Caplacizumab: TMA Camila Masias ASH 2022 Complement-Mediated HRES Debate

Caplacizumab: TMA Camila Masias ASH 2022 Complement-Mediated HRES Debate

By Camila Masias, MD

How will Caplacizumab help patients with TMAs? I will be discussing the clinical diagnosis and treatment of pregnant women with a prior diagnosis of TMAs or thrombotic microangiopathy. This is very important because while thrombotic microangiopathy (TMA), specifically TTP and complement-mediated HRES are rare diseases, patients eventually may become, want to become pregnant, and there’s a number of uncertainties in this field.

Should we monitor them? How do we monitor them? How frequently, what labs do we use for. And the reality is that complement plays an a very important role in pregnancy. It serve as a regulator for healthy pregnancy, can promote inflammation, and both Complement and ADAMTS-13 activity have been involved.

In the development, not only of our relapse of TTP or a relapse of complement HRES, but also in the pathophysiology of health and preeclampsia that we see quite commonly in pregnancy. And we also know that patients moving into the TTP patients that want to become pregnant. We know that these patients are at a higher risk factors for another relapse and for fetal death and miscarriage. And we know that from a number of case series from expert centers, including the UK, Hopkins, and more recently, St. Michael’s Hospital in Canada. And what all of these reports have in common is that these patients are at high risk of hypertension, fetal death, miscarriage, and a relapse of their disease.

So what experts are suggesting is that we need to monitor these patients. If a patient has a history of TTP, ideally she should have a discussion with their hematologist before becoming pregnant, we should check their ADAMTS-13 activity, and if it’s less than 20%, we may want to offer preemptive (immunosuppressive) therapy with Rituximab, Cyclosporine or Azathioprine, to increase their ADAMTS-13 activity before becoming pregnant. Once we’ve achieved that, then we can move on to monitor periodically, ideally every 2 or 3 months, the ADAMTS-13 activity the kidney function, and that, that way we’ll try to have a safer pregnancy. And I think one of the important conclusions of this presentations also is that the monitoring doesn’t end right before the delivery.

But we also need to be careful in that early postpartum period that it carries a risk for relapse as well. Our other conclusion is that these drugs are, have been safe during pregnancy for the most part. So they, we feel safe that they can be given either, either at the early pregnancy or through pregnancy and postpartum.

And if we moved to complement-mediated HRES, these patients are also at a higher risk of relapse. And we, there’s a number again, of uncertainties in this population. We know that patients that have pregnancy HRES can have an, can have a relapse. Not only during pregnancy, but also postpartum. They carry significant more perinatal and maternal mobility and increased mortality, including severe renal involvement end stage renal disease or even requiring a renal transplant.

And these came from recent studies published from the global complement-mediated HRES. To overcome these difficulties, we recommend the use of Eculizumab during pregnancy. We have data on the use of this drug, not only for complement-mediated HRES, but also for other diseases such as PNH and Myasthenia Gravis (MG). We know that this drug is not gonna be present in breast milk.

And the observed levels in the umbilical cord have not been enough to decrease the complement levels of the newborns. Moreover, patients that receive eculizumab during pregnancy do not appear to have infectious complications, either mothers and neonates. And this drug really improves renal outcomes in complement-mediated HRES. Whether triggered by pregnancy or not. So it’s important to raise awareness that this drug so far been safe to use during pregnancy.

What is Caplacizumab?

A medication administered in conjunction with plasma exchange and immunosuppressive therapy to treat acquired thrombotic thrombocytopenic purpura (aTTP). aTTP is an uncommon blood condition characterized by the formation of blood clots in the body’s small blood arteries. Caplacizumab binds to a protein called VWF, which may prevent the formation of blood clots. It is a nanobody kind (a tiny antibody). Also known as Cablivi.

Common Questions From Your Colleagues

So one question is in patients with TTP that get pregnant and have a TTP relapse during pregnancy, is there a role of caplacizumab. During pregnancy and we need to balance the risk and benefits of this drug, right? Caplacizumab may potentially increase the risk of pregnancy specific hemorrhagic complications, specifically retroplacental hematoma (HRP). But at the same time, you can have placental damage from ongoing TMA in peri-placental perfusion. There’s been a case report on the use of Caplacizumab during pregnancy with the covid that this case report occurred when the baby was nonviable. And they looked at the Caplacizumab levels in the amniotic fluid and fetal blood, and it was present.

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However, while it was present, there appeared to be no apparent bleeding complications. Specifically, there was no Rey hematoma, so it may be an alternative for very refractory pregnant patients with tt. The other question that we get is what about rituximab? The use of, specifically the use of rituximab for preemptive therapy in patients with a history of TTP that want to become pregnant, but their LMC certain activity, still less than 20%. Again, rituximab has been used for a number of diseases, not only of OTB, but lymphoma, lupus, ITP, rheumatoid arthritis, and the evidence showed that it appears to be saved. About 76% of the patients resulted in full-term deliveries. There were some 24% of infant born prematurely, but more than 30 weeks.

And there were some observed neonates with low blood cell (platelet) counts and infections, but taken together it appears to be safe. Another question that we ask is there other alternatives for this preemptive therapy during pregnancy? And yes, it would be their Cyclosporine or Azathioprine, and those 2 medications do not appear to be major human teratogen, although Cyclosporine may be associated with an increased risk of prematurity. And then moving into atypical HRES. One of the things that we get asked a lot from our colleagues is can we use Eculizumab during pregnancy? And I’ve, talked about this on the other question, but certainly there’s no question that Eculizumab is gonna improve their renal outcomes in our pregnant patients with complement-mediated TMAs. And it appears that this it’s safe for both mother and baby in the sense that the  report show that they don’t have a high risk of infections. And while Eculizumab is present in the umbilical core blood, it hasn’t been associated with a lower risk of with lower levels of compliment.

What is the ADAMTS13 gene?

The ADAMTS13 gene contains instructions for the production of an enzyme that regulates blood clotting. Clots protect the body after an injury by sealing off damaged blood arteries and limiting further blood loss. The ADAMTS13 enzyme processes the von Willebrand factor protein. This protein is involved in the initial step of blood clotting at the site of an injury, which includes helping platelets adhere to the walls of blood arteries and form temporary clots. The ADAMTS13 enzyme fragments von Willebrand factor to control its interaction with platelets. In this manner, the enzyme stops von Willebrand factor from initiating the production of blood clots during normal circulation.

Will This Data Affect Clinicians Today?

This data will affect clinicians today in that we will learn that patients with a history of TTP that want to become pregnant are at a higher risk of fetal miscarriages and at a higher risk of relapses. And patients with a complement-mediated HRES are also at a higher risk of having another episode given pregnancy. Therefore, clinicians should be aware of very close monitoring in these two populations. In patients with a history of TTP, they need to have their ADAMTS13 activity more than 20% before pregnancy, ideally, and then it should be monitored periodically. Typically, we say every 2 to 3 months, along with hemolysis markers.

Next Steps For This Research?

There’s a number of uncertainties in this population. Just because of the nature of it, it’s really hard to do clinical trials in patients that are pregnant, of course. And so one of the uncertainties is what sort of these safe number of ADAMTS-13 activity in patients that have a history of TTP and want to become pregnant, is 10% enough or do we need to be a normal ADAMTS-13 activity before becoming pregnant? Another question is, how long do we wait? If a patient has a diagnosis of TTP and is doing fine, can she get pregnant in 6 months or should we wait a year? Another area of interest is on complement-mediated HRES, right now we have patients that have the diagnosis and have been treated with Eculizumab. And since they’ve stopped this drug because they recovered the renal function, the question is if they become pregnant, do we need to start eculizumab again. And finally the third question that will be answered in the future is the role of preeclampsia in pregnant patients with TTP relapse.

What exactly are TMAs?

Tissue microarrays (TMAs) are a reasonably high-throughput technique that permits the simultaneous study of hundreds of distinct tissue samples. Compared to standard marker screening approaches, this method dramatically minimizes inter-sample variability as well as the amount of time, tissue, and reagents required.

A TMA is a paraffin block containing a variety of tissue cores from healthy and sick tissues. A TMA block design includes multiple cores from each patient samples to improve sampling accuracy and screening dependability. Multiple cores assist eliminate mistakes caused by tumor/disease sample heterogeneity when incorporated. To compensate for losses during processing and to provide numerous samples for assay validation, a minimum of two to six replicate tissue samples from the same morphologic region are introduced into the array. TMA blocks are sectioned for new assay development and reagent validation. Every fiftieth segment is stained with H&E to verify histology and give a visible quality control method.

Key Takeaways From This Trial

I would say I several things. One is that we need to acknowledge the role of Compliment and ADAMTS-13 in the development of a healthy pregnancy, and also the role of Complement an ADAMTS-13 activity in the development of health and preeclampsia. The other key point is that patients with a history of TTP and complement-mediated HRES requiring close monitoring before, during, and after pregnancy. And finally the role of preemptive therapy with either Rituximab, Cyclosporine, or Azathioprine to raise ADAMTS-13 activity levels before pregnancy and with, in an attempt to decrease relapses, and improve neonatal outcome measures.

Final Thoughts

I would like to add that while these are rare diseases, we are doing a phenomenal job treating diseases. Patients are doing well and they’re living their normal lives and becoming pregnant is part of it, and we really should have a multidisciplinary approach to help these patients become pregnant in a safe way.

Camila Masias, MD – About The Author, Credentials, and Affiliations

Dr. Camila Masias Castanon, a oncological hematologist specializes in internal medicine, and the diagnosis and treatment of blood disorders, including iron-deficiency hemolytic anemia, thrombosis hemophilia, sickle-cell disease, leukemia, and lymphoma. She works with the multidisciplinary team at the Miami Cancer Institute as a health care provider that provides patients with individualized, comprehensive treatment.

Dr. Masias performs clinical trials to enhance the treatment and prognosis for patients with blood diseases and blood malignancies. She is widely published in medical journals with peer review and is an invited speaker at educational and scientific conferences. Her academic, clinical, and scientific accomplishments have earned her a multitude of honors. Memorial Sloan Kettering Alliance is comprised of the Miami Cancer Institute. Baptist Hospital, Doctors Hospital, Homestead Hospital, South Miami Hospital, and West Kendall Baptist Hospital are affiliated with this facility, in internal medicine, and hematological oncology.

Reference

1. 1. NIH – Caplacizumab. NIH, 2022

   2. Medline Plus – ADAMTS13 gene. Medline Plus, May 1, 2021

   3. UPMC – Tissue Microarray (TMA). UPMC, 2022