We learn about the pathophysiology, diagnosis, management, and prognosis of these two clinical entities. We are joined by Tanya Watt, MD, Associate Professor of Pediatric Hematology and Oncology at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern Newborn Nursery. Welcome back to the podcast. In today's episode, we'll be discussing transient myeloproliferative disorder and neonatal leukemia. We are recording remotely due to the ongoing COVID pandemic. We are joined today by Dr. Tanya Watt, Associate Professor of Pediatric Hematology and Oncology at UT Southwestern.
Dr. Tanya Watt:
Hello.
Dr. Neeta Goli:
Hi Dr. Watt, thanks for joining us today.
Dr. Tanya Watt:
Thank you so much for having me.
Dr. Neeta Goli:
When we are caring for newborns with trisomy 21, or Down syndrome, part of our routine evaluation is to obtain a complete blood count. This is used to screen for transient myeloproliferative disorder and neonatal leukemia. Today, we will separately discuss both of these clinical entities.
Dr. Neeta Goli:
Dr. Watt, to start off with, let's talk about transient myeloproliferative disorder. Please, can you remind us first, what constitutes a diagnosis of transient myeloproliferative disorder, or TMD?
Dr. Tanya Watt:
Transient myeloproliferative disorder or TMD is defined when we see a patient who has trisomy 21 and the presence of peripheral blasts. So for us when we get called to make the diagnosis, we need two things. So we need documentation that the patient has trisomy 21 via cytogenetics or FISH. And then we need to send a flow cytometry sample that shows that the peripheral blasts that are being seen fall into the abnormal myeloid population.
Dr. Neeta Goli:
How many blasts is too many?
Dr. Tanya Watt:
Any peripheral blasts are actually too many. There is a reaction called a leukemoid reaction that can sometimes happen in healthy neonates or even neonates with trisomy 21 that will be even more transient than what we see in TMD. But really any time you see blasts, we should always get called from the oncology team.
Dr. Neeta Goli:
How common is TMD?
Dr. Tanya Watt:
So it's really difficult to determine an exact incidence actually, just because we know that TMD occurs in two different phases. So both a proliferation phase, which is typically where we are able to make the diagnosis, and then a regression phase. There've been some population studies; most of them think that the incidents in children with trisomy 21 is somewhere between 4 and 10%, but there's not a ton of confidence in those numbers just based on the kind of figuring out exactly when we're able to make the diagnosis.
Dr. Neeta Goli:
Why is it that TMD is just in infants with trisomy 21?
Dr. Tanya Watt:
So what we believe and what we've learned over the years is that TMD is associated with a somatic mutation that occurs in the GATA-1 gene. So GATA-1 is responsible for allowing megakaryocytes to develop normally. And what we have found to happen is that in cells that have trisomy of chromosome 21 and this GATA mutation, then it makes it so the cells are not able to produce the full length of the GATA-1 protein, therefore making it so the megakaryocytes cannot actually go through normal differentiation. And this mutation seems to only occur in children with trisomy 21. It can occur in kids with mosaic trisomy 21 also, so you don't have to have the full trisomy 21, but will only occur in those cells that actually have trisomies of the 21st chromosome.
Dr. Neeta Goli:
Is the GATA-1 gene actually on chromosome 21?
Dr. Tanya Watt:
Yes.
Dr. Neeta Goli:
Other than trisomy 21, are there any other specific risk factors which would put these infants at a higher risk of developing TMD?
Dr. Tanya Watt:
Sure. So, we don't really know for sure; I mean, we know that the children that have this GATA-1 mutation are much more likely to develop TMD than children that don't have the GATA-1 mutation. And there are actually some early studies that are kind of hypothesizing the, depending on which GATA-1 mutation you actually have, kind of determine how severe your TMD is, how likely you are to go on to develop AML. But we don't really know of any other significant risk factors that predispose children to developing TMD.
Dr. Neeta Goli:
Are there any physical exam findings we should look for, for these babies?
Dr. Tanya Watt:
So, it's a wide range. We've discussed that they have to have trisomy 21. What we know happens with the leukemic blasts or this myeloproliferation is that it often leads to fibrosis in the liver and sometimes the spleen, so most of these kids will have some degree of hepatosplenomegaly. They can have pleural or pericardial effusions. The most severe cases will develop hydrops or significant ascites, but usually only less than about 5% of children with TMD have those severe findings.
Dr. Tanya Watt:
And then there's a pretty characteristic rash, again, only in about 5% of the patients. Starts out as vesicles but then over a few days becomes more confluent and crusted.
Dr. Neeta Goli:
If we do see blasts on the CBC and we call you for help, what is our expected management of this?
Dr. Tanya Watt:
So, it really depends on how the child is doing. As we discussed, the natural history of the disease is to regress on its own. However, we do know that some of the children will actually die from TMD, and so our goal is always to try and determine which ones of the kids are going to get really, really sick before the regression phase and use low-dose chemotherapy to start to treat those.
Dr. Tanya Watt:
Our typical reasons for treatment include hyperleukocytosis with a white blood cell count greater than 100,000, significant hepatic fibrosis or hepatomegaly that's actually leading to respiratory compromise, or heart failure. I always find the heart failure a little bit difficult to really figure out because lots of these children will also have congenital heart disease. And so, in theory we should only treat the children with TMD and heart failure if we believe that the heart failure is actually due to leukemic infiltrate and not the results of other congenital heart issues. Fortunately the treatment is relatively low doses of chemotherapy and quite quick. So usually about a week, sometimes two weeks of low doses of cytarabine, and that's usually enough to kind of decrease the leukemic burden and allow further regression of the disease.
Dr. Neeta Goli:
So if an infant is well-appearing and asymptomatic but is found to have this, they still receive the same chemotherapy?
Dr. Tanya Watt:
No, if they're asymptomatic, we don't do anything. We just watch it real closely and make sure they don't develop symptoms.
Dr. Neeta Goli:
Okay. And I think you already mentioned the co-morbidities that we should be aware of, so potential hepatic fibrosis, pleural effusions, heart failure you mentioned, any other co-morbidities we should be aware of to watch out for?
Dr. Tanya Watt:
Some studies have shown that they think prematurity increases the risk of death from TMD, but the numbers, as you can imagine, are really small and so it's kind of hard to know how significant that co-morbidity or that correlation actually is.
Dr. Neeta Goli:
Okay. And then you mentioned that if a baby is asymptomatic then you just kind of watch for regression. What is the expected course of TMD?
Dr. Tanya Watt:
So usually, in a few months we'll see the peripheral blasts completely go away. So typically in a well-appearing child, we will just follow them as an outpatient, usually every week at the beginning, checking their liver and making sure they're not having any hepatotoxicity, making sure their peripheral blasts are trending down. And usually, within a few months their peripheral blasts are gone.
Dr. Neeta Goli:
What is the long-term prognosis for infants diagnosed with TMD?
Dr. Tanya Watt:
Fortunately, most of them do really, really well. If they don't require any treatment, overall survival is about 92%, but even those who actually do require those low doses of chemotherapy have an overall survival somewhere between 80 and 90%. So, most children do quite well.
Dr. Neeta Goli:
And what is the relationship, you mentioned this earlier, between TMD and leukemia, you mentioned AML (acute myeloid leukemia)?
Dr. Tanya Watt:
About 20% to 30% of infants who have TMD will later go on to develop AML. We talked a little bit about earlier and what will help us if the studies kind of continue to bear out, showing us that certain GATA-1 mutations will make it more likely for patients to develop AML will obviously help us to screen these patients. Right now we'll screen any child with Down syndrome who had TMD up until the age of four, sometimes five years of age, making sure that we don't see any signs of development of AML. The reason for that time point is that if children are diagnosed with AML before the age of four, they do significantly better than the general population and have an overall survival of about 80% in contrast to the general population with AML that has about an overall survival of about 60%.
Dr. Neeta Goli:
So does that correlate at all with the disease severity of the TMD in that if a baby was severely symptomatic with TMD initially at birth, are they more likely to be one of the ones who develops leukemia or AML?
Dr. Tanya Watt:
It's a great question and no, right now we don't see that correlation specifically.
Dr. Neeta Goli:
Okay. How do you counsel these families?
Dr. Tanya Watt:
So I think it's important, right? With any Down syndrome patient counseling them that they do have a higher risk of leukemia, regardless of whether they had TMD at the beginning or not. We spend a lot of time talking about the fact that TMD is transient, and definitely does not mean that you're going to go on to develop leukemia, but that we want to be looking out for the signs of it. So, if they have fever that's unexplained, if they start to look more pale than normal, if they have petechiae or bruising that isn't explained that we'd want to be called earlier rather than later.
Dr. Neeta Goli:
Okay. And that was a good segue into our next topic of discussion for today. So let's transition now from talking about transient myeloproliferative disorder to neonatal leukemia.
Dr. Neeta Goli:
Childhood cancer is fortunately a relatively uncommon diagnosis, with approximately 14,000 cases diagnosed annually. Hematologic malignancies, such as leukemia, constitute approximately a third of these diagnoses. Though leukemia typically manifests in childhood, it can rarely present in the neonatal period as well. To start our discussion today, please, can you review for us the physiology and pathophysiology of neonatal leukemia?
Dr. Tanya Watt:
So neonatal leukemia by definition occurs within the first 28 days of life. About two-thirds of those patients will have acute myeloid leukemia (AML) and the remainder have B-cell acute lymphoblastic leukemia. Regardless of which type of leukemia they have, the vast majority have a KMT2A rearrangement. This was previously known as MLL or Mixed Lineage Leukemia, which is most commonly a translocation of t(4;11)(q21;q23).
Dr. Neeta Goli:
How common is neonatal leukemia?
Dr. Tanya Watt:
Fortunately neonatal leukemia is very, very rare, accounting for less than 1% of all childhood leukemia. Average incidence we think is about three cases per million live births here in the United States.
Dr. Neeta Goli:
Okay. Which infants are at higher risk?
Dr. Tanya Watt:
There are no real known risk factors other than trisomy 21, which results in a separate phenomenon that's known as transient myeloproliferative disorder. Otherwise, people have tried and tried to understand why some children develop neonatal leukemia and really cannot figure out a good risk factor.
Dr. Neeta Goli:
Is it typically diagnosed symptomatically or found incidentally in lab work?
Dr. Tanya Watt:
Usually these children are really sick and so it was diagnosed symptomatically. Most of the kids are quite anemic and so very lethargic, a lot of pallor, kind of not progressing along their milestones the way you would expect, and then the pediatrician will often do a CBC which will typically show hyperleukocytosis, anemia, and thrombocytopenia.
Dr. Neeta Goli:
What other symptoms or physical exam findings might we expect to see?
Dr. Tanya Watt:
Most of the children will have hepatosplenomegaly, often the liver's so large that they can lead to respiratory distress. And then a good majority of the children will have leukemia cutis, which presents as basically purple infiltrates of leukemic blasts in the skin or subcutaneous regions. So it looks like that blueberry muffin rash that we learned about in medical school.
Dr. Tanya Watt:
And about 50% of the children will have disease in their spinal fluid and brain. So therefore it can present, almost like a meningitis, with bulging fontanelle, lethargy, the worst cases have cranial nerve deficits.
Dr. Neeta Goli:
How is the diagnosis made?
Dr. Tanya Watt:
So it's made based on the presence of peripheral blasts with a high white count. Usually these children are anemic and thrombocytopenic. And then to determine which specific type of leukemia, we'll send flow cytometry that'll look at the proteins on the abnormal cells to determine the actual type.
Dr. Neeta Goli:
And then once the diagnosis is made, how is it managed?
Dr. Tanya Watt:
So, children receive chemotherapy to manage it. Usually they present with very, very high white counts, somewhere over about 300,000. And so while we're waiting to make the diagnosis, most of the children will receive a manual exchange transfusion. But as soon as we have a diagnosis, we like to start chemotherapy.
Dr. Neeta Goli:
And how does the prognosis of neonatal leukemia differ from that of leukemia diagnosed later in childhood?
Dr. Tanya Watt:
So unfortunately the prognosis is significantly worse. Children that are diagnosed at less than 30 days of age have a much, much higher risk of relapse, but also have a much higher risk of death from infections and other complications, and so supportive care becomes imperative in these patients. So making sure that we're having them on prophylactic antibiotics, having them on prophylactic antivirals, usually we'll use Fluconazole for an antifungal, make sure that they'll get Synagis when it's RSV season, just kind of doing everything we possibly can to decrease their risk of developing infection while they're getting intensive chemotherapy.
Dr. Neeta Goli:
And then if they do survive the intensive chemotherapy period in the initial phases, are there things that we should look out for as they get older?
Dr. Tanya Watt:
They get a lot of chemotherapy just because the prognosis is so poor, and so they're definitely at risk for long-term side effects. The main ones that we'll think about are secondary leukemias unfortunately. They can have some anthracycline-induced cardiomyopathy from the daunorubicin and doxorubicin that they receive, and then they receive a lot of steroids, so the complications that go along with that, so osteoporosis, cataracts, poor bone health.
Dr. Neeta Goli:
Okay. So lots of things that we need to kind of keep an eye out for.
Dr. Tanya Watt:
Yes.
Dr. Neeta Goli:
How long do you all follow these children after the diagnosis?
Dr. Tanya Watt:
We follow them lifelong. The way that our clinic works is that we will see them in the oncology clinic until they're two years from the end of their chemotherapy regimen. We do that because their highest risk of relapse is within that two-year period. And then we transition over to our survivor clinic, which we call the After the Cancer Experience or ACE clinic, where we follow them for long-term toxicity.
Dr. Neeta Goli:
Okay. And then to end the episode today, do you have any advice for our listeners while they care for newborns?
Dr. Tanya Watt:
Just that we always love to be called and so definitely if you see peripheral blasts at any point, please give us a call. Like I said, occasionally they're associated with a leukemoid reaction and nothing to worry about, but more often than not, they are things that we want to pay attention to.
Dr. Neeta Goli:
Thanks for joining us today Dr. Watt.
Dr. Tanya Watt:
Thank you.
Dr. Neeta Goli:
Thanks for listening to Newborn News; we hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests, and do not necessarily reflect the views of the university.