Consultant in Paediatric Haematology, Oncology, Immunology and Bone Marrow Transplantation
Dr. Rela Institute & Medical Centre
Vimal has over 10 years of experience as a consultant in pediatric hematology. He specializes in Stem Cell transplantation and management of blood and cancer disorder and has undertaken international fellowships at the Imperial College London Healthcare Trust in the UK. Vimal is comfortable sharing his experiences with both autologous and allogenic stem cell transplantation practices in India.
Section 1: Current SCT Therapy
1.1. How would you describe the current SCT patient journey?
Let me talk to you about initially allogenic transplant. Once we decide that this patient needs a transplant, we look at the diagnosis and what the severity or the stage of the disease is. For example, if it is a malignancy, we are thinking of doing a transplant, the need to do a bone marrow examination. For example, leukemia or lymphoma, make sure the disease is in remission. So, we look at bone marrow, we look at the minimal residual disease and once we are sure that the MRD is negative, the minimal residual disease is negative. Then we are convinced to go ahead with transplant. Some patients do have a high disease load during a transplant, or when we decide on a transplant. In those cases, we decide on giving some form of chemotherapy to bring down the disease burden because the higher the disease burden at the time of transplantation, the higher the risk of the relapse or disease coming back; this is for malignancies.
Non-malignant conditions, there are conditions like hemoglobinopathies, thalassemia, sickle cell disease. These patients that are on blood transfusion. So, how is their iron overload? Are they adequately chelated with iron chelators? Because, the higher the iron overload, the higher the risk of complications. We generally do overall investigations in the form of blood investigations. Then, we look at the heart and the liver, to look at iron overload in the heart and we do MRI scans of liver and heart, liver biopsies to assess the iron overload. This is the work-up with regards to the patient and also to complete the work-up we do the vital investigations, HBsAg, HIV, hepatitis C, and echo to make sure the patient has adequate cardiac functions, GFR or glomerular filtration rate for checking the kidneys.
These are the workups towards the patient. Coming to the donor, before we decide on the transplant, obviously for allogenic, we look at the HLA typing. We do a high-resolution HLA typing and make sure whoever the donor is, either it could be a matched family donor. If there is no match in the family, we use donors from unrelated bone marrow registries, various international registries, like DKMS and DB, which is a US registry. DKMS is the largest registry, which is the German registry. We look at the HLA typing, make sure that there is a 10 by 10 match or full match. Once the donor is identified, the donor workup has done. For example, if it is a matched family donor, the donor is available with the patient. So, the entire workup is done in the hospital, along with the donor. If it is an unrelated donor, obviously the donor registries take care of all the work up.
These are the work-up towards the donor and the patient. Once we are done with these two steps, then we proceed with the transplant. The patient is given some form of conditioning chemotherapy, which includes a combination of chemotherapy. There are drugs to ablate the bone marrow or destroy the bone marrow and combination of immunosuppressive drugs, which help in preventing graft failure. It’s usually a combination of these two medications, depending on the condition. For example, if you’re deciding on transplants for leukemia, then we add radiation as well, total body radiation. Usually this phase of conditioning, which is a process by which we take out the bone marrow, or we ablate the bone marrow of the recipient. This takes place over a course of seven days. If a patient is admitted in a HEPA filtered positive pressure BMT unit, we usually put in a central line, central venous catheter. This helps in the administration of medications, as well as doing blood investigations, instead of repeatedly poking the patient for investigations. I mean, all the radiology workup and everything. We get the STEM cells from the unrelated registries.
These are the work-up towards the donor and the patient. Once we are done with these two steps, then we proceed with the transplant. The patient is given some form of conditioning chemotherapy, which includes a combination of chemotherapy. There are drugs to ablate the bone marrow or destroy the bone marrow and combination of immunosuppressive drugs, which help in preventing graft failure. It’s usually a combination of these two medications, depending on the condition. For example, if you’re deciding on transplants for leukemia, then we add radiation as well, total body radiation. Usually this phase of conditioning, which is a process by which we take out the bone marrow, or we ablate the bone marrow of the recipient. This takes place over a course of seven days. If a patient is admitted in a HEPA filtered positive pressure BMT unit, we usually put in a central line, central venous catheter. Which helps in administration of medications, as well as doing blood investigations, instead of repeatedly poking the patient for investigations.
This phase of conditioning lasts over a week. Over this one week of we do investigations on a daily basis. We look at the blood count. We look in the renal liver functions, make sure they’re all right. What we expect is the blood count gradually goes down because of the chemotherapy or the radiation we are giving. The patient is admitted in a BMT unit. He is given strict dietary precautions like neutropenic food. What we mean by neutropenic food is double boiled food and we do not allow anything raw, raw vegetables, or raw fruits.
There is only one attender allowed for the patient. It’s usually like if it is a child it’s usually the mother. If it’s an adult patient, someone from their own family and we provide 1:1 nursing. Every shift, there is just one nurse who takes care of a particular patient. Once the conditioning chemotherapy is done, which lasts over a period of five to seven days, then the next process is this process of STEM cell infusion. The donor, if it is a matched donor who is in the family, we harvest the STEM cells from the donor. We give five days of injection, the granulocyte colony stimulating factor.
Then, we harvest the STEM cells. Depending on the condition we might choose for peripheral blood STEM cells, which is collected by a procedure called apheresis or sometimes, it could be a bone marrow harvest. Bone marrow harvest is done in a theater under general anesthesia and STEM cells are harvested from the iliac crest or the pelvic bone of the donor. This has done on the same day as the day of infusion. We harvest STEM cells from the donor in the morning.
That is done in-house. Most of the centers in India, they have in-house a flow cytometry unit, hemato-pathology unit. They do quantification of the STEM cells, the CD3 T-lymphocytes. The quantification of those cells are done, and we generally get a report within a couple of hours. Depending on the quantitative titles of the STEM cells harvested, we calculate the amount of STEM cells that the patient needs to receive. We generally gave CD34 or STEM cell dose of around 5 to 6 million per kilogram. We do not generally go beyond 8 million per kilogram because of high risk of graft versus host disease. The STEM cells are infused to the patient over a period of one to two hours through the central venous catheter.
After that, it’s a process of waiting and watching. Usually the donor cells take around two weeks to go and settle into the patient’s body. All these two weeks, the patient is admitted in a bone marrow transplantation unit. He is given neutropenic care, measures to prevent infections. If at all there are any complications, most of the centers have an ICU unit on standby to cater to the needs.
1.2. What are the common complications with SCT?
The most common complication we generally see is infections, sepsis. In India, our biggest challenge for a successful transplant is, we have lots of multidrug resistant bugs, gram negative bacteria. That is the biggest challenge we face. Whenever the patient develops a fever, we do blood cultures, we do all this big work-up. We start the patients on appropriate antibiotics. Then, it’s a period of waiting for 12 to 14 days, by which time the donor cells settle in. Most of these patients are on immunosuppression and we do monitor the levels of tacrolimus, or cyclosporin, whatever calcineurin inhibitor the patient is on. This is done every two to three days. The patient undergoes regular investigations like, routine blood counts, liver and renal functions, electrolyte levels. Most of these patients have diarrhea during this time. This is because of all the chemotherapy; the patient has a raw gut.
They have ulcers. They have a raw epithelium. So, these patients tend to have diarrhea. Some of these small children, we put in a nasogastric tube to take care of the nutrition. So, they are given a semi elemental milk diet through a continuous NG tube. Some patients we do put on TPN, total parental nutrition, if they have prolonged diarrhea, weight loss, and all. Once it’s 14 to 15 days, then we do generally see the STEM cells engrafting. Gradually we see the WBC, the white blood cells going up, platelets going up. That is what we call as engraftment.
When your neutrophil count is more than 500 for 3 consecutive days, we call it as neutrophil engraftment and the platelets are more than 20,000 for 7 consecutive days. We call it as platelet engraftment. Once engrafted, we generally keep the patient inside the hospital for around a week, make sure that they don’t have any graft versus host disease, or any complications related to the transplant. Thereafter, they are discharged. Once it’s around 20, 25 days, post-transplant they are discharged, and they generally stay very close to the hospital. So that, in case of any complications they are able to come to the ER or emergency at any time.
We do blood investigations on them roughly twice a week. We do check for any viral reactivations. Commonly, we see cytomegalovirus, adenovirus, all these viral reactivations, depending on the risk category of the transplantation. Generally, we keep the patient under close follow-up for three months.
Beyond which, we do allow them to go back to their native place. Many of them come from outskirts or the rural places. They are allowed to go back to their own although we do have a primary care physician at their local place who is able to as a joint care, we are able to coordinate with them. In case of any minor issues we do liaise with the local physician there. This is for an allogenic transplant.
For an autologous, here the patient is himself the donor. Autologous transplant is done for many lymphomas or myeloma, multiple myelomas. These are the conditions where autologous transplantation is done. Basically, a high dose chemotherapy and followed by autologous STEM cell rescue. Before giving this high dose chemotherapy, we harvest the STEM cells from the patient himself. That is cryopreserved and the STEM cells are mixed with a substance called DMSO, dimethyl sulfoxide and they are cryo-preserved at minus 180 degrees. Then, the patient undergoes the high dose chemotherapy following which the STEM cells are given back to the patient.
This is the process of autologous transplant and it takes around 10 to 12 days for the STEM cells to go and settle in his own body. It’s a question of neutropenic care, make sure the patient is free of infections. The only difference is, in autologous transplant they’re not on immunosuppression.
Once the white blood cells come up, then there is no question of GVHD or graft versus host disease because, the donor and the patient are the same. This is the usual flow of a transplant process here in India.
1.3. What are the main bottlenecks in the SCT patient journey?
The unmet needs would be I feel, a much lesser conditioning regime, as we talked about reduced toxicity or reduced intensity regime, which would enable more patients to undergo a transplantation. If you look at an age group of 70, 75-year-old with multiple co-morbidities, it is difficult to convince the family to undergo a transplant. With the current consortium of drugs if we have a lesser toxic, reduced intensity regime, which gives an equivalent survival compared to the existing drugs, then I think that would be the way to go in the future. Other bottlenecks I feel would be, in our country, the challenge of gram-negative infections, especially the multi-drug resistant infections. If we have a patient of more than two weeks of neutropenia who is immunosuppressed for more than two weeks invariably, they do end up with a multi-drug resistant gram-negative sepsis.
They end up needing very high dose of high-end antibiotics, like Colistin, Tigecycline, all those things. I worked in UK for a year, for a couple of years and we never used those drugs there. There, we used to use only basic antibiotics but to all those antibiotics, the bugs are resistant here in India. Unfortunately, we do end up with using higher level of antibiotics, which leads to more resistance.
Section 2: Future of SCT Therapy
2.1. How will the patient journey for SCT change in the future?
We have the Indian society of bone marrow transplantation. We have this meeting every year where we discuss the overall trend in the transplants which have been done over the last 20 or 30 years. It all started with 1983 when the transplants were firstly done in India. Then, if you look at the current data that around 2,500 transplants, which are done in India every year. There are around 200 to 210 centers for bone marrow transplantation. Out of the 2,500 transplantations around 1500 is allogenic and around 1,000 are autologous.
If you divide it among adult and pediatric, it is approximately 60% adult and 40% pediatric. The indications in pediatric is mostly allogenic. Around 80% of transplants are allogenic and 20% are autologous. The reason being the conditions or diseases needing autologous transplant are rare in pediatrics compared to adults. In adults, it’s more of autologous transplants, where transplants are done for conditions like myelomas, lymphomas, AML, acute myeloid leukemia.
Coming to allogenic transplants, recently there is a growing incidents of haploidentical transplant. Where haplo is a half-matched donor. If you see over the period of last 10 years and gradually the matched unrelated transplant incidents has gradually gone down, the haplo donors transplants have shot up. This is because of various factors with improved evidence, the physicians are more willing to go ahead with the haploidentical transplant and we have a good supportive care system also. That is regarding to the transplant.
As you see going forward, one, regarding the type of transplant, we see more of allogenic and haploidentical transplants going up. Autologous transplants, there are newer and newer drugs which are coming up for diseases like multiple myeloma and AML. These patients may not even need an autologous transplant in the near future.
Even conditions like multiple myeloma, the number of patients going towards transplants are drastically coming down. Other indications probably where transplants could go down are gene therapy. Many conditions like thalassemia, sickle cell disease, immuno-deficiencies where gene therapy is coming up; maybe that would be one of the reasons. There are also newer, immuno-therapy drugs coming up which could lower the incidence of indications for transplant in the future.
2.2. What oncology indications will see future SCT treatment?
Coming to the oncological indications, for most of the multiple myelomas many physicians are managing with the newer drugs, instead of a transplant. As it’s an older age group that are more chances of transplant related mortality with the transplant. People do prefer using newer drugs and there is also good scientific evidence behind that. So coming to other indications, among the adult population, it is still diseases like acute myeloid leukemia, acute lymphoid leukemia, relapsed acute lymphoblastic leukemia and, these are indications for allogenic.
Autologous transplants, various non-Hodgkin lymphomas. People do transplants for those. Among the pediatric indications for malignancies, we don’t see chronic leukemias or multiple myelomas in children. Most of the indications are for acute myeloid leukemia and relapsed acute lymphoblastic leukemias. Some of the autologous transplant indications, people do for neuroblastomas, Ewing sarcoma of the bones and medulloblastoma brain, germ cell tumors of the ovary and other indications. Going forward, we have most of the leukemias, there are newer drugs which are coming up. So, indications for transplant might go down the because of improved survival rates with the first-line chemotherapy itself.
Definitely, because the one factor which we worried about is the transplant related mortality. There are two types of transplant as you understand. One is the myeloablative transplant where, we give very stronger doses of chemotherapy and radiation. Basically, it depends on the condition or the underlying disease for which transplantation is done in an adult age group. Most of these patients who have co-morbidities like diabetes, hypertension, renal issues, they do not tolerate the myeloablative conditioning very well.
These patients are in desperate need of a transplant and reduced intensity conditioning is the way to go because, you are able to achieve cure with the much less toxic regimens. Even if you see the pediatric indications, there are conditions like immune problems, immune deficiencies, or patients who have had recurrent infections, who do not have a very good general health condition. They do not tolerate myeloablative conditioning also. We individually do have a discussion with the family and reduced intensity condition is one option which has definitely improved the survival, particularly for the high-risk transplants, especially the older age group. So, going forward, I think this one of the very good ways to go. Because previously, we were using drugs like busulfan, which had a very high toxicity. It has been replaced by much safer drugs, reduced toxicity drugs, like treosulfan and fludarabine. So, reduced intensity is definitely a way forward.
Even now, there are many centers which offer outpatient transplantations, especially with the reduced intensity conditioning. An outpatient type of transplantation would work well for an autologous transplant because, the complications are less and we don’t generally do regular investigations for testing the levels of immunosuppression, like tacrolimus and all because, the patients are not on these drugs.
Outpatient transplants, if the patient is able to have a safe stay at home, or at any safe place rather than being an inpatient, once the STEM cells are induced, they can ideally be kept in their home, or any center there that is safe. It does work well. Many of the centers here in India do out-patient type of transplantation. It is very difficult to do that in an allogenic setting but autologous transplant, especially with the renewed intensity conditioning where we don’t expect much of toxicity, it is very much feasible.