Rafael F. Duarte, MD, PhD, FRCP, presents 2 real-world clinical cases in which the investigational monoclonal antibody narsoplimab demonstrated clinical benefit in patients with hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
Rafael F. Duarte, MD, PhD, FRCP
During the 2020 European Society for Blood and Marrow Transplantation Annual Meeting, Rafael F. Duarte, MD, PhD, FRCP, of the Hospital Universitario Puerta de Hierro Majadahonda in Madrid, Spain, presented 2 real-world clinical cases in which the investigational monoclonal antibody narsoplimab (OMS721) demonstrated clinical benefit in patients with hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA).
“Because the selection of patients for clinical trials has limitations, and more so, because running a trial is a hard endeavor for this difficult complication, [I wanted to share] some hands-on experience that we have had with narsoplimab outside of the trial with some case studies of patients who have been treated in a compassionate-use basis,” said Duarte.
First, Duarte shared a case of a 19-year-old female who received narsoplimab following matched-sibling allogeneic HSCT to treat her B-cell acute lymphoblastic leukemia (B-ALL) in first complete remission.
At 5 months, the patient experienced late-onset acute graft-versus-host disease (GVHD) and severe HSCT-TMA with lower gastrointestinal (GI) bleeding and ischemic ulcers. While skin involvement of GVHD resolved, she received initial treatment with 1 dose of eculizumab (Soliris) due to persistent GI symptoms after steroids, mesenchymal stromal cells, and extracorporeal photopheresis. Additionally, she received 4 mg/kg of narsoplimab once or twice weekly for a total of 18 doses.
“We asked for narsoplimab purely on the basis that this was a severely immunocompromised patient who had experienced complications before and who had been receiving a lot of immunosuppression for the treatment of GVHD,” said Duarte. “We tried to minimize immunosuppression, so we thought narsoplimab would be a good option.”
According to Duarte, the patient’s GI bleeding and microangiopathy hemolytic anemia resolved quickly and dramatically after starting narsoplimab. Additionally, she became transfusion independent with platelet counts above 100 x 109 per liter.
At 21 months, the patient remains in complete remission (CR) of B-ALL and is devoid of signs of HSCT-TMA after discontinuing narsoplimab.
Subsequently, Duarte presented another, more complex case of a 48-year-old male with HIV and Hodgkin lymphoma who was in his third CR.
Following CCR5-∆32/∆32 HSCT, the patient experienced very early HSCT-TMA on day 0. Subsequently, he had rapid severe renal failure that required hemodialysis.
Initial treatment with calcineurin inhibitor withdrawal did not elicit any response, so he was started on narsoplimab at 4 mg/kg twice weekly on day 6. He received a total of 8 doses of narsoplimab.
The patient’s lactate dehydrogenase (LDH), bilirubin, and schistocyte counts improved rapidly following narsoplimab initiation. Additionally, the patient derived partial improvement of renal function and fluid management, although he required continued dialysis.
Despite this, at 31 days post-transplant, the patient had multiple secondary complications as a result of the CCR5-∆32/∆32 HSCT and experienced sudden death. The death was not thought to be related to TMA and no autopsy was granted.
“We don’t have a better explanation regarding what happened with this patient, unfortunately,” Duarte explained. “We think we are seeing that many of the patients who undergo transplant with this mutated CCR5-∆32/∆32 tend to have greater mortality and greater complications than HIV-positive patients who undergo transplant with standard [procedure].”
Duarte also presented findings from the pivotal, phase 2 trial, in which narsoplimab demonstrated high rates of CRs, as well as improved laboratory and clinical markers among patients with HSCT-TMA.
Narsoplimab was previously granted a breakthrough therapy designation by the FDA for the treatment of patients with high-risk TA-TMA. In addition, the agent was granted an orphan drug designation for TA-TMA therapy and complement-mediated TMA prevention.
Findings from the single-arm, open-label phase 2 trial demonstrated a 54% CR rate in all treated patients (n = 28) with the mannan-binding lectin-associated serine protease-2 inhibitor (95% CI, 34%-72%). Additionally, patients treated per protocol recommendations (n = 23), which entailed 4 weeks or more of dosing, achieved a CR rate of 65% (95% CI, 43%-84%).
At 100 days following HSCT-TMA diagnosis, 68% of all treated patients, 83% of patients treated per protocol, and 93% of treatment responders (n = 15) were alive.
Eligible patients had to be 18 years of older at screening, which occurred during the patient’s first visit. Additionally, patients had to have persistent HSCT-TMA as defined by a platelet count less than 150,000 per µL, evidence of microangiopathy hemolysis such as the presence of schistocytes, serum LDH greater than upper limit of normal, or haptoglobin less than the lower limit of normal, and renal dysfunction defined as doubling of serum creatinine compared with pre-transplant level. All of the following had to be present for at least 2 weeks following modification or discontinuation of calcineurin inhibitors.
Patients who had eculizumab therapy within 3 months of screening, positive direct Coombs test, or active systemic bacteria or fungal infection that required antimicrobial therapy beyond prophylactic antimicrobial therapy as a standard of care were excluded from the study.
Response-based efficacy requiring improvement in TMA laboratory markers of platelet count and LDH and improvement in clinical status, as well as safety, served as the primary end points of the trial. Secondary end points included survival and change from baseline laboratory markers.
Regarding laboratory markers, LDH had to be less than 1.5 µL. For patients who had a baseline platelet count of 20,000/µL, improvement was defined as a tripling of baseline platelet count more than 30,000 and freedom from platelet transfusion. For patients with a baseline platelet count of more than 20,000, improvement was defined as an increased count of least 50% and absolute count of more than 75,000, as well as freedom from platelet transfusion.
Clinical improvement was based off any of the following improvements in specific organ function. Patients could derive blood improvement defined as transfusion freedom; renal improvement defined as a reduction of creatinine of more than 40%, normalization of creatinine and more than 20% reduction of creatinine, or discontinuation of renal replacement therapy; pulmonary improvement defined as extubation and discontinuation of ventilator support, or discontinuation of non-invasive mechanical ventilation; gastrointestinal improvement defined as improvement assessed by MAGIC (Mount Sinai GVHD International Consortium) criteria; or neurological improvement defined as limited to stroke, posterior reversible encephalopathy syndrome, seizures, and weakness.
Eligible patients had an average age of 48, and 71% were male. Moreover, 96% of patients had malignant underlying disease. Regarding risk factors, 64% had GVHD, 75% had significant infection, 14% had non-infectious pulmonary complications, such as idiopathy pneumonia syndrome or diffuse alveolar hemorrhage, and 50% had neurological signs.
Moreover, the study population was defined as high risk as 93% of patients had multiple risk factors associated with poor outcome.
Regarding safety, any-grade toxicities were observed in 92.9% of patients treated with narsoplimab. The most common adverse effects (AEs) included nausea, vomiting, diarrhea, hypokalemia, neutropenia, and fever.
Additionally, 21% of patients died while on study; however, all deaths were attributed to common complications of HSCT.
Investigators concluded that similar AEs are associated with patients who undergo transplant and that narsoplimab was generally well tolerated.
“These are very highly encouraging results with narsoplimab in patients with very severe TMA who are unresponsive to other treatments. These results suggest that narsoplimab may be of benefit in these severely ill, complex patients with TMA, including those in the most complex clinical scenarios,” Duarte concluded.
Duarte R. MASP-2 inhibition with the investigational agent narsoplimab for the treatment of HSCT-TMA: overview of data and case discussion. Presented at: 2020 European Society for Blood and Marrow Transplantation Annual Meeting; August 30-September 2, 2020; Virtual. Session IS28-4.