aplastic anemia basics | Aplastic Anemia and MDS International Foundation

aplastic anemia basics

Hematopoietic Stem Cell Transplantation in Aplastic Anemia

Interview: 

How do you currently think about the role of stem cell transplantation in aplastic anemia?

This is an exciting time for advances in stem cell transplantation, with marked improvements in outcomes for unrelated donor transplants. When considering treatments for newly diagnosed aplastic anemia, we explain to patients the short- term and long-term risks and benefits of the different treatment alternatives. For young patients, the risks of matched sibling donor transplantation are low and outcomes are excellent. Stem cell transplant is the only curative therapy for aplastic anemia, so if there is a matched sibling donor, that is the treatment of choice for young patients. This has low upfront and long-term risks for young people, so the pediatric and young adult populations are the best candidates.  

For young patients lacking an HLA-matched sibling donor, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine has been considered the first-line therapy. Up to 80% of patients become transfusion-independent and attain adequate neutrophil counts, and a smaller number of patients attain normal blood counts. Limitations of IST have included refractory disease, relapse and long-term risk of developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).  Many patients treated with immunosuppressive therapy do not need transfusions, but continue to have low blood counts that impair their quality of life.

Recently, the outcomes of unrelated donor transplantation have markedly improved. Previously, there was a high risk of adverse outcomes with unrelated donor transplants. The preference was to use immunosuppressive therapy (IST) because the upfront risks were low. In the past, when unrelated donor transplantation was much riskier, it was only resorted to as a third-line therapy, depending on the status of the patient.

Now we have retrospective data from Europe, and from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), a non-randomized prospective study in patients failing immune suppression undergoing unrelated donor bone marrow transplantation (BMT). This shows equivalent survival rates in young patients with unrelated donor transplant compared to matched sibling transplants. There appeared to be a long-term benefit when comparing unrelated donor transplant to immunosuppressive therapy. However, it is important to keep in mind that these studies were non-randomized, small and with a limited duration of follow-up. An important aspect of these studies was that in addition to excellent survival, the risk of events such as relapse, refractory disease, or clonal progression that we see with IST, was not seen after transplantation.

For the pediatric population, where we expect many years of life post-treatment, these long term issues are critical to consider. Although we do not have long-term data specific to transplantation for aplastic anemia on these regimens, these agents have been used for transplants at these types of dosages for many years with lots of long-term data. Overall, in discussion with my transplant colleagues, concerns of long-term effects are low, but still need to be studied carefully.

Should IST be tried first?

It could be asked what the potential downside is for trying IST first before going to transplant and resorting to unrelated donor transplant only if there is failure, relapse, or poor response to IST. After all, unrelated donor transplants are still associated with risks such as engraftment failure and graft versus host disease (GVHD).

However, potential transplant risks may increase with delayed time to transplant, which is especially true with refractory disease. With prolonged neutropenia, the risk of infection, particularly fungal infections, increases transplant risk. With multiple transfusions, the risk of failure of engraftment may increase when a stem cell transplant is finally performed. Iron overload from frequent red cell transfusions over a long term can increase transplant risk. We have observed that the rate of iron overload can be surprisingly rapid in some aplastic anemia patients with refractory disease.

Also, remember that if aplastic anemia develops into MDS or AML, then outcomes aren’t as good. The survival is lower due to increased treatment-related toxicities as these conditions have to be treated more aggressively – especially for AML. Even for MDS, you can’t use the standard conditioning regimen that would be used for aplastic anemia. You now have to give more intensive therapy to eliminate pre-malignant clones, which is associated with higher toxicity. With MDS and AML, you now have to also deal with the risk of relapse of the malignant cells. Relapsed MDS or AML is much more challenging to cure. It all just becomes more complicated.

We currently need more data to inform the role of unrelated donor transplant as upfront therapy for young patients lacking a matched sibling donor. Based on this, the North American Pediatric Aplastic Anemia Consortium (NAPAAC) in collaboration with the Pediatric Blood and Marrow Transplant Consortium (PBMTC) has begun a randomized, prospective analysis of IST versus matched unrelated donor transplants in pediatric aplastic anemia for patients lacking a matched sibling donor.

How does the diagnosis of a genetic bone marrow failure disease affect treatment?

A small subset of patients with aplastic anemia have a genetic cause of their disease.  The identification of a genetic cause affects decisions about the course of treatment. Patients with genetic bone marrow failure disorders generally have poor, partial, or transient responses to IST, so a transplant is the preferred treatment. However, these patients often have increased sensitivity to the standard chemotherapy and radiation regimens that are routinely used for an unrelated donor transplant. This calls for an individually tailored therapy, depending on the underlying disorder, to avoid excessive toxicity.

Does the use of eltrombopag in treating aplastic anemia affect the decision to proceed to stem cell transplantation?

Eltrombopag has been one of the most exciting recent advances in non-transplant treatment for refractory aplastic anemia. Results of the NIH trial of upfront treatment with eltrombopag plus IST are eagerly awaited. What is not known is if eltrombopag affects the risk of secondary events such as relapse and clonal progression, especially in the pediatric population. These are concerns that still need to be studied and fully evaluated because at this stage we don’t know.

Are there any other factors to mention?

For unrelated donor transplants, it takes time to identify the donor and harvest the bone marrow, so there is a delay in starting treatment. IST can be started right away.  However, responses to IST are typically not seen until 3 to 6 months of treatment, while recovery of blood counts after transplant is typically much sooner, typically within 3 to 4 weeks of initiating transplant. Whether eltrombopag might change response rates to IST remains to be determined. An important consideration when deciding between IST versus transplant is how quickly an HLA-matched donor can be found and cleared for collection. Donor availability will inform the decision as to which patients could consider an unrelated donor transplant.

So although recent data with unrelated donor transplants for young patients with aplastic anemia are very encouraging, more studies are needed to determine whether outcomes are superior to those with IST and to identify the factors that guide treatment decisions for each patient.

Dr. Kasiani Myers: Acquired and Inheirited Bone Marrow Failure

Interview: 

What is the difference between acquired and inherited bone marrow failure disease?

Hereditary bone marrow failure results from a genetic predisposition that makes marrow failure more likely to occur. There’s a wide variety of inherited bone marrow failure diseases that are caused by mutations in a wide range of pathways. Some involve DNA repair issues, some involve ribosome issues, (which are the enzymes that help translate the protein in our bodies) and others involve telomere diseases (the ends of our chromosomes that protect our DNA).

The mutations that lead to these diseases are in the DNA right from birth. The problems with these pathways lead to bone marrow failure. These often involve the accumulation of damage to the function of fast-dividing cells, such as in bone marrow.

Acquired aplastic anemia is thought to be primarily an autoimmune, or immune-mediated disorder. So a trigger of some kind sets off the immune system to destroy bone marrow stem cells. Usually acquired aplastic anemia patients don’t have other issues associated with it, but inherited aplastic anemia patients may have issues outside of the bone marrow, including other organ toxicities or functional issues that go along with the disease.

Even though the origins of bone marrow failure can be different, are the treatments the same?

Knowing how aplastic anemia originated is important because it helps determine the proper course of treatment. Some treatments are the same, but some are not. The common treatment they share is bone marrow/stem cell transplantation. This provides a new immune system to replace the one that no longer works, and has been functionally destroyed.

We do use chemotherapy for both categories of aplastic anemia, but the type and strength of this chemotherapy is often very different. The majority of inherited marrow failures are very sensitive to specific types of and doses of chemotherapy and the patient could be harmed if the wrong type of chemotherapy was chosen.

In acquired aplastic anemia, there’s an opportunity to reset or ‘reboot’ the abnormal immune system. In some patients who don’t have a matched sibling donor, instead of going to transplant we can try to reset the misbehaving immune system to retrain it to work properly and get rid of the cells that are attacking and destroying stem cells -- thus allowing the stem cells to repopulate the bone marrow. That’s not an option in inherited aplastic anemia—most patients have no response or if they do, it’s very short-lived if this is tried.

Why is that inherited aplastic anemia sometimes has other very rare disorders that also occur with it?

Inherited aplastic anemia is a systemic disease, so the entire body has a particular genetic predisposition toward it. This is generally a problem with a particular pathway that tries to prevent accumulation of DNA damage over time or helps fast dividing cells like stem cells. Because the bone marrow is such an active part of the body, it often runs into trouble in these diseases because it is busy all the time creating blood.

Conditions such as Fanconi anemia, Shwachman-Diamond syndrome and a few others are really the pathways to inherited aplastic anemia—different pathways, but the end result is the same. And because the pathways are somewhat different, the treatments are somewhat different.

These processes may have been going for years without anyone knowing it. But once patients start having symptoms of aplastic anemia, then they have medical examinations that trace back the cause and that’s when the discovery of inherited aplastic anemia and a family history is made.

Even though MDS has far less of a link to a hereditary component, there are still very rare instances where multiple members of a family, (including parents, children and grandparents) have MDS. What is at work here?

That’s an area of current, active research. Many of the inherited marrow failures also have a predisposition to MDS. So if you have multiple family members with MDS you should think about inherited marrow failure syndromes. There are many more diseases that are just beginning to be discovered, such as GATA-2. This a recent example showing that people who may not be predisposed to aplastic anemia may have a high risk of MDS. There are particular pathways at work that lead to the development of MDS, and research is ongoing to understand just why this happens.

How important is it for patients and families to be concerned about the origin of the disease if the real focus is be on treating it?

It’s critical, especially in pediatrics. 20 to 30% of pediatric aplastic anemia is thought to be inherited. So that’s a quarter of this pediatric population whose treatment could be dramatically different!  Here, you could really cause harm by choosing the wrong therapy, and that would also be a reason to make sure other family members aren’t at risk. Another reason why it is important to know about inherited aplastic anemia is because a potential sibling donor could also have it, even if they are asymptomatic, and then the transplant wouldn’t be successful.

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.

Making the Most of Office Visits with Your Specialist

Dr. Christopher Cogle is an associate professor of medicine at the University of Florida, Gainesville, Florida. He has clinical and research expertise in the

Interview: 

Communications with a medical team will often contain complex information. What would be the most important questions a patient should consider asking to let the members of the medical team know he/she needs to have concepts and specific instructions explained again?

The first thing the patient should be sure they understand and should ask is, “What is my diagnosis and is this the right diagnosis?”

With bone marrow failure disease, the diagnosis might be a little murky or unclear because of the degrees of various overlap syndromes that can occur with myelodysplastic syndromes (MDS), aplastic anemia, and paroxysmal nocturnal hemoglobinuria (PNH). Sometimes, it truly can be hard to tell where one disease stops and another one starts.

It is ok for a patient to say “I don’t understand. Will you please rephrase or restate the diagnosis in a different way?” I’m encouraged when my patients ask this. It shows that they are engaged and intently listening and want to understand what I have said.

Another thing I encourage, especially on the first few visits, is for a patient to bring a family member or close friend and ask that person to take notes or even make an audio recording of the conversation to capture what the physician and the clinical team are saying. Often, with everything occurring at once, there will most likely be something that the patient missed in the discussion. It’s good to have another person who can remind you of what your doctor said.

What resources are typically available when there is a language barrier between doctor and patient?

Patients have the right to ask for a translator. Clinics have the responsibility of providing a translator, and especially so if a clinical trial is being discussed. Call before the clinic visit and ask that a translator be available. Often times a certified medical interpreter will be on the telephone to help with the visit.

What type of questions should be addressed by the doctor and what questions should be addressed by the nurse?

In day-to-day practice, doctors have a limited amount of time, so they often focus their discussion on diagnosis, prognosis, treatment options and management of complications.

With your doctor, make sure you have a clear understanding of the diagnosis. That being said, your blood disease diagnosis may be a mixture of blood diseases. For example, your MDS may have some elements of aplastic anemia and PNH. When discussing prognosis, ask how your doctor came up with the life-expectancy estimates. Also ask how your prognosis will change with the various treatments. During the treatment discussion, ask about all available options.

For each treatment option ask about the benefits and risks. Your doctor should be able to give you specific percentages based on the published literature. You should also ask your doctor how many patients he/she has treated with each treatment option and what his/her individual experience has been. Finally, your doctor should also explain how he/she would provide blood transfusions, and prevents and treats infections and iron overload.

Nurses typically focus on the important topics of pain, side effects, fatigue, diet/exercise, taking medications, and central venous line maintenance. Social workers can help with accessing resources such as housing, transportation and food assistance. Financial representatives can help explaining your health insurance benefits, limitations, and out-of-pocket payment expectations.

How do you tell your doctor that you want a second opinion?

Signs that you may need a second opinion include: if your doctor has difficulty explaining your disease and treatment, if he/she doesn’t have time to talk with you, if he/she has little experience treating your disease.

Many patients are reticent to get a second opinion because they don’t want to offend their doctor. But in actuality, it’s usually the doctor that initiates the second opinion. In my experience, most doctors welcome a second opinion. For diagnosing and treating blood diseases, more information and perspective is helpful.

My guidance to my patients is that if you’re wondering about getting another opinion, do it quickly. With blood diseases, time is usually of the essence. Thus, the second opinion, if requested, should occur rapidly.

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.

Aplastic Anemia and MDS Overlap Syndrome

Significant attention has been paid to

Interview: 

How common is one of these diseases coexisting with the other?

This is a complicated topic because the bone marrow failure overlap syndromes are in fluid motion in the diagnostic pathway. Classically, MDS has a hypercellular marrow – too many cells. In contrast, aplastic anemia has a hypocellular marrow, showing a very low number of cells. But there is a subset of MDS called hypocellular MDS. This means there’s a low number cells, but it is still more like MDS than aplastic anemia – and the two diseases are closely linked. What is most often thought of as the defining difference between hypocellular MDS and aplastic anemia would be the presence of chromosomal abnormalities observed when the karyotype of the bone marrow is examined, with MDS being far more likely to have these chromosomal abnormalities. Aplastic anemia has these more rarely.

Are there overlapping symptoms of these two disease that would initially be cause for confusion or misdiagnosis?

Despite the difference I mentioned, the symptoms of both are very similar. Patients with either disease often have low red cells, low white cells, and low platelets. Thus, the confusion could lie in the similar blood counts, but the reason for these low blood counts is different. In aplastic anemiam there are no cells to make new blood, but in MDS,  there are too many bad cells that are not effective in making blood,crowding out the good ones. 

Are cases as a dual diagnosis such as these counted along with the individually diagnosed cases or are they regarded as a separate category?

This is an area of a lot of scientific debate. Usually, they’re more often as classified as MDS if they have the chromosomal abnormality I have mentioned. Aplastic anemia, with a normal karyotype and an empty marrow, is really the only condition that is categorized this way.  Once there has been an evolution – a changing of the chromosomes, this moves away from aplastic anemia to MDS, some call that the overlap syndrome but they are usually treated more as an MDS patient. Hypocellular MDS is often treated initially like aplastic anemia,  with immunosuppressive therapy.

Is treatment each disease any different than when they appear separately?

The first line treatment for an older adult with pure aplastic anemia is immunosuppressive  therapy. In older adults with hypocellular MDS, immunosuppressive therapy could be considered, but would never be considered in MDS where the standard of care should be hypomethylating agents, azacitidine (Vidaza®) and decitabine (Dacogen®), which of course are not used in aplastic anemia.

Should patients who have been diagnosed for one of these diseases be tested for the other?

The testing is same for both. A bone marrow biopsy is performed and chromosomal abnormalities are looked for in both. The observation of dysplasia would be checked for in both diseases.  Measurements of the earliest progenitor cells (or blasts) that are CD34 positive can be helpful to distinguish as well.

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.