paroxysmal nocturnal hemoglobinuria (PNH) | Aplastic Anemia and MDS International Foundation

paroxysmal nocturnal hemoglobinuria (PNH)

AAMDSIF Virtual Film Festival

Over the past few years, several documentaries and dramas about people living with aplastic anemia have been created by independent filmmakers and by patients themselves. These depict the everyday lives of patients coping with a diagnosis, the challenges presented by treatment and the hardship caused by inadequate medical insurance coverage.

Whether fictional movies, or stories about actual patients and families, these portrayals bring you into the world of bone marrow failure disease in an uncompromising and straightforward manner.

Pregnancy in Bone Marrow Failure Disease

Interview: 

What is the impact of bone marrow failure disease and its treatment on pregnancy?

Bone marrow failure diseases frequently occur in women who are young and of child bearing age. People with these diseases have legitimate concerns about whether a pregnancy will cause their infants to suffer from the disease or its treatment, or whether their own disease will relapse. But the goal of modern therapy and modern obstetrics is to minimize both maternal and fetal complications.

Experience from published reports suggests that in the past ten years, both maternal health and fetal outcomes have improved in women with aplastic anemia and PNH. However each bone marrow failure disease (aplastic anemia, MDS, PNH) has to be evaluated separately for pregnancy complications. The issues are different for each condition.

Fertility appears to be unchanged in people with these disorders compared to people without them. But in people who have had an allogeneic stem cell/bone marrow transplant, the immunosuppressive medications may affect the ability to become pregnant.

For PNH, has the use of eculizumab in pregnancy been studied?

There are cases of women who have been successfully treated with eculizumab. Recent information shows that with modern obstetric care, women with PNH can successfully give birth to children, but there is an increased incidence of complications compared to people without PNH. The major complication is premature birth. Other complications include the need for blood and platelet transfusions, anticoagulation with blood thinners, thromboses (blood clots) and hemorrhage. However, fetal outcomes are also improved with this drug.

Use of lenalidomide (Revlimid®) during pregnancy is known to be harmful because it can cause birth defects. Does this mean only other drug therapies can be used?

Lenalidomide is a derivative medication of the drug thalidomide. In the late 1950s and early 1960s, thalidomide was used as an anti-nausea medication during pregnancy. This caused babies to be born with abnormal body parts, and significant birth defects are associated with its use.

Lenalidomide is used in people with low-risk stages of MDS, and particularly in the 5q-MDS subtype, but it must be stopped if pregnancy is even being considered. This applies to both men and women! Other medications or transfusions can then be used to treat the anemia.

The company that manufactures lenalidomide maintains a risk evaluation and mitigation strategy program (REMS) which requires that in a series of interviews, patients taking lenalidomide are carefully screened and strongly encouraged to prevent pregnancies.  In addition, pharmacists and doctors are all asked to assess their patients for careful use of this medication.

What is most important for patients to know and remember about fertility and pregnancy in bone marrow failure?

Much progress has been made, and modern obstetrics is able to support both mother and fetus through high-risk pregnancies. However, there are still significant issues in people with bone marrow failure diseases that can affect successful pregnancies. The mother is still considered to be in a high-risk pregnancy even though the majority of these pregnancies are able to be successfully managed with current techniques.

Problem areas that remain are in high-risk MDS and fertility in people who have received an allogeneic stem cell transplant. There is a risk of relapse of aplastic anemia during pregnancy, although the response rate to treatment for relapse has been good. Eculizumab can successfully be used during pregnancy to control PNH.

Interviews with the Experts: Dr. Bart Scott on PNH

Bart L. Scott, MD, MS, is Assistant Professor at the University of Washington Medical Center and Assistant Member at the Fred Hutchinson Cancer Research Center in Seattle, Washington. He received his medical degree from the University of South Alabama and his masters of Science in

Interview: 

How did your medical career get started and what led you towards studying PNH?

When I was in high school, my mother was diagnosed with breast cancer and that got me interested in medicine in a general way. Once I started studying bone marrow disorders, I was drawn to PNH because it’s ultra-rare. 

Does the exceptional rarity of PNH present challenges in studying it in an effective way?

It really does. Because it is so rare, it’s hard to design a clinical trial to study the disease in a comprehensive manner. So few have it, and they are dispersed around the world, making it difficult to have a suitable number of patients to study for this disease.

What you do think are the most important advances in research and treatment of PNH?

By far the biggest advance was the FDA approval of eculizumab (Soliris®), which has radically changed treating the disease. It has helped patients significantly by reducing transfusion dependence and thrombotic risk, increasing quality of life. There are so many positive benefits from this medication that it really changes the whole way we look at PNH.

Does the occasional association of PNH with aplastic anemia and, more rarely, MDS complicate its study and treatment?

Not really. It has instead led to a great understanding of why people develop bone marrow failure. We know that aplastic anemia patients have an autoimmune process where the bone marrow stem cells are attacked by the immune system, and now it seems like this autoimmune process recognizes one of the antigens missing in PNH. The association between aplastic anemia and PNH stems from the fact that PNH is allowed to grow and expand in an aplastic anemia environment because it escapes this autoimmune process.

What do you think PNH Awareness Week can do for patients and research?

Building awareness is always a great idea. These patients are generally in their early 30s when diagnosed, and, without proper treatment, this disease can have devastating effects. People who have just learned of their PNH diagnosis should seek the opinion of an expert in the field as soon as possible.

Interviews with the Experts: Side Effects of PNH Treatment

 

This is the third part in a series of interviews about PNH. Read the first and second parts.

Interview: 

Although eculizumab (Soliris®) is known to be effective in treating PNH, it has some side effects including colds, nausea, and headaches. Are these side effects treated the same way as if caused by other conditions?

The most frequently reported side effects of eculizumab in the PNH randomized trial were: headache, nasopharyngitis, back pain, and nausea. Interestingly, adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo (inactive ingredient).

Among 193 patients with PNH treated with eculizumab on two other studies, the side effect profile was similar to that reported in the randomized study mentioned above , affecting16% of  patients enrolled, with the most common being: viral infection (2%), headache (2%), anemia (2%), and fever (2%). These side effects are typically treated with supportive measures.

Treatment with eculizumab can also lead to a potentially serious problems -- infection with the meningococcus bacteria that causes meningitis. What should patients know about this? Are alerts and antidotes needed?

Meningococcal infections have been reported in patients treated with eculizumab. Because meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early, the following steps must be followed :
 
•    Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) and all prescribers, and patients must enroll in the program
•    Treating Physicians must be aware of and compliant with the most current Advisory Committee on Immunization Practices recommendationsfor meningococcal vaccination in patients with PNH.
•    All patients should be immunized with a meningococcal vaccine at least 2 weeks prior to administering the first dose of eculizumab, unless the risks of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection in which case an antibiotic can be prescribed  concomitantly with eculizumab therapy to prevent an infection during the first two weeks of therapy. It should be noted that the benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving Soliris have not been established.
•    A group B meningococcal vaccine became available in 2014, which can also be utilized in this patient population.
 
Patients should be educated on, and monitored for early signs of meningococcal infections. -all patients should be provided with a Patient Safety Card, and instructed to seek medical attention if they develop the following:
•    headache with nausea or vomiting
•    headache and a fever
•    headache with a stiff neck or stiff back
•    fever
•    fever and a rash
•    confusion
•    muscle aches with flu-like symptoms
•    eyes sensitive to light

Do other types of treatments for PNH (such as prednisone) have similar of different side effects that patients should be aware of?

Prednisone is a steroid that can decrease hemolysis caused by PNH. It may also increase counts of white blood cells and platelets in some people. Prednisone may not be effective in controlling hemolysis, nor does it stop all hemolysis in a given patient. Furthermore, it has a lot of side effects, especially if taken for a long time. For those reasons combined, doctors disagree about whether or not it should be prescribed for people with PNH. Brief treatment courses with prednisone given in pulses may be helpful to control hemolysis in some patients. Large prospective randomized trials evaluating the role of prednisone in this patient population is lacking.

Interviews with the Experts: The Complement System in PNH

 

Interview: 

Apart from the association it has with PNH, what is the function of the complement system?

The complement system initially got that name because it complemented the body’s ability to defend itself against pathogens, in addition to antibody formation. Today, we think of it as an integral part of the innate immune system. We regard the innate immune system as part of the entire human immune system, which is of course intended to defend the body from invading organisms.  The innate immune system can’t be altered—we are born with it and it provides an instantaneous response in an almost reflexive manner against infections and non-self particles. It can be triggered in a variety of ways, but the outcome is that it triggers a cascade of proteins that form the system with the purpose of eliminating bacteria and invading pathogens. It also serves to draw in the immune system cells to clear all the dead tissues and byproducts of inflammation, and also educate the adaptive immune system as to how prevent similar events that may occur in the future.

What is the sequence of events leading to PNH and why is a genetic mutation responsible?

When the complement system is activated, it triggers a variety of events leading to cleavage of one component known as C5. Once C5 is cleaved, a variety of events occur that propagate the formation of the membrane attack complex. This member attack complex generates pores, or holes, in cells ultimately leading to the cell’s demise.  

So when you have such a powerful system, regulators of the system are needed. These regulators sit on the outer membrane of cells, so the complement system recognizes that these cells are of the self. When those regulators are missing, as is the case in PNH, this leads to the destructions of the cells that are missing these protein shields.

Some of those shields, (2 proteins known as CD 55 and CD 59) are anchored the cell surface by a ‘tail’. We call this tail a GPI anchor – but in PNH this GPI anchor is missing because of a mutation in a gene called PIG-A. This defective gene leads to cause the cell’s inability to form this GPI anchor. So the complement regulator proteins are lost because they aren’t anchored to the cell surface.  When the complement system becomes highly active from infections, surgery, or similar events, it creates increased cell death of those cells missing this protein shield.

What happens when the complement system identifies red blood cells with the defective PIG-A gene?

So because of the missing  CD 59 protein [note: CD 55 is not mentioned here] on the surface of the red blood cell, the membrane attack complex takes place,  which makes the holes and pores on the cell surface, releasing the hemoglobin inside the cell through the holes –  the hemoglobin escapes the cell walls. This is the point where hemolysis occurs. Eventually the cell completely ruptures, releasing all the free hemoglobin intravascularly. That has a variety of consequences, including hemolytic anemia, thrombosis because of inflammation, and kidney problems because of free hemoglobin filtering through the kidney tubes—leading to hemoglobinuria (red urine). Continued hemoglobinuria can lead to kidney damage.

What is subclinical PNH?

In its normal form, patients present with overt hemolysis and hemoglobinuria. Subclinical PNH implies that you have a PNH clone [state that PNH is defective red blood cell??] that isn’t manifesting with hemolysis.

The ability of high-sensitivity flow cytometry to identify a small amount of PNH clones has resulted in the classification called ‘subclinical PNH’. So these patient may not present with hemolysis but once a PNH cline is identified, it is important to monitor the sized of the clone and understand the potential consequences of clone growth and the potential for hemolytic events to begin.

Clinical Trials: What Are Phases, and What Happens in Each One?

Interview: 

Clinical Trials: What Are Phases, and What Happens in Each One?

Generally, clinical trials go through three phases.

A Phase 1 study may represent the first time a drug has ever been used in human beings, but for our purposes, it’s more common that it’s the first time a drug has been used in someone with MDS. Frequently the drugs we use in a Phase 1 setting are ones that have been used for other conditions, and we’re now trying to find out if they are safe or have any effect at all in MDS.

The goal of a Phase 1 study is basic – just to determine the best dosages, and/or the best schedule for taking the drug, and that the drug is safe to give. Most people who enter a clinical trial are most interested in whether a drug works, though, which is counter to the express purpose of these trials! Drug efficacy is actually a secondary aim in Phase 1 trials, though sometimes we are pleasantly surprised at how effective even a Phase I trial drug can be. Everyone in a Phase 1 trial gets the drug.

A Phase 2 trial is often similar to a Phase 1 trial in that everyone in the trial gets the drug. There is often no placebo arm of this trial. This is called a ‘single arm’ study. However some newer Phase 2 designs do have a control arm, whether it is a placebo or another therapy – and this is known as a two-arm study. By ‘control therapy’ we often mean a known, existing therapy in use that is being tested against the new drug being evaluated. The primary goal of a Phase 2 study is to see whether or not the drug works. In MDS, this could mean eliminating blood transfusions or improving blood counts.

A phase 3 study is always randomized and always has a control arm, whether a placebo or standard therapy. The primary goal of these studies is to see whether a new therapy or a new combination of therapies, works better than an established therapy, or a placebo. These trials are frequently used for registration purposes, meaning for a drug to be approved by the FDA.

Interviews with the Experts: Hemolysis in PNH and Beyond

 

Interview: 

What is hemolysis and what its relationship to PNH?

Hemolysis is a term we use to describe destruction and/or rupture of red blood cells.  In paroxysmal nocturnal hemoglobinuria (PNH), hemolysis occurs within the blood vessels and is typically induced by the complement system, which is an integral part of the immune system. The purpose of the complement system is to eliminate ‘non-self’ elements, including infectious organisms, foreign bodies, etc. PNH cells tend to be prone for destruction by the complement system, because they do not have complement shielding proteins. 

What happens in PNH is that an acquired mutation in a gene (PIG-A gene) in hematopoietic stem cells results in their inability to form a specific structure (GPI anchor) that carries a variety of cell surface proteins and, included in them, a variety of complement shielding proteins. Because of the loss of the GPI anchor, blood elements lose their cell surface proteins and that makes them more likely to be recognized by the complement system as if they were a foreign body that merit destruction.

Is hemolysis associated with any other conditions besides PNH?

PNH is a very rare cause of hemolysis.  Hemolytic anemia is broadly divided by the presence or absence of certain antibodies attached to the red cell, which are detected by a test known as Coombs’ test.  PNH tends to be Coombs test negative, meaning there are no specific antibodies attached to the red cell outer membrane which leads to their elimination by the spleen. PNH is a rare cause of Coombs' negative hemolytic anemia but there are many other causes such as hemoglobinopathies, hereditary red cell membrane defects, certain infections or drugs. After a physician identifies a Coombs negative hemolytic anemia, a diagnostic workup needs to be performed to exclude other causes of hemolysis before arriving at a diagnosis of PNH.

Are there degrees of hemolysis or hemolytic activity?

Yes, because the alternate pathway (one of the three known arms of the complement system) is always turned on – and that is why there can be ongoing, but low-level hemolysis In PNH. However, the complement level of activity and capacity to cell-destruct can be intensified by a variety of events, such as infections, surgery or pregnancy. These properties explain pronounced episodes of hemolysis to coincide with significant complement activation and resultant symptoms of anemia, hemoglobinuria and jaundice.

What are the symptoms of hemolysis? How does it make PNH patients feel?

Symptoms of PNH depend on the severity of disease, associated hemolysis, and whether the patient has other features of bone marrow failure such as low platelet or neutrophil count. Most patients with PNH develop anemia and some can have classic associated symptoms such as fatigue, and shortness of breath, depending on their level of anemia. There may be jaundice – yellowness of the eyes and skin --because of bilirubin, which is a byproduct of red cell destruction. Some patients describe dark urine, which is the result of hemolysis, and the presence of free hemoglobin in the urine (hemoglobinuria). Other symptoms include abdominal pain, dysphagia (difficulty swallowing) and clotting. If the hemolytic episode is severe, it can lead to kidney dysfunction.

How is hemolysis treated?

Since hemolysis in PNH is induced by complement activation, one way to control this process is by blocking the action of complement.  Eculizumab (Soliris®) is an antibody to a component of the complement (C5). It works by blocking the action of that part of the complement and prevents complement-induced red cells destruction.  Eculizumab has been studied in several clinical trials and is approved by the FDA for the control of hemolysis associated with PNH.

It should be stated that treatment for patients with PNH should be individualized.  Patients need to discuss the specifics of their disease and therapeutic options with their providers.

Overlap Syndromes: When PNH Appears with Aplastic Anemia or MDS

Although even rarer than

Interview: 

How common is PNH appearing in patients with MDS or aplastic anemia?

The dual diagnosis of PNH and aplastic anemia is quite common. Perhaps half patients with PNH will have some sign of aplastic anemia, and a little less than half of aplastic anemia patients will develop the PNH clone. There are patients who fall more on one side of the spectrum or the other. Some will require treatment for PNH, some for aplastic anemia, some for both, and some for neither.

PNH can present with MDS, but that is a much rarer occurrence. There are some features of PNH that can be confused with MDS, such as the fact that patients with PNH often also have a hypercellular marrow, and 25% of patients with PNH can have a chromosomal abnormality. So by just looking at these features, one can see how PNH and MDS could be confused with each other.

However, the PNH/MDS category should be limited only to those who have significant increase in blasts (leukemia cells), a complex cytogenetic (chromosomal) abnormality or those with monosomy-7 if they are not responding to immunosuppression.  Those would be the three types of patients that I would think have PNH/MDS, and I have seen patients like this only rarely.

There are two other overlap syndromes to mention: one is PNH/AML, which is even rarer than PNH-MDS. This would be a patient who probably had PNH/MDS, where the MDS transformed to acute myelogenous leukemia. Then there’s the very rare PNH/MPN category, only seen in a handful of patients, where the MPN stands for ‘myeloproliferative neoplasm’. In my view, this only applies to patients who have myelofibrosis (scarring in the marrow), a chronically high white blood cell or platelet count, especially if they have the JAK2 mutation.

Does PNH appear concurrently with the other diseases or does it manifest after the other diagnosis has been made?

It can be either way. With aplastic anemia/PNH, PNH can occur before, at the same time, or after the aplastic anemia is detected. With MDS/PNH, usually it’s PNH occurring beforehand, or maybe at the same time. PNH does not generally develop after an MDS diagnosis, if they didn’t already have PNH to begin with.

Are there any areas where the boundaries or definition of one disease appears to overlap with another?

With aplastic anemia/PNH, both of those can be associated with anemia, although this happens for different reasons. In classic PNH, there is breakdown of red cells and the reticulocyte count is high, but with aplastic anemia, there is low production of red cells and the reticulocyte count is low. Sometimes what happens in aplastic anemia/PNH is the reticulocyte count will be elevated, but not to the level it should be. With PNH/MDS, even though hemolysis is a primary symptom of PNH, hemolysis can occur in rare patients with MDS for other reasons. This could be due to a few things – the acquired hemoglobin-H syndrome, or acquired pyruvate kinase deficiency for example.

Is PNH treated any differently when it appears in a dual diagnosis?

Patients with either overlap syndrome would be treated differently from a patient with only PNH. Patients having classic PNH may need eculizumab (Soliris®) or anticoagulants to prevent blood clots. Aplastic anemia patients need immunosuppression, generally being horse ATG followed by cyclosporine.

But patients with PNH/aplastic anemia overlap maybe not respond as well to eculizumab if they have a low reticulocyte count. They may need immunosuppression first, and may not be not be able to receive anticoagulants if their platelet count is low.

Conversely, for a PNH/aplastic anemia patient, there can be problems with ATG treatment. The reaction patients get with ATG can trigger hemolysis.  In patients a with large PNH red cell population who need aplastic anemia treatment, one thing to do is give them enough red cell transfusions, in order to dilute their PNH red cells so there are very few of them still there that can hemolyze when they receive ATG.  This might be two units of red cells a week every week for three weeks, for example. This could be enough to prepare someone with many PNH red cells to get ATG.

In the PNH/MDS overlap syndrome, at least in the very narrow definition I use, those patients should generally be treated with a stem cell transplant, if they have a donor. To prepare them for the transplant, it may be necessary with to treat them first with methyltransferase inhibitors to normalize their marrow, before going into a transplantation.

Are there possible complications from these treatments?

One thing to keep in mind is that patients with aplastic anemia typically get iron overload, sometimes requiring treatment for this, but patients with PNH often become iron deficient, and patients with aplastic anemia/PNH can have either situation, depending upon where they are on the spectrum.

Another way that the overlap syndrome can be important has to do with kidney function. Patients with aplastic anemia who require cyclosporine can experience an effect of the drug on their kidneys, and rare patients with PNH will develop a serious loss of kidney function as well. I suspect that the use of cyclosporine in a patient with a large PNH clone will be more likely to have an effect on the kidney function-- unless they are also on eculizumab.

Another consequence of the overlap syndrome is the effect of the combination of eculizumab and cyclosporine. In practical terms, if a patient is on either drug, they must go immediately to the hospital if they develop a fever. For cyclosporine, this is to make sure that they do not have one of many possible infections. For patients on eculizumab, in general this would be to make sure that they do not have meningococcal infections. For patients on eculizumab who are also on cyclosporine, there is always a theoretical concern that they might not be able to make antibodies in response to a vaccination because of the effects of the cyclosporine, and that they would be doubly immunosuppressed. However, if one uses this type of caution, patients who need both can be on both.

There are rare cases where patients have a triple diagnosis – PNH, aplastic anemia, MDS. Is there anything different about these?

These are exceedingly rare, at least when the narrower definitions and criteria for overlap syndromes are applied. In the case of PNH/aplastic anemia/MDS overlap syndrome, when the criteria for MDS is excess blasts, complex cytogenetic abnormalities, or monosomy7 with lack of response to immunotherapy, these cases should be considered for a stem cell transplant. But this only applies if this criteria is used. If you have a patient with PNH/aplastic anemia, and trisomy 8, this does not give a triple diagnosis according to the strict criteria that I would use. Trisomy-8 can be seen in PNH or aplastic anemia, but it doesn’t secure a diagnosis of MDS.

Should patients with an aplastic anemia or MDS diagnosis be concerned about the possibility of also having PNH?

All aplastic anemia patients should be tested for PNH at diagnosis and then maybe every year. Their LDH level should be periodically checked, as that can be an early sign that PNH is emerging. Early stage MDS patients should be tested for PNH at diagnosis, and if the result is negative, they don’t need to be tested further.

Then conversely, patients with PNH should be monitored for MDS, which would require a different treatment. The way to do this is to monitor blood counts. If patient with PNH has stable blood counts or is responding well to immunosuppression, then they’re presumed not to have MDS.  However, if they have falling blood counts, or if they’re responding initially to aplastic anemia treatment and their counts are coming back down, then those patients should have a repeat bone marrow biopsy because the reasons for the low blood counts could be MDS.

A falling blood count in a patient with PNH should also prompt a workup for an enlarged spleen as that can be a consequence of blood clots in the spleen or liver. A falling blood count in PNH doesn’t always mean aplastic anemia or MDS – it could be a blood clot causing an enlarged spleen. So a patient with PNH who is doing well, whose platelet counts have fallen, should have a bone marrow biopsy and a sonogram of the abdomen to check the spleen and blood flow in the abdomen.

Overlap Syndromes: When PNH Appears with Aplastic Anemia

Although even rarer than

Interview: 

How common is PNH appearing in patients with aplastic anemia?

The dual diagnosis of PNH and aplastic anemia is quite common. Perhaps half patients with PNH will have some sign of aplastic anemia, and a little less than half of aplastic anemia patients will develop the PNH clone. There are patients who fall more on one side of the spectrum or the other. Some will require treatment for PNH, some for aplastic anemia, some for both, and some for neither. With aplastic anemia-PNH, the PNH can occur before, at the same time, or after the aplastic anemia is detected. All aplastic anemia patients should be tested for PNH at diagnosis and then maybe every year. Their LDH level should be periodically checked, as that can be an early sign that PNH is emerging.

Are there any areas where the boundaries or definition of one disease appears to overlap with another?

With aplastic anemia/PNH, both of those can be associated with anemia, although this happens for different reasons. In classic PNH, there is breakdown of red cells and the reticulocyte count is high, but with aplastic anemia, there is low production of red cells and the reticulocyte count is low. Sometimes what happens in aplastic anemia/PNH is the reticulocyte count will be elevated, but not to the level it should be.

Is PNH treated any differently when it appears in a dual diagnosis with aplastic anemia?

Patients with the overlap syndrome would be treated differently from a patient with only PNH. Patients having classic PNH may need eculizumab (Soliris®) or anticoagulants to prevent blood clots. Aplastic anemia patients need immunosuppression, generally being horse ATG followed by cyclosporine.
But patients with PNH-aplastic anemia overlap maybe not respond as well to eculizumab if they have a low reticulocyte count. They may need immunosuppression first, and may not be not be able to receive anticoagulants if their platelet count is low.

Conversely, for a PNH-aplastic anemia patient, there can be problems with ATG treatment. The reaction patients get with ATG can trigger hemolysis.  In patients a with large PNH red cell population who need aplastic anemia treatment, one thing to do is give them enough red cell transfusions, in order to dilute their PNH red cells so there are very few of them still there that can hemolyze when they receive ATG.  This might be two units of red cells a week every week for three weeks, for example. This could be enough to prepare someone with many PNH red cells to get ATG.

Are there possible complications from these treatments?

One thing to keep in mind is that patients with aplastic anemia typically get iron overload, sometimes requiring treatment for this, but patients with PNH often become iron deficient, and patients with AA/PNH can have either situation, depending upon where they are on the spectrum.

Another way that the overlap syndrome can be important has to do with kidney function. Patients with aplastic anemia who require cyclosporine can experience an effect of the drug on their kidneys, and rare patients with PNH will develop a serious loss of kidney function as well. I suspect that the use of cyclosporine in a patient with a large PNH clone will be more likely to have an effect on the kidney function-- unless they are also on eculizumab.

Another consequence of the overlap syndrome is the effect of the combination of eculizumab and cyclosporine. In practical terms, if a patient is on either drug, they must go immediately to the hospital if they develop a fever. For cyclosporine, this is to make sure that they do not have one of many possible infections. For patients on eculizumab, in general this would be to make sure that they do not have meningococcal infections. For patients on eculizumab who are also on cyclosporine, there is always a theoretical concern that they might not be able to make antibodies in response to a vaccination because of the effects of the cyclosporine, and that they would be doubly immunosuppressed. However, if one uses this type of caution, patients who need both can be on both.

There are rare cases where patients have a triple diagnosis – PNH, aplastic anemia, MDS. Is there anything different about these?

These are exceedingly rare, at least when the narrower definitions and criteria for overlap syndromes are applied. In the case of PNH/aplastic anemia/MDS overlap syndrome, when the criteria for MDS is excess blasts, complex cytogenetic abnormalities, or monosomy7 with lack of response to immunotherapy, these cases should be considered for a stem cell transplant. But this only applies if this criteria is used. If you have a patient with PNH-aplastic anemia, and trisomy 8, this does not give a triple diagnosis according to the strict criteria that I would use. Trisomy-8 can be seen in PNH or aplastic anemia, but it doesn’t secure a diagnosis of MDS.