Oncohematology Mikhail Maschan: Of good intensive care, breakthrough technologies and puppies in the hospital

About a revolutionary technology in CAR-T — the only chance for survival for some patients with leukemia, opportunities and barriers to treatment, good resuscitation and tunnels in the minds of doctors — says the Deputy General Director of SMRC pediatric Hematology, Oncology and immunology. Dmitry Rogachev, hematologist Mikhail Maschan.

Mikhail Maschan. Photo: podari-zhizn.ru

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CAR-T therapy is one approach of immunotherapy — perhaps the most promising direction in Oncology. Taking the patient’s T-lymphocytes (immune cells), inserted into the DNA of these cells the gene encoding the modified receptor specifically, it can recognize malignant cells and kill them. Such modified cells received in the English language the name of the CAR-T (chimeric antigen receptor). Then these “trained” T-cells re-administered to the patient.

In our patients no puppies, but there is a remote school, a radio Studio and a film club

— If you watch documentaries about the Western hospitals, there to be practised: Friday — day puppies from a shelter, when they are brought by volunteers. Have fun all: and ill children, and doctors, and puppies. And now you just want this here.

— Unfortunately, due to health concerns we are not animals. Although, of course, really want.

— And American — can, and no harm to the patient?

— I’m afraid that the answer is very simple – because there’s just other health standards. To be honest, I think we’re in our center, thanks to the leadership position – pushed the boundaries in a particular clinic. Start – access to the intensive care unit.

In the past this was a big problem: although there were many hematological patients will get a parent in the intensive care unit, largely dependent on the perspective of who is on duty tonight. Was more kind resuscitator that could bring, but was more evil – which could not be allowed. It was the eternal struggle, which ended when we moved here.

— You just scored the only kind of resuscitation?

— Not so. We are happy that in our ranks there were people who share our beliefs, although this is not easy. Even for a very positive minded emergency physicians is a very heavy load, it’s not like you can just open the door and say — and now it’s all included. This is a huge burden on staff who had never been taught how to behave in the presence of relatives.

What the doctors say, how they say it – from some things that may seem cynical. In fact, the cynicism is not irrelevant, it is just a professional method of coping with daily stress. Doctors can discuss the patient’s condition in two-three sentences, which may seem disrespectful or dismissive. But it is not so. But to understand where you are at the moment: with relatives — one in the examining room – another not so easy.

— When in a stressful situation is an adult, he can understand what it is threatened by disease and weighing all their chances, more meaningfully, perhaps, it has than the child. And how are the children?

— They also felt the situation treatment. Very hard to say – harder or easier. Easier in the sense that up to a certain age they are not so feel and understand what death is, don’t Wake up as an adult, depressed every day with the idea that it could end badly. But the child grows and develops, and the disease is wedged in its normal growth and development, in those moments when his mind is formed, including in its relations with the relatives.

We have a very strong psychological service that tries to help children and families to carry them through difficult moments. There are plenty of things about which we think little. No situation daily terrible pain, but there are absolutely other situation – the child in the clinic, mom is in the hospital, the second child away from dad or grandma. All the attention is linked with the one who is sick right now. A child who is far away, feels abandoned. Mom feels guilty. Stories, when at the time of the disease one of the parents – often it is the dad leaves the family.

Rehabilitation and assistance needed by all. Someone manages to emerge from the devastation and stories of loss healthy, and someone breaks down or broken family, even when the probability of recovery of 90%.

— If children are in your centre for a month or more, as the issue with the school and their social needs?

Our center is very much engaged and, I think, is in the forefront. First, patients who are transplanted, spend not a month but at least 3-4. Because you have to be here before the transplant and after. A patient who is being treated for AML, organizes 6-8 months, as this chemotherapy. There is a special educational program, online school, radio Studio, film club. In General, the space.

— It’s all organized by volunteers?

Is the official unit within the centre of Rogachev. Volunteers play a big role in the activities of the centre, but training children is a professional teacher.

First-graders at the Center for pediatric Hematology. Photo: Fund “give life” / Facebook

— SMRC them. Dmitry Rogachev treat only children?

— Up to 18 years, we have the right to be treated in the budget. To 25 years we treat for extrabudgetary funds, the vast majority of such patients are our former patients who have had a relapse and we don’t want to quit, which the Fund “give life” takes care of and pays for treatment at our center.

And it’s not quite right: I don’t really understand why 25-year-old patient, the state may pay for treatment at the cancer research center, or SMRC Hematology, and can not do — SMRC them. Dmitry Rogachev. For what reasons? The license for the adults we have, but the state does not allow us to spend on adults budget money. Legally we are unable to treat them. But do it rarely, because it turns out very expensive.

— If the patient is over the age of 25?

— Throughout history we have repeatedly taken for such patients, but I try not to do it. Legally we have the right but not professionally feel very entitled. The fact is that 30 years of hematologic diseases in children and adults the same, young adults suffer the same leukemia, closer to the child.

The older you are – the farther from our zone of competence. And why not get into the business? There’s just have their own problems – chemotherapy person with coronary heart disease – perhaps, but in my experience, such patients were not. And it would be unfair to the patient to take on such a situation. Or perhaps SMRC Hematology huge experience of treatment pregnant – well, what are we here to do then.

And adult hematologists, respectively, do not undertake the treatment of children?

— There is a small gap. Sometimes teenagers 16 and 17 years fall into the adult section. But most often under 18 years — children’s services, older adults. Not in all countries is the same, in the US patients up to 21 years are treated at pediatric hematologists in Israel, is the separation of teenagers and young adults, where patients up to 35 years, I think.

— Any other clinic, except SMRC them. Dmitry Rogachev, engaged in such hematological patients?

— Unfair and wrong to say that the light has converged a wedge on SMRC them. Dmitry Rogachev. There are at least two major Federal-level center – Institute of pediatric Oncology, Hematology and Transplantology. Raisa Gorbacheva and the RCCH and our “Alma mater”. This three centre, making transplantation to children from across the country.

There is an Institute of pediatric Oncology at the cancer center (SMRC Oncology. Blokhin) – the situation is a little more complicated, they must open a new case, and we expect that after this power they will become the center of a very high level. Recently, the center started functioning in the Morozov CST.

Even with the support of Fund “gift of life” is pretty great for the last 2-3 years has changed the situation in the Urals, where the regional children’s hospital No. 1 in Yekaterinburg – the only regional hospital that does transplant on Federal quota. They make about 35 transplants per year is a lot.

— And how you doing?

— About 200.

—As our hospital and Institute. R. M. Gorbacheva?

— RCCH about 80, research Institute. R. M. Gorbacheva is about 150. That’s a lot. Centres in Europe that perform more than 50 transplants per year, less than 10. It in children, in adults, several different story — there are centers making a few hundred a year. In General, if you add up the figures for the transplantation of adults and children, Europe’s largest center of TCM, I think, is the clinic of Raisa Gorbacheva.

In the US there are industrial monsters, where the rates under a thousand, but you have to understand that there are autologous transplantation in myeloma, where the chemotherapy is carried out in one day, and then transfused back to the patient’s own cells, there is immune complications. And there are patients who receive two transplants. And if all this folded – figure is space. This does not mean that they do not work, it’s just another technology. There is no comparison to allogeneic transplantation, is very difficult.

Mikhail Maschan. Photo: podari-zhizn.ru

We still can’t do this type of therapy is legal

— In General, leukemia in children treated better than adults?

— Yes, incomparable. Generally, all leukemias are divided into two groups. Acute myeloid leukemia (AML) is mainly a disease of adults and the elderly. There is no exact statistics, but if you extrapolate population data from Western countries, in Russia the expected number of sick children with AML is about 250 per year, adults expect the incidence of approximately three thousand cases. That is, the older you are, the greater the risk. But acute lymphoblastic leukemia (ALL) children get sick more often, the number of newly diagnosed adults and children about the same – at 800-900 a year.

When ALL the children have chances to recover about 85%, and adults – 40%. In AML in children, 60-70% in adults – 20-30%. I put the average world statistics, Russia is adequate data for the acute leukemias, in my opinion, simply does not exist. This is a big problem, but in Pediatrics, again, a little better – less sick, they all are treated in certain places and offices, their fate easier to track. And from a certain age, patients generally become too fragile for treatment, that is not even treated, especially in the provinces – may not even reach the point where someone could take their treatment. Therefore, the whole picture, I think we cannot even imagine.

— Children’s leukemia are treated better – because children’s doctors are getting better at pick up protocols?

— There are three reasons. First and foremost – the biology of the disease. In adults, the biology of leukemia a little closer to solid tumors and in tumor cells there is an accumulation of mutations over many years. At the time when a person is sick, it can be many types of failures and their combinations to treat such a tumor is very difficult. In children, as a rule, the disease is the result of one or a small number of failures. That is, children’s leukemia something simpler.

The second important reason: in adults there is often associated with the type of disease — heart, liver, kidneys, lungs. Therapy — hard, and not every adult can transfer that capable to transfer the child. That is part of the adult patients we lose because of complications.

And the third reason, indeed, that in Pediatrics increasingly used to treat on well-defined protocols. In adult medicine patients are often treated on a territorial basis, where you live. For children’s medicine the norm that we will come to the patient from Khabarovsk. In adult medicine such mobile scheme is much more complicated.

— In the medical community talk a lot about the technology of CAR-T cell. Whether to it was not long breakthroughs in the treatment of leukemias?

— Yes, for acute leukemia in two, if not three, decades almost no new drugs. When trying to make a generalization, there will always be someone who will say that you’re wrong, but, I think, does not lie, saying that between 1985 and 2005-2006 new products are not registered.

Then there are several new medicines for use in the second and third lines of therapy, they took a very small niche — was used in very healthy patients, which had to prepare for transplantation. These medicines have not able to first line therapy — they had no such advantages over conventional products, they have their own, big, toxicity, and the price usually very high. That is, the value generally does not correspond to the benefits they provide.

And in the last three or four years there has been a clear breakthrough. For AML is the emergence of new small molecules, mainly – targeted therapy. But for ALL the breakthrough associated with CAR-T technology. She became more famous because small molecules is not new, they are developed for many solid tumors. Small molecules occupy a niche limiting chronic therapy as a rule, they do not cure, but help contain the disease, sometimes for a very long time.

In the elderly is in a sense, is desirable and productive treatment. But in children this type of therapy does not seem productive – their life expectancy is measured in decades, in this case, the drug that prolongs life for a year or two, neither patients nor parents, nor doctors do not is perceived as a valuable option.

The first major difference CAR-T all used now methods of treatment that the mechanism of action of this technology is similar to the function of the immune system. She finds the infected cells and destroys them, not block their proliferation, and most kills. Based on this principle, this therapy is potentially curativa if it’s not too pretentious it sounds.

There is no guarantee that it will cure all patients, but the mechanism of its action gives hope for full recovery in case of success. The second difference is a completely new thing: 10 years ago, only the pioneers and developers of the method to understand how it should work.

It was hard to imagine that we can so deeply into the human biology — bioengineering methods to change the function of its cells. These cells, coming back into the body, start to do something that normally, they do not know how. It’s like a spacewalk.

CAR-T is different from technologies for the development of molecules when the drugs are stamped at the factory, the doctor they prescribe, and the person receives them or receives intravenously. Here the procedure is somewhat more exciting.

And how is it performed?

Therapy approved in the United States and receives approval in Europe, built in the following way: the patient’s own cells take using a simple procedure, in principle, it is possible to just take the lymphocytes by means of donation of whole blood. Then special agents, these cells are activated, cultivated, grown outside the body and then they added a special reagent vector carrying the gene encoding a chimeric antigen receptor. That is, the lymphocytes of the patient we can refer to any antigen on any target in the body.

Then the fun begins: the question arises – what targets to attack? The weapons of T-lymphocytes is a super-effective killer cells, if you direct them to healthy cells, they hurt, and can kill the patient. And the choice of target was a critical point for the development of all this technology. And patients with ALL and b-cell lymphomas in this sense, lucky – on the surface of cells of leukemias and lymphomas of this type have molecules which are not present in any other healthy body tissues. To be quite honest, this therapy is not aimed at the tumor target, and on tissue with tumor, we destroy all b cells. The good news is that no cell can live. We can destroy them for many weeks or even months, but with the help of transfusions of immunoglobulin function In cells can be replaced.

While in chronic lymphocytic leukemia, this therapy was not approved, yet quite promising results, but for two other diseases — ALL and b-cell lymphomas after several years of research approval has been obtained. The main hope, in principle, justified. Nothing similar from the point of view of the effectiveness of the medicine does not know: all of the previous generation of chemotherapy in patients with refractory tumors were given a remission rate of 10-15% is considered a good response, enough to propel medicine to further research and application.

Photo: podari-zhizn.ru

Here the study of the first phase has already been received frequency of complete remission in 70% to 90%. In principle, no one saw, it produced a bombshell. For CAR-T cells were not phase III studies, comparative studies, so it is obvious their efficiency. And second, after two or three years of observations of patients, published in remission, it became clear that there are about 50% of children and 40% adults. In principle, the duration of life in patients with refractory ALL — a few weeks or months. The fact that this patient survived for 2-3 years, can say that he’s actually cured.

— Dissimilarity to anything of this technology is not complicated the case is in its implementation in practice? After all, the cancer Institute of the U.S. first financed the project but then when I needed money for the treatment of the first patients to sponsor is refused, therapy patients received thanks to donations from philanthropists.

— Indeed, when it was necessary to obtain financing for the first clinical studies, this technology mainstream science was perceived as so marginal that they want to Fund was not. The cost of treatment was very high in one patient it was necessary to spend hundreds of thousands of dollars to show that it works. So it’s a very expensive experiment.

But in the States, philanthropic support is a good tradition. We are in a sense trying to learn: in children’s medicine is much easier to do than in the adult, but in this case here not just to seek funds. What we have done in the center, made entirely at the expense of benefactors.

— We also went research?

– Not quite. In Russia there are several research groups interested in this topic. For pediatric Hematology ALL — the number one disease. Treated with standard chemotherapy, good – recovers 80-85% of patients. Patients in whom standard chemotherapy and bone marrow transplantation (BMT) do not help, in Russia, about 100 a year. In 2013 appeared the first publication about CAR-T. We at the SMRC them. Dmitry Rogachev acted not only as researchers but as clinicians as soon as possible I want to give patients ‘ access to this technology.

It would be possible to start from scratch with your research, to reinvent the wheel in a particular country. But our goal was to make the therapy available if not at the same time with patients in the West, not much later. This would have to do the transfer already quite advanced technology. The fact that to CAR-T cells in different ways: manually, automatically, you can transfer a gene from one virus to others or no virus by using bioreactor and open way, in clean rooms. Many details that had to be build in the production chain, to understand what is possible in Russia and what not. What we in the center and worked.

And when you started to work?

— Very active, we began to work in 2015.

Therapy since that time patients have already received?

— Have received treatment five children. One of the main problems is that we have the regulatory framework so far – and since the adoption of the law “On biomedical cell products” two years does not allow for this type of therapy legal.

We would like to make it available, but now to apply it, we can only for health reasons, on the basis of the consultation, patients who have no other treatment. This situation is very complicates our life. Plus there are regulations that are still pending. And the law itself was written based on industrial history. In my opinion, this is a big brake on technology development.

What do you mean under the industry?

In the United States all that was done before 2013, and all first advances have been made in academic research — they were not initiated by the pharmaceutical companies, the projects are not developed in the bowels of the pharmaceutical companies. The technology was funded either by the state or philanthropists, all practices which then Novartis and Kite Pharma brought to market is 95% of the technology made by scientists in universities with taxpayers ‘ money. And I think, it must be borne in mind.

When this technology kicks off, one of the key conditions for its development – some flexibility: when you things can quickly change, to make quick decisions near the patients. The story of pharmaceutical companies are inertial, by definition, a pharmaceutical company must invest the funds in one kind of CAR-T cells, which then unfold on the go and change the technology becomes extremely difficult. Pharmaceutical companies are needed and necessary at the stage of scaling of the technology and ensure access to treatment for large numbers of patients.

But at an early stage with which we are dealing now, academic centers and laboratories will continue to play a big role. While the regulations prescribed under the pharmaceutical company puts us as an academic centre in very difficult conditions.

Here is a simple example: to obtain permission to manufacture cells for clinical trials of cell therapy, you need to have a license to manufacture the thing itself is not trivial to state academic institutions. We still don’t know how it is – no one else didn’t get it because it has not adopted rules for this. But it’s not so bad: in the list of documents for obtaining a license is a statement on the state registration to the application of the cell preparation.

Question: what to do if we do not want and do not plan to register the drug? With the industry all is clear: if they did something, their only task — to bring it to the stage of medicines, to register and sell. But we have no such problem, our goal is to treat patients. That is, by definition, we are unable to collect a package of documents to register a drug, we want to explore technology and to cure patients.

— You talked about the group of patients – about 100 people per year, for whom CAR-T may be the only chance those who did not help the chemistry did not work with bone marrow transplantation. Why the transplant failed — not found a donor.

— It gets trickier. The fact is that when ALL the transplant has a chance to succeed only if the number of remaining tumor cells is very small. We have to change at the moment when the tumour is almost gone – the cells are “outlasted” chemicals, and they are something we use transplant if you want, finish off. But if at the time of transplantation in the body there is quite a lot of tumor cells transplant is the thrown out money. Such patients inevitably recur within several months after transplantation.

There are patients relapsing after transplantation, there are patients who cannot even be taken for a transplant, because the body too much of the tumor. CAR-T is now used in two situations – in patients retidivirovanii after transplantation, and patients who need to prepare for transplant – they CAR-T becomes this bridge.

Photo: Fund “give life” / Facebook

And the patients that transplantation is now impossible to do it after therapy CAR-T?

— Here now just sewn some uncertainty. We know that after the application of CAR-T cells in ALL children about half of them recovers – remains in long-term remission. Of those who remained in remission, some have managed to transplant, and some not, for various reasons – someone refused, someone is already second or third transplant and the parents refused, where it did not find a donor.

And while there is no way to predict who of the patients need and CAR-T, and transplant to stay in remission, and who may remain in remission only after CAR-T. And that is what will determine in the coming years. For this you need a separate, very difficult organized clinical study.

— Conditionally speaking, two groups of patients – one to do the transplant after CAR-T, and not the others?

— About. On a very large group of patients. And understand it’s not easy, people aren’t mice, they couldn’t just put on the transplant, because it is decided by the doctor. Someone will say: no, if without a transplant you can do what I want without it. And someone on the contrary: I in any case want. To organize such a study is very difficult, and there is also a large role of academic centers, because pharmaceutical companies will do not.

— It would be hard to organize? Or they would not be very interesting if someone after CAR-T transplantation?

— Transplantation of companies is in principle irrelevant, you’re right. But in the end, I think it will be interesting: it’s the only way to prove that CAR-T is an independent healing method and not just a bridge to transplant. Time will put everything in its place. This in Pediatrics is relatively easy to transplant, because there are no such issues with finding a donor.

We easily began to make transplantation from parents to children. And Pediatrics the situation “did not find a donor,” I just don’t know with what to compare, because so you could say 15 years ago. In 2018, it is possible to tell if the patient is an orphan from a very rare ethnic group. Then indeed might not be able to find a donor.

But adults and the elderly is difficult to transplant, it is dangerous. I guess there will be many patients that will simply refuse it. And gradually, I think, will accumulate a mass of people that received CAR-T, but did not receive a transplant. And just following their destinies, you can make any conclusions. That is not all you can think of clinical study.

Photo: podari-zhizn.ru

No way of dealing with burnout in pediatric Oncology you can’t stay

— After 2016, you became Deputy Director of the center, you added administrative work?

— I personally? Yes, adding. And, frankly, greatly diminished clinical.

— And there are still scientific. And what is the ratio?

— Research dominates. I just many times in my life was very lucky, but were particularly lucky with the colleagues with whom I work the last years. It’s so high-class clinicians and doctors that a few years ago I was able to move away slightly from the clinic and to engage in such innovative projects, which required many more organizational work. Not of the scientist, and the project management solving medical problems.

But the connection with the clinic I’m not losing – because of the good organizational work and because this is an area of medicine where patients are treated not like today thinks and feels doctor, and by very clear diagrams. And there is a possibility to control the processes of treatment a very large number of patients coming to him every day in the house, and discussing the key things with the treating doctors or the heads. In clinical terms, I now rather, have found themselves in the position of consultant.

— And thought, “I’ll go patapedia in the chamber” no?

— I know there are concerns, and rightly so, that a person who is not looking patients every day, eventually loses shape. You must stay on the cutting edge of decision-making for individual patients. In the mind of the physician for each patient there is even not a cell but a tunnel where decomposed all that was before: tests, condition, history of illness that it was before, there is a certain planning horizon – what you want to achieve for a particular patient. Is today – the point of decision-making: from very small – antibiotics, transfusions, talk with parents, to very large – for example, today came the information that has relapsed or therapy has not worked.

And the head office in the head a dozen such tunnels with patients. And of course, to keep a large number of patients in the field of a active intellectual attention very difficult. And if you don’t do it every day, the skill is lost. I think I’ve already lost. But thanks to the system, the fact that the disease has its laws and types of treatment, I know approximately where you want the part where I can help the doctors in decision making, because in some situations, on the contrary, need a certain detachment to see the bigger picture.

— You went into medicine for the brother. And why Pediatrics?

And in Pediatrics for brother, and in the Hematology — brother. I wanted to be a doctor when I went to College, he entered the pediatric faculty there was less competition. I didn’t have a brilliant academic results at the time, I’m not sure I would be in the year of entry came to lectek. It’s not the only reason, but nonetheless.

Alexei Maschan and Mikhail Maschan. Photo: podari-zhizn.ru

And your children, you are not jealous – you go, alarmed by the fate of another child, or paying much attention to someone else, a sick, child?

— First, I, frankly, try not to broadcast all of their professional house alarm. This is not right. But I think they understand. Like any children whose parents work a lot, they probably would have wanted us to spend more time with them. But – as much as you can.

Doctors often ask about the burnout syndrome, many people just say they saved, coming home to my kids.

— The problem of burnout does exist, but it seems to me that there are no universal recipes. The man who has found in himself a system of combating burnout in pediatric Oncology could not stay.

Here you need to come to study, work, and in 2-4 years for one to understand how he personally can and should deal with burnout, or he leaves. The reasons for burnout, stress, grief, and failures here so much that it’s impossible to get around. Not sure what the recipes from the series “I go fishing”, “kickboxing” work, is ridiculous.

The main recipe is, probably, not stop to see the meaning in what you do when you are faced with a dead end.

I probably would have burned out if I had realized that there is no hope to improve the situation. And, unfortunately, the truth here is that for each individual patient, such a deadlock can occur. And there are dozens of patients who died from progression of disease or complications from treatment that is still psychologically difficult for the doctor. The inability to help a particular patient — the most difficult for the doctor. He comes now, he will come next year.

But globally, we see that the bare results have improved, definitely every year we save more patients if compared with figures 5, 10, 15 years ago. Always had a vision of where we’re taking the next step. Sometimes it’s one step forward and two steps back, but still. The feeling that this is not a deadlock, and the work that needs to be done tomorrow and the day after to come in the future, is always preserved.

And my version is that this vision is one of the protective mechanisms for people remaining in the profession. The ability not to lose common sense. Now at least, sooner more often you can’t save the patient, sometimes very favorite patient, patient with the parents who had friendly relations. However, you still have hope that next year will be better.

— When I read about you, always having positive feedback about you and your brother. And people writing it on humanly important things for them. Here is the humanity in you from? Of the family? Or is it not there?

— First of all, I think with a certain degree of self-irony to refer to such positive responses. And I know a lot of patients in the case which was a failure and who went with different words – so I think it is enough… clearly, that’s not a word, but the share of self-criticism.

But clearly all of the family. I said that I was lucky in life, and with family too – the store of love which I received in childhood, is still not the end. I have something to give in this sense. Too much love and support I received in childhood and adolescence from loved ones. Some infinite supply.

Mikhail Maschan. Photo: podari-zhizn.ru

— From the family as a whole? Or is it the story where an important figure of one of the family members?

— No, I think it is about the whole family. It was literally such an atmosphere of unconditional love, acceptance and admiration, which was accompanied by the children – me, my brother, our cousins. And by far the main source of power.

— And still?

— Well, Yes. Thank God parents are alive and healthy, and are now supporting us. Yes, in adult life a person accumulates a huge number of problems, everyday stories. But this baby charge it as momentum into the future.

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