Question 1

Patients often reach India late, as adults or near-adults with comorbidities, and a sibling may not be a full match, so the donor is often a parent or another relative. Can you explain the rationale behind donor choice?

Dr. Dharma Choudhary · Accepted Answer

Allogeneic transplant needs a suitable HLA-matched donor. A full-match sibling donor was the historic standard, and allogeneic transplant brings a graft-versus-tumour effect, at the cost of graft-versus-host disease, more infection and a risk of rejection. Infection rates have come down with better antibiotics, antifungals and immunosuppression, and rejection has fallen because high-resolution HLA typing identifies the best donor; for unrelated and haploidentical donors, 10 alleles at five loci (A, B, C, DRB1 and DQB1) are typed. With one sibling there is a 25% chance of a full match, and the chance improves with family size. Where no matched donor exists, haploidentical transplant with post-transplant cyclophosphamide has become the standard of care, the number of haploidentical transplants has risen exponentially since 2010, and the outcome is almost the same as with matched donors, including in sickle cell disease, with graft rejection at about 5 to 10%, almost equal to a matched sibling. Young patients under 15 can have a full-intensity myeloablative transplant; reduced-intensity or non-myeloablative conditioning is used for patients who are less fit or have comorbidity, so every patient has a chance of cure.

Question 2

Can you take us through the phases on your slide: pre-BMT, the day of BMT and post-BMT?

Dr. Dharma Choudhary · Accepted Answer

There are three phases. Pre-BMT is conditioning, BMT itself is just the stem cell infusion, and post-BMT is waiting for engraftment. Donor and recipient both receive a detailed work-up. The patient gets secure venous access and then the conditioning regimen, drugs with or without radiation, which kills the recipient's marrow and creates space for the donor cells; the higher the intensity, the higher the toxicity, so non-myeloablative and reduced-intensity regimens are used for less fit patients and myeloablative regimens for fit patients. Every patient receives graft-versus-host disease prophylaxis to prevent the fight between donor and recipient T cells. Unlike liver and kidney transplant recipients, who need lifelong immunosuppression, our patients take it for six months to one year at most, and they remain immunodeficient for about that long; after a year most have immune reconstitution, are revaccinated and are free of that infection risk. Patients need close monitoring for the first 30 to 100 days and long-term follow-up for about five years for late complications. In malignancy, graft-versus-host disease is a boon because it carries a graft-versus-malignancy effect: patients with controlled acute and chronic GVHD have a relapse rate of less than 10%, whereas twin transplants have no GVHD but a very high relapse risk. Other complications include veno-occlusive disease and haemorrhagic cystitis. Infertility is very common after transplant, so wherever possible we collect semen or ova beforehand, which matters greatly to African families, but in children under ten we cannot collect semen or preserve the ovary. Post-transplant vaccination starts after one year. No sibling should receive a live vaccine, particularly oral polio vaccine, because they shed the virus and the transplanted patient can develop paralysis; injectable polio vaccine is used instead.

Question 3

Can you help us with the pathology of the stem cell, and what are the effects of the transplant? For example, one patient asked you in a consultation how their life would be after transplant.

Dr. Dharma Choudhary · Accepted Answer

The stem cell itself has no pathology. It is the mother cell, present in every human being and every mammal, that produces blood; here we are talking about the haematopoietic stem cell. Sickle cell disease is a single-gene defect, a single base pair in the beta-haemoglobin chain, so it is the haematopoietic stem cell that is defective, and we need to replace it with healthy stem cells. As for the effects of transplant, which are essentially its complications: 70% of patients have nothing, and 30% will have graft-versus-host disease. In the acute phase, neutropenia can lead to sepsis and infection, which we treat. After infusion there is a risk of mucositis, mouth ulceration that causes pain, vomiting and diarrhoea, and some patients are treated with narcotic analgesics. Haemorrhagic cystitis, passing blood in the urine, follows the radiation or cyclophosphamide received during conditioning and damages the bladder epithelium; prevention is hydration, and once the counts recover, the great majority of patients recover. Veno-occlusive disease of the liver can occur because chronic haemolysis, iron overload from transfusion and hepatitis B or C infection all predispose to damage and blockage of the small veins and sinusoids of the liver, causing a tender, painful liver, ascites and jaundice, which we must prevent. The two most important complications are acute and chronic graft-versus-host disease. Chronic GVHD, with dry eyes, dry skin, dry mouth and lung problems, impairs quality of life, and these patients are already predisposed to lung fibrosis and pulmonary arterial hypertension from recurrent sickle crises, so the transplant has to be done with reversing that in mind. Infertility is another complication, and patients who need steroid immunosuppression can develop cataract and avascular necrosis.

Question 4

When you list infertility as a side effect of bone marrow transplant, does that mean only the inability to reproduce, or sexual dysfunction as well?

Dr. Dharma Choudhary · Accepted Answer

Infertility means the inability to reproduce, which is different from sexual dysfunction. It is ovarian or testicular failure, meaning spermatogenesis and ovulation are affected. Because the ovaries and testes also make hormones, some patients develop early menopause or low testosterone, which is treatable with hormone replacement; sexual and social life are not affected after transplant.

Question 5

Apart from transplantation in symptomatic sickle cell patients, is there no therapy for asymptomatic patients to prevent homozygous transmission?

Dr. Dharma Choudhary · Accepted Answer

No. It is a gene defect, and there are two different groups: sickle cell carriers and sickle cell disease patients. Sickle cell disease means both parents were carriers. A carrier has only one gene affected and can pass sickle cell disease on to their children if their partner is also a carrier. Other than gene therapy and transplant, there is no cure for sickle cell disease. An asymptomatic patient does not need a transplant: many are mild sicklers who reach adulthood and live a normal life. Where there is no phenotypic expression of the genotypic disorder, transplant is not warranted, because every transplant carries a risk of morbidity and mortality.

Question 6

At what age can patients undergo bone marrow transplant? Younger age gives better outcomes, but is there an upper age cut-off beyond which the benefits no longer outweigh the risks?

Dr. Dharma Choudhary · Accepted Answer

I always advise that the youngest should be more than two years of age. At six months or one year the child has had only one episode of crisis, and very young children cannot take the immunosuppression properly. Transplant is sometimes done that early as an emergency for leukaemia, but for sickle cell disease and thalassaemia it should be offered after two years of age. There is no upper age limit: every patient has the right to live, and whether the result is 70% or 80% does not matter for that individual. The decision to go for transplant depends on the patient and family. In leukaemia we transplant even with a 30% cure rate because there is no other treatment, and if recurrent sickling crises make life miserable, transplant should be done at any age, with conditioning chosen from non-myeloablative to reduced intensity and the treatment designed around the patient's profile. The patients who are not candidates are those with organ failure: liver or kidney failure, paralysis from a severe stroke, lung failure with a diffusion capacity below 70 percent, or cardiac failure. Otherwise age has nothing to do with whether transplant can be done. The oldest patient I have transplanted was around 36 or 37 years old.

Question 7

Every family hearing a 70% or 80% success rate wants to know which bracket their own child will fall into. How do you explain these percentages?

Dr. Dharma Choudhary · Accepted Answer

Statistics are for the doctor. When I transplant 100 patients I can draw a percentage; with five patients I cannot. So I tell every patient that, as an individual, you are one in a hundred. I can tell you the outcomes for 100 patients like you, but even if I quote a 99% success rate, if you land in the 1% your outcome is zero, and if I quote 30% and you fall into that 30%, you are cured.

Question 8

What measures are in place to reduce graft-versus-host disease in allogeneic transplant, where donor cells attack the body?

Dr. Dharma Choudhary · Accepted Answer

In every allogeneic transplant there is a risk of graft-versus-host disease, even with a full-match sibling; only an identical twin is exempt. No transplant is done without immunosuppression, which every patient receives to prevent GVHD and rejection. Better drugs are now available, such as ruxolitinib, for treatment and also for prophylaxis. Using ATG during transplant brings the risk of GVHD to a minimum, though never to zero. The risk depends on several factors: the conditioning, the immunosuppression and the stem cell source, since peripheral blood stem cells carry more risk of GVHD than marrow, and a doctor who gives a higher stem cell dose for fear of graft rejection causes more chronic GVHD. The transplant physician must be wise enough to do the right transplant, not just any transplant. Some resource-constrained centres remove ATG, a really expensive medicine at roughly one-tenth of the cost of the whole transplant, to cut costs, and that raises the risk of GVHD. A safe transplant costs a little extra, and a cheap transplant should never be done: if a doctor offers to do it at half the cost, he is doing something wrong. Bone marrow transplant is a medical procedure, not a surgical one; it is not cut and paste like liver or kidney transplant, and better medicine costs more.

Question 9

Bone marrow transplant is expensive, but in India it remains cost-effective compared with Europe and the US. What is the cost implication for the patient?

Dr. Dharma Choudhary · Accepted Answer

Cost is dynamic, and it depends on the country where you practise and that country's GDP; if everything in the US is expensive, treatment there will be expensive by the same factor. The medicines are the same and good medicines cost much the same in most places, apart from local taxes. The saving comes from hospital and bed charges, which are lower in Asia than in America and Europe, and from supportive care and healthcare consumables, which are cheaper in India. We work at roughly one-fifth of the cost of America or the UK, perhaps one-tenth compared with America. For Africans who travel, my advice is to go to the best centre in India, where they can get treatment without any compromise.

Question 10

What is the survival rate after transplant by race according to current statistics, and is race a factor in the success of transplant?

Dr. Dharma Choudhary · Accepted Answer

Race does not affect the outcome. African sickle cell patients are more severely affected than Indian sickle cell patients, who do not have such severe symptoms, so the presentation differs, but the outcome is the same, just as leukaemia in Africa and leukaemia in India have the same transplant outcome. Transplant outcome is affected mainly by patient factors (disease stage and comorbidity) and donor factors (full match, half match or mismatch), and then by treatment factors. If you choose the right conditioning, the right immunosuppression and the right supportive care, outcomes across the globe will be similar, whether the transplant is done in America, Tokyo or India.

Question 11

Are there any clinical nutritional considerations before and after transplant?

Dr. Dharma Choudhary · Accepted Answer

We encourage good nutrition. Patients can eat whatever they like; there is no prohibition other than avoiding street food. Any hygienic food eaten with the family, with good nutrition and a good amount of protein, supports a good transplant outcome, as it does for every healthy human being.

Question 12

Under a model where the patient's local physician makes the referral and stays in the loop, for how long should the patient keep returning to that physician after going home?

Dr. Dharma Choudhary · Accepted Answer

I have been transplanting international patients for 15 to 17 years, and for 60 or 70 of every 100 international patients I am directly connected with the referring doctor. I always send the patient back with a referral note on what to do, what not to do, how to monitor and how often. The success of transplant is not what we do here in the first 30 or 100 days; it depends on how you monitor afterwards. If patients go home and stop immunosuppression, they reject and die, or they end up with chronic GVHD. The treating or referring physician should be in contact at least once a month for one year, until the patient is off immunosuppression. Depending on whether the transplant was for leukaemia or sickle cell disease, patients are immunosuppressed for six months to one year; apart from those with very bad chronic GVHD who need long-term immunosuppression, almost 90% are off it by the end of the year, after which they are revaccinated. Working together this way, we can improve outcomes by 20 to 30% compared with patients lost to follow-up. We also give patients our email and phone number so they can reach us by email or WhatsApp in an emergency.

Question 13

In some countries even HLA typing is not available. How should a physician collect samples from a patient or siblings, what precautions should be taken, and how should the samples be transported so they can be tested at a centre like yours?

Dr. Dharma Choudhary · Accepted Answer

I will circulate full information from my lab doctor on the prerequisites for an HLA sample, so that it can come to India: the temperature, how many hours it can travel, how many millilitres of blood are needed, or whether a buccal swab can be used. Laboratory networks such as Metropolis are now present in most countries.

Live Discussion with Dr. Dharma Choudhary