Caplacizumab: TMA Camila Masias ASH 2022 HRES Discussion
Caplacizumab: TMA Camila Masias ASH 2022 HRES Discussion
By Camila Masias, MD
How will Caplacizumab help patients with TMAs? I will be discussing the diagnosis and treatment of pregnant women with a prior diagnosis of TMAs, or thrombotic microangiopathy. This is very important because while thrombotic microangiopathy, specifically TTP and complement mediated HRES, are rare disease in these patients.
Eventually, 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 that? And the reality is that compliment plays an a very important role in pregnancy if 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 our relapse of complement related 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, 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 TTP.
What the 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 her hematologist before becoming pregnant, we should check their ADAMTS-13 activity. And if it's less than 20%, we may want to offer preemptive 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 HRES and, the ADAMTS-13 activity the kidney function, and that way we'll try to have a safer pregnancy. And I think one of the important conclusions of these 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. Now 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 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 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 mor perinatal and maternal mobility and 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 complements. 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 going to 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 could be safely used during pregnancy.
In conjunction with plasma exchange and immunosuppressive therapy (not immunosuppressive therapy alone), a drug used to treat acquired thrombotic thrombocytopenic purpura (aTTP). aTTP is a rare blood disorder characterized by the production of blood clots in the small blood arteries of the body. Caplacizumab binds to a protein known as VWF, which may prevent blood clot formation. It is a nanobody sort (a tiny antibody). Also called Cablivi.
Common Questions From Your Colleagues about this Clinical trial?
So one question is in patients with TTP that get pregnant and have a TTP relapsed 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 retro placental hematoma.
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 caveat 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.
However, while it was present, there appeared to be no apparent bleeding complications. Specifically, there was no retroperitoneal hematoma, so it may be an alternative for very refractory pregnant patients with TTP. 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 ADAMTS-13 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 counts (platelet count) 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 two medications do not appear to be major human teratogens.
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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 going to improve that 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 shows that they don't have a high risk of infection. And while Eculizumab is present in the umbilical core blood, it hasn't been associated with a lower risk of with, I'm sorry, with lower levels of complement.
What is ADAMTS13?
The ADAMTS13 gene encodes the synthesis of an enzyme that modulates blood clotting. After an injury, clots protect the body by sealing off damaged blood vessels and restricting additional blood loss. Protein von Willebrand factor is processed by the ADAMTS13 enzyme. This protein participates in the initial phase of blood clotting at the site of an injury by assisting platelets in adhering to the walls of blood vessels and forming temporary clots. Von Willebrand factor is fragmented by the ADAMTS13 enzyme to regulate its interaction with platelets. Thus, the enzyme prevents von Willebrand factor from initiating blood clot formation 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 ADAMTS-13 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 ADAMTS13 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 ADAMTS13 activity before becoming pregnant? Another question is, how long do we wait? If a patient has a clinical 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, I'm sorry, eculizumab again. And finally the third question that will be answered in the future is the role of Caplacizumab in pregnant patients with TTP relapse.
What are TMAs?
Tissue microarrays (TMAs) are a relatively high-throughput method that enables the examination of hundreds of unique tissue samples simultaneously. This method significantly reduces sample-to-sample variability, as well as the amount of time, tissue, and reagents needed, compared to conventional marker screening techniques.
A TMA is a paraffin block containing a variety of healthy and diseased tissue cores. A TMA block design incorporates numerous cores from each patient sample to enhance sampling precision and screening reliability. Incorporating many cores helps decrease errors caused by tumor/disease sample heterogeneity. To compensate for losses during processing and to provide adequate samples for assay validation, a minimum of two to six replicate tissue samples from the same morphologic region are incorporated into the array. TMA blocks are sectioned for the development and validation of novel assays and reagents. Every fifth segment is stained with H&E to validate histology and provide a visible way of quality control.
Key Takeaways From This Clinical Trial
I would say I several things. One is that we need to acknowledge the role of complement and ADAMTS13 in the development of a healthy pregnancy, and also the role of complement an ADAMTS13 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 outcomes.
I would like to add that while these are rare diseases, we are doing a phenomenal job treating these 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 safely way.
And for that it's usually an expert center may be appropriate. And there's always ways to contact one, there is a United States Thrombotic Micron Neuropathy Consortium in which experts in the field are willing to answer questions about local hematologists with these in these situations.
Or we can also, patients may be seen at their referral centers and then sent back to the hematologist. So I would like to just say that these are challenging cases and usually an expert opinion would be ideal.
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.
NIH - Caplacizumab. NIH, 2022
Medline Plus - ADAMTS13 gene. Medline Plus, May 1, 2021
UPMC - Tissue Microarray (TMA). UPMC, 2022