Expert Sheds Light on Rare Complement-Mediated Hematologic Disorders

Ronald S. Go, MD

Thrombotic microangiopathy (TMA) and paroxysmal nocturnal hemoglobinuria (PNH) are 2 of several rare hematologic disorders that, although not malignant, can lead to extreme complications for patients.

The causes vary, but these complement-mediated hematologic disorders have treatments lined up if diagnosed accurately and in a timely fashion. Moreover, to build awareness and educate the public further on these rare diseases, Mayo Clinic researchers published a Mayo Clinic Proceedings consensus statement on the complement alternative pathway and TMA diagnosis and management.

“These are rare diseases we should always be on the lookout for,” said Ronald S. Go, MD. “However, we shouldn’t be overly enthusiastic to make a diagnosis, because they are rare. Many common diseases will present the same way, and probably 9 out of 10 times it is going to be the common diseases, rather than these rare diseases. However, once we make a diagnosis, it is very helpful to know what is the right approach and what is the right treatment.”

OncLive: Can you provide some information on these rare disorders?

In an interview with OncLive, Go, an associate professor of medicine at Mayo Clinic, provided perspective on these rare hematologic diseases, including how community physicians can properly diagnose and treat them. Go lectured on the topic during the 2017 OncLive^® State of the Science Summit on Hematologic Malignancies.Go: My task was to talk about the complement-mediated hematologic diseases. It is not exactly cancer or malignancies, but these are not-so-common conditions that are seen in practice but can be very challenging to treat.

First, I spoke briefly about the complement pathway and some of the diseases, particularly hemolytic anemias that have pathogenesis or pathophysiology related to the complement pathway, and how current research and even clinical practice is utilizing drugs that target complement to treat these disorders. The 2 main disorders I discussed are TMA and PNH.

The bottom line here is, at our group at Mayo Clinic, we have developed a working group to address how to approach patients presenting with a TMA-like picture. TMA is a complicated condition because it can be due to a dozen disorders and treatment can vary according to the causes or the types.

It is a broad differential diagnosis and you need to know what labs to order, how to diagnosis and, when the diagnosis is made, how to treat the conditions.

Where exactly do these disorders stem from?

For PNH, the diagnosis is more straightforward. I spoke about how patients present and how they are diagnosed but went straight to how physicians treat these patients. These are rare disorders. There are probably a couple hundred—if not less than 1000—overall cases in the country every year. Where do they come from? These are conditions in which the red cells are destroyed so there is hemolysis and platelets are consumed.

The commonality is, at least for TMA, clots are formed in the body so there is thrombosis and organ damage—whether it is the heart, myocardinfarct, prominent renal failure, or a stroke. Those are the consequences.

Can these conditions transform to hematologic malignancies?

Are these types of disorders often misdiagnosed?

PNH can affect the kidneys, [cause] blood clots, and not so much affect the brain, but it can have a lot of complications. That is a very good question. For the most, part, with TMA, the disease is not associated with cancer, although it can occur in the setting of a cancer. For PNH, it is actually not uncommonly associated with some hematologic malignancies, including myelodysplastic syndromes and aplastic anemia—which is not malignant but the treatment is actually bone marrow transplant, so it is very similar to hematologic malignancies.I have to say that, yes, the diagnosis can be missed, especially for PNH, because it is so rare. It is likely that, for a community hematologist who is not specializing in PNH, one may see 1 case in 10 years. For TMA, it is also very uncommon and [physicians may see] probably 1 case per year. It is that rare.

However, for most clinicians it would be easy to suspect TMA because there are signs in the blood smear, histiocytosis, low platelets, and hemolytic anemia. Therefore, it is frequently suspected to be TMA, but most of the time it is not TMA because it is such a rare disease.

What are the current standard treatments for these conditions, and are novel approaches being studied?

Most clinicians will have limited experience in managing each of these types of disease in their career unless you specialize in these conditions. If you are at a big referral center, then you will see more. For TMA, the treatment varies but 1 treatment that is prominent is plasma exchange, which is a treatment that we use for most of the patients presenting with TMA if the cause is not obvious. We have to treat right away because there is a high mortality rate—up to 50% or more—if left untreated in some of these subtypes. Frequently, we do plasma exchange even if we don’t have a firm diagnosis. Then, we wait for the results to come back and then [if we find out that] it is not TMA, then we stop the plasma exchange. If it is TMA then we continue plasma exchange, and [debate whether we] should we add other treatments. One of the other treatments we use for TMA, especially for complement-mediated TMA, is a drug called eculizumab (Soliris), which is a monoclonal antibody against C5. It’s a drug also approved for PNH.

What ongoing clinical trials are investigating these disorders further?

What are the main points for community oncologists to take home and apply to clinical practice?

Eculizumab has been approved for at least 8 years in PNH and for about 4 years in TMA. There is a lot of worldwide experience with this drug regarding its safety and use, and it’s actually not difficult to use. The immediate side effects are pretty manageable. It is very broad. With PNH and the other complement-mediated disorders, there are certainly several trials and attempts to block the complement pathway upstream of C5. There are some clinical trials ongoing, and some will be opening that will compete with eculizumab and possibly complement it. For PNH, it is more straightforward; however, for TMA, it is so vast and so complex. We have a paper that was published in September 2016 at the Mayo Clinic Proceedings that has a consensus statement coming up. It is a comprehensive discussion of TMA.

It is essentially a care plan. If you see [these symptoms or get this diagnosis], this is what you do and then you go to the next step. It is like a flow chart—an algorithm—and that is very useful for community physicians and also for academic physicians.

Go R, Winters JL, Leung N, et al. Thrombotic microangiopathy care pathway: a consensus statement for the Mayo Clinic complement alternative pathway-thrombotic microangiopathy (CAP-TMA) disease-oriented group. Mayo Clinic Proceedings. 2016;91(9):1189-1211. doi:10.1016/j.mayocp.2016.05.015.