Khaled was joined by a panel of adult and pediatric hematology-oncology experts who provided an overview of TA-TMA, including findings that raise suspicion of this complication, strategies they use for making the diagnosis, and how they intervene given limited treatment options. They also discussed some off-label treatments and the emerging treatment narsoplimab (OMS721), a human monoclonal antibody that is under review by the FDA.
TA-TMA is triggered by injury to endothelial cells, such as from radiation, use of calcineurin or mTOR inhibitors, infections, or chemotherapy. However, this first hit to the endothelial cells is not considered sufficient to cause TMA. A second hit is needed, which the panelists explained is activation of the complement system, a part of the immune system made up of many distinct plasma proteins that react with one another in a cascade to destroy pathogens and fight infection. The same factors that damage endothelial cells also activate the complement system, the panelists noted.
Injured endothelium exposes certain molecules, known as DAMPs [damage-associated molecular patterns], which bind a molecule known as MBL, mannan-binding lectin. MBL then activates MASP-2 [mannan-binding lectin-associated serine protease-2], which is an important enzyme in the cascade of a part of a complement system known as the lectin pathway. When activated, the lectin pathway itself can also then turn on the alternative path-way of complement. It is always on at very low levels waiting for a foreign invader or endothelial cell injury. Now you have marked activation of the lectin pathway and the complement pathway and the alternative pathway of complement in this system. If you cant shut it off and its progressive, that can lead to 1 of these TA-TMAs, Jeffrey Conrad Laurence, MD, explained.
The panelists said that there are some key differences with TA-TMA in pediatric vs adult patients. One distinction is that they are seen almost exclusively with allogeneic transplants in adults, whereas they occur with both autologous and allogeneic transplants in children. Only Khaled reported seeing a few cases in adults undergoing autologous transplants. At City of Hope we had a protocol for an autologous transplant for scleroderma, and I saw a couple of cases on that protocol, he said, noting that he has also seen 1 or 2 cases over the last 12 years in patients who received autologous transplants for myeloma.
Another key distinction is that TA-TMA in pediatric patients appears to have a genetic component, whereas in adults no gene polymorphisms appear to contribute to the condition. [In a study by Jodele et al1], upward of 30% to 40% of her pediatric patients who developed TMA had some recognized mutation in a complement coagulation or complement-regulatory factor gene. Whereas in our studies at Weill Cornell Medicine, we never found that. In many other series in adults, its incredibly rare to find those kinds of genetic mutations. There may be something special about that [pediatric] population with higher underlying inability to control complement that makes the incidence much greater, Laurence said.
Determining the incidence of TA-TMAs is challenging because diagnostic criteria did not exist until relatively recently and those now available also vary somewhat. In fact, it depends on whether you really want injury to happen and then make a diagnosis, or do you want early diagnosis. The more stringent the criteria you apply, the less the incidence will seem, Parameswaran Hari, MD, MRCP, said. Nevertheless, based on his experience, he suspects the incidence in adult patients to be in the 10% range for TA-TMAs that are of clinical consequence following a first allogeneic transplant. He noted that the incidence increases with a second transplant, reaching 15% to 20%.
In pediatric patients, the panelists noted the incidence is higher than in adults, ranging between 20% and 30%. When I think about the difference between the adult and pediatric populations and the incidence, one of the questions that comes to mind is: Is it a difference in the patients, is it a difference in the treatment, or is it a difference in the providers? Christine N. Duncan, MD, said. She explained its probably a combination of these factors, but that one of the main contributors is likely the screening criteria that were developed for children, which have helped raise awareness of the disease in the pediatric setting.
A variety of diagnostic criteria for TA-TMA now exist, including those by the LeukemiaNet International Working Group, Blood and Marrow Transplant Clinical Trials Network, and the Jodele criteria, among others.2-4 In pediatric patients, Duncan said there is relatively uniform acceptance of the Jodele criteria (Table4). Were looking if you can meet 4 of the 7 criteria...but we dont necessarily always say you have to meet all those points. If we have someone who has hypertension and proteinuria, were not going to wait and check everything else off to make sure they absolutely fulfill the criteria, Duncan said.
Table. Laboratory and Clinical Markers Indicating TMA per Jodele Criteria4
The other available diagnostic criteria look at many of the same measures, with some also examining additional markers, such as the direct Coombs test, which should be negative in the setting of TA-TMA; coagulation studies, which should be normal; haptoglobin levels, which may be decreased; and creatinine levels, which may point to TA-TMA when elevated to twice the baseline level.2,3 The panelists proceeded to discuss the clinical and laboratory markers that they pay particular attention to. Hari said lactate dehydrogenase (LDH) level is a big marker at his institution, which implemented a policy to check patients LDH levels twice weekly while they are in the hospital following transplantation. He said this measure has helped them identify more TA-TMA cases. On the pediatric side, Duncan said they also test LDH levels in all patients once or twice weekly. You dont even have to think about it much if that is part of your routine on an inpatient, and if you see that with your lab values, that helps to trigger [a diagnosis], she said. Duncan said another red flag in the pediatric setting is hypertension since this population rarely has it as a preexisting condition, though some degree of blood pressure elevation is expected from use of calcineurin inhibitors, steroids, and other agents.
Although ADAMTS13 activity is not part of any diagnostic criteria for TA-TMA, Laurence and Hari said they perform this test on all their transplant patients to help rule out thrombotic thrombocytopenic purpura (TTP). Making the distinction is important because patients with TTP can benefit from plasma exchange, whereas those with TA-TMA do not. I noticed that in 3 large transplant studies5 the aggregate hematologic response to plasma exchange in a TA-TMA was 55%; that included a decrease or normalization of the LDH, increase in haptoglobin, and increase in platelet count. That 55% response rate to plasma exchange had no impact on mortality...the patients died with normal numbers, Laurence said. He added that he no longer performs therapeutic plasma exchange for his TA-TMA patients.
One of the key treatment strategies for TA-TMA is to stop any offending agents, including any calcineurin or mTOR inhibitors. We recommend substituting higher doses of steroids and CellCept [mycophenolate mofetil], Laurence said. He explained another important measure is to look for and treat any underlying or coexisting conditions, such as infections, graft-vs-host disease (GVHD), or hypertension. The literature suggests these measures may be sufficient to resolve 50% to 60% of TA-TMA cases.6 The remainder require consideration of a variety of off-label or experimental agents, Laurence said, particularly agents that target the complement system, such as eculizumab (Soliris), defibrotide (Defitelio), or narsoplimab, since there are currently no approved treatments for TA-TMA and resolution of TA-TMA is imperative for improving overall survival (OS).
Eculizumab is a monoclonal antibody that inhibits complement protein C5.7 It is approved by the FDA for the treatment of atypical hemolytic uremic syndrome (aHUS), another complement-mediated disease. [In TA-TMA,] its probably more used in pediatric population than in the adult population, Khaled said.
Thus far, eculizumab has been studied in a small clinical trial of 64 pediatric patients with high-risk TA-TMA and multiorgan injury.8 One year after hematopoietic stem cell transplantation (HSCT), the survival was 66% in the eculizumab-treated group. This was a significant improvement from the 16.7% survival rate observed in a previously reported untreated cohort that had the same high-risk TMA features. Patients with a higher sC5b-9 level at the start of eculizumab therapy were found to be less likely to respond to treatment and to require more drug doses.8
We use [eculizumab] quite frequently. If [a patient has received a diagnosis] of TA-TMA and has any degree of significance or injury to them, theres always a conversation, Duncan said. She noted that there are several key challenges with the use of eculizumab, including a lack of consensus on how long patients need to be treated, uncertainly regarding optimal dosing (eg, when to go up, how to space), and challenges receiving authorization for this drug in the outpatient setting. Additionally, its use requires prophylactic immunization and antibiotics against a variety of infectious organisms, including Neisseria meningitidis and N gonorrhea in adults, as well as a variety of encapsulated organisms in pediatric patients.7
Defibrotide was approved by the FDA for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD) with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation in 2016,9 but Hari said this drug has been used for decades in Europe. While its precise mechanism of action remains unknown, he said its an anti-inflammatory agent [that] can be thought of as an endothelial stabilizing agent.
Defibrotide has shown some promise in treating TA-TMA. There is definitely a subgroup of people who respond to itnot as promising as a dedicated mannose-binding lectin pathway inhibitor, perhaps, but I think that 1 hit of the endothelium might be able to be helped by this agent, Hari said. However, a challenge is its bleeding risk, which is especially problematic in a patient population that is already at high risk of hemorrhage. Cost is another issue. We dont use too much of [it], unless we have some evidence of liver damage, because of the payment issues, at least in this country, Hari said.
Narsoplimab is an inhibitor of MASP-2, which is the effector enzyme of the lectin pathway of the complement system.10 The FDA has granted this agent breakthrough therapy designation for high-risk HSCT-TMA and orphan drug designation for the prevention of complement-mediated TMAs and for the treatment of HSCT-TMA.10 The drugs manufacturer, Omeros Corporation, has submitted a biologics license application to the FDA for narsoplimab as a treatment of HSCT-TMA, and the FDA has extended its review period, setting a new action date of October 17, 2021.11
Narsoplimab has shown benefit in a small, single-arm, open-label pivotal trial that included 28 adult patients (median age, 48 years) with HSCT-TMA and high comorbidity burden.12,13 Protocol-specified treatment was IV narsoplimab 4 mg/kg or 370 mg once weekly for 4 or 8 weeks, with a 6-week follow-up period. The primary end point was complete response (CR) rate, which required improvement in 2 categories: laboratory markers of TMA (ie, LDH, platelet count) and organ function (ie, kidney, pulmonary, gastrointestinal [GI], neurological).
The complete response rate was actually very appealing: It was 61% of all treated patients and 74% for the per-protocol set....Those are the patients who received 4 weeks or more on protocols, Khaled said. Among both cohorts, 72% of patients showed substantial improvement in organ function, with greater than 65% showing improvements in kidney function, 50% showing improvements in neurological function, and 100% showing improvement in GI function.13
When looking at the median OS, it was 274 days for all treated patients and 361 days for the per-protocol patients, with the median OS not reached in patients who had a CR.12 This is really compelling data for this molecule, Khaled said. The other panelists agreed. I think the availability of a pathophysiologically targeted agent addresses what really is at the bottom of the problem, Hari said.
What makes the data even more compelling is that narsoplimab appears to have a highly favorable safety profile. Unlike eculizumab, it does not require the use of prophylactic immunization or antibiotics and it was found to be well-tolerated, even in a population with a high comorbidity burden. The most common adverse effects (AEs) included pyrexia, diarrhea, vomiting, nausea, neutropenia, fatigue, and hypokalemia, all of which are common in the setting of HSCT.12 In total, 6 patients died during the core study period, with the causes of death being common in HSCT (eg, septic shock, GVHD, TMA).
In addition to narsoplimab, several other agents are in late-stage development, including ravulizumab, a long-acting C5 inhibitor engineered from eculizumab. It is currently being studied in 2 phase 3 trials, including 1 in pediatric patients (NCT04557735) and 1 in adolescent ( 12 years) and adult patients (NCT04543591).14,15 Another promising agent is nomacopan (Coversin), a bifunctional inhibitor of C5 and leukotriene B4 that is being studied in a phase 3 trial in pediatric patients aged 6 months to 18 years who develop TMA within 100 days of HSCT, which is the period when most TMAs requiring intervention occur.16
In his concluding remarks, Laurence encouraged health care providers to think about the pathophysiology of TA-TMA when caring for their HSCT patients. Dont just tread water doing things like plasma exchange or Rituxan [rituximab] unless theres a specific indication for an autoantibody present. Think about trials of these newer experimental agents, which look very promising, he said.
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