Dr. Lakshmanan Krishnamurti: Hope for Sickle Cell Patients

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We are physicians and professors at Yale University. We’re trying to get closer to the truth about health and healthcare. This week, we will be speaking with Dr. Lakshmanan Krishnamurti, but first, I want to bring us back to last week’s podcast, where you and I talked about the efforts to transition us out of the pandemic, as if we have control over that. We both worked with a group led by Zeke Emanuel, who hopefully is going to join us in a few weeks, on a plan or a roadmap to a “next normal,” as we described it. Such a plan is not costless, and we don’t know the actual cost of this transition, but estimates are that it requires over a hundred billion dollars over the next several years to help us mitigate and mediate long-term harm.

But shortly after we recorded the podcast, Speaker Pelosi removed the down payment, just $15 billion, from the pending budget bill. Democrats were pushing back on Republican demands that these funds should be recouped from states that have unused allocated funds from prior COVID. GOP were unwilling to commit to the use of new funds for this purpose. You and I have talked previously about the challenge of bipartisan legislation, but this one is particularly concerning as we see cases skyrocketing in Scotland, in East Asia, in other areas of Europe. The world’s distracted by war, but COVID is not done with us. How do we mobilize folks to the seriousness of this challenge?

Harlan Krumholz: Well, I think we were both disappointed to see the COVID fund stripped from the bill. Again, $1.5 trillion bill, only $15 billion there to keep the COVID efforts alive both here and internationally. I think both of us felt that the $15 billion was actually far too small for what the government needed to be able to do this. Some people raised very sensible concerns about how accountable we’ve been for those funds that have been dispersed and whether we need to be more careful in the future, and for sure, we all agree with that, but the stripping of it from the bill at a time when the bank is more or less empty on the COVID side for the government really handicaps us.

This is occurring at a time where the BA.2 variant is now really rising, 23% of all the infections, according to CDC, there’s been an uptick in wastewater, COVID wastewater, indicating that maybe the virus is starting to actually increase again. Certainly too early to know if this is going to continue, but it’s a concern. You’ve got a country like South Korea with its deadliest day yet in the pandemic, just recently and all throughout Asia, their concerns and surges. Then you’ve got China, where their lockdowns, Hong Kong seemingly beginning to be overrun with Omicron. In Europe, hospitalizations are increasing again.

So look, for anybody who thinks it’s time to move on from this, you only have to look at at the peaks and valleys that we’ve experienced so far to know that even as things look a little better in the moment, and by the way, people are still dying in large numbers, but the overall infection rates are dropping dramatically. We’ve been here before. In fact, last March, we were at a very similar point in terms of the number of cases. We had a period of a hiatus, and then it came back. I’ve been calling this the need for pandemic defense. This is really defense, prevention, response, but in a way, our country is in a battle with this virus. Yeah, in the end, we may have to learn to coexist, but these investments are vital for us to be able to strengthen our systems so that we can mitigate the harm to individuals, to the economy, and I think this has implications for our national security as well.

Howard Forman: So just so our listeners understand what we’re talking about here, we’re talking about testing and access to tests. We’re talking about Evusheld availability for people who are immunocompromised in order to protect them when vaccines will not protect them. We’re talking about vaccines and boosters, both for populations that already get it as well as populations that may yet get approved, and we’re talking about Paxlovid, which is a treatment for individuals who have had infection but are at very, very high risk for a bad outcome. All of this is at risk for $50 for every man and woman and child in this country right now. Just to put that in perspective, we are not talking about a thousand dollars for every man, woman, and child. We’re talking $50 for all of those things that we have learned to count on and we know are critical at this time.

Harlan Krumholz: Well, and it’s also our place in the world. Some of this money is to help with vaccines around the world. Lest you not care about what happens outside the United States, know that new variants emerge from very different places. It is in our interest, and I’d like to think as a country, we believe it’s the right thing to do, to be able to use some of our ability to fund these things for other countries to help ensure access. But it’s also in our interest, because if the virus, it rampages elsewhere, variants will emerge, more likely to emerge, and it will come back to us.

So this is about us having a really grand strategy about this. Right now, we’ve actually depleted the amount of money available to the extent that it’s in danger. This isn’t crying wolf. This is a big deal. From the moment I saw it stripped out, I was shaking my head going, “Oh my gosh, this is something that we can’t lose focus on.”

Howard Forman: Yeah, no, I couldn’t agree more, and I am worried about it, and I do really pray that both parties can put aside partisanship and figure out how to come to an agreement on funding this, because I think it’s that necessary.

Harlan Krumholz: That’s great, Howie. Let’s go on to our guest.

Howard Forman: I’m excited to introduce Dr. Lakshmanan Krishnamurti. Dr. Krishnamurti is the chief of pediatric hematology and oncology for Yale’s Department of Pediatrics and Yale New Haven Children’s Hospital. He’s an accomplished pediatric hematologist-oncologist and an international leader in bone marrow transplantation and hemoglobinopathies. His research focuses on sickle cell disease, especially how bone marrow transplantation and gene therapy can be used to cure it. Before joining Yale, he was a professor of pediatrics at Emory University School of Medicine. Thanks for joining us.

As I understand it, roughly a 100,000 people in the U.S. and many, many more from around the world suffer from sickle cell disease, and many more than that have the trait. It is a disease characterized by a considerable morbidity and decreased quality of life and life expectancy, and even in the United States, life expectancy remains under the age of 50. All of this is incredibly discouraging, considering that we have understood much about this disease for many decades. As someone who cares for patients and researches this disease, can you start off by telling us a little bit about what sickle cell disease means at the patient level, rather than my sort of sterile statistics?

Harlan Krumholz: And maybe a little bit about what it is. Many people may not even know what it is, exactly.

Lakshmanan Krishnamurti: Sure. So as you are aware, sickle cell disease is an inherited disorder of the red blood cell. The red blood cell, as you know, carries oxygen from the lungs to the tissues. In order to do that, it has a protein inside it called hemoglobin, which is dissolved like salt and water, and normally this red blood cell is like a flexible, filled-in donut. When you have this genetic abnormality, the hemoglobin crystallizes. It’s like putting a balloon filled with water in the freezer. It just becomes very hard for this red cell to roll around down the blood vessel, and it gets an abnormal shape called the sickle, like the instrument used for cutting grass, and it also becomes rigid, breaks down, causes obstruction of blood vessels, sticks to the lining of the blood vessels. So distal to the point of that obstruction, the body is starved of oxygen. So the problems such as pain and organ damage are all a result of this rigid, sticky, abnormal red blood cell. So that, I think, sort of basically is what sickle cell is, and you already gave data about it.

How does it affect patients? Well, it affects them right from the beginning. We have to do a newborn screening to pick up, because some babies might die before even being diagnosed with sickle cell disease, because one of the organs called the spleen that’s important for preventing infections by severe pneumonia-producing organisms can cause a child to be dead before we even diagnose it. So every child in the 50 states and D.C. is screened for sickle cell disease. So it starts right then, that they have to be on special precautions for fever and antibiotics and things like that.

Then, starting in very early childhood, the manifestations of obstruction of the blood vessels starts with swelling of the hands and feet, unexpected recurrent episodes of pain, severe, bone-crushing pain. That’s what the original descriptions are in some African dialects. Then from then on, it’s multiple complications, organ damage affecting the lungs, we call that acute chest syndrome, can affect the bones, can affect the head of the thigh bone, the femur, causing the hip joint to be destroyed, and then kidney and liver and multiple organ damage. So you’re born with it. It’s a chronic illness—relentless, recurrent, unpredictable. So that sort of is, in a nutshell, what sickle cell disease is.

You already said about 20 years loss of life expectancy, quality of life is, from the studies that have been done, in children is slightly better than patients with cancer who are undergoing treatment. While in adults, the quality of life of somebody with sickle cell disease is worse than somebody undergoing treatment for cancer. So it is sort of like the undergoing cancer treatment, except all your entire life. So that is gives you a sense of what the quality of life is.

Harlan Krumholz: Thanks so much. Last year, you published a paper in the New England Journal of Medicine on a really novel approach, one in which you’re really actually seeding those cells that can produce hemoglobin in someone to replace or to overwhelm the number of deformed cells, the cells that are causing disease. Can you just explain a little bit about this approach, this LentiGlobin for sickle cell disease? Because I was really fascinated by it and how it evolved, but maybe you can just give us a sense of what this breakthrough represents for people.

Lakshmanan Krishnamurti: Sure. I think sickle cell was the first molecular disease. It was described before we had a term for molecular biology. The year was 1949, and we thought the cure was at hand at the time. So up until now, the only way to cure sickle cell has been to do a bone marrow transplant, which means you take blood-making cells or blood-making stem cells out of a bone marrow from a donor, and then give it to the patient after you first wiped out their bone marrow with chemotherapy. The body’s not designed to get somebody else’s cells with somebody else’s immune system, and so you have immunosuppressed these patients to prevent the donor cells from attacking the host’s body, something that’s called graft vs host disease. That can be pretty bad.

Then you have to have a really good match for on the white blood cells, what we call the human leukocyte antigen, just like we match red cells for blood transfusions, you have to match white cells for bone marrow transplant. So it was very difficult, less than 15% of patients have a donor that’s suitable, and then after that, you have the transplant and you’re still at risk for graft vs host disease. It can be early or it can be chronic.

Harlan Krumholz: About how many of those have we been doing a year in the United States?

Lakshmanan Krishnamurti: So about 140 a year, so far about 2,500 worldwide. Even though the first transplant occurred in 1986, about half the transplants have occurred since 2013. So it’s really recently—

Harlan Krumholz: So Howie’s saying maybe a hundred thousand people with the disease, maybe a hundred people a year actually get this treatment, and then you’re saying not all of them are successful, because there’s a lot of issues in trying to do this.

Lakshmanan Krishnamurti: Correct. Well, really young children do really well, if they have a matched sibling donor. Most of the people don’t have matched sibling donors. So that’s why it’s a lot harder—

Harlan Krumholz: I see.

Lakshmanan Krishnamurti: ... to do that. Then it’s six months or a year of immune suppression. So it’s quite a long and arduous treatment for bone marrow transplant.

Harlan Krumholz: Then at the end of that, are those people cured?

Lakshmanan Krishnamurti: At the end of that, they are substantially cured, in the sense that they’re no longer making sickle hemoglobin. They do have the burden of residual organ damage from whatever occurred before that, and then any complication long-term from the transplant itself.

Howard Forman: Do they still require immunosuppression over time or is that—

Lakshmanan Krishnamurti: No. Over time, your donor’s immune system and your immune system learn to live with each other, what we call tolerance, kind of like an Indian marriage. Everybody, then, it’s an arranged marriage, and they happily live ever after off immunosuppression. That’s how this is different from bone marrow organ transplant, where you’re on lifelong immunosuppression.

Harlan Krumholz: Then so there’s been this breakthrough, a lot of work on gene therapy.

Lakshmanan Krishnamurti: Yes, and this has been going on for quite some time. So this is one of the approaches is a gene addition.

Harlan Krumholz: Gene addition. Yeah.

Lakshmanan Krishnamurti: Gene addition. So what it is is an engineered beta globin gene. So to take a step back, the hemoglobin molecule is made of two types of globin molecules, heme and globin hemoglobin, and the two globins are alpha and beta globin. The type of the genetic mutation is in the beta globin gene in sickle cell. So if you can add a beta globin gene that somehow inhibits sickling, then you could have sickle cell, but you have this other beta globin gene that prevents this hemoglobin from crystallizing, polymerizing if you will. That’s exactly what has happened in this, is they have genetically created an adult beta globin gene, and that is engineered to inhibit the polymerization of beta globins in the hemoglobin molecule. In order to deliver this into the blood-making stem cells, they use a carrier, if you will, it’s lentivirus, which is a HIV family virus. It’s not the entire HIV virus, and it’s just some components of it, and this can only take one beta globin gene into one cell. It cannot go from one cell to the other.

Harlan Krumholz: Everyone should know this vehicle is not dangerous. Just because you’re calling it HIV virus, people may think... This is not, this is just a vehicle, a way to transport it in. Right?

Lakshmanan Krishnamurti: Multiple tests have been done on these patients about any replication-competent lentivirus, and they’ve found no patient with replication-competent lentivirus, and this has been applied in multiple diseases. We are talking about one disease, sickle cell disease. So it’s the delivery of these LentiGlobin viruses. The virus puts the beta globin gene and then the virus disappears or the components of virus disappear. Then the new hemoglobin is formed and you can actually track it, because it’s a genetically engineered hemoglobin. You can do the blood test, and you can detect how much genetically engineered hemoglobin you made.

Howard Forman: You’ve been part of a multicenter group that has done a trial on this. Can you tell us a little about overall success and why it might not work sometimes?

Lakshmanan Krishnamurti: Yeah, so the paper that was just published in the New England Journal reported on 35 patients. So this study over the last several years has gone through several iterations. So the challenges are collecting blood-making stem cells. So initially, they collected blood-making stem cells by putting needles into the bone marrow and sucking out and collecting enough cells, and that’s called a bone marrow harvest. So the problem with that was that the bone marrow itself was abnormal, and so the yield of blood-making stem cells was low.

So one of the changes that they made was collecting blood from peripheral circulation after giving a drug called Plerixafor for the bone marrow to yield up the stem cells into the circulation. So that was one innovation that was done. This was not trivial, because this had not been done in sickle cell before, because there was some danger of getting a whole bunch of stem cells into the circulation, getting the white cell count up, and getting a sickle cell related-complication like stroke or pain crisis. So that was done safely in the study for the first time.

The next thing is a laboratory process itself of getting the lentivirus into enough stem cells and enough numbers. So that took a couple of laboratory process improvements. So this reports this third group that had all of these innovations in place, and that’s, what, in 35 patients. They followed the patients for about 17 months, and the report is really on patients who’ve been at least six months out. So it’s actually pretty well tolerated. It’s a transplant of their own stem cells, which means that there is no graft vs host disease. That’s the most important difference between transplanting from somebody else as opposed to getting your own cells. Second, in terms of toxicity, it was people get outsourced when you get high doses of chemotherapy. So this is quite similar to an autologous transplant that you might, say, do in a patient with lymphoma.

So on an average, they were about 19 days before their cell count came back, and they stayed in the hospital for about a month overall. Patients benefited, on an average, the average hemoglobin prior to transplant was at about eight and a half grams per deciliter and went up to 11 grams per deciliter or more. So 11 is officially the cutoff for anemia. So they no longer had anemia. Most patients with sickle cell will have a hemoglobins of eight to nine. As far as the patients, they had an average three to four episodes of severe vaso-occlusive episodes, which means that they had to be in the hospital or emergency department. Then on an average, after six months after transplant, the median was zero. So there’s substantial reduction in vaso-occlusive pain episodes is what it... People have looked at quality of life and all of those things as well.

Harlan Krumholz: Yeah, no, I thought that was impressive. Just for people listening also, to hear about the anemia, maybe a normal hemoglobin level is something like 13 to 15 or maybe a little bit lower for women, maybe 12 to 14 or something, but to eight is going around low-ish. That was addressed here. The thing I thought was really interesting was that, like you said, these number of events, these adverse events, which are so debilitating and damaging, in the months before, the two years before, they were about almost four per person. Meaning that in the two years, people experienced four of these major episodes. In the months afterwards, in the 36 months, three years afterwards, zero. Zero events. I just thought that was just so impressive and amazing, and really salute you and your collaborators for bringing to fruition the possibility that many more people will be able to be treated.

Look, I wanted to pivot to one other thing, just while we have you here, because this is amazing work you’re doing and with the potential for cure for so many people. But you seem to also have an interest in complementary approaches. So I saw your paper on music therapy, and I saw your very sort of early paper on yoga. I’m just interested in your thoughts about these things. I think I’ll just share my view. I think we do not exploit the possibilities of art, music, things like yoga, tai chi, other things like that that can really help, non-pharmacologic approaches to helping people calm their minds and to be able to bring the force of their minds to bear, to help them in ways that can mitigate the need, lessen the need for medications and other things.

But I was so happy kind of to see you pursuing these. At the same time you’re on the cutting edge of molecular biology, you’re also on the cutting edge of actually novel approaches to many things that have been available to us for a long time, but maybe underutilized in medicine. I wonder if you could just reflect on that a little bit.

Lakshmanan Krishnamurti: Yeah. So one genetic mutation, many different manifestations, right? So one approach is to go back and look at all the other genes that may be changing things, but also there’s environment. There is how you’re coping with it. Do you catastrophize, Chicken Little and the the sky is falling, or coping? What is your family? What is your faith? So all of these are in the mix. I want to tell you that while they were in there getting their gene therapy, some of my patients were getting acupuncture on the bone marrow transplant floor for calming them down. It actually is a prolonged process of rehabilitation for them to have positive expectations. I expected my patients to enroll in a college class while they were undergoing bone marrow transplant and to have positive plans for the future. I think it’s all of the about, whether it’s mind-body approach, yoga, tai chi.

Harlan Krumholz: No, I’m so happy to hear that. Let me just jump in one more thing, Howie, on the music, just to say. I know it was an early study, but the results seem really promising. Are you going to follow that up?

Lakshmanan Krishnamurti: Absolutely.

Harlan Krumholz: It seemed like the music made a big difference. The yoga, there were issues about people following through on the program, and that needs to be addressed, but on the music side, I get it, and you were very circumspect in your conclusion. You said we need to do more research, but it was very promising, I thought.

Lakshmanan Krishnamurti: Yeah, I think the first author of that paper on music has as a long-term commitment to... He’s a music therapist, and I think that music therapy is actually used quite extensively on the bone marrow transplant floor, for instance. Often these people are funding themselves, writing grants and things like that. So I think that it behooves us as a health system to think about incorporating and paying for all these other things that improve the quality of experience, improved outcome.

Howard Forman: Thanks. I’m curious to know, like you’re trained as a pediatrician, and yet the majority of a sickle cell patient’s lives will be spent in adulthood now. I’m curious to know what your thoughts are in how do we care for patients that have a chronic disease that obviously crosses over from pediatrics into adulthood in a more holistic way so that we’re not always thinking about transitioning from pediatric to adult care? Is someone like you able to continue treating someone into their forties and fifties and beyond? What do we do?

Lakshmanan Krishnamurti: Well, two things. The problems in life are often already in place very early on in childhood. Like somebody said, the most important grade is first grade, and the second most important grade is second grade. So I think excellent pediatric care, excellent all-around care for the entire family. One thing that must be said is sickle cell unfortunately seems to affect the most disadvantaged. It’s all African American population. I work in India in sickle cell disease. It’s the Aboriginal population there and the people at the bottom end of the caste system. So everywhere sickle cell is a perfect storm of social deprivation, economic inequity, healthcare inequity. So I think those need to be addressed. Clearly continuity of care is extremely important.

So at Yale, for instance, we have a pediatric-trained pediatric hematologist, Dr. Cecelia Calhoun, who actually is employed by the Yale Cancer Center. So she works in the adult side as well as she comes to the pediatric clinic and starts seeing people who are getting ready to transition to the adult side. So 16 and about, she sees them. So you really have to integrate pediatric and adult programs, and that really requires some forward thinking, because these are mostly patients on Medicaid, and for a lot of reasons, they don’t have services available to them, especially in adult care. So I think that our institutions have to pay attention to that.

Harlan Krumholz: That’s terrific. That’s terrific. Well, thank you so much. It’s so great to have you on.

Lakshmanan Krishnamurti: I appreciate it. Bye bye.

Howard Forman: Thanks very much. I am always inspired by our colleagues who are innovating and advancing science. Sickle cell is particularly pernicious, and I am heartened that we have legitimate advancements bringing hope. So Harlan, what has been on your mind this week?

Harlan Krumholz: What’s been on all our minds, this Ukraine war, the possibilities of Armageddon. I mean, the brinkmanship, the loss, tragedy. I took time to just watch that 20 minutes of Zelenskyy address Congress. I thought it was a very important moment actually in world history. The one thing I wanted to bring up with you today, just because it’s in our world, is the debate that’s going around about academic journals and their point of view around continuing business as usual with Russian science. Now, we all know that there are many Russian scientists of good will who are against this invasion, but a lot of the science in Russia is funded by the government, as it is here. But a lot of that science is controlled by the government in ways that doesn’t happen here. But even beyond that, the question is, do we isolate Russia with a scientific embargo in addition to everything else we’re doing?

What I’ve heard people say is, “No, science needs to be above politics.” I don’t know what world they’re from, but yeah. Okay. And that we don’t want to hurt the Russian scientists who are standing up against the war, but the economic sanctions are equally damaging to Russians of good will who are against invasion. There are means to put pressure on the country. Should science be sequestered from that pressure to join the boycott, the sanctions? Or should we say that we’re above that and continue to do that?

I will say in the beginning, I thought, “No, we need to continue lines of communication.” As I hear Zelenskyy, as I look at the world response, as I see what’s going on, I begin to wonder whether this is a time for us to say that that country, given its actions, needs to be isolated, and that, yeah, that has consequences for the population, just as the economics do. But I’m beginning to wonder whether or not scientists are being tone-deaf. That is, the journals are being tone-deaf to the moment we’re in and the ways in which pressure can be applied so that the people of good will can ultimately emerge out of that situation. But I’m curious what you think.

Howard Forman: Yeah. I’m admittedly ambivalent about this topic, because on the one hand, the more that we can maintain lines of communications, even including scientific exchange during this time, the better we are. We’ve always sort of embraced scientists as being outside of the political realm. At the same time, it seems a little awkward for us to claim that our industry somehow should be immune from the blockade that we’ve created and the isolation that we’ve created on Russia, and that any breakdown in that desire and ability to isolate the country may ultimately allow them to further their government and political advantages that they have had up until this point. We are really in a bigger war than I think the public realizes. This is not about Ukraine versus Russia. This is about self-determination, the West, democracy, and an authoritarian effectively dictatorship in Russia.

Harlan Krumholz: And, by the way, China. And China.

Howard Forman: And China. No, I agree with you. I was going to say, look, what goes on in Russia already obviously includes Belarus. It already includes some adjacent provinces that they may not have authority over, but claim nonetheless, and it does extend to China, and China extends to their sphere of influence.

Harlan Krumholz: So let me ask you this. What about sports? People want to say things are sequestered. If the world is going to stand up and isolate a country that’s finding this to be acceptable, it really is murder. It’s murder that’s being conducted. There’s no going back on this. Russia is bombing innocents in order to gain jurisdiction over an independent country and without any provocation. So the question is, in my mind, without overt provocation, I know there are people who argue about that. I don’t see it. I didn’t see it. I don’t see it, and so don’t know. Like I said, sports can also say we’re above it all, Russian athletes, but in the end, they’re representing Russia. Almost all scientific work out of Russia is, in some ways, government-sanctioned.

Howard Forman: Yeah. No, look, Thomas Friedman was on CNN I think a little over a week ago. I just thought it was an amazing five-minute segment where he said that Russia’s either going to lose early with significant casualties, or they’re going to lose late with massive casualties. I’m of that opinion that Russia never wins this, but what we can do by exerting maximum isolation in every way, shape, and form is minimize the overall long-term harm from something that goes on for too long. So for the moment, I favor doing as much as we can, but it is not without some, as I said, ambivalence over this, because I realize there are some very... The majority of the people in Russia are very innocent of all of this. They are being harmed, and I’m very sympathetic to them, but nonetheless, this is their government. We have to hope that they will rise up to the extent that they can and that they can help force change from within as we exert change from without.

Harlan Krumholz: Yeah. Tough situation, for sure. Interested if anyone listening wants to tweet us about this. Particularly, I’m interested in the issues around the journals, something that maybe we can control, and interested in people’s opinions. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback or to keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m at H-M-K-Y-A-L-E, that’s hmkyale.

Howard Forman: And I’m @thehowie. That’s @ T-H-E-H-O-W-I-E.

Harlan Krumholz: Health & Veritas is produced with the Yale School of Management. Thanks to our researcher, Sherrie Wang, and to our producer, Miranda Shafer. Talk to you soon, Howie.

Howard Forman: Thanks very much, Harlan. Talk to you soon.