60 +1 Questions About Acute Lymphoblastic Leukemia in Children with Scott Howard

Professor Scott Howard is the Deputy Director at Yeolyan Hematology and Oncology Centerand the CEO of Resonance (ResonanceHealth.org). He is a pediatric hematologist/oncologist at St. Jude Children’s Research Hospital and a health economics professor at the University of Tennessee. He co-founded the Acute Leukemia Research and Care Network and the Global Neuroblastoma Network, advancing research in these areas.

Gevorg Tamamyan is the Editor-in-chief of OncoDaily, President-Elect of SIOP Asia Continental Branch and Pediatric Oncology East and Mediterranean (POEM) Group, and the CEO of the Immune Oncology Research Institute (IMMONC). He is the Chairman and Professor of the department of Haematology and Pediatric Oncology at Yerevan State Medical University.

He is a Co-Founder and Board Member of the Armenian Association of Hematology and Oncology, City of Smile Charitable Foundation, Co-Founder and Chairman of the Board of the Institute of Cancer and Crisis, the Former President of the Harvard Club of Armenia.

00:00 What is leukemia?
00:39 Discovery of leukemia
1:08 Subtypes of leukemia
1:18 Acute and chronic leukemias
2:18 Incidence of acute lymphoblastic leukemia
3:36 Risk factors for pediatric ALL
5:04 Environmental factors and ALL
6:42 Leukemia genetics
7:51 Immunodeficiencies and leukemias
9:28 Symptoms of pediatric ALL
10:52 Differential diagnosis of pediatric ALL
11:43 Pediatric ALL diagnostics
13:18 Atypical lymphocytes and lymphoblasts
15:24 Additional tests for childhood ALL
16:20 Skeletal changes in ALL
17:58 Bone marrow aspiration and/or biopsy?
20:30 M1, M2, and M3 in the classification of ALL
21:30 White blood cell count in diagnosing ALL
22:51 CNS disease
26:22 ALL immunophenotypes
26:45 Enlarged testis in ALL
27:50 Role of immunophenotyping
29:22 Lymphoid, myeloid, mixed lineage ALL, and biphenotypic leukemia
30:35 Role of genetic testing in ALL
32:01 Role of the Philadelphia chromosome in ALL
33:49 Philadelphia chromosome-like (Ph-like) ALL
35:15 Significance of translocation 12;21 in B-lineage ALL
37:11 Genetic abnormalities in ALL
39:26 Role of measurable minimal residual disease
42:19 Role of central venous catheters in the treatment of pediatric ALL
44:53 Main phases of treatment for ALL
46:08 Non-pharmacologic therapies in the treatment of pediatric ALL
47:52 Drugs for induction therapy in ALL
49:01 Consolidation therapy
49:44 Role of maintenance therapy
53:18 Male-female differences
53:50 Acute complications of pediatric ALL
55:28 Intramuscular chemotherapy in ALL treatment
57:33 Cranial irradiation in the treatment of pediatric ALL
58:07 CAR-T cell therapy for ALL
1:00:13 Potential side effects of CAR-T cell therapy
1:01:47 High-dose methotrexate
1:02:53 Methotrexate level monitoring
1:06:45 Treatment differences: Infants vs. adolescents
1:08:15 ALL in adolescents
1:09:44 Down syndrome and ALL
1:10:34 Relapse in pediatric ALL
1:11:27 Refractory pediatric ALL
1:12:34 Stem cell transplantation
1:13:02 Blinatumomab
1:13:58 Tyrosine kinase inhibitors
1:14:52 Molecular targeted therapy
1:15:46 Immunotherapy in ALL
1:16:43 Survival rate for pediatric ALL
1:17:18 Favorable and poor outcomes in pediatric ALL
1:17:56 Hyperdiploidy, hypodiploidy, and DNA index ploidy in ALL
1:19:17 Prognostic factors in pediatric ALL
1:20:01 ALL in LMICs and MICs
1:21:12 Current research
1:22:28 Most promising drugs in 2024 for ALL
1:25:15 AI and ALL

Gevorg Tamamyan: What is leukemia?

Scott Howard: Leukemia is one of the most important cancers of all humans, especially children.

One-fourth of all childhood cancer is acute lymphoblastic leukemia. But what is leukemia in the first place, and why do they call it that? It’s actually a disease that’s in the blood and the bone marrow.

And one cell of the bone marrow or the blood becomes a cancer. It doubles, then it quadruples, then it octuples. So then there’s 16 cells, 32.

It eventually reaches a trillion cells, and that’s enough to actually have symptoms and come to the doctor and get diagnosed.

Gevorg Tamamyan: How was leukemia discovered, and what is the meaning of its name?

Scott Howard: It was actually named based on the discovery. Leuke means white, and heme means blood. So leukemia makes sense.

White blood. And what happened is if you have a very high white count in your blood, you take your blood out, and it looks white in the tube instead of red. So they said, why is this blood of this person white?

And then when they looked in the microscope, they saw hundreds of thousands of unusual-looking white blood cells that turned out to be leukemia.

Gevorg Tamamyan: What are the main subtypes of leukemia?

Scott Howard: There’s two big branches, which is acute and chronic, and then each of those has subbranches that we’ll discuss in later questions.

Gevorg Tamamyan: What are the differences between acute and chronic leukemias, and how did these terms originate?

Scott Howard: I am glad you asked. So acute means something that happens fast. It’s just a one-time thing, happens fast, and sometimes goes away fast.

Unfortunately, acute leukemia, it’s something that comes on quickly, and it’s acute because the person would die very soon without treatment. Chronic things, on the other hand, are things that come along slowly and tend to slowly progress over many years.

So you could have acute kidney injury.

It means your kidney got damaged quickly. Or chronic kidney disease means your kidney is damaged over a long period of time. So acute leukemia comes on fast, needs immediate, urgent treatment to be cured.

Chronic leukemia comes on slowly, and you’ve got a little bit of time to think and really be careful about starting the treatment. And usually the treatments for the acute things are short. You cure the patient, or not sometimes, and you’re finished.

Chronic sometimes needs lifelong therapy.

Gevorg Tamamyan: What is the incidence of acute lymphoblastic leukemia among children, and which age group is primarily affected?

Scott Howard: Yeah, incidence is tricky. So the way incidence, or the meaning of incidence is the number of cases divided by the number of people who could have gotten that problem. So the incidence of leukemia, you have to say, well, if there’s 100 people who get leukemia out of a million people who could have gotten leukemia, then you say the incidence is 100 out of a million.

The tricky part is, in children, the incidence of leukemia, for example, in a newborn baby, is extremely rare. It can happen, you can actually be born with leukemia, but it’s like one in a million. It’s actually even less than one in a million.

But by age five, that’s the peak, where the most leukemia occurs. The average age is right there at age five. And at age five, actually, the incidence is 160 children per million per year, at that peak age group.

And then it rapidly falls off. And even adults get acute lymphoblastic leukemia, which slowly goes up in the 60s, 70s, and 80s. But the main peak is there at children aged two to ten years old, with the real peak, the peak of the peak, at age five.

That’s for acute lymphoblastic leukemia. There’s another one, acute myeloid leukemia. And that one is just more and more.

The older you get, the more myeloid leukemia you get. So it’s more common in adults, by far.

Gevorg Tamamyan: What are the known risk factors for developing pediatric ALL?

Scott Howard: There are very few known risk factors. And one of them is genetics. So there are certain ethnic groups that actually have a higher risk of leukemia.

The best study to be used is actually people who are Native American, have Native American ancestors. Of course, in North America, Native American is almost always mixed with Europeans or Asians or various other ethnic groups. So there are only a few countries, one of them is Guatemala, where there’s a high percentage of Native American ancestry in most people.

And it turns out, in Guatemala and places like it, there’s a higher risk of leukemia based on genetics. But it’s nothing to be worried about if you happen to be from Guatemala. Why?

Because imagine that Guatemalan people have 20% more risk of getting leukemia. That sounds bad, right? 20% more risk.

But if your risk of getting leukemia was already one chance in 100,000, and now it’s 1.2 in 100,000, it still means it’s not going to happen. Whereas if you have a 20% chance more risk of getting a car wreck, well, your chance of having a car wreck in a 10-year period is going to be 1 in 3. So a 20% increase is really bad if you’re talking about a car wreck.

But if you’re talking about something really rare like leukemia, it’s not something you should even think about at all, neither when you wake up nor when you go to sleep, because the risk is so tiny.

Gevorg Tamamyan: Is there a link between environmental factors and ALL?

Scott Howard: Yeah, the link between… So ALL is acute lymphoblastic leukemia, the most common leukemia in children. And the link here is that there are many things that have been accused of causing ALL.

Power lines. There were people who lived near power lines, and several of their children got ALL. So people said, it must be you live near a power line, you get ALL.

That could be bad. But then they did a study of everybody who lives near power lines, and a study of everybody who’s way far away from power lines and power generators. And it turns out it was exactly the same.

People studied certain schools. There were some schools where in one class two children got ALL. And so they said, what’s wrong with this school?

There must be something. Does two people have a one-in-a-hundred-thousand thing happen to them? How is that possible?

But it turns out there are hundreds of thousands of schools all around the world. So it’s very likely that two children will get ALL in the same school, sometimes even in the same year, if you think about all the schools that are out there. And sure enough, when they studied all the schools and the things that are in schools, the paint they use, the books they use, everything you could imagine about the school, nothing could be found that was increasing the risk of ALL.

So, so far, there’s nothing in the environment that will increase the risk of ALL. But you can guarantee there’s going to be some bad luck place where two children get ALL in the same time, and somebody’s going to think whatever happened there is the problem. But probably it won’t turn out to be the case once the big study is done.

Gevorg Tamamyan: What genetic and constitutional conditions can predispose to developing leukemia?

Scott Howard: Hmm, yeah. So now I have to put a nuance on what I said before, because we talked about your genetics and your ancestry. Native American has a slightly increased risk.

We talked about the environment. Environment doesn’t matter. But there are certain conditions.

One of the most common one is called Down syndrome or Trisomy 21. And this is an inherited genetic problem where you’re born with an extra chromosome 21. And this comes with all sorts of problems.

It can have heart problems and thyroid problems, but also a much higher risk of leukemia. And what’s interesting is in Down syndrome, it’s not just a 20% increase like if you were in Guatemala. It’s not a 0% increase like if you’re near a power line, but it’s actually a massive increase, maybe even a hundredfold increase.

I don’t actually remember the number, but the good news is imagine now you have a child with Down syndrome, and now instead of a 1 in 100,000 risk, now it’s 1 in 1,000. That’s a hundredfold increased risk, but it’s still only 1 in 1,000. So again, it’s not something you would need to worry about day by day as you’re raising your child.

Gevorg Tamamyan: How do immunodeficiencies increase the risk of developing leukemias such as acute lymphoblastic leukemia?

Scott Howard: Yeah, that’s a great question. So they do it in two ways. So the first way is people with immunodeficiencies often have some other problem.

So we just talked about Down syndrome. People with Down syndrome, I mentioned thyroid, I mentioned heart problems, I mentioned leukemia, I didn’t mention immune system problems. But people with Down syndrome actually have differences in their immune system, and that’s one of the reasons that they have a higher risk of leukemia.

But anybody who has a problem with their immune system can also have a higher risk of leukemia and other cancers. Where do we learn this? Unfortunately, we learned this with the AIDS epidemic because then we had hundreds of thousands, millions of people around the world who had terrible immune systems because the HIV, the virus that causes AIDS, had destroyed parts of their immune system.

So what we learned, unfortunately, is that after the immune system is gone, a bunch of different cancers can emerge with a higher risk of lymphomas, leukemias, melanomas. And it turns out the immune system has always been critical to control cancer. We just didn’t know until there were millions of people with a bad immune system.

It turns out when a cell turns into cancer, maybe it’s trying to become a melanoma, one melanoma cell, then two, then four, then eight, and it’s slowly growing, the immune system can sometimes see that cell and that mass of cells and recognize it’s not supposed to be there and wipe it out. And would I know that that happened? I wouldn’t know.

All I would know is I don’t have melanoma today, but I wouldn’t know that a year ago I would have had melanoma except my immune system took care of it. So any time the immune system is altered, the risk of cancer can unfortunately increase.

Gevorg Tamamyan: What are the most common symptoms of pediatric ALL?

Scott Howard: The most common, well, there are five actually.

I’m not sure which is the most common, but the one that most often is little petechiae. And what is a petechiae? It’s a tiny red flat dot that usually is caused by low platelet count.

But the petechiae can be caused by many other things. So it’s a symptom of leukemia, but it’s a symptom of anything else that can lower the platelet count or decrease the platelet function. Fever is also one of the top five.

Of course, fever is much more likely to be some infection than it is to be leukemia. A large spleen, though, is really helpful. So if you have a very large spleen, the list of problems that can cause a large spleen is much narrower.

So now imagine if you have petechiae and a high white count and a large spleen, then suddenly you’re focusing in on cancer as a more likely cause. However, there are plenty of infections that can cause those three things. Anemia, which is a low red blood cell count, can also be caused by leukemia.

And fatigue from anemia, headaches from anemia, any symptom of anemia can be present in a person with leukemia. And then the fifth one is if the white count gets really high, there could be neurologic symptoms and respiratory problems. That’s less common.

So top five would be fever, large spleen, large liver, and anemia, any symptom of anemia.

Gevorg Tamamyan: What are the key differential diagnoses to consider for childhood acute lymphoblastic leukemia?

Scott Howard: Yeah, so let me extend what I said just now, which is if you have a low red cell count, anemia, then any symptom of anemia. But imagine the cause of anemia, iron deficiency anemia, sickle cell anemia, thalassemia, which comes with anemia.

There are just dozens, perhaps hundreds of causes of anemia. Low platelet count, thrombocytopenia. Again, many causes of thrombocytopenia, but we don’t want to imagine what they could all be.

If you have thrombocytopenia, there’s a certain series of steps you go through to find out the cause. And high white count infections can also cause high white count fever infections. So mostly infections are the great mimicker of leukemia.

And that’s the first thing that you have to figure out before you diagnose leukemia.

Gevorg Tamamyan: How is acute lymphoblastic leukemia diagnosed in children? What routine lab tests are used and what abnormalities are typically observed in these tests?

Scott Howard: Yeah, the diagnosis is the most important thing. You can’t treat leukemia unless you know it’s leukemia. And let me just emphasize, if somebody has suspected leukemia, you must not start treatment.

So don’t start steroids or prednisone or dexamethasone. And I’ve personally received patients where the ER doctor said, Oh, they have some big lymph nodes. Let’s give some steroids and shrink those lymph nodes down.

This is terrible because sometimes this can hide the leukemia and delay the diagnosis because there is a temporary response to the steroids. They can never cure leukemia, but they can certainly shrink lymph nodes, which is another, the sixth most important thing in leukemia is large lymph nodes. So the key for diagnosis is, first of all, to not treat until you have a diagnosis.

And then second of all, it’s always a blood test. And so the blood test will show anemia, thrombocytopenia and high white count, but not always a high white count. Half of people with ALL have a normal white count, 10,000 or lower.

The other half have 11,000 or higher. So high white count is not required to diagnose leukemia. But if you have a high white count, 100,000 or 200,000, almost always it is leukemia or some other type of leukemia type cancer.

And the diagnosis then is just a simple blood test, which goes to the lab. We look at it in the microscope. We do flow cytometry and take it from there.

If there’s not a lot of white cells in the marrow, in the blood, we can do a bone marrow aspirate and get the cells out that way and examine them in the lab the same exact way.

Gevorg Tamamyan: How can atypical lymphocytes be differentiated from lymphoblasts?

Scott Howard: So we’re talking about three types of cells. A lymphocyte is a normal cell that fights infection. An atypical lymphocyte is a lymphocyte that looks strange.

And a lymphoblast is a lymphocyte that is in a very early lymphocyte that can be normal, or it’s a very early lymphocyte that has mutated to become cancer and is now growing and causing lymphoblastic leukemia. So all leukemias are named after their cell of origin. And in fact, all cancers are named after their cell of origin.

Colon cancer is named after the colon because it’s a colon cell that became cancerous.

So leukemia, we know it’s white blood, cancer in the blood. But where did it come from?

There was a lymphoblast, a normal lymphoblast, that then developed a mutation. And instead of going on and becoming a lymphocyte, instead it just started dividing out of control and never differentiating into a lymphocyte. And those lymphoblasts have a characteristic appearance, but most of us aren’t so good that we can tell the difference in an atypical lymphocyte and a lymphoblast.

And the key there are specialized tests like flow cytometry.

Gevorg Tamamyan: How can granular ALL be identified?

Scott Howard: This is another example. So granular ALL is just a lymphoblast that has some granules in it. And those granules are, say, typical.

Otherwise, it would be normal. But it’s not typical of lymphoblasts to have granules. But they can have granules.

And why? Because when a cell becomes cancerous, it starts dividing out of control.

One mutation happened to cause the cancer to start.

That’s called the driver mutation. So it drives that thing forward. But then there’s secondary mutations and third mutations and fourth and fifth.

And those other mutations can make the cell behave in a strange way. It can make the cell produce granules, for example, that it’s not supposed to produce. But it’s a cancer cell, so it’s doing all kinds of crazy things.

And these granules then have a very characteristic appearance in the microscope. So most people can determine granular lymphoblasts versus normal lymphocytes. But the best test is flow cytometry because that gives you the final answer.

Gevorg Tamamyan: What additional tests and procedures are used to diagnose childhood ALL and what abnormalities are seen?

Scott Howard: I’m glad you asked because flow cytometry has been mentioned before. And flow cytometry is the way to go. So what is flow cytometry?

You pass the cells through a column. And the column has antibodies and like an anti-CD20 antibody. So if that cell has CD20 on the surface, it will stick to the antibody.

And you’ll know that cell was CD20 positive. There are different colors of lasers that go through there and tell you which cells are positive for which surface antigen. So the surface antigens on lymphoblasts are very different than the ones on lymphocytes.

And so you can tell what is a lymphoblast by the panel of markers that’s beyond the scope of this course today. But that panel of markers can tell you for sure is it myeloid leukemia or lymphoblastic leukemia. If it’s lymphoblastic leukemia, is it T-cell leukemia or B-cell leukemia?

And I’ll talk about that in later questions.

Gevorg Tamamyan: What skeletal changes can be observed on X-rays in patients with acute lymphoblastic leukemia?

Scott Howard: There are a bunch of skeletal changes. And so these are… Most of us don’t do any X-rays on people with leukemia as part of the regular diagnosis.

But they often arrive already having X-rays from the emergency department. And why? Because the seventh symptom that you can come with leukemia is bone pain.

And the bone pain is because there’s leukemia in all the bone marrow. And it causes swelling and inflammation in the bone marrow. But you don’t say, oh, I have bone marrow pain.

You feel just bone pain throughout the bone because it’s in the marrow. It’s on the periosteum around the bone. And so this bone pain can be pretty disturbing.

And if you have bone pain like in the spine, people might think, oh, maybe you have a spinal fracture. Or if you have bone pain in your arm, maybe they think you have a fracture of your arm or some trauma to your arm. So sometimes people arrive with different X-rays.

The most common thing to see is thin bones, osteopenia. And osteopenia is there because the leukemia is producing all kinds of cytokines that make the bones thin out. The calcium in the bones leaches out.

In fact, kids with leukemia can actually have kidney stones from leaching out the calcium from their bones. And then they have high calcium in the urine, which can actually precipitate as a kidney stone. The second finding, though, is vertebral compression.

And so this is the vertebral bodies when they get really thin. Then even normal things, you step off a curb, and you can have a spontaneous fracture, just like an elderly person with osteoporosis might have. Even children can have these skeletal fractures, vertebral fractures.

So that would be the two most common is thin bones and vertebral fractures.

Gevorg Tamamyan: Is it recommended to perform bone marrow aspiration and or biopsy for diagnosing pediatric ALL? And what are the procedures for each?

Scott Howard: Yeah, so the diagnosis of all acute leukemias and all chronic leukemias depends on having enough cancer cells to do all the tests. And what are all the tests? So test number one, look in the microscope.

Test number two, flow cytometry. Test number three, molecular biology and cytogenetics, looking for very specific mutations. So no matter which body part, you can get all those cells.

It’s perfectly fine. For me, the best place to get those is the blood, because you just do a simple blood test, get four or five tubes of blood, and send those off to the different places to do those different tests. That only works, though, if you have plenty of leukemia in the blood.

And I mentioned earlier that half the people don’t have a normal white count, so they don’t have hundreds of thousands of white blood cells, leukemic white blood cells circulating around. So in that case, they need a bone marrow aspirate. Bone marrow biopsy is not really necessary anymore because bone marrow aspirate is sufficient for pretty much every test, including flow cytometry, molecular tests, and morphology in the microscope.

So it’s a good question because there was an evidence review, and in the evidence review, it was for the country of Colombia. And this was commissioned by the government of Colombia, and they hired a bunch of epidemiologists, and they wanted the best evidence. And in their evidence review, they said you have to do a bone marrow for diagnosis of leukemia.

And for 30 years, we’ve been not doing bone marrows. We’ve been taking the peripheral blood, and it’s perfectly fine. We get a good diagnosis.

But nobody ever wrote a paper about that because it’s not very interesting to say we made a normal diagnosis, just like normal people do every single day, just by getting the leukemia cells from the blood or the bone marrow. Either place is fine as long as there’s leukemia cells. So there was no paper about this.

So then the epidemiologist said there’s no published evidence that it’s okay to take peripheral blood. So this evidence, I don’t think it should ever be published because it’s not interesting. And then I was thinking maybe sometimes we should write these papers about uninteresting topics just so that people can find out these topics and realize there is plenty of evidence, and the evidence is hundreds of thousands of children, adults, old people, young people have been diagnosed by a blood test, not by a bone marrow aspirate.

And what’s great is some of those people never have to have a bone marrow aspirate, which can be quite painful. And so in kids, we do it under anesthesia, and anesthesia can have some side effects. So if you can avoid a bone marrow aspirate, I would definitely avoid it. 

Gevorg Tamamyan: What do M1, M2, and M3 represent in the classification of acute leukemia?

Scott Howard: Yeah, so the M1 through 3, there’s two M classifications, and so it’s easy to get confused. So one is in acute myeloid leukemia, there are seven. So they say it’s AML, actually there’s eight.

AMLM0, AMLM1, AMLM2, all the way to AMLM7. And that refers to the way it looks under the microscope. None of those really matter because now we do genetic testing, and that tells you what you need to know.

But for lymphoblastic leukemia and for myeloid leukemia, there’s another M classification, which is the marrow response. And so M in that case is for marrow, not for the morphology. So AMLM0, M1, M2, M3, M4, M5, that’s the morphology of the AML.

But the M1, M2, M3 is the marrow response. And if you do a marrow, and you say there’s tons of leukemia here, that’s M3, if there’s 25% or more leukemia. If there’s 5%, less than 5%, then it’s M1, and if there’s 5 to 25, it’s M2.

Gevorg Tamamyan: What role does the white blood cell count play in diagnosing acute lymphoblastic leukemia?

Scott Howard: Yeah, it plays three roles, and it’s lucky because it gives me a chance to review some of the previous questions. So the first role is when you think of differential diagnosis, what could this disease be? Is it leukemia or is it anything else?

If the white count is 10,000, and the person has some symptoms, fever, and a white count of 10,000, it’s a lot of times it’s infection. But what if they have a fever and a white count of 200,000? There’s very few infections that raise the white count up to 200,000.

So the higher the white count, the more likely it is to be leukemia. If the white count is above 200,000, it’s almost always leukemia. Even though leukemia is quite rare, it’s not rare in people who have a 200,000 white count.

So you found that rare, the needle in the haystack, because you got rid of all the other hay, and so now there’s just the needle in one piece of hay, because there’s hardly anything besides needles that gives you 200,000 white count. But the other thing it tells you is you don’t have to do a bone marrow biopsy or bone marrow aspirate, because if there’s 200,000 white cells in the blood, leukemia, white blood, you can pull that blood and you can see it in the tube sometimes that it’s leukemia.

But of course, you can take it to the lab and it would be very obvious, and that one blood test would be enough for all of the tests.

So high white count means it’s likely to be leukemia. It also means it’s easy to diagnose that leukemia without a bone marrow aspirate.

Gevorg Tamamyan: What is central nervous system CNS disease? How is it diagnosed and manifested? And what do the CNS1, CNS2, and CNS3 classifications indicate in acute leukemias?

Scott Howard: Yeah, this is a great question, because this is a rapidly changing area. And so central nervous system, or CNS is for central nervous system, makes sense. So people with leukemia can actually have the leukemia invade into their central nervous system.

And the way this is diagnosed is with a lumbar puncture. And then you go look at the spinal fluid, and if the spinal fluid has five white cells or more, and presence of leukemia, then it’s CNS3. If it has no white cells at all, or it has white cells but no leukemia, then it’s CNS1.

And if it’s anything else, it’s CNS2, the intermediate category. There’s another way, though, to be CNS positive, and that’s to have a neurologic symptom. And the typical neurologic symptom is actually a cranial nerve palsy.

So usually it’s like the facial nerve palsy, so you’ll see a drooping face, or sometimes a cranial nerve 3 palsy, so you’ll see eye findings, or a droopy eye, or the strabismus, and the eyes don’t converge. So a CNS status is two things. One is a neurologic exam, mandatory in every person with new leukemia.

And number two, a careful neurologic exam, not like a quick one that you might do for someone with pneumonia, but a really good one. And the second thing is to do a spinal tap and see how many white cells are there, and if there’s leukemia there. But, but, but, it’s a rapidly changing field.

And it turns out, for the past 70 years, we’ve been doing a spinal tap, and it turns out, after every spinal tap, there’s bleeding into the spinal fluid. And now imagine you have leukemia, there’s leukemia cells in the blood, in almost all leukemia patients when they arrive. So when you do a spinal tap and now there’s bleeding into the spinal fluid, you’re bleeding leukemia into the spinal fluid.

And now leukemia can then hide there, and most of the chemotherapy that we use doesn’t reach the spinal fluid. A few things do, steroids do, asparaginase does, high-dose methotrexate does, but lots of the other treatments don’t reach the spinal fluid. So it’s called a sanctuary site where this leukemia can hide.

And in the old days, we did a lumbar puncture to make the diagnosis, and then a day or two or three later, we said, oh, yep, it’s leukemia, and they have a CNS disease, we do another lumbar puncture to give chemotherapy directly into the spinal fluid, intrathecal chemotherapy. And so it turned out that second lumbar puncture was almost always had blood in it. And I wondered, when we were evaluating this, why did it always have blood in it?

And the reason is the blood is leaking from the first lumbar puncture. So it turns out, if you do the first lumbar puncture way later, seven days later, or ten days later, or twelve days later, it’s much safer, and you’re less likely to bleed leukemia cells. One study in Taiwan, they did the first lumbar puncture ten days later, after starting all the treatment.

So many of the patients had no leukemia left in their blood. They had the best protection of their central nervous system. But it hides, there’s no CNS2, there’s no CNS3, there is no CNS disease if you do that strategy, because you’ve cleaned up the CNS disease by giving the steroids and asparaginase to those patients.

So the classification in the future won’t matter at all, because the most important thing is to treat the patient the right way. We used to think we had to classify them. Now we know we’d better not classify them, because if we classify them, it means we have to do a lumbar puncture, and we’re putting leukemia cells directly into their spine, in their spinal fluid, with the bleeding after the lumbar puncture.

Gevorg Tamamyan: Which ALL immunophenotypes are most likely to have CNS disease at diagnosis?

Scott Howard: There are two main phenotypes of T lineage ALL and B lineage ALL, and the T lineage is most likely to invade the CNS. There are a few special, though, special molecular translocations, like a 119, which is more likely to go to the CNS. So even though translocation 119 is B lineage, it has a higher CNS risk.

Gevorg Tamamyan: What is the significance of an enlarged testis in ALL, and how frequently does it occur?

Scott Howard: Yeah, that’s a great question. So I mentioned doing a good neurologic exam. Anybody with new leukemia, if it’s a boy or a man, they also need a careful testicular exam.

And even if it’s an adult, they might not have noticed that when there’s leukemia in the testicle, it’s painless. And so usually, if it’s a small child and it’s a big testicle, the parent might have noticed changing their diaper. But if it’s an older child or an adult, nobody might have noticed, the person themselves might not have noticed.

So every male patient needs a careful testicular exam. And why? Because the testicle is like the spinal fluid.

It’s a sanctuary place. And many different chemo agents don’t get into the testicle. So if the testicle is infiltrated with leukemia at diagnosis, that patient needs extra treatment to make sure the testicle can be treated to remission.

Luckily, with modern treatment, there’s hardly ever any testicular relapse. This used to be a big problem in the 80s and 90s. But with the current protocols, it’s really very nicely controlled.

Gevorg Tamamyan: What role does immunophenotyping play in diagnosing acute lymphoblastic leukemia? How is it performed? And what are the immunophenotypic characteristics of ALL?

Scott Howard: Yeah, that is another interesting question. So what is immunophenotyping? It sounds quite magical, but really it’s all in the word.

Immuno and phenotype. So a phenotype is what something looks like. A genotype is the genes that make it look like that.

So my phenotype is I have pink skin. Why? Because my genotype is Irish.

But the phenotype of a leukemia cell is measured by all the things on the surface. And so an immunophenotype is you’re using antibodies, antibodies like from the immune system, to identify markers on the surface. And so flow cytometry, what is flow cytometry?

Cytometry, again, is cytometric, cells that get counted. So flow cytometry is you flow a bunch of cells through a column and count them. And you’re counting each cell.

Is this cell CD20 positive? Is the next cell CD20 positive? Is the next one CD20 positive?

And as they’re flowing through there, is it CD3 positive, CD4 positive, CD8 positive? So all these markers are looking for each of the things on the surface. And they’re called CD, which is a long story.

But basically, there’s CD3, CD4, CD8. And if you have this panel of CD markers, some panels show that it’s T cell, T lineage, or T immunophenotype. All three of those mean the same thing.

Or B lineage, B cell, B immunophenotype. All three of those mean the same thing. It just means the panel of markers tells you this thing came from a B lymphoblast, this other one came from a T lymphoblast.

But patients have to have either one or the other, or some special situations that we’ll talk about later.

Gevorg Tamamyan:  What are lymphoid, myeloid, mixed lineage, ALL, and biphenotypic leukemia, and how are they diagnosed?

Scott Howard: And when I say talk about it later, I mean right now, the very next question. So mixed lineage, what does that mean? That means, yes, every cancer starts as one single mutated cell.

But it doesn’t necessarily finish there, because that cell is growing out of control. Imagine one cell grows and grows and becomes a trillion cells. If any of those trillion cells switch the way they look, or switch the way they behave, they might show up instead of as a B lineage cell, now it’s a T lineage cell.

And so if you have a mixed lineage, it means in the trillion cancer cells, there’s some T lineage and some B lineage. Or sometimes the mix is not an ALL, it might be a mix of myeloid leukemia and lymphoid leukemia. So you might have a myeloid clone and a T lymphoblastic clone.

So mixed lineage means there’s more than one type of leukemia cell. Of course, they always have the same origin. I’ve never heard of a case where someone had two simultaneous different cancers that had a different driver mutation at the beginning.

So at the beginning, it’s always one cancer cell, but as it grows, it can differentiate into multiple subtypes.

Gevorg Tamamyan: What role does genetic testing play in acute lymphoblastic leukemia, and what are the common genetic changes associated with this condition?

Scott Howard: There are many types of genetic testing. So cytogenetics, boy, this feels like an English vocabulary lesson. So cytogenetics is the genetics of a cell.

And it’s where you take a cell that’s in the mitotic phase, the M phase, and you look in there and see which chromosomes are rearranged. And there’s a whole bunch of them that can be rearranged. But many children with ALL and AML, myeloid leukemia, they have cytogenetics that can be normal.

So there’s not always something that you see there. But there are certain driver mutations that we’ll talk about later that have a very important meaning. They need a different treatment, or they need a different amount of chemotherapy.

And so basically the cytogenetics and the other genetic tests are all great. But they will all be replaced eventually by next-generation sequencing. And next-generation sequencing is where you sequence the entire genome of the cell.

And the great thing about 2024 is that you can now do this cell-by-cell-by-cell. So you’re not sequencing the average of a trillion cells. You can do single-cell sequencing and find out exactly the features of that leukemia.

And right now today, it’s very hard to translate those hundreds of millions of pieces of data into a treatment plan for the patient. But that’s going to be fixed pretty soon. We’ll talk about that at the end.

Gevorg Tamamyan: What is the role of Philadelphia chromosome in ALL? How was it discovered and why it is named that way?

Scott Howard: Well, you might guess Philadelphia chromosome was discovered in Philadelphia.

And lots of things were named that way over the years. I don’t think it happens so much these days. But there’s a syndrome called Nijmegen-Breken syndrome.

And it had the bad luck to be discovered in Nijmegen. Which is a city in the Netherlands. So you hope to discover everything in an easy to pronounce city like Philadelphia.

So in this case, it was discovered in Philadelphia. And what they discovered was chromosome 9 and chromosome 22. A broken piece of chromosome 9 had attached to a broken piece of chromosome 22.

And when it attached, it put one gene in front of another gene. So the chromosome is the whole batch of thousands of genes. But at the site of attachment, the first gene is BCR and the second gene is ABL.

So it’s called BCR-ABL translocation because it’s translocated to put those next to each other. And it turns out the ABL gene makes cells grow and proliferate. The BCR gene makes cells not turn off.

So it’s like pushing overdrive, grow, grow, grow. So normal ABL has before it a nice part of the gene that tells it when to turn on and when to turn off. And some cells need to grow like the brain.

It grows a lot in a baby, you know, as the baby is being formed in utero. And once the baby is born, it grows a little bit more and then it quits. And if the brain kept growing after the skull is finished, it would be a disaster, right? So the brain has to know when to grow and when to stop growing.

But imagine now, instead, you put the always grow gene in front of the growth gene. That’s what happened with the Philadelphia leukemia, Philadelphia positive leukemia. So then people said, well, it’s either Philadelphia positive or Philadelphia negative.

And that’s one way to divide leukemias into two categories. And it matters a lot because of the treatment is quite different for Philadelphia positive.

Gevorg Tamamyan: What is Philadelphia chromosome-like (Ph-like) ALL?

Scott Howard: Yeah, so pH-like is, so they had to stick with pH for Philadelphia starts with P and H. So P positive, pH positive is the abbreviation in the medical literature.

And Philadelphia-like means that these cells have certain genetic characteristics that remind you of Philadelphia positive. They’re not Philadelphia positive. They don’t have the BCR in front of the ABL.

But they have other changes that make them grow out of control and look like Philadelphia-like. But it turns out to be really important to distinguish between these two. Because Philadelphia chromosome is treated with tyrosine kinase inhibitors.

In fact, the first and best targeted therapy was imatinib. For Philadelphia-like acute lymphoblastic leukemia, it was actually discovered in chronic myeloid leukemia. Same translocation is present in chronic myeloid leukemia.

Which is lucky because we got for free an extra medicine for acute lymphoblastic leukemia that was discovered for the other cancer. But Philadelphia-like doesn’t respond the same way to imatinib or dasatinib or nilotinib or conatinib. It actually requires a much more detailed molecular analysis to know how to treat it.

But it does have a worse prognosis. So you have to really think carefully about how to treat Philadelphia-like. It’s different from… So now you have Philadelphia, Philadelphia-like, and non-Philadelphia, non-Philadelphia-like.

So now you could say there’s three categories. One way to think about it.

Gevorg Tamamyan:  What is the significance of translocation 1221 in B-linage ALL?

Scott Howard: So translocations always mean I took a piece of one gene and I attached it to a piece of another gene.

And they always do the same thing. Which is they either make the cell grow more, or they make the cell unable to stop growing. Or they make it unable to differentiate.

So that it just keeps growing like the lymphoblast. It’s destiny when it’s formed.

Lymphoblasts are a normal cell in the body.

They’re supposed to be there. So you start out with a stem cell. Then it becomes a lymphoblast.

And then it becomes a lymphocyte. And then it does its job. If you give it a mutation, you can stop this differentiation.

And now it’s stuck as a lymphoblast. And instead of going on to become a lymphocyte, it just starts dividing and dividing and dividing. And when you get a trillion of them, now you have lymphoblastic leukemia.

Because a trillion cells is enough to make a mass of cells that you can measure. And that causes symptoms. So what is the translocation 1221? It’s just one more of those translocations that starts the process of driving excessive growth of the leukemia cell.

It turns out, though, these translocations are a little bit useful for treatment. Because 1221 is a low-risk leukemia. It usually means it responds very well to the standard chemotherapy.

Like old chemotherapy from the 60s and 70s is enough to cure like 80% of people with 1221 translocation. By contrast, the Philadelphia positive and the Philadelphia like had a much lower cure rate in the 60s and 70s. Because there were no targeted therapies.

And they were resistant to some of the standard chemotherapies. So the translocation is interesting from a biologic point of view. Because it tells you what started that leukemia in the first place.

But it’s also useful from a treatment point of view. Because it tells you is this a low-risk patient or a medium-risk patient or a high-risk patient. This one needs less chemo.

This one needs more. And this one needs a lot. Or some targeted treatments.

Gevorg Tamamyan: What genetic abnormalities are most likely to be seen in the infant ALL? Less than 12 months old.

Scott Howard: Yeah. So infant ALL is a really important group. Even though it’s so rare. So, so rare.

But imagine you have a new baby. Your baby is 6 months old and now develops leukemia. It turns out this infant ALL used to have really terrible results.

Like 50% survival. Compared to 5-year-old who develops ALL had 85% survival. So really big difference.

And why? A lot of reasons. So one is an infant has different mutations. Different driver mutations.

And one of them is called MLL or KMT2A. There’s actually a bunch of different ways to cause an infant ALL. Almost all of them are bad.

But you can go look it up if you have a baby with MLL rearrangement. There’s a few MLL rearrangements that aren’t so bad. And a few that are really terrible.

But pretty much most are terrible. So that doesn’t help you though. Because until recently there’s been no targeted therapy for babies.

No matter what the translocation they have. Now there’s some new treatments called menin inhibitors that are relevant for some of these patients. But the most important thing that’s come recently is Blinatumomab.

And Blinatumomab is great because it doesn’t care what type of leukemia you have. As long as it has CD19 on the surface. The Blinatumumab can find that cell and help the immune system to kill that cell.

So what’s great is a resistant leukemia. Philadelphia positive. Philadelphia like.

Infant ALL. And they’re resistant. But you can’t say something is resistant.

Unless you say resistant to what? Because it’s resistant to the old chemo from the 70s, 60s and 70s. It’s not resistant to the new chemo like Blinatumumab. Because Blinatumomab doesn’t care what’s inside the cell.

The biology of the cell. All it cares is does it have CD19 on the surface. I’m going to bring in a T cell and kill it.

And it doesn’t matter if it had resistant mechanisms inside it. The biology of the cell is irrelevant if you’re killing it from a surface attack. So the great thing about the modern day is we have all the old tools.

Great chemotherapy, methotrexate and prednisone. And mercaptopurine from the 50s and the 60s. And that works great for most patients.

And then we can add to it the surface attacks for cells that have a resistant biology. Like Philadelphia. Philadelphia like.

And infant ALL.

Gevorg Tamamyan: What is the role of measurable minimal residual disease studies in the workup of pediatric ALL? Why is it important and how is it checked?

Scott Howard: Yeah, so MRD is a very popular buzzword. MRD used to be minimal residual disease.

And then we all started arguing, well what is minimal? Is it really, is it .1% leukemia? Is it .01% leukemia? Is it .001% leukemia? And so ultimately people said measurable residual disease. And this is a, I love this new term. Why? Because measurable means you can measure it.

Minimal, it depends on which way you measured it. If you use flow cytometry, you say you count a million cells. And if 100 of them are cancer, that’s 1 in 10,000.

.01%. And flow cytometry couldn’t really get you much lower than .01%. Then you have molecular biology. That’s looking for a special, that mutation, that translocation. And that can be detected with a PCR test, polymerase chain reaction test.

So the PCR test could find 10 cells out of a million. Because it’s very, very sensitive. It amplifies the translocation and then measures it.

So it can amp up the sensitivity. But next-gen sequencing actually can find one leukemia cell out of a million cells. And so measurable, the definition of measurable has changed as new measurement techniques came on board.

Flow cytometry, 1 in 10,000, .01%. Molecular biology, 1 in 100,000, .001%. And next-gen sequencing, 1 in a million, .001%. So any of those mean measurable disease. And why does it matter? If you can still measure the disease, that patient has billions of leukemia cells. So remember, 1 cell, you can’t measure it. 2, you can’t measure it. 4, 8, 16, 1,000, 2,000, 100,000, you can’t measure it. Only when you have a trillion cells does the patient develop symptoms.

Because that would be a cancer mass like the size of an orange. A trillion cancer cells.

So then you can measure that.

As you’re treating it, you go from a trillion to 100 billion, to 10 billion, to 1 billion, to 100 billion, to 10 billion, to 1 million. And so now let’s think, from a trillion to a million, that’s .001% of what we started with. And now we can measure .001%. So if the next-gen sequencing is positive, it means you’ve got at least a million cancer cells in that patient.

At least a million. If you can measure it. And that’s plenty to cause a relapse.

You’ve got to treat that thing all the way down to 10, 1, and 0. It only took 1 cell to become the cancer. It’s got to be down to the last cell, eliminated, to prevent a relapse of the cancer. So being able to measure more and more sensitively gives us an idea of when we can’t measure it anymore, but we know there’s still a million left, so we still have to finish the treatment.

But at least we know we’re making progress. So measurable residual disease is a marker of making progress. If it’s still positive, it’s really a disaster.

Especially later on in the treatment.

Gevorg Tamamyan: What is the role of central venous catheters in the treatment of pediatric ALL?

Scott Howard: Central venous catheters are just one way to put the chemo into the patient. Nowadays, what is chemotherapy? Chemotherapy doesn’t have to be something that comes intravenously.

It could be pills. Mercaptopurine is a pill. Prednisone is a pill.

Prednisone, I know what you’re thinking. Is prednisone really chemotherapy? It’s a steroid. We use it for asthma, not for cancer.

It’s funny, because at our hospital where I worked for a long time, we would argue, does prednisone require two signatures? Because if you have chemotherapy, it’s got to be signed by two doctors before you can release it. Because it could be so risky to the patient. And we said, but prednisone, sometimes I’m using it if they have asthma.

Sometimes I’m using it to treat their leukemia. So do we need two doctors to sign it, or not? And is it chemo? So the answer is, it’s chemo if you’re using it to treat cancer. So anything used to treat cancer is chemotherapy, even if it’s something you already knew about, like prednisone.

And it turns out methotrexate is great for many different types of lymphoblastic leukemia. But it’s also used for rheumatoid arthritis. So is methotrexate chemo? No, only if you’re using it to treat cancer.

So by convention, we say if you’re using it for cancer treatment, it’s chemotherapy. Or targeted therapy, is another thing we could call it.

Well, if it’s IV chemo, you can give it in a peripheral vein.

 

But if you have to give hundreds of doses, that’s a lot of peripheral veins that you have to stick. Many countries just do that. So they’ll stick this vein, the next time they’ll stick this vein, the next time this one, this one.

And they’ll finish all the treatment with no central catheter. In most high income countries, people put a central catheter for the convenience of the patient and the nurse and the doctor. The good thing about that is you can just push the medicine right into the central venous catheter.

The bad news is you can also get infection into the central venous catheter. So in some places, in one place where a friend of mine works, they were so happy they got a donation of a bunch of central venous catheters. And they had to use only IVs before that.

So they were so happy, they put in a hundred venous catheters into a hundred patients from this donation. And several of those patients got severe infection and nearly died of infection. So they took out the other 98 after those two severe infections.

And so if you’re going to use a central venous catheter, you’ve got to be very careful how you use it, how you clean it, who’s allowed to clean it, who’s allowed to access it, what special training do they get. In some cases, the parents actually can access it if they have the right training and they’ve been certified to be capable to do that.

Gevorg Tamamyan: What are the main phases of treatment for ALL?

Scott Howard: Yeah, ALL treatment is beautiful because it’s all built into the name.

So you have an induction therapy. What is induction? You induce a remission. So you come along, you have active disease, you’ve induced a remission.

What does remission mean? No detectable cancer. And when I say detectable, I mean using traditional old school methods. So remission would be you do a bone marrow aspirate, you don’t see any cancer on the bone marrow.

As we talked about earlier, you can still detect it with a measurable MRD. You can measure it with flow cytometry, you could detect it. But undetectable by traditional means.

So you’ve induced a remission and the next phase of treatment is called consolidation. And what is consolidation? You consolidate the remission by giving additional blocks of treatment. And the next phase is called maintenance.

Why maintenance? Because you maintain the remission. So you induce the remission, consolidate the remission and maintain the remission. And maintenance is also called continuation, which just means you continue the remission or maintain the remission.

It’s the same thing. So the names of the treatment blocks, it doesn’t really matter. Some people call it block A, B and C. But I like the inducing the remission, consolidating it and maintaining it.

Because it’s all about the remission. And you maintain the remission for the rest of their life and then they’re cured.

Gevorg Tamamyan: Which non-pharmacologic therapies are used in the treatment of pediatric ALL?

 

Scott Howard: Non-pharmacologic therapies is a long topic, not 60 seconds.

But I would say the best non-pharmacologic therapies in ALL would be none. And by none, you even have to be careful about a vitamin. And why? Because one of the treatments for acute lymphoblastic leukemia, ALL, is methotrexate.

And methotrexate, it turns out, if you give methotrexate and then you give folic acid or folate, which is in many different vitamins, you counteract the effects of the methotrexate. So now you’re giving a chemotherapy and you’re giving the antidote to the chemotherapy at the same time. So it’s easy to think, ah, you know, I want to stay healthy during my cancer treatment.

I think I’ll take this vitamin. It might be the worst idea ever. So before you use some non-chemotherapy treatments to complement your chemotherapy treatments, always bring that medicine or that vitamin.

Or if you have some herbal remedies that your friends recommended, just bring it to the doctor and the pharmacist and let them review what’s in it. Because sometimes a remedy has surprising ingredients. And sometimes the surprise is a terrible surprise that it counteracts some of the chemotherapy.

Not only that, every now and then, the side effect of the herbal treatment or the non-chemotherapy treatment interacts with the side effect of the chemo and makes it far worse. So some chemo can be hard on the liver. Some herbal remedies can be hard on the liver.

You take them at the same time, you can have a disastrous liver problem. So the answer is don’t do it. If you must do it, though, bring it to the pharmacist, bring it to your doctor and review it so you can make sure that it’s safe.

Gevorg Tamamyan: What drugs commonly are used for the induction therapy in ALM?

Scott Howard: Yeah, induction therapy has been very similar since 1978. And why? Because prednisone from the 1940s, methotrexate, 1953, mercaptopurine, 1953. Remember, penicillin is just 1947.

So almost all these medicines are from the 40s and forward. But in 1978, asparaginase was the last new one that’s now commonly used for induction treatment. So all of these are great classic medicines with a 40- to 50-year track record.

And we use prednisone, vincristine, daunorubicin or doxorubicin, and asparaginase.

And that’s called a four-drug induction. And that’s enough to achieve a remission in 98% of patients.

And the 2% need extra work to get them into remission. But induction with four drugs is very standard. And actually, three drugs is a lot safer in some places.

And a three-drug induction, you can actually maybe have the safest induction of all. So most patients, a three-drug induction is actually the best.

Gevorg Tamamyan: What about consolidation? Which drugs are commonly used?

Scott Howard: And here things go all over the place.

There’s lots of effective ways to consolidate a patient with ALL. So high-dose methotrexate is used for some patients. They call it block therapy, so block 2, block 3, protocol 2, protocol 3, block M. There’s all different ones.

But usually they have a more intense treatment. And you give a light induction to get the patient into remission without excessive toxicity. And then a heavy consolidation to consolidate their remission.

Because by then, they’ve recovered from most of the problems of the leukemia itself.

And now they can tolerate higher doses of chemo. So usually it’s some kind of block that’s given.

And often it’s a combination block with multiple intense therapies.

Gevorg Tamamyan: Let’s go to the maintenance therapy. What’s the role of maintenance therapy in the treatment of pediatric ALL? What drugs are used? How long does it last? And are there differences for the male and female patients?

Scott Howard: Maintenance therapy is critical for acute lymphoblastic leukemia.

And I say that, but it’s probably always wrong to have binary thinking. Like yes, no, good, bad, always good, always, never. This is probably never correct in medicine to have binary thinking.

And by never correct, I mean almost never correct. Because otherwise I would be using binary thinking. So maintenance therapy for ALL we think is absolutely critical for every patient.

And why? Because the first patients to be cured were back in the 60s. And they were getting two drug maintenance. They got methotrexate once a week and mercaptopurine every day.

And they got that for one year and two years and three years. And they stayed in remission. But nobody knew if they were cured or not.

Cured means you’re in remission. You stopped all the treatment and you stayed in remission. Because cured means that last cancer cell is gone.

But how do you know if somebody is cured? You can’t measure. You could have a million cancer cells and you don’t know. Because it’s not measurable.

It’s not residual measurable disease. It’s residual unmeasurable disease. And a million is way too many.

One is too many. So the way they decided about maintenance were some families, this was learned in children first and later in adults. But the patient was getting five years, seven years, nine years of treatment.

And then everybody said, well what if they’re cured? Maybe they’re cured. Nobody had ever cured anybody before. They usually just treated until they relapsed and died.

And so the fact that they might be cured, some families agreed we’re going to stop the treatment and hope for the best. And after stopping after five years, nobody relapsed. Stopping after eight years, nobody relapsed.

So they said, well five years, that’s enough maintenance. What about four? What about three? And so the maintenance got shorter and shorter and shorter until it was down to two and a half years of maintenance. And then in one study in Japan, they tried one and a half years of maintenance.

And the cure rate went from 80% down to 60% because that extra year of maintenance turned out to be important. So we know five years is too much. Two and a half years is just right.

Or two years, also good. One and a half years is not enough. So why is maintenance so important? Maintenance is so important because the maintenance treatment is called anti-metabolite, mercaptopurine methotrexate.

And it only kills cells that are in the process of cell division. But ALL cells, they can turn on and divide and make some daughter cells, and then they can go quiet. And while they’re quiet in the G0 state, G0 just means a cell that’s not dividing, it can just sit there in your bone marrow.

It can sit there in your spinal fluid for months, weeks or months, or even years. And when it comes out and starts dividing again, if you’re taking the maintenance therapy, it kills it as soon as it tries to divide. So maintenance therapy is basically just waiting for that cell to come out and start dividing again, and then to die.

Because when it starts dividing, it’s immediately killed by the mercaptopurine and the methotrexate. So for now, maintenance is critical. As new therapies come on board, we have to re-evaluate how much maintenance we need.

Because what if we killed every last cancer cell in the first six months with new therapies? Then we don’t need maintenance. So it’s never correct to say maintenance is always required, or maintenance is never appropriate. We used to say in acute myeloid leukemia, they don’t need maintenance, and now, in some settings, they actually do benefit from maintenance therapy.

Gevorg Tamamyan: You didn’t want to answer about male-female differences.

Scott Howard: Male and female differences is a great question. And in the old days, boys used to relapse more than girls.

And nobody knew why, and right now today, nobody still knows why that used to happen. But that happened in the 80s and the 90s, and with the newer treatments, it doesn’t happen anymore.

So now boys and girls get the same amount of induction, the same amount of consolidation, and the same amount of maintenance.

But in the old days, they got six more months of maintenance in the boys, because otherwise they would have higher relapse risk.

Gevorg Tamamyan: What are the acute complications of pediatric ALL?

Scott Howard: There are so many acute complications. So again, we’re back to that word acute.

And so we divide acute complications. Almost all the complications of ALL are acute. The two chronic ones are osteonecrosis, which is a damage to the bone from steroids, and pancreatitis, which can be damage to the pancreas from asparaginase.

And that can be a chronic pancreatitis or diabetes after pancreatitis. So those are chronic. But acute is something that happens, and then you fix it, and it’s not happening anymore, like thrombosis, like mucositis, like all the hair loss is a very good example.

Almost every person with ALL loses almost all their hair for a period of months until they get into the maintenance therapy. So there are lots of acute side effects. But there’s another kind of acute side effect that’s from the leukemia itself, not from the treatment.

So that’s anything that happens in the first two weeks, could be the leukemia itself. For example, if some patients have a large mediastinal mass, it can compress their airway, and they get central airway compression syndrome.

Or they have a large mediastinal mass, it can compress the vena cava, and you can get the superior vena cava syndrome, which is blockage of the vena cava and backflow of the blood and high pressure of the backflowing blood.

So that’s acute. Hyperacute is the complications of the leukemia itself. After two weeks, the leukemia is mostly gone, 90% gone, 95% gone.

And all the side effects after two weeks are from the treatment itself. And each medicine has its own list of possible side effects. So it depends which medicine you’re getting determines which side effects you’ll be at risk for.

Gevorg Tamamyan: What is the purpose of intramuscular chemotherapy in ALL treatment? What drugs are involved, and how is it administered?

Scott Howard: Yeah, so intrathecal therapy is to control the spinal fluid. And so why do you have to control the spinal fluid? Remember, it’s a sanctuary site. And it’s a sanctuary from all the chemo, there’s plenty of chemo that never gets into the spinal fluid.

And that’s actually pretty good. Because vincristine, if it gets in the spinal fluid, you die. Because it’s a neurotoxin.

So if you put it in the vein, it’s great. It’s great for the bone marrow, it’s great for the blood. But it doesn’t get into the spinal fluid, sanctuary site, and it does not get into the testicle.

So when you’re treating a patient with leukemia, they have a risk of hiding in the spinal fluid and then relapsing in the spinal fluid. How do we manage that? Well, dexamethasone is a steroid that goes into the spinal fluid very well. In fact, it causes people to feel terrible.

And anxiety, and lack of sleep, and irritability. When you feel terrible, that’s kind of like you know it’s working, because you know it’s right in your brain, penetrated into your brain. High-dose methotrexate also penetrates the brain.

Asparaginase. There is no sanctuary site from asparaginase, because it lowers the asparagine and starves the leukemia. And it lowers the asparagine in the blood, and in the bone marrow, and in the testicle, and in the spinal fluid.

All of that, though, is not quite enough. You still need one more way to really treat the spinal fluid directly. And so intrathecal therapy is you do a spinal tap, you put the needle right into the spinal fluid, you let some spinal fluid drain out.

If you’re going to put in 12 cc’s of chemo, you let 12 cc’s of spinal fluid drain out, and then inject the three drugs, or the one drug. So methotrexate is always used. And some places also use hydrocortisone and cytarabine, which are great for treating acute lymphoblastic leukemia.

Some people don’t use hydrocortisone, they use dexamethasone, because it’s supremely effective. And I would recommend it if you’re trying to decide what protocol to do. I would add dexamethasone to your intrathecal therapy, because it’s extremely potent.

Gevorg Tamamyan: What is the role of cranial irradiation in the treatment of pediatric ALL?

Scott Howard: Hmm. Nowadays, it has no role whatsoever. So if you have an ALL, in the old days, we used to have to do everything I just talked about, plus cranial irradiation.

And now we have enough spinal taps, intrathecal therapy, enough asparaginase, enough dexamethasone, enough hydrocortisone, enough hydrocortisone, enough hydrocortisone, that you don’t need cranial irradiation in any patient. No matter how much leukemia they had in their spinal fluid at the beginning, cranial irradiation should never again be used in frontline patients. If the patient relapses, that’s a different story.

Gevorg Tamamyan: What role does CAR-T cell therapy play in the treatment of ALL, and how effective is it?

Scott Howard: CAR-T treatment is an amazingly wonderful thing. It has arrived, and it’s changing everything, but in the usual way that change happens in cancer treatment. You first use it in a patient who’s relapsed on the normal thing, and then relapsed on the next thing, and relapsed on the third thing, and there’s nothing else to offer.

So now we pull out the most experimental thing with the least track record, and that used to be CAR-T cells. And it turned out they were so good that they went from the fifth relapse to the fourth relapse to the third relapse to the second relapse, and now the very first relapse can be treated with CAR-T cells. And what is a CAR-T cell? It’s a T cell.

Remember, we talked about T cells with Blinatumomab. Blinatumomab is a molecule that pulls the T cell and attaches it to a leukemia cell, and while that T cell’s attached, it just starts to kill the leukemia cell. It knows what to do.

If you pull it over there, it knows what to do, kill the leukemia cell. CAR-T cells are actually T cells that you take out of the patient, specially engineer them to go after leukemia or lymphoma, or sometimes actually solid tumors. There’s CAR-T cells for neuroblastoma and for all kinds of things that are now being used.

And so that CAR-T cell then finds the leukemia and kills it. And the great thing is it works based on the surface attack. So a leukemia that’s resistant to every type of chemo and every type of tyrosine kinase inhibitor and every type of small molecule might still be sensitive to a CAR-T cell because it’s a surface attack.

The only time it would not be sensitive is if it loses the surface antigens. So CD19 was the first CAR-T cell. Blinatumomab attacks by CD19.

CAR-T cells attack by CD19. So now imagine you’re a leukemia cell and you want to survive. One way to survive is to eliminate the CD19 from your surface.

And that’s how cells can resist CAR-T and Blinatumomab in some cases. So it’s very effective. It’ll be better probably in frontline, but there are some long-term toxicities that need to be figured out before it can be used as a frontline therapy.

But super good for first relapse.

Gevorg Tamamyan: What are potential side effects and complications associated with CAR-T cell therapy?

Scott Howard: Yeah, so CAR-T cells are great at killing lymphoblasts, but the CD19 on the lymphoblast is also present on normal lymphocytes. So bad news, that CAR-T cell wipes out all the leukemia cells and all the normal lymphocytes reliably.

So it turns out those lymphocytes had a job to do. They were there to fight infections, especially viruses.

Lymphocytes also are responsible for making antibodies.

And so patients who don’t have any lymphocytes, their antibody levels that they had made before they had leukemia start to drop lower and lower. So they have a really low, it’s called low immunoglobulin, because immunoglobulin is just a measure of all the antibodies put together.

So if the immunoglobulin gets low, suddenly the patient will start to have lots of virus infections and some fungus infections.

So they need replacement with IVIG, which is an intravenous immunoglobulin that just replaces what the body would make. But the IVIG, it has some side effects. It’s expensive.

It has to be given as an IV. So it’s an inconvenience and potentially can cause headache and serum sickness. And most importantly, it’s not quite as good as your own immune system.

It’s a substitute for your own immune system, but it’s not a perfect substitute. So that’s the main long-term side effect of CD19 CAR-T cells. And blinatumomab does the same thing.

So for six months after blinatumomab, you have to measure immunoglobulin levels and replace if needed.

Gevorg Tamamyan: What is high-dose methotrexate? What is its role in the treatment of ALL, and why is it used?

Scott Howard: Yeah, so methotrexate is an anti-metabolite. It kills dividing cells.

Most cancers divide very quickly, including ALL. And so if you have the ALL cells dividing very quickly and you give methotrexate, you can expect it will be effective. And if you give at low dose, 20 milligrams, 40 milligrams, that’s what you get for maintenance therapy.

But at high doses, it penetrates into the brain and the spinal fluid and the testicle. So the benefit of high-dose methotrexate, and when I say high dose, I mean high dose. Normal low dose is 40.

High dose is 500 to 5,000 in acute lymphoblastic leukemia. So the definition of high-dose methotrexate is 500 milligrams per meter squared of body surface, or higher. But the typical dose in ALL is 5,000 milligrams.

So now imagine in maintenance, you’re giving 40, 40, 40, 40, waiting for that last cell to wake up. In consolidation, you’re giving 5,000 to try to sterilize and clean up the spinal fluid and the testicle and the brain. And it’s really good at that.

Gevorg Tamamyan: Is monitoring methotrexate levels necessary during the treatment, and what are the risks of not doing so?

Scott Howard: Yeah, so the way you monitor high-dose methotrexate is by measuring methotrexate levels after the infusion is finished. You measure the levels periodically until the methotrexate clears. This is the gold standard.

In every country that can do this, every center that can do it, should do it. But in centers that can’t do it, you’re stuck with a tough choice. Do I not give the high-dose methotrexate because I can’t monitor it?

Or do I give the high-dose methotrexate and try to monitor in other ways or take extra precautions? Fortunately, well, unfortunately, there are many places where methotrexate monitoring has not been possible or feasible or it’s too expensive or the machines or the reagents aren’t available.

And many of those places have studied how high a dose can they safely give without monitoring. So a recent study out of Chandigarh, India, did hundreds and hundreds of courses, five grams, 5,000 milligrams per meter squared of high-dose methotrexate in patients who needed it. And what they said is, if our patient needs it, first we’re going to cure the leukemia.

Then we’re going to figure out how to manage the side effects of high-dose methotrexate. So what they did was they would just do creatinine measurements every 12 hours for the whole time and give extra IV fluids and make sure about the urine output. So they watched everything they could watch.

They watched with extra caution. And they gave three extra doses of Leucovorin Rescue to make sure just in case the patient had extra methotrexate on board that they didn’t know about, they would rescue it with the extra six doses of Leucovorin, instead of just three doses. Much better to monitor methotrexate.

And there are a couple of organizations that are actually working on bedside methotrexate monitoring where you just put some blood on a strip and put the strip in a reader and then at the bedside do this. None of those are approved. None of those are in active use right now, but there are two that are in advanced stages of research.

So I hope when that becomes available, then we’ll never again have to worry about high-dose methotrexate without the right monitoring. Let me say one more thing about this. And the best monitoring, even monitoring of high-dose methotrexate, has improved in the last two years.

It used to be we give the high-dose methotrexate a day later, check the methotrexate level. Then we learned that after the high-dose methotrexate infusion, the most important time to monitor is right afterwards. And right afterwards, the methotrexate level should be dropping really fast.

And if you measure a methotrexate level and four hours later another one and calculate how fast that level is dropping down on the slope of the elimination, that actually predicts who’s going to have trouble. And so if you find out that patient is in trouble, it means they’ve already had acute kidney injury during the methotrexate infusion. And we used to think, oh, they have an injury after the methotrexate infusion because that’s when the creatinine goes up.

So we mistakenly thought, oh, the rising creatinine means they’ve had damage. That’s when the damage occurred. But now we know the damage actually occurs during the infusion.

The creatinine rises later because it’s a late and unreliable biomarker of acute kidney injury. Early methotrexate clearance is an early and accurate biomarker of acute kidney injury during high-dose methotrexate infusion. So two things we know that are new now.

We know when the damage occurred during the infusion, which actually makes sense, right? Once a day after the infusion, there shouldn’t be new damage. There should be residual damage, but not new damage. So the damage is during the infusion, and the way to detect it is right after the infusion, the early clearance biomarker.

So that’s a new thing that just got published in the last six months, but the early clearance biomarker is going to make methotrexate even safer in places that can measure the levels. And then when those new machines come on board, hopefully that’ll be all places. So it’ll be a nice convergence of a new technology plus a new insight into how to detect problems.

Gevorg Tamamyan: How is acute lymphoblastic leukemia treated differently in infants compared to older children?

Scott Howard: So infants are almost all high risk, but they’re also at high risk of side effects. And in fact, it’s the pharmacokinetics of most chemotherapy drugs are not well understood in infants, especially under the age of six months. And it turns out almost every medicine is either eliminated by the kidney or by the liver.

And the infant kidney is different from the adult kidney, and the infant liver is different from the adult liver. So we’ve been arguing for decades how much dose reduction to do for babies. And in the United States, we would give like 50% of the dose or 30% of the dose or 25% of the dose, and lots of small children relapsed.

And nobody ever knew, is it because they have resistant leukemia or is it because they didn’t get enough chemo? Fortunately, there was a recent publication from the Japanese Infant Leukemia Group, and they didn’t reduce nearly as much as we did in the US. And they had the best results ever for babies with acute lymphoblastic leukemia. So now we know the answer.

One of the causes, it wasn’t that their leukemia was so resistant, it was resistant, and we undertreated it. So at least we can treat it intensively and overcome some of that resistance and adecatumumab, which overcomes a lot of the resistance because it’s a surface attack and not a metabolic attack.

Gevorg Tamamyan: What are the specific challenges and considerations when treating ALL in adolescents?

Scott Howard: Babies are special. Adolescents are special. So adolescents have more Philadelphia chromosome, so they need a maximum number of satinib-targeted therapy.

They also have more Philadelphia-like, so they need special testing to see if they need a targeted therapy in addition to chemotherapy. But the third way that adolescents are special is unique, different from infants. And that is, they often can decide for themselves if they’re going to swallow their pills or if they’re going to show up for their appointments.

And so imagine you’re a two-year-old. The parents get to decide if the two-year-old will swallow their medicines or not. And they get to make sure.

If you’re a teenager, you might choose to just spit it out or flush it down the toilet or hide it. So it turns out teenagers have 15% more risk of relapse compared to younger children. And as a result of several studies of adherence, it was discovered that one in five teenagers has terrible adherence to their treatment.

Like, they don’t take their medicine. They skip at least one day a week, sometimes two days a week, sometimes all the days of the week. And if they do that, they have four-fold risk of relapse.

So not just 10% relapse now, it’s actually 3.9-fold, 39% relapse, just from skipping one day a week or more. So adherence, imagine if adherence were a medicine, we would prescribe it to everybody. Because imagine you could reduce relapse from 39% down to 10% just by swallowing your pills every day.

That’s a pretty good, good medicine.

Gevorg Tamamyan: Is there any difference treating Down syndrome patients with pediatric ALL?

Scott Howard: Yeah, Down syndrome is interesting because the patient is born with three chromosome 21s, trisomy 21. That’s the definition of Down syndrome. And it turns out then, all of their normal cells have trisomy 21, 321 chromosome, and all their leukemic cells also, which makes their leukemia usually very sensitive to treatment.

But it also makes the rest of them very sensitive to treatment, because cells that have three chromosome 21s are more likely to suffer toxicity. So typically, they get lower doses of high-dose methotrexate and dose reductions of some other key medicines in certain settings. And they still have a very high cure rate.

So the great thing about Down syndrome is, the bad thing is, they have much higher risk of having ALL. The good thing is, if they get ALL, it’s much more curable, even with lower doses of chemotherapy.

Gevorg Tamamyan: How is relapse managed in pediatric EALL and what strategies are employed to achieve remission?

Scott Howard: Yeah, relapse is a big mess. Even in the modern day with CAR T-cells, with blinatumomab, patients who relapse need very intense salvage therapy, targeted therapy, which has toxicity and extremely high cost. And then many of them need a bone marrow transplant, allogeneic bone marrow transplant.

An allogeneic transplant, it’s not just that it’s expensive, it also has a risk of death. 2-5% of people die during the transplant process. And afterwards, almost everyone has long-term side effects after an allogeneic transplant.

So curing the patient first try is the only thing to do. This is true for all cancers, but it’s especially true for acute lymphoblastic leukemia, where we can cure 90% of people if we do everything right, including them swallowing their pills.

Gevorg Tamamyan: How is a second relapse or refractory pediatric ALL treated?

Scott Howard: I don’t even want to talk about second relapse. The only treatment for second relapse is to make sure it never happens. And how do you make sure?

By making sure they don’t have a first relapse. And how do you make sure? By making sure you induce the remission, consolidate the remission, and maintain the remission.

We’re at 90% right now. We can get to 100% probably with the medicines we already have. How do I know?

Because the cure rate for ALL, 1978, was the newest, the latest, greatest medicine, asparaginase. And for the next 30 years, there was no new medicine from 1978 till, you know, the year 2000. Nothing new.

And yet the cure rate went up by 25%. Why? We learned how to use each medicine exactly right.

And then if we even learned how to do adherence to those medicines exactly right, then we got 25% more benefit with the same medicines by using them all in the right combinations, the right doses, the right sequence. We can do the same with the medicines we have right now today. I think when we know exactly how to use them, we’re probably going to hit very close to 100%.

Gevorg Tamamyan: What is the role of stem cell transplantation in the management of ALL, and when is it?

Scott Howard: Yeah, that’s the other good news. It’s never needed in first remission. So if you can induce the remission and consolidate it and maintain it, you don’t need a bone marrow or allogeneic stem cell transplant in anybody.

No role whatsoever. So, yes, it’s very useful in relapse. But relapse means we’ve already lost the battle.

So we need to focus on winning the first battle so we never have to fight again.

Gevorg Tamamyan: What is Blinatumomab and how does it fit into the treatment regimen for ALL?

Scott Howard: Blinatumomab is a tiny molecule that binds T-cells and it binds leukemia cells, the CD19. The T-cell then attaches to the CD19 positive leukemia cell and kills it. And then as soon as it kills it, the Blinatumomab goes and binds another one, calls another T-cell and kills that one.

It’s supremely effective, unbelievably effective. In the study of infant ALL, four weeks of Blinatumomab raised the cure rate by, I think it was 18%, 15 to 20%, somewhere in there, one four-week cycle. So a bunch of chemo and just one four-week cycle of Blinatumomab boosted 15 to 20%.

And similarly, in almost every other group, adding Blinatumomab has had dramatic results. That’s why I think we can probably get to 100% without even inventing another medicine, just by exactly using the ones we have.

Gevorg Tamamyan: What are tyrosine kinase inhibitors and in what scenarios are they used for treating ALM?

Scott Howard: Yeah, so tyrosine kinase inhibitors, it’s all in the word. There’s an enzyme called a tyrosine kinase and tyrosine kinase attaches a phosphorus to other proteins. A tyrosine kinase inhibitor prevents that.

So if you have Philadelphia positive leukemia, a tyrosine kinase blocks the effect. That mutation, the BCR-ABL mutation, translocation, it’s blocked by the tyrosine kinase. And so the tyrosine kinase inhibitor will keep it from doing its job and cause the cells to die.

So it gets added to chemotherapy and is similar to Blinatumomab. You have chemotherapy was only curing 30% of people with Philadelphia positive ALL. Chemotherapy plus imatinib, put that up 40% higher, just by adding imatinib onto the chemotherapy.

And then now we have dasatinib and nilotinib and ponatinib for patients who have special situations.

Gevorg Tamamyan: What is the role of molecular targeted therapy in the treatment of pediatric ALL?

Scott Howard: Yeah, molecular therapy is amazing. It’s great. So an example of molecular therapy is imatinib or dasatinib for Philadelphia positive leukemia.

And so it essentially just blocks the mutation, the specific mutation. So where that’s great is if you have a specific mutation, the trouble is Philadelphia positive leukemia, that’s 25% of adults, it’s only 2 or 3% of children. So imatinib has been amazing for those patients, but it’s only helping 1 fourth of adults and 2 or 3% of children.

In a way, this is why it’s complemented by surface attacks like Blinatumomab for CD19 because 85% of ALL is B lineage with CD19. So Blinatumomab is useful for 85% of children with ALL, whereas imatinib or dasatinib is useful for 2 or 3%.

Gevorg Tamamyan: What role does immunotherapy play in the treatment of ALL and what are its advantages?

Scott Howard: So immunotherapy is anything that’s targeting the surface. CD19, CD22. I talked about Blinatumomab, I didn’t talk about inotuzumab.

That’s attacking CD22, which is just another marker on the surface. Now imagine you had Blinatumomab and inotuzumab and also chemotherapy, hitting dividing cells, and vincristine, hitting other cells during any cell phase, and steroids, killing cells regardless of the cell cycle, and imatinib or dasatinib, blocking the tyrosine kinase, inhibiting it. It means we’re having multiple ways to kill the same leukemia cell.

And when we use all these together, adding immunotherapy on top is miraculous in its benefits, like I told you, the Blinatumomab in infant ALL. Dramatic results with only four weeks of extra therapy.

Gevorg Tamamyan: What is the overall survival rate for pediatric ALL?

Scott Howard: So overall survival means you survived even if you relapsed. So an even better question is what is the event-free survival? In other words, first remission and surviving in the first remission.

And it’s about 90% right now, 85%, 90%. We don’t know yet because you have to wait five years to know what it is today. But five years ago, it was 85%.

And now we know today that it was 85% five years ago. And it’s only getting better as the new therapies are being layered in on top of the old therapies.

Gevorg Tamamyan: What genetic abnormalities are associated with favorable and poor outcomes in pediatric ALL?

Scott Howard: Yeah, we’ve kind of already hit the highlights. So Philadelphia, bad, used to be bad, until we had imatinib. And Philadelphia-like, used to be bad, but now we know how to characterize it and find the targeted mutation.

12, 21, used to be good, still very good. So those patients really don’t need targeted therapy. They don’t need anything because they were already at like 97%.

So probably two weeks of panitumumab, we’ll put them to 100, and then we can relax. So I think probably there’s 20 other translocations we could talk about. And we’ll do the next 60 questions later.

Gevorg Tamamyan: What is the prognostic significance of hyperdeploidy, hypodeploidy, and DNA index ploidy in ALL? And how do these factors correlate with chromosome count?

Scott Howard: Yeah, so the hyperdeploidy and hypodeploidy just means, diploid means you have 46 chromosomes. Hyperdeploid means more than 46. Hypodeploid means less than 46.

So again, hyper always means more. Hyperactive person has more activity. Hypoactive person, lower activity.

Hyperthyroid, more thyroid. Hypothyroid, less thyroid. So hyperdeploid is just about how many chromosomes.

You can count them. And that’s probably all that really matters for this purpose. Prognosis is a very important idea.

Prognosis, again, it’s a Greek word. Pro means ahead of time, and gnosis means knowledge. So prognosis means what you know ahead of time.

So if somebody walks in the door and says, I’m a 90-year-old and I have Philadelphia-positive leukemia, 400,000 white count, I would tell that person, you have a bad prognosis. Because it means I know ahead of time, it’s not going to go well with your leukemia. But if they come in and they’re five years old and they have 1221 translocation and Down syndrome, I know they have a good prognosis.

I know ahead of time that even with simple chemo, they’re going to have a high chance of cure. So each translocation has its own prognosis associated with it, but the prognosis depends on one key factor. And this next question will get to that key factor.

Gevorg Tamamyan: What is the most important prognostic factor for the pediatric ALL?

Scott Howard: There is only one. And if you remember nothing else, the first 59 questions, please remember this. Treatment is the most important prognostic factor.

In 1950, nobody was cured of ALL. Even if they were five years old, even if they had the best genetics, the best hyperdiploid, everything good. No cures.

Now, even people with all the worst things, 70% can be cured with modern therapy. Probably more with the most modern therapy. So the most important prognostic factor is how we treat that patient and how the patient treats themselves.

They’ve got to swallow their mercaptopurine to make sure they get their cure.

Gevorg Tamamyan: How does the treatment approach for ALL vary in low- and middle-income countries compared to high-income countries?

Scott Howard: Yeah, it’s very complicated because it’s not so much about the country. It’s more about what that patient has access to. So we’re sitting right now here in Yerevan, Armenia, and it’s a middle-income country, so patients don’t have access to, you know, a health insurance program that will pay for their Blinatumomab.

But every patient here, every child here, gets Blinatumomab if they need it. And why? They can’t afford it.

The government can’t afford it. Nobody can afford it. But the City of Smile Charity can afford it because they get donations.

And those donations are coming from not just one rich person who says, here, have a billion dollars. It’s coming from thousands of people, possibly millions of people, who are chipping in as they can to pay for a very expensive chemotherapy that’s a game-changer to take that baby from not cured to cured and with very few side effects. So I don’t think low-income country, middle-income country, that’s not what matters.

What matters is what we can do to make sure each person has the access to the best treatment that they need. And then they’re going to have the same cure rate that they would if they’re sitting in the richest place in the world.

Gevorg Tamamyan: What are the current research focuses on emerging therapies in pediatric care?

Scott Howard: Yeah, so this is where all we need is a time machine. Because if in 1978 we could know then what we know now, if they could have come forward 50 years, read all the protocols, and go back, they could have already cured 85% of people with what they had in their hands in 1978. So now imagine today we have panitumumab, we have inotuzumab, we have nilotinib and ponatinib and menin inhibitors.

All these new things that are already approved or soon to be approved. If only we knew exactly how to use them. Exactly when to layer them on to the chemotherapy or when to replace a toxic chemotherapy with a less toxic targeted therapy.

I think we could be at 100% today if we could go forward maybe 10 years. We don’t have to go forward 50 years. They come right back here.

So for me, the most important research for the next 10 years is going to be exactly how to sequence what we already have in our hands. And of course, discovering a few more new things would be great. But again, we’ve got to cure them first try.

Not to research bone marrow transplant, to research how we’ll never need bone marrow transplant again. Not to research CAR T-cells except to say, how can we give a safe CAR T-cell when the patient walks in the door and cure them before they even relapse the first time.

Gevorg Tamamyan: What are the most promising drugs in 2024 for the pediatric ELMO?

Scott Howard: The most promising drugs in 2024 are this brand new medicine called Mercaptopurine. 1953 it was made. But we just learned that you have to swallow it every single day to make it work.

And if you have this 1953 medicine, 71 years it’s been around, but the study that said you’ve got to swallow it 7 days out of 7, not 6 out of 7. If you’re 6 out of 7, 39% relapse instead of 10%. So the newest drug is called Adherence to the old drug that we should have been swallowing all along.

But other new drugs, I’ve talked about Blinatumomab, miraculous game changer in frontline treatment. Also very good in relapse, but I don’t want to talk about relapse because nobody should relapse in 2024. Other new medicines, Inotuzumab, great drug.

Right now it’s not used so much in the frontline in children. In adults, especially at MD Anderson, they’re so creative and they’ve put together some really amazing regimens where they took out all the chemotherapy and just used targeted therapy, another targeted therapy, a tyrosine kinase inhibitor and put that package together. Very novel and very creative.

In children probably we don’t even have to be that creative because we’re already at 85 or 90%. A little creativity will get us to 100%. So my vision for the future would be layering on Blinatumomab in just the right places, in just the right sequence, getting rid of some of the most toxic treatments, especially anthracyclines, Daunorubicin and Doxorubicin and layering on Inotuzumab, CD22, for a different surface attack.

If the cell becomes CD19 negative, it’ll stay hopefully CD22 positive. So we could sort of bring the MD Anderson creativity into children, but keep some of the classic old chemo because the classic old chemo is really non-toxic in children and so cheap. Like a $1 for a week of pills is typical for Mercaptopurine.

So it’s available to the poorest child in the world, the richest child in the world, needs to swallow that pill every day. And when we have access to Blinatumomab for every child in the world, then again, it’ll be even better. I also have to raise my glass to Amgen, who makes Blinatumomab because there are 73 countries where they realized they’re never going to be able to commercialize Blinatumomab.

So they developed a donation program to say, how can we give for free in the places where we’re never going to be able to have a viable sales strategy in certain countries, but we want to make sure that every person can have the cure they need. So they’re actually giving their Blinatumomab for free in selected countries where they don’t plan to commercialize it. I hope every company will follow this model to say, you know, we know we can’t sell this drug everywhere, but maybe we could sell it in some places and make our profit that we need to keep going and use it everywhere to save every life because every life counts.

Gevorg Tamamyan: And the last question, how might artificial intelligence impact ALL treatment?

Scott Howard: Artificial intelligence has some work to do, but so we need to start with human intelligence and really apply it well. And even with human intelligence, not artificial, the real kind, like our moms taught us, we can do a lot. And especially, this is especially important because intelligently using all the medicines in our hand, that’s what the research is all about.

But artificial intelligence has one big advantage which is the next-gen sequence. It’s too complicated for the human brain. And one day, you’re going to do a next-generation sequence and say, this patient has 17 mutations and 43 copy number variations and 15 hypermethylations, and that whole package needs these four medicines followed by these two medicines, followed by this one medicine, followed by maintenance with every other day of that fifth medicine.

And the human brain won’t be able to do that. So artificial intelligence will be the next stage. But frankly, if we get to 100% with our human intelligence, we can save our artificial intelligence from either leukemia or brain tumors or something where we’re still working hard to try to get to 100% cure.

Gevorg Tamamyan: Thank you so much.

Scott Howard: It is such a pleasure to be with you. 60 questions, 60 minutes and 60 ways to improve your patient’s life.