Sickle Cell Transplant Aftercare: GVHD and Follow-Up

After a sickle cell transplant, about 70% of patients have no significant complication and about 30% develop graft-versus-host disease (GVHD), according to Dr. Dharma Choudhary, Chairman - Haemato Oncology & BMT, BLK-Max Super Speciality Hospital, New Delhi, India. Sickle cell transplant aftercare then centres on immunosuppression, which lasts six months to one year, and he wants the transplant team and the referring doctor to be in contact monthly until it stops.

That last point is the one he stresses most. The first 30 or 100 days at the transplant centre are not, in his words, what decides success: what decides it is how the patient is monitored after returning home. This article covers the complications of transplant and how they are prevented, fertility, immunosuppression and vaccination, and the follow-up partnership between the transplant team and the local physician. For the overall case for transplant, see bone marrow transplant as a cure for sickle cell disease; for donor choice and conditioning, see haploidentical versus sibling donor transplant.

Early complications: the first weeks

The acute phase follows conditioning and stem cell infusion, while blood counts are at their lowest. Dr. Choudhary listed the complications the transplant team expects to see and treat.

• Neutropenia and infection. With very low white cell counts, patients are at risk of sepsis and other infections, which are treated promptly.
• Mucositis. After the infusion, inflammation and ulceration of the mouth and gut lining cause pain, vomiting and diarrhoea. Some patients need narcotic painkillers.
• Haemorrhagic cystitis. Some patients pass blood in the urine because cyclophosphamide given during conditioning damages the bladder lining, or later because of BK virus reactivation. Hydration and mesna are the main prevention, and once blood counts recover, the great majority of patients recover.
• Veno-occlusive disease of the liver (also called sinusoidal obstruction syndrome). The small veins of the liver become blocked, causing a tender, painful liver, fluid in the abdomen (ascites) and jaundice. Sickle cell patients are predisposed because chronic liver disease, iron overload from transfusion and hepatitis B or C infection acquired through transfusion all damage the liver. Prevention is the priority.

These complications are concentrated in the period of close monitoring, which runs for the first 30 to 100 days.

Graft-versus-host disease: the central risk

GVHD is the central risk after transplant, and about 30% of patients develop it. It occurs when immune cells from the donor recognise the recipient's tissues as foreign and attack them. Dr. Choudhary describes acute and chronic GVHD as the two most important complications of transplant, and chronic GVHD as the one that can ruin quality of life.

Acute GVHD typically appears in the first months and affects the skin, gut and liver.

Chronic GVHD resembles an autoimmune disease: dry eyes, dry skin, dry mouth and lung problems. In sickle cell disease the lungs are a particular concern, because recurrent crises have often already caused lung fibrosis and pulmonary arterial hypertension, with low oxygen part of the cycle. A transplant for sickle cell disease has to be designed to reverse that damage, not add to it.

Every allogeneic transplant carries a GVHD risk

Even with a fully matched sibling, there is a risk of GVHD; only an identical twin donor is exempt. That is why, as Dr. Choudhary told a referring doctor from Kenya in the session, no transplant is done without immunosuppression, which every patient receives to prevent both GVHD and rejection.

In leukaemia, some GVHD is useful: it carries a graft-versus-malignancy effect, so patients who develop chronic GVHD relapse less often, whereas transplants from identical twins have no GVHD but a much higher relapse risk. Sickle cell disease is not a malignancy, so there is nothing to gain from GVHD, and prevention is the goal.

How GVHD is prevented

Dr. Choudhary identified the levers that determine GVHD risk:

1. Conditioning and immunosuppression. Every patient receives GVHD prophylaxis.
2. Anti-thymocyte globulin (ATG). Using ATG during the transplant brings the risk of GVHD to a minimum, though never to zero.
3. Stem cell source. Peripheral blood stem cells carry more GVHD risk than bone marrow.
4. Stem cell dose. A doctor who gives a higher stem cell dose out of fear of graft rejection causes more chronic GVHD.
5. Newer drugs. Better drugs for treating GVHD, such as ruxolitinib for acute and chronic GVHD, can also be used for prophylaxis. Ruxolitinib is approved for treating steroid-refractory GVHD; its use for prevention is still being studied.

His summary was that a transplant physician has to be wise enough to do the right transplant, not just any transplant.

Why a cheap transplant is a false economy

ATG is the clearest example of where cost and safety collide. It is an expensive medicine, roughly one-tenth of the cost of the whole transplant, Dr. Choudhary said, and some resource-constrained centres remove it from conditioning to reduce the price. Removing ATG raises the risk of GVHD. A patient may be lucky and avoid it, but otherwise ends up with a serious problem.

His advice to referring doctors and families is blunt. A safe transplant costs a little extra, and a cheap transplant should never be done. If a centre offers to perform a transplant at half the usual cost, he said, it is doing something wrong. Because a bone marrow transplant is a medical procedure rather than a surgical one, the outcome depends almost entirely on the medicines used, and better medicines cost more. The cost comparison between countries is covered in the pillar guide.

Fertility after transplant

Infertility is very common after transplant, and Dr. Choudhary described it as a major concern for African families, for whom having their own children is a priority.

Infertility is not sexual dysfunction. Asked to clarify the point in the session, he explained that infertility here means the inability to reproduce because the ovaries or testes fail, so that ovulation or sperm production stops. Infertility does not in itself impair sexual function. Ovarian or testicular failure can still lower sex hormone levels, so symptoms such as early menopause or low libido should be reported, because hormone replacement treats them.

Preservation should be planned before conditioning. Wherever possible, semen or eggs are collected and stored before transplant. Children under about ten years old are the difficult group: semen and eggs cannot be collected, and the alternatives, freezing ovarian tissue or (still experimental) testicular tissue, are available at few centres, so infertility remains a real problem for their future. Families should discuss fertility with the transplant team before treatment begins, and the conditioning choice described in the conditioning section is part of that conversation.

Other late effects

Patients who need steroids as part of their immunosuppression can develop cataracts and avascular necrosis, a risk compounded in sickle cell disease, where avascular necrosis is already common. Long-term follow-up for about four to five years watches for these and other late complications, particularly infection.

Immunosuppression and immune recovery

Unlike liver and kidney transplant recipients, who need immunosuppression for life, Dr. Choudhary's patients take it for six months to one year at most. While they remain on it, they are immunodeficient. Depending on whether the transplant was for leukaemia or sickle cell disease, immunosuppression lasts six months to one year; apart from patients with very severe chronic GVHD who need long-term treatment, almost 90% are off immunosuppression by the end of the first year.

After about a year, most patients have immune reconstitution: their new immune system has matured enough to protect them, and they are free of the heightened risk of infection.

The danger lies in stopping too early. If patients go home and stop their immunosuppression, Dr. Choudhary warned, they reject the graft and die, or they end up with chronic GVHD.

Vaccination after transplant

A transplant wipes out the immunity built by childhood vaccines, so patients are revaccinated. Every patient leaves with a vaccination chart. Inactivated vaccines such as pneumococcal vaccine start from three to six months after transplant, and live vaccines wait until at least two years.

There is one rule for the household that referring doctors should communicate clearly. Siblings of a transplanted child should not receive live vaccines, particularly the oral polio vaccine (OPV). Children given OPV shed the vaccine virus, and a transplanted patient exposed to it can develop paralysis. International guidelines (IDSA 2013) restrict only oral polio vaccine for household contacts and allow other live vaccines such as measles-mumps-rubella with precautions, so families should confirm the sibling schedule with the transplant team.

Nutrition

Families often ask about diet. Dr. Choudhary encourages good nutrition and places no prohibitions on what patients eat, apart from avoiding street food. Hygienic home-cooked food, eaten with the family, with a good amount of protein, supports a good transplant outcome, as it does for any healthy person.

Sickle cell transplant aftercare: the referring doctor's role

The referring doctor's role is to stay in monthly contact with the transplant team for the first year and to monitor the patient at home. Dr. Choudhary has been transplanting international patients for 15 to 17 years. For 60 to 70 of every 100 international patients, he is directly connected with the referring doctor. Every patient goes home with a referral note setting out what to do, what not to do, how to monitor and how often.

His request to referring physicians is specific: stay in contact with the transplant team at least once a month for one year, until immunosuppression has stopped. Working this way, he estimates, transplant teams and local doctors together can improve outcomes by 20 to 30% compared with patients who are lost to follow-up.

What the local doctor should watch for follows from the complications above:

• Adherence to immunosuppression throughout the first year.
• Signs of infection, which need prompt treatment while the patient is immunodeficient.
• Signs of chronic GVHD: dry eyes, dry mouth, skin changes or breathlessness.
• Revaccination, according to the chart.
• Live vaccines in siblings, particularly oral polio vaccine, which must be avoided.

Patients and referring doctors are also given the transplant team's email address and phone number, so they can make contact by email or WhatsApp in an emergency. As Dr. Choudhary put it, doing the procedure alone is not enough for the right outcome; 30 or 100 days at the centre, on their own, have no meaning.

He sees close follow-up, long-term monitoring, shared reporting and doctors seeking help from each other as the way to bring the risk of transplant down. Further questions from referring doctors, including on GVHD, fertility and follow-up, are answered in the masterclass Live Discussion. For when to start the referral process, see when to refer sickle cell disease for bone marrow transplant.