New Rules of the Road in TTP Management

In July 2020, the International Society on Thrombosis and Haemostasis (ISTH) issued its first-ever guidelines for the treatment of thrombotic thrombocytopenic purpura (TTP), helping clinicians make sense of some new, and not-so-new, treatment options for this rare and potentially fatal syndrome.

While the guidelines may help clarify decisions about when and how to use the anti-CD20 monoclonal antibody rituximab in the treatment of patients with TTP, there is still plenty of debate on the appropriate role of the anti–von Willebrand factor (VWF) agent caplacizumab, which became the first drug approved for acquired TTP (aTTP) in February 2019.

“The jury is still out,” Iberia Romina Sosa, MD, PhD, Assistant Clinical Professor of Hematology at Fox Chase Cancer Center in Philadelphia, told ASH Clinical News. Dr. Sosa said she is waiting for more studies on caplacizumab before she will be convinced that it significantly lowers mortality in these patients.

The TTP Times Are Changing

For a disease that hasn’t had a major breakthrough since the identification of ADAMTS13 in 2001 or arguably the use of rituximab in the mid-2000s, the past 2 years have been tumultuous in the TTP world.1,2

The publication of the HERCULES study results in January 2019 put a spotlight on caplacizumab as a potentially game-changing treatment.3 Just 1 month later, it was approved by the FDA, in combination with plasma exchange and immunosuppressive therapy, for the treatment of aTTP.4 Then, in July 2020, the ISTH issued its first guidelines on TTP diagnosis and treatment, along with a set of Good Practice Statements that fills the gaps in the evidence-based guideline.5-7

Currently, a diagnosis of TTP is based typically on clinical presentation, although the use of plasma ADAMTS13 testing is increasing. Validated clinical scores, like the PLASMIC score and the French score, may also aid diagnosis and early management of patients with suspected TTP.

Treatment of acute episodes of aTTP routinely requires plasma exchange and routinely employs corticosteroids. Increasingly, rituximab has been used off-label in the management of TTP, either up front or at the time of exacerbation or relapse. Now, clinicians are also wrestling with whether – and when – to incorporate caplacizumab.

“Steroids and plasma exchange are a must,” said Adam Cuker, MD, a hematologist and Associate Professor of Medicine at the University of Pennsylvania. “I personally use rituximab for my patients who are presenting with acute TTP.”

ISTH Recommendations

In June 2018, the ISTH convened an international panel of experts, including hematologists, nephrologists, neurologists, transfusion medicine specialists, intensivists, and two patient representatives, to craft recommendations on the diagnosis and treatment of TTP. The panel tackled 12 clinical questions related to the management of aTTP and hereditary/congenital TTP (cTTP).

“[The guidelines] resolve certain controversies and provide guidance for how clinicians should approach TTP appropriately and in a timely manner,” said X. Long Zheng, MD, PhD, co-chair of the ISTH TTP Guideline panel and the Russell J. Eilers MD Endowed Professor and Chair of the Department of Pathology and Laboratory Medicine at the University of Kansas Medical Center.

The evidence-based guideline used GRADE methodology, with evidence quality that ranges from “very low” to “moderate” certainty. Notably, the guidelines do not compare treatment modalities because of a lack of high-quality evidence.

The small body of evidence represented one of the biggest challenges in creating these guidelines, Dr. Zheng said. Because TTP is a rare disorder, “much of the evidence is based on either retrospective or single-arm studies, and sample sizes are small,” he explained.

The target audience for these guidelines includes hematologists, clinical pathologists overseeing transfusion medicine, and intensivists. The panel has laid out a range of treatment scenarios, so the guidelines will be especially useful for clinicians who don’t treat TTP every day, commented Spero R. Cataland, MD, one of the guideline coauthors and a Professor of Internal Medicine in the Division of Hematology at The Ohio State University Wexner Medical Center.

“Preventing [TTP] exacerbations is important, but not the same as saving lives. How much are we willing to pay for preventing an exacerbation?”

Adam Cuker, MD

The panel issued four strong recommendations. The first is for adding corticosteroids to plasma exchange for a patient experiencing a first acute episode of immune-mediated TTP (iTTP) or a relapse. However, the panel was unable to make a more detailed recommendation on a preferred dosage or type of corticosteroid (e.g., prednisone or methylprednisolone).

“Given the known cardiac, endocrine, and neuropsychiatric adverse effects of corticosteroids, the panel feels that special attention to adverse effects should be paid to susceptible populations, including those with hypertension, diabetes, psychiatric comorbidities, and advanced age, etc.,” they wrote.

The panel also made a conditional recommendation for adding rituximab and caplacizumab in patients who experience acute first events and relapses of iTTP.

While data are limited, the panel noted that rituximab has “a beneficial effect in preventing disease relapse.” In addition, the risk of subsequent relapse may be higher in patients who have previously relapsed, adding to the argument for using rituximab in that group of patients.

The panel evaluated caplacizumab’s role in TTP management based on findings from the TITAN and HERCULES trials.8 Although these are randomized, controlled studies , they were still graded as providing only “moderate certainty” evidence. The panel noted that patients who received caplacizumab had a clinically and statistically significant reduction in the number of disease exacerbations (defined as disease recurrence during therapy or within 30 days of stopping plasma exchange). At the same time, there was a clinically and statistically significant increase in the number of relapses, defined as disease recurrence after 30 days at 12 months.

“This suggests that caplacizumab may stave off recurrence within 30 days of stopping plasma exchange but leave patients prone to experience later recurrence owing to the unresolved underlying ADAMTS13 deficiency and inhibitors,” the authors noted.

Due to the drug’s unique mechanism of action – blocking platelet-VWF interactions and preventing the formation of microvascular thrombi – the panel members suggested that caplacizumab be used early in disease course, preferably at the time of diagnosis. Practically, this could mean starting administration even before seeing the results of plasma ADAMTS13 testing.

Another factor in making the “conditional” recommendation was access to the medication. The list price for treating a typical acute TTP episode is $270,000 and its access is not uniform.9

“If you look at the issue without the financial consideration, there’s obviously a benefit,” Dr. Cataland said, adding that access varies around the world, and even hospital-by-hospital within the U.S. In its recommendation, the ISTH panel noted an urgent need for studies on caplacizumab’s cost-effectiveness.

In the case of asymptomatic iTTP with low ADAMTS13 activity, the panel issued a conditional recommendation for rituximab. However, for pregnant asymptomatic patients with iTTP, they conditionally called for prophylactic treatment. For asymptomatic patients with cTTP, the panel issued a strong recommendation for prophylactic plasma infusion during pregnancy; outside of pregnancy, they conditionally recommended either plasma infusion or a wait-and-watch approach.

One of the major take-home lessons of the guidelines is that “care doesn’t stop after the disease is in remission,” Dr. Cataland said. Clinicians must continue to monitor patients for the risk of relapse and treat accordingly.

It is also critical to put that treatment in the context of future life events, like pregnancy. “TTP is a lifetime, long-term disease,” he noted.

The Role of Old and New Therapies

In their recommendations, the guideline panel affirmed the role of off-label rituximab in TTP management, said Keith McCrae, MD, a staff physician and Director of Benign Hematology at Cleveland Clinic’s Taussig Cancer Center and Professor of Molecular Medicine at Cleveland Clinic Lerner College of Medicine.

Dr. McCrae was pleased to see the guideline panel recommend rituximab for the initial course of therapy and during relapse. While the anti-CD20 monoclonal antibody is not approved for use in TTP, the recommendation “solidifies its acceptance” as a standard part of therapy.

But he noted that questions remain about exactly when to use it in the first course. Should rituximab be used at presentation or in the outpatient setting after a patient’s disease enters first remission?

Dr. McCrae pointed to a 2013 study showing that, compared with rituximab given more than 3 days after admission, early administration of rituximab in patients with acute de novo TTP shortened hospital stays from 23 days to 16 days.10 While these findings are encouraging, they have not been widely replicated. It seems evident that the use of rituximab significantly delays the time to relapse, he said, although it may be less effective in Black patients.

Dr. McCrae also supported the guideline panel for recommending the use of caplacizumab in acute episodes and relapse, noting that it may ease anxiety about using the new medication in practice.

While improved survival has not been definitively proven, the data are intriguing, he said. There is also no information concerning the effects of caplacizumab on long-term neurocognitive sequelae of TTP, such as aphasia, seizures, hemiplegia, and cognitive impairment. He added, however, that the drug’s ability to rapidly impair platelet agglutination in the cerebral microvasculature may reduce this risk.

“Not everyone is going to have severe disease or refractory disease. We have absolutely no way of somehow prognosticating who is going to have ‘bad TTP’ or ‘good TTP.'”

—Katerina Pavenski, MD

Ara Metjian, MD, Associate Professor at the University of Colorado Anschutz Medical Campus, was an investigator on the HERCULES and TITAN trials. He said the two studies, which are the largest trials ever performed in TTP, are likely to change practice based on the benefit demonstrated.

In HERCULES, the median time to normalization of the platelet count – the primary outcome – was shorter with caplacizumab than placebo (2.69 vs. 2.88 days). A secondary outcome – a composite of TTP-related death, recurrence, or major thromboembolic events – was 74% lower with caplacizumab than placebo (12% vs. 49%).

The hesitancy to use caplacizumab is related to its cost, Dr. Metjian said, echoing Dr. Cataland’s concerns. Its high price has created barriers to its use, making it difficult for clinicians to access the drug for early treatment.

“The data tell us that if it is used up front, immediately, we are most likely to see the benefit,” Dr. Metjian said. “There haven’t been any data to tell us whether or not delaying its use or withholding its use until a patient’s disease becomes refractory is of any benefit. Pragmatically, we can assume that if we wait until the TTP is resistant to plasma exchange for 2 weeks, we may have already missed the boat.”

Withholding caplacizumab is even worse, he added. “If that patient sustains a stroke, a heart attack, or some other complication related to the thrombotic microangiopathy, then we are just giving caplacizumab after the fact.”

But Dr. Cuker said he is not ready to start using caplacizumab for the majority of his TTP patients. “I’m not there, at least not yet,” he said. “I don’t doubt that it works [to prevent exacerbations]. My major reluctance is that it’s a very, very expensive drug.”

Dr. Cuker said he uses caplacizumab selectively for patients with severe disease, where he worries about the risk of death, including patients with severe neurologic symptoms and those with organ damage. Patients with refractory disease are also good candidates for this newer drug, he added.

He isn’t convinced of the need to use it in less severe patients solely to prevent exacerbations. “Most of our patients did very well before caplacizumab,” he said, with survival rates around 90%. “Preventing exacerbations is important, but not the same as saving lives. How much are we willing to pay for preventing an exacerbation?”

Cost-effectiveness is not the only question that gives Dr. Sosa pause about using caplacizumab. While the drug reduces exacerbations, the effect is not sustained. Recurrence rates were higher during the follow-up period after discontinuation of the drug, consistent with relapse and persistent autoimmune disease. “From an immune standpoint, the drug does not do anything,” she said. “That doesn’t appeal to me.”

Dr. Sosa also questioned the mortality benefit observed in the HERCULES trial, noting that the rates reported in the study were seen in a patient population with less severe disease than is typically seen in the clinic. “Mortality has dramatically improved with total plasma exchange,” Dr. Sosa said. “I find it hard to see how we’re going to commit to the expense of the drug with the mortality rates reported in the trials.”

Dr. Metjian pushed back on the idea that the mortality rates in the HERCULES trial reflected less severe disease and selection bias. Instead, he suggested that, since HERCULES was performed at high-volume TTP centers where trial participants received highly specialized care, the rates were lower than could be expected in a clinical setting.

“In these centers, it’s not surprising that they would have lower mortality rates than in places where TTP occurs much less commonly or where suspected TTP cases are transferred,” he said. “If anything, I would assert that the improvement in survival with caplacizumab at these centers demonstrates the drug’s benefit in TTP.”

Katerina Pavenski, MD, a clinical hematologist at St. Michael’s Hospital in Toronto, was an investigator on the HERCULES trial, but did not participate in the TITAN study. She sees the availability of caplacizumab as a “huge game changer” because the drug can arrest the microvascular thrombosis associated with TTP, getting patients out of the hospital. With caplacizumab, she said, “you can stop this malignant onslaught of disease,” giving clinicians time to address the underlying autoimmune disease.

Still, determining which patients should receive caplacizumab is controversial and that’s an unknown right now, she explained.

“We know that not everyone is going to have severe disease or refractory disease,” she said. “We have absolutely no way of somehow prognosticating who is going to have ‘bad TTP’ or ‘good TTP.’ And because the majority of patients with TTP are women in their prime, can you take a gamble and not treat and wait until they are worse off and then just use caplacizumab as a salvage therapy? Maybe the outcomes will be equivalent, but you really need to have a trial to answer that question because we’ve never studied it.”

What Comes Next?

As clinicians look to the future of TTP, the question on everyone’s mind is whether the disease can be treated without the use of plasma exchange. That answer – not addressed by the ISTH guidelines – may be a long time coming.

Recent case reports have described patients who refused plasma exchange and still achieved good outcomes with caplacizumab and rituximab. The next step would be designing an ethical study that includes an arm without plasma treatment, Dr. McCrae said. “I don’t think it’s unethical. I could certainly see how you could build in plasma exchange as needed,” he said.

Dr. Zheng agreed that treatment without plasma exchange appears to be the next area of study. “Logically it seems to work, but we do not have the high-quality evidence as of yet.”

Plasma exchange is currently the only treatment that addresses the replacement of missing or inhibited ADAMTS13, but trials of recombinant ADAMTS13 or platelet-delivered recombinant ADAMTS13 could help solve that deficiency.

Recombinant ADAMTS13 is much closer to becoming a real treatment possibility in cTTP, Dr. Pavenski predicted, since trials are underway and the required doses would be small. For iTTP, where the necessary doses would be much larger, recombinant ADAMTS13 could be 5 years away, she said. “It has to be done in a stepwise way.”

Barring a dramatic shift, like moving away from plasma exchange, Dr. Cuker said he anticipates continued small refinements as clinicians begin to address TTP as a chronic illness. Instead of simply attempting to raise ADAMTS13 levels high enough to avoid relapse, clinicians can begin monitoring levels to avoid other risks, like stroke.

“Even in remission, the bar is going to be raised,” he said. “We’re not just trying to keep them from severe ADAMTS13 deficiency.” —By Mary Ellen Schneider


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