When to consider targeted therapies in thrombotic microangiopathies in the modern era: walking the tightrope between cost, safety, and efficacy

Abstract

Thrombotic Microangiopathy (TMA) is a heterogeneous collection of syndromes that encompasses TTP, HUS, and other processes characterized by thrombocytopenia, microangiopathic hemolytic anemia, and, if untreated, organ failure and death. Novel therapies have recently been approved for the management of certain thrombotic microangiopathies, including caplacizumab for immune-mediated TTP, and eculizumab for atypical HUS. These options have complicated the standard workflow, which includes initiation of plasma exchange until ADAMTS13 testing can be resulted. Given such results may take several days, there is indecision regarding the appropriate initial management of TMA. Decisions regarding caplacizumab and eculizumab are complex, and include considerations over costs, side effects, and efficacy. In the following forum, we discuss the current data and pose possible management strategies in patients with TMA before final diagnosis can be obtained.

Introduction

In the modern era thrombotic microangiopathy (TMA) has become a heterogeneous disease subclassified based on the causative pathophysiology including autoimmune destruction/inhibition of ADAMTS13 (immune- mediated thrombotic thrombocytopenia purpura, TTP), congenital deficiency of ADAMTS13 (congenital TTP or Upshaw-Schulman Syndrome), compliment mediated TMA (atypical hemolytic uremic syndrome, aHUS), bacterial endotoxin mediated TMA (classic hemolytic uremic syndrome, HUS) or TMA secondary to medication use, organ transplantation, cobalamin deficiency, HIV, lupus, and pregnancy [1]. Prior to the FDA approval of eculizumab for aHUS in 2011, no targeted therapies were available for the acute management of TMA aside from plasma exchange and immunosuppression if immune-mediated TTP was suspected. Recently however the von Willebrand factor targeted nano-body caplacizumab was approved for immune-mediated TTP, bringing with it a novel mechanism in the acute management of TMA. While caplacizumab improved certain clinical endpoints as outlined below, it increases bleeding risks and adds substantial costs to the treatment of TTP [2]. Furthermore, it may take several days to arrive at an accurate diagnosis of immune-mediated TTP. The sine qua non of immune-mediated TTP is the detection of deficient ADAMTS13 activity (generally < 10%) in the presence of an auto-antibody [1]. ADAMTS13 activity and antibody testing is performed at only a few commercial laboratories in the United States. Turnaround times vary between 1 and 3 days before results return, with some labs omitting weekend testing. Lack of immediate TTP diagnostics has mandated the use of empiric treatments for TMA until an accurate diagnosis can be made.

The aforementioned factors (unclear clinical benefit, bleeding risks, costs, and potentially several days of diagnostic ambiguity) have led to equipoise at our center and likely others over the appropriate algorithm for the management of patients with acute idiopathic TMA. In the following manuscript we outline our discussions on potential approaches to acute TMA in the post caplacizumab era, highlighting the potential positives and negatives of each.

Clinical data on the use of caplacizumab

In February of 2019, the FDA approved caplacizumab for adult patients with immune-mediated TTP in combination with plasma exchange and immunosuppressive therapy based on the results of the Hercules trial [2]. In this randomized, placebo controlled trial caplacizumab use resulted in quicker normalization of platelet counts, (2.69 days vs. 2.88 days P = 0.01) and a decrease in the composite outcome of TTP-related death, recurrence of TTP, or of major thromboembolic events (12% vs. 49% P < 0.001). However, benefits came with costs, as caplacizumab had increased rates of bleeding related adverse events (65% vs. 48%) and bleeding events defined as serious by the trial (11% vs. 1%). Patients may have only received 1 day of plasma exchange prior to enrollment and while a definitive diagnosis of immune-mediated TTP was not required for enrollment, ADAMTS13 activity at enrollment was ultimately below 10% in 85% of included patients [2]. The HERCULES trial also evaluated health care resource utilization noting that caplacizumab use led to fewer days of plasma exchange, lower volumes of plasma infusion, and on average 65% shorter ICU stays, and 31% shorter duration of hospitalization [2]. The U.S. list price, or wholesale acquisition cost, for treating a typical case of immune-mediated TTP with Caplacizumab is estimated to be approximately $270,000 for a full treatment course [3].

The heterogeneity of TMA and predictors of immune-mediated TTP

The incidence of true ADAMTS13 deficiency (< 10%) in patients with TMA is not well described. In two large cohorts of US TMA patients the incidence of severe ADAMTS13 deficiency was 62/214 (29%) and 71/152 (47%) with detectable inhibiting ADAMTS13 antibodies in 52/214 (24%) and 64/152 (42%) respectively [4]. The same cohorts were utilized for the derivation and validation of the PLASMIC score, a seven-component clinical prediction algorithm consisting of platelet count; combined hemolysis variable; absence of active cancer; absence of stem-cell transplant or solid-organ transplant; MCV; INR; and creatinine. A PLASMIC score of 0–4 denotes low risk (recorded in 0–4% of patients with severe ADAMTS13 deficiency), a score of 5 denotes intermediate risk (5–24%), and a score of 6 or 7 denotes high risk (62–82%) for an ADAMTS13 level of < 10% [4]. PLASMIC score has been validated in several populations with some data suggesting it improves cost effectiveness [5, 6].

Management of TMA with ADAMTS13 activity over 10%

While the management of immune-mediated TTP involves plasma exchange in combination with immunosuppressive therapies, idiopathic TMA cases with ADAMTS13 activity over 10% (not associated with shiga toxin producing bacteria, culprit medications, cancer, organ transplant, or critical illness) are generally treated with eculizumab [1]. Eculizumab, a terminal compliment inhibitor currently listed as costing anywhere between $400,000 and 500,000 dollars annually, was tested in a single arm clinical trial of TMA patients with ADAMTS13 activity over 5% without shiga toxin exposure and resulted in improvement in platelet counts and time dependent renal function [7, 8]. Pathologic compliment mutations are later found in a subset of such patients, however whether mutations are present or not, relapse rates are high if compliment mediated therapy is stopped [1]. In October of 2019 the FDA approved the longer acting Ravulizumab for the same indication [9]. While some authors have suggested complement serologic analysis (C3, C4, CH50, AH50, etc.) as a potential means to identity aHUS prior to results of ADAMTS13 testing, no clinical data exists to support the routine use of such testing for initial decision making [10]. Eculizumab does carry a risk of meningococcal disease mandating the use of vaccination and often times prophylactic penicillin [7].

Managing the acute idiopathic TMA patient in the modern era

The approval of caplacizumab has led to pause about empiric treatment for idiopathic TMA given the drug’s side effects and health care costs, contrasted by its potential benefits. One intervention that has been suggested is point of care ADAMTS13 testing, although no assays have been cleared for clinical use to date [11]. There is variety in turnaround time and weekend availability of ADAMTS13 activity performed in commercial laboratories, and, although seeking out labs that can perform the tests quicker, it may not be feasible for many practices. With these limitations in mind, we have laid out the following clinical algorithms for consideration and discussion as outlined in Table 1.

Table 1.

Proposed algorithm for management of TMA

Traditional workflow (A)

Traditional TMA management involves immediate implementation of plasma exchange after detection of TMA. Further treatment decisions are made once the ADAMTS13 levels return.

• Benefits: Prevents unnecessary use of caplacizumab or eculizumab. Cost saving compared to empiric approaches. Providers are comfortable with the workflow, as this approach is familiar.

• Limitations: Potential clinical benefits from targeted therapy will be omitted for the first several days of treatment.

PLASMIC score based (B)

The PLASMIC score may reasonably differentiate patients with immune-mediated TTP from those with other forms of TMA to allow for empiric therapy. However, the operating characteristics of this test will result in some false positive results which could expose some patients to unnecessary risks and costs.

• Benefits: Allows for early initiation of targeted therapy with potential clinical benefit.

• Limitations: Potential clinical benefits from targeted therapy will be omitted for the first several days of treatment which may have an impact on long term outcomes.

Empiric caplacizumab (C)

Similar to the Inclusion criteria to the HERCULES trial, patient admitted to the hospital with idiopathic TMA would receive empiric caplacizumab along with PLEX and possible immunosuppression.

• Benefits: Could possibly improve clinic outcomes and would mimic the inclusion criteria of the HERCULES trial.

• Limitations: A reasonable proportion of patients may receive caplacizumab inappropriately. This strategy will also increase costs and possibly increase bleeding risks.

Conclusion

Options for the treatment of TMA have expanded greatly over the last decade. While prior therapies, including PLEX and immunosuppression, did offer benefit, many patients still suffered from significant morbidity and mortality. With new targeted therapies, such as caplacizumab and eculizumab, clinical endpoints have dramatically improved. These options, however, have put providers in a difficult situation as its unclear how to balance potential benefits with the detriments when empirically treating patients with acute TMA. We would encourage further discussion regarding the best management in such settings and further development of rapid ADAMTS13 testing will be important. Given the rarity of TMA and the cost involved in its treatment, institutions may benefit from development of internal guidelines. Further research is needed to help clarify which empiric treatment algorithm is best to pursue.

Highlights.

• We discussed TMA and its historical management strategies.

• Described pros and cons of caplacizumab.

• Compared and contrasted different management strategies of TMA for a more efficient workflow.