Legacy interview – Dr. Mammen Chandy
Bone marrow transplantation and Haematology in India
Dr. Mammen Chandy, an alumnus of the Christian Medical College Vellore, is a pioneer in the field of bone marrow transplantation in India. He was involved in setting up the first sustained bone marrow transplantation programme in the country, in Christian Medical College, Vellore in 1986. Despite initial hiccups, this programme has grown to become the most prominent stem cell transplantation programme in the country in terms of volume, research publications and training. The first bone marrow transplant for Thalassemia in the country was done in CMC Vellore and the Hematology department that he founded has contributed to the training of many of the hematologists in India. After his retirement from CMC, he took over as the director of the Tata Medical Center, Kolkata, where he has set up a bone marrow transplant unit as well. In a candid interview he traces the genesis and growth of the bone marrow transplant programme in CMC Vellore and explains the processes involved in a transplant.
Tell us a little bit about yourself. How did you decide to specialise in hematology?
I joined CMC in 1967 and graduated in 1972, after which I did my sponsorship obligation in Christian Fellowship Hospital, (CFH) Hospital, Oddanchatram for 2 years. Following this I realized that I wanted to do medicine and joined the MD Medicine post-graduation programme in 1975, at Christian Medical College, Vellore. During my undergraduate period, the department of Clinical Pathology had what I would still consider one of the best teaching modules in Hematology. There were brilliant lectures by very eminent personalities like Dr. S.J. Baker, Dr. Cyrus Kapadia, Dr.Robert Carmen, and Dr. A.B.A. Karat. Each lecture was followed by a practical session for two hours. This was absolutely formative in creating a desire to do hematology, even as an undergraduate. This shows that a well structured undergraduate teaching programme can influence an individual, even at that early stage in his life to make a career choice.
While doing my MD post-graduate course, I was involved in treating patients with hematological malignancies like leukemia. I noticed that the treatment of patients with Acute Myeloid Leukemia (AML) in CMC was very inadequate and was not backed by research. The treatment administered was more out of a sense of compassion and duty than based on scientific rigor. This was when I decided that hematology was the field of medicine that I would like to specialize and work in.
Following my MD, I joined the Department of Medicine 1 in CMC as a consultant. At that time, the office of the division of Medicine consisted only of a small room for the secretary and three 4 x 7 feet rooms for consultants. While working there, I looked after hematological patients as well because the unit had a tradition of Hematology teaching by Dr. S.J. Baker who worked in the WELLCOME laboratory. He was an Australian physician working in CMC and was the one who conceived and developed India’s National Anemia Programme in association with Dr. Ramalingaswamy. After working for about a year, I realized that I needed some specialised training in Hematology. However, there was no formal course in clinical hematology in India at that time. With the help of Dr. B.M. Pulimood, I joined the Hematology and Pathology fellowship in Westmead Center, Sydney, Australia and was trained by Dr. Peter Castaldi, who was an eminent hematologist at that time. After completing the fellowship, I returned to Vellore and joined the Department of Medicine 1 in CMC.
I was initially given one intern to help me. Thus in 1984, the intern and me in one 7 x 4 feet office constituted the Department of Hematology nested within THE Medicine-1 unit. Later on, I was given a small room in the outpatient department to do bone marrow biopsies. The first bone marrow trephine biopsy was done using a Jamshidi bone marrow needle donated by a patient. Initially I began, by seeing general medicine cases along with hematology cases, then slowly restricted myself to only hematological cases. In the beginning, no one would refer hematology cases to me. There were informal queries on management of some cases by post-graduate registrars but no formal referrals. It took some years before hematology cases were referred to me.
I have noticed that when young doctors come back after having studied something new elsewhere, they are often impatient to put their new-found knowledge into practice. My advice to them would be to wait and give it some time. Just keep doing good work quietly and you will surely be noticed and will be able to find enough work to keep you satisfied. After the initial slow start, we found that we were overwhelmed with work and patients were being referred to us even for management of iron deficiency anemia. Gradually, other clinicians who had specialized in hematology joined me and we formed a small team. This was how the Hematology department started and grew. About 5 years after I finished my hematology training, the Department of Hematology was formally inaugurated as a separate unit in 1986.
The concept of component therapy
When I came back from Australia, I realized that if I wanted to start a new division of Hematology, I would need the help of several other people. Unlike a plastic surgeon who only needs an anesthetist to do his job, a hematologist needs the support of numerous other specialties. The most important of these is the Department of Clinical Pathology. We had an excellent department in CMC Vellore and they formed a good bedrock which supported the growth of the Hematology department. I also needed a good blood bank which would provide the blood components required. In those days, in CMC, blood was still collected in bottles and was not separated into its components. When I introduced the concept of component therapy, I was met with resistance and I realized that I would have to teach and persuade clinicians to use components like plasma, platelets and packed red blood cells rather than whole blood. I started this process by conducting regular academic sessions in the department of Anesthesia (as they used about 75% of the blood from the Blood Bank), showing them for example, that a person who needs two units of whole blood for low hemoglobin would only need two units of packed RBC – the plasma and platelets were not necessary. These components could be used for other patients who needed them. I was successful in getting them to understand, accept and support this. The Blood Bank was the next in line to be convinced of the rationale and utility of blood components.
The first patient who helped us realize the importance of blood components was a person with Hemophilia who was bleeding from his gastrointestinal tract. Everyone assumed he was bleeding because he had Hemophilia but I rejected this idea because I reasoned that if his Hemophilia was the cause of the bleeding, then he should be bleeding into his joints and other regions as well. I got a gastroenterologist to do an endoscopy on him and he discovered a large Arteriovenous malformation in his gastro-duodenal region – this was why the patient was exsanguinating. To resect this lesion, he would require surgery and there was no Factor VIII available at that time to provide cover during the surgery. The only way we could stop the bleeding was by transfusing a large volume of fresh frozen plasma (It is not possible to transfuse 100 units of whole blood to provide the necessary plasma). In order to do this, we organized 100 medical students and collected blood from them in the blood bags that I had brought back from Australia in my luggage. We then separated the blood into fresh plasma and packed RBC’s. Under the cover of the fresh plasma, Dr. Sitaram and Dr. Prakash Khanduri operated and removed the malformation. The patient is alive today. The case was reported in the Annals of the British Journal of Surgery.
Was the plasma frozen at that time?
No, we used it as fresh plasma; it was not frozen. This was in 1985. The patient’s total protein went up to 22 gm% but he survived. After this case, the programme took off and today about 99% of blood collected is separated and used as components rather than as whole blood.
Once the help of the Clinical Pathology department was harnessed and the blood component programme was initiated, the next step was to develop an HLA laboratory because HLA typing is essential for matching patients for a bone marrow transplant (to see if the donor and recipient are compatible). We were, at that time, sending our samples for HLA testing to a laboratory in the Madurai Kamaraj University where a gentleman with several publications in the field of HLA did the HLA typing for us. To verify the results, I sent the third HLA typing sample that he had sent me, to Australia as well, and the report I received from Australia was that the HLA typing was totally wrong. That particular patient did not survive the transplant. Through Mrs. Pulimood, we therefore invited Dr. Paul Ichiro Terasaki who was a world authority on HLA typing at that time and we had a workshop in Vellore. After this, the blood bank in CMC started doing HLA typing and we had access to reliable HLA typing for the transplant programme.
The Bone marrow transplant programme
When I was in Australia, throughout the period of my training, I was constantly looking for things that I could apply in CMC Vellore, in order to set up a bone marrow transplant unit there. After I came back to Vellore, I approached the Director, Dr. LBM Joseph if I could use two rooms in the private ward for setting up a bone marrow transplant unit. He was gracious enough to grant me the use of the two revenue earning rooms. Once we had the rooms, we started trying to set up a HEPA filtration system for the transplant room. I was naïve; the training abroad does not equip you with engineering knowledge on how to set up a transplant room. Sister Anne Bothamley, who had been trained as a transplant nurse in the Royal Marsden hospital in the U.K, was a great help in this. She also helped in developing and training nurses to look after the transplant unit. In this way, we somehow cobbled together a transplant unit. It constituted of two rooms, with an entry and changing room and a small nursing station. This was the first bone marrow transplant unit and we started the bone marrow transplant programme in 1986.
The first patient
Before the first human bone marrow transplant, we harvested bone marrow on dogs in the Pharmacology Department, just to make sure that we were doing things right. We anesthetized dogs, harvested bone marrow and standardized procedures to ensure that the sample did not clot and was suitable for transplant etc. This helped in reducing the apprehensions regarding the actual harvest.
The first patient that I took up for transplant was a 26 year old man named Antony from Kerala with Acute Myeloid Leukemia with multiple relapses. He had given up all hope and was ready for anything. We performed the first bone marrow transplant on him; he survived for about 2 weeks and finally died of severe pseudomonas septicemia. This patient taught me several things. The most important lesson was regarding gut sterilization. In Australia, I had learnt that gut sterilization with antibiotics was important before a transplant, but what I realized was that this only killed the drug-sensitive bacteria and allowed the resistant bacteria to survive. Now I do not do gut sterilization in Indian patients.
When was this bone marrow transplant done and was it the first in India?
This was in 1986. Bone marrow transplant was an established procedure in the Western world; it had been in existence for 20-30 years before this. In India, the first allogenic bone marrow transplant was done by Dr. S.H. Advani in Tata Memorial Hospital, Mumbai and CMC Vellore was probably the second. We in CMC, were the first to do a bone marrow transplant in a patient with Thalassemia, and this was the first institution to have a sustained bone marrow transplant programme in the country. The transplant programme in Vellore is the most active one of its kind in India and more than half of the bone marrow transplants in India are done in CMC Vellore.
The second transplant
The second transplant was done on a girl child from Orissa with Chronic Myeloid Leukemia (CML)who had a twin sister (monozygotic twin). The twins were born in a mission hospital in Orissa and their mother died in childbirth. The babies were adopted by the missionary couple who ran the hospital and one of them developed CML. She successfully survived the transplant but subsequently relapsed later.
Disaster, despair and hope
The third transplant was on a person who had acute leukemia, who died because the HLA typing was wrong (the one referred to earlier). This was a disaster. After the third transplant patient died, we were really, really depressed. The nurses were so involved in the programme that they were actually crying. I still remember we were cleaning up the unit (doctors joined in cleaning duties those days), when Dr. Pandey, the head of Nephrology, from the Renal transplant unit just opposite to our unit, walked over and met me. He put his arm around my shoulder and said, “Don’t give up. If you need more money, I will support your programme from the Nephrology fund if necessary, just don’t give up.” This was a great encouragement to us. We continued our work and subsequent to the third transplant, we never looked back and went from strength to strength.
Growth and Development of the Hematology department
As we were expanding the bone marrow transplant programme, I realized that in order to ensure the enduring success of the programme, we would need more research. Dr. Dennison and Dr. Alok Srivastava who were working with me at that time suggested that we should develop a molecular genetics laboratory for blood diseases. They felt that was the only way to move forward. So we approached the Indian Institute of Science and they agreed to train a technician for this purpose. However, when our technician went there, he was asked to sit outside with a book and was not allowed into the laboratory to learn techniques. At that time while at a meeting in Bombay, by serendipity, I met Dr. Krishnamurthy, a research director from the INSERM Laboratory in Paris. After the meeting, he approached me and offered to help me in any way he could.
At that time Dr. Poonkuzhali from Vellore had been working on a research project as part of her Ph.D.to develop an assay to measure Busulfan levels in blood (which is a key agent in preparing a patient for a transplant). Bio-RAD had promised to develop this assay for us but were not able to, so she was sent to Dr Ehninger’s lab in Dresden, East Germany but the results using a published method in his lab proved to be wrong when the same samples were analyzed in the INSERM laboratories in Paris ( with the help of Dr. Krishnamurthy). With the help of Dr Eileen Jaques in Paris she developed an assay for measuring Busufan levels using HPLC. She came back and successfully established the assay in Vellore.
At that time, we had also hired Dr. Shaji to work in the laboratory as a research scientist and he went on to finish his Ph.D. He was very good with techniques and was sent for training to the USA to work with Dr. John Cunningham (who was the head of the molecular biology laboratory in the University of Chicago). He was so good that, during his training, he was offered a tenured position in Chicago. He however, chose to come back to Vellore. Today we have a well established and active research programme in CMC Vellore which has trained many Ph.D students, and which provides a wide range of diagnostic molecular biology tests for blood disorders. I don’t think there is any other department in the country that does this.
The next step was to start a DM programme in Hematology because there was no formal post graduate training course in this subject in India. So we set up a programme and applied for recognition. A person from Delhi came over for inspection and told us that we could not have the programme. So I replied with a six page rebuttal to the Directorate General of Medical Education, New Delhi, explaining why that assessment was incorrect. I went to Delhi and had a chat with the Director General who said he could grant permission, but wanted another assessment, this time by a person of my choice. The person who I chose said that an assessment was not necessary and was willing to sign the papers even without an assessment, but I insisted that he come: we had another assessment, a report was sent back, and permission was granted for the DM Hematology course, which I believe is the best training course in Hematology in the country today. Dr. Vikram Mathews was the first DM candidate and he is currently the head of the department in CMC. Over the years we have trained many of the hematologists in the country.
What are the notable features of the Hematology department in CMC Vellore and what were the contributions of this department over the years?
The hematology programme in CMC Vellore is most prominently known for stem cell transplantation. We have completed around 2000 stem cell transplants. We are the largest and most active transplant center in the country and we have contributed significantly to the science of transplant in the world in terms of research publications.
Second, we are known internationally for the Hemophilia work that is being done here in association with the laboratory in the Transfusion Medicine department, with the Physiotherapy and Orthopedic departments and Dr. Alok Srivastava is spearheading the programme. Today, we are recognized internationally as a Hemophilia reference and training center.
Under the stewardship of Dr. Vikram Mathews, we are recognized internationally as one of the centers advancing research in Promyelocytic Leukemia. We are also actively contributing to the science and research of Thalassemia through our Thalassemia programme.
In India, CMC is at the forefront of research and diagnostics in the field of molecular genetics in Leukemia, looking at the various aspects of this
disease. As mentioned earlier, the first bone marrow transplant in Thalassemia was done in Vellore and we have the largest and most active transplant programme in India in terms of training, service and research. In terms of sheer volume, CMC has the most active transplant programme – we do about 10 allogenic and 8 autogenic transplants a month while most centers do about 3 to 4 transplants every month.
Which are the other centers in India where bone marrow transplants are done and what was the role of CMC Vellore in this?
Bone marrow transplantation was started in Tata Memorial Hospital, Mumbai, but for some reason, the programme never took off initially. CMC Vellore was the second place to start transplant. This programme went on to become the most prominent contributor to bone marrow transplantation in India in terms of volume, training and research. Subsequent to this, the Bombay center started its transplant programme again. Today bone marrow transplantation is done in other centers as well – in AIIMS, New Delhi, Narayana Hridalaya in Bangalore; there are three centers in Pune and also in many of the corporate hospitals like Apollo hospitals around the country. Many of the hematologists practicing in these centers have had training in CMC Vellore. In the promotion of the science and training in bone marrow transplant, I think CMC Vellore has played a much more important and prominent role than other centers.
What do you think are the possibilities for research in a peripheral medical center? What does it involve and how feasible is it?
For most of us, research is conceptualized as some scientist sitting in a laboratory doing experiments with test tubes and high-tech equipment. That is a wrong understanding of research. I think research consists of fundamentally three steps 1) analyzing what you are doing: what are you doing in your center for a particular problem? This involves collecting data, documentation, looking at your results and then making a conclusion about what you are doing. 2) The next step is to look at results of research from other centers all over the world and compare it with what you have done. 3) Finally, done with your research and having understood the issue, you work towards applying what you have learnt practically in your context and then make it known to the world. To me that is clinical research and it is possible in any setting whether primary, secondary or tertiary. The tools required for this are dedication to clinical care, measuring and collecting data, analysis of the data and making a conclusion. For example, if you are in Orissa, you probably know the mortality rate due to cerebral malaria. Now, if you perform certain interventions, how much of a difference does it make to the mortality rate – that is research, and it is very feasible as long as you set your mind to it.
Looking back, why did you decide to come back to Vellore after your training abroad?
I was pretty sure that I would continue working in CMC Vellore after my training.. When I did my undergraduate training in Vellore, there were enough stories of inspiration that made me feel that this was the best place to work. Looking back after retiring from CMC, I am absolutely sure that the choice was right and I wouldn’t have wished it any other way. The immense satisfaction of being able to set up something that was relatively new and making a contribution to this great institution is something that will always be there with me. I don’t think there was any desire to stay back in Australia during my training. The satisfaction of contributing something to your own countrymen, where you are valued much more, is something you will not get by working abroad.
Why do you think you were able to do what you did, while in CMC?
I think, I was able to do what I did because I enjoyed what I did. At no point of time did I feel that I was ‘sacrificing’ anything to work in Vellore. Anyone who feels that he is giving up a lot to work in a place like Vellore is not correct; he or she should in fact consider it a special privilege. If you enjoy what you do you will go far, and things will work out. Hematology as a discipline enjoys one advantage, in that it involves a lot of molecular biology and genetics. So many cutting edge technologies come quickly into clinical practice, so there is a lot of excitement.
The Hematology department today
The Hematology department in CMC Vellore currently sees about 1200 new outpatients every year and admits about 700 patients every year for inpatient care. These patients come from all over India and cover the whole spectrum of blood diseases. About 30 autologous & 80 allogenic bone marrow transplants / stem cell transplants (SCT) are done annually. The post-graduate course in hematology (D.M.) started in 1999 for the first time in India remains a highly sought after course in the country. The department also offers Ph.D. programmes and post-doctoral fellowships in Molecular Hematology. It remains in the forefront of research in Hematology in the country with significant publications in the field of stem cell transplant, Thalassemia, Leukemia and hemostasis/thrombosis. After his retirement from CMC Vellore, Dr. Mammen Chandy took over as the director of the Tata Medical Center, Kolkata, where he has set up a bone marrow transplant unit as well.
BONE MARROW / STEM CELL TRANSPLANT
Could you describe in simple terms, the steps involved in a bone marrow transplant?
The first step is to identify the person with a hematological problem which cannot be cured by an easier, simpler method. For example, consider a 25 year old person with severe bone marrow failure and an absolute neutrophil count of less than 200, his best chance of survival is with an allogenic bone marrow transplant.
The second step is to find siblings or relatives or others who can be potential donors.
The third step is HLA typing to match a potential donor to the patient and determine if both are compatible. If a donor’s HLA type is compatible with that of the recipient, the chances of successful implantation of the graft are high.
Conditioning the recipient
Once a HLA matched donor has been identified, the patient is prepared for the bone marrow transplant. A Hickmann catheter is inserted for continuous venous access and the person is conditioned. Conditioning does two things – 1) it destroys the immune system of the recipient so that the graft is accepted and 2) it creates the space for accepting the grafted bone marrow. Today we know that it is not necessary to create space; suppression of the immune system is enough. This process of conditioning is done using certain drugs which destroy most of the hematopoietic cells in the bone marrow.
Stem cell harvesting
The stem cells of the donor are then harvested. One way of doing this is to collect cells from the bone marrow of the donor. This is done in the operating theater under strict aseptic conditions. The bone marrow cells are aspirated from the iliac crest or other suitable sites into a collecting bag. We collect enough aspirate to obtain 300 million nucleated cells/kg of the recipient – this contains enough stem cells for the transplant. This material is obtained through multiple punctures (an average of 60-70 punctures) into the iliac crests on both sides. Three to four ml of aspirate is taken after each puncture; beyond that we would only obtain sinusoidal blood.
The other more elegant way of doing this is through a peripheral blood stem cell transplant. This is done by giving the donor a growth factor (G-CSF) SC daily for four days. This growth factor pushes the stem cells into the peripheral blood. The donor’s blood, which is now rich in stem cells, is collected in a bag using a cell separator which selects only the mononuclear cells and returns the rest of the blood back to the donor. The disadvantage with this procedure is that there are more T cells in this graft and so there is a slightly higher rate of graft vs. host disease.
Infection control measures
The patient who is being conditioned and transplanted is very prone to infections because he is immune-suppressed. To reduce the risk of infections as far as possible, certain precautions are followed. The patient is placed in a HEPA filtered room breathing only filtered air, is given only pressure-cooked food and drinks only filtered water. Even the water he uses for a shower goes through a 0.3 micron filter. The sheets are autoclaved and the doctors and nurses wear autoclaved garments. HEPA (High Efficiency Particulate Air filter) is a system that filters air through a 0.3 micron filter to prevent air-borne viruses or fungi from entering the room. The process of conditioning takes around 8 days and during this period drugs that destroy his immune system are administered. On the 8th day, stem cells from the bone marrow of the donor are collected.
How do you know that the patient has been adequately conditioned and is ready for the transplant?
There is no technology to tell us that. We do not do a bone marrow biopsy to see if the bone marrow is empty. We just assume that the drugs have worked and the patient has been adequately conditioned for the transplant. The bone marrow is usually never completely empty – that takes time, but 8 days of conditioning is sufficient for accepting the graft.
Now the stem cells collected from the donor are infused into the recipient just like a blood transfusion. The miracle is that the stem cells have little molecules on their surface that make the cell home into the bone marrow and soon latch on to the remaining stroma of the bone marrow. These molecules are called adhesion molecules (they were called addressins or ‘Mecca molecules’ earlier) and the stem cells latch on to the niche or nest of cells in the bone marrow composed of adipose cells, osteoblasts and fibroblasts. These ‘niche’ cells are not destroyed by the conditioning process.
Post- transplant period
Once the transplanted stem cells establish themselves in the bone marrow, the peripheral blood counts start going up. This takes about 2 weeks and during this period, the patient is a sitting duck for infections of all kinds because he has no cells to confer immunity. During this period, the patient will therefore require several blood components like packed red blood cells and platelets. His white cell count would be almost zero if he got an infection and he would require several antibiotics and anti-fungal agents to combat the infection.
Graft vs. host disease / Graft vs. Leukemia
Once the graft has been accepted and the peripheral blood counts start increasing, the possibility of graft vs. host disease becomes a concern. By doing HLA typing we assume that the donor and the recipient are immunologically compatible; however, we are only looking at the tip of the iceberg. There may be several other molecules which the donor cells consider as foreign and this leads to the graft cells attacking the cells of the host. The skin, the liver and the intestine are the commonly involved organs. There are grades of graft vs. host disease from 1 to 4. If you have grade 4, your skin looks like you have had a third degree burn all over your body. The patient may have diarrhea, jaundice and other symptoms.
Today we abort graft vs. host disease using cyclosporine and methotrexate and it is rare to see grade 4 disease. The commonly seen grades are 1 or 2. This is good because it is the immunological differences between the recipient and the host cells that help to kill the remaining leukemic cells. Chemotherapy is not the only way the marrow is cleared of leukemic cells. This is called Graft vs. Leukemia reaction. The immune system of the donor helps in preventing a relapse of the disease. This is why in a transplant between two identical twins, the chances of relapse are high in case of malignancies – because of a lack of this Graft vs. Leukemia reaction. This is usually not an issue if transplantation is done between twins for bone marrow failure.
Today, most bone marrow transplants for malignancies are done using peripheral blood stem cell transplant because the Graft vs. Leukemia reaction is desirable. This process is also technically easier and approximately 3 out of 4 transplants are done using this method even though there is a slightly higher chance of Graft vs. Host disease.
Autologous bone marrow transplant is a mode of therapy for malignancies. Here the patient’s own stem cells are collected, his bone marrow is killed using chemotherapy and the collected stem cells are re-infused back into his system. This type of transplant can be used for lymphomas and myelomas and they are fairly effective. Here there is no risk of graft vs. host disease with autologous transplants.
Following a transplant, the patient is kept on immunosuppressant agents for about 6 months. Unlike a renal transplant patient who has to be on immunosuppressant agents for his entire lifetime, the drugs are tapered after 6 months and by one year almost all patients who have had a bone marrow transplant are off immunosuppressants. Children with Thalassemia can now go to school; they need no transfusions – they can lead a normal life.