was depressed. Initial urinalysis revealed proteinuria, but urine culture was negative. The patient became febrile 3 days after initial presentation, and repeat urine culture at that time grew Escherichia coli ≥100 000 colonies/mL. Treatment included blood transfusion, eculizumab (single dose), increased corticosteroids (5 mg/kg/day intravenous methylprednisolone), and other supportive therapy. TMA resolved after 4 weeks and nephrotic-range proteinuria resolved 3 months after initial presentation, but hypertension persists. Genetic testing showed heterozygous variants of unknown significance in the actinin alpha-4 (ACTN4) and FAT atypical cadherin 1 genes. We have reported 3 children with SMA who developed TMA following onasemnogene abeparvovec therapy. These cases share several similarities. TMA developed approximately 1 week following onasemnogene abeparvovec infusion, 2 of the 3 children suffered from vomiting, 2 of the 3 had previous exposure to nusinersen, and 2 had infections with encapsulated organisms. Patient 1 had an infection preceding TMA with a new infection shortly after infusion, and patient 3 developed an infection shortly after infusion. All 3 children recovered from TMA. One recovered with supportive measures only. The other 2 resolved with additional therapies such as plasmapheresis, increased corticosteroids, and/or transfusions. TMA is a syndrome of microvascular hemolysis and kidney injury that results from various etiologies, including drug exposure. Several medications and herbal supplements have been associated with TMA, including quinine, cyclosporine, and tacrolimus.4Al-Nouri Z.L. Reese J.A. Terrell D.R. Vesely S.K. George J.N. Drug-induced thrombotic microangiopathy: a systematic review of published reports.Blood. 2015; 125: 616-618Crossref PubMed Scopus (167) Google Scholar Drug-induced TMA is theorized to result from immune-mediated reactions or a dose-/duration-dependent direct toxic effect. Differentiating criteria include early temporal association with drug administration in the former as opposed to a delayed onset from a cumulative exposure in the latter. Our 3 patients developed TMA approximately 1 week after administration, suggesting an immune-mediated etiology. Other causes and presentations of TMA include hemolytic uremic syndrome resulting from shiga toxin-positive E coli; thrombotic thrombocytopenic purpura resulting from a reduction of ADAMTS13, the protease that cleaves von Willebrand factor (vWF); hereditary deficiencies in regulation of coagulation or alternative complement pathways3Dixon B.P. Gruppo R.A. Atypical hemolytic uremic syndrome.Pediatr Clin North Am. 2018; 65: 509-525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar; and a wide variety of infectious pathogens, including encapsulated organisms.6Brocklebank V. Wood K.M. Kavanagh D. Thrombotic microangiopathy and the kidney.Clin J Am Soc Nephrol. 2018; 13: 300-317Crossref PubMed Scopus (101) Google Scholar In addition to exposure to onasemnogene abeparvovec, each of the 3 patients had contributory factors that could be putatively associated with TMA. Potential triggering factors include concurrent infection with encapsulated bacteria and recent vaccine exposure. It is unknown what additional risks to onasemnogene abeparvovec, if any, previous exposure to nusinersen confers. One patient had a gap of 4 months between the most recent nusinersen exposure and treatment with onasemnogene abeparvovec. Few studies have specifically addressed the safety of onasemnogene abeparvovec following exposure to nusinersen, and vice versa.7Harada Y. Rao V.K. Arya K. Kuntz N.L. DiDonato C.J. Napchan-Pomerantz G. et al.Combination molecular therapies for type 1 spinal muscular atrophy.Muscle Nerve. 2020; 62: 550-554Crossref PubMed Scopus (11) Google Scholar,8Waldrop M.A. Karingada C. Storey M.A. Powers B. Iammarino M.A. Miller N.F. et al.Gene therapy for spinal muscular atrophy: safety and early outcomes.Pediatrics. 2020; 146: e20200729Crossref PubMed Google Scholar Two of three children first developed vomiting, which may have been an early symptom of TMA and potentially resulted in inadequate prednisolone absorption. Two of the cases were associated with increased complement activation by the alternate pathway. One patient had received eculizumab, a humanized monoclonal antibody targeted against complement C5, without subsequent improvement in symptoms.5Kaplan B.S. Ruebner R.L. Spinale J.M. Copelovitch L. Current treatment of atypical hemolytic uremic syndrome.Intractable Rare Dis Res. 2014; 3: 34-45Crossref PubMed Google Scholar Whether children with SMA are at increased risk for TMA is unknown. Children with SMA have been reported to have coagulation abnormalities. Specifically, Wijngaarde et al reported data from 98 patients with SMA (types 1-4; median age of 7.4 years), revealing significant prolongation of both activated partial thromboplastin time and prothrombin time, as well as increased platelet counts.9Wijngaarde C.A. Huisman A. Wadman R.I. Cuppen I. Stam M. Heitink-Pollé K.M.J. et al.Abnormal coagulation parameters are a common non-neuromuscular feature in patients with spinal muscular atrophy.J Neurol Neurosurg Psychiatry. 2020; 91: 212-214Crossref PubMed Scopus (4) Google Scholar The vWF antigen and vWF activity were also significantly decreased, and this was related to disease severity. No other significant abnormalities in coagulation factors II, V, VII, VIII, or X were observed. Future studies are needed to elucidate the role of genetic complement-mediated predisposing factors and coagulation abnormalities in the pathogenesis of TMA in SMA. Nephrotic syndrome at presentation is not a classic feature of TMA. Patient 3, who had persistent nephrotic syndrome, did not have proteinuria or other signs of nephrotic syndrome during nusinersen treatment. She did, however, have a family history of chronic kidney disease and was found to have heterozygous ACTN4 and FAT1 variants of unknown significance. These variants are not clearly pathogenic, but ACTN4 mutations are associated with familial focal segmental glomerulosclerosis. Irrespective of contributory factors, these 3 case reports, from approximately 500 patients exposed, indicate a plausible association between onasemnogene abeparvovec with TMA based on their temporal association. Of note, TMA has been reported following treatment with other gene therapies using an adeno-associated vector, including cases in a Duchenne muscular dystrophy program.10Fierce BiotechNo respite for Solid Bio’s troubled Duchenne program as FDA keeps it on hold.www.fiercebiotech.com/biotech/no-respite-for-solid-bio-s-troubled-duchenne-program-as-fda-keeps-it-holdDate accessed: August 25, 2020Google Scholar These cases have been reported in a clinical trial of adeno-associated viral vector human gene therapy for Duchenne muscular dystrophy, but case details are not available to determine whether there are further similarities with our cases.10Fierce BiotechNo respite for Solid Bio’s troubled Duchenne program as FDA keeps it on hold.www.fiercebiotech.com/biotech/no-respite-for-solid-bio-s-troubled-duchenne-program-as-fda-keeps-it-holdDate accessed: August 25, 2020Google Scholar Because thrombocytopenia is a key feature of TMA, platelet counts should be monitored, as already recommended in the onasemnogene abeparvovec US prescribing information.1Zolgensma (onasemnogene abeparvovec) prescribing information, 2019.www.fda.gov/media/126109/downloadDate accessed: August 25, 2020Google Scholar If thrombocytopenia is present and there is a clinical suspicion of TMA, further evaluation including hemoglobin and testing for hemolysis and renal dysfunction (including urinalysis) also should be obtained. Early recognition of TMA is imperative, as TMA may require therapeutic intervention such as plasmapheresis, dialysis, or pharmacotherapy, to lessen associated morbidity and mortality. We thank Christina Fleming, PhD, a Novartis Gene Therapies contract employee, and Michael Nissen, ELS, Novartis Gene Therapies, for medical writing and editing support.

Topics & Concepts