When to Refer Sickle Cell Disease for Bone Marrow Transplant

Refer sickle cell disease for bone marrow transplant at the first serious sign of severe disease: an overt stroke or other neurological event, an abnormal transcranial Doppler, or recurrent acute chest syndrome or pain crises despite hydroxyurea. Dr. Dharma Choudhary, Chairman - Haemato Oncology & BMT, BLK-Max Super Speciality Hospital, New Delhi, India, advises transplant from age two, sets no upper age limit and excludes only patients with organ failure.

Many patients reach a transplant centre late, with comorbidities and damage that transplant cannot reverse already established. This article sets out the evidence on timing, the guideline indications, the age question and the patients who are not candidates, from the perspective of the referring physician. For the overall picture of transplant as a cure, see bone marrow transplant as a cure for sickle cell disease.

Why timing matters: the damage accumulates

The case for early referral rests on the natural history of the disease. Dr. Choudhary walked through the organ damage that builds up in patients who are not transplanted.

Brain. Neurological injury is the complication everyone recognises. About 11% of children with sickle cell disease have an overt stroke before adulthood, and around one-third develop silent strokes (small infarcts seen only on MRI) by the age of 15. Most patients with neurological injury have some cognitive dysfunction. Transcranial Doppler (TCD), an ultrasound measurement of blood flow velocity in the brain's arteries, identifies children at high risk before a first stroke. Across all ages, Dr. Choudhary put the proportion of patients affected by stroke at almost 24%.

Lungs and heart. Acute chest syndrome, a sickling episode in the lungs with chest pain, fever and low oxygen, is common. Over the long term, repeated episodes lead to pulmonary arterial hypertension and, eventually, right heart failure. Dr. Choudhary also noted that recurrent crises can leave lung fibrosis, so that low oxygen becomes part of a self-reinforcing cycle.

Kidneys, spleen, bones and blood. Renal insufficiency develops over time. Repeated infarction of the spleen leaves patients effectively without one (autosplenectomy), which makes them highly vulnerable to infection. Recurrent vaso-occlusive crises cause pain, bone infarcts and avascular necrosis of the hip or other joints, and chronic transfusion leads to iron overload.

The point for referral is that transplant cures the disease but cannot undo all of this. In Dr. Choudhary's words, you can cure sickle cell disease but you cannot recover the neurological injury that has already happened. A child left with paresis, a focal deficit or cognitive dysfunction keeps it after a successful transplant.

When to refer for bone marrow transplant: the guideline indications

The guideline indications call for transplant in severe disease, defined by neurological injury, recurrent chest or pain crises, or organ involvement. Dr. Choudhary presented the established indications for haematopoietic stem cell transplant in patients with severe sickle cell disease, together with the recommendations of ASH, the American professional society for haematology. He stressed that these are guidelines, not a bible, and that physicians, general practitioners and paediatricians should read each criterion carefully.

When a matched sibling donor is available

Transplant from a matched sibling should be considered for patients with any of the following:

• An overt stroke, or a neurological event lasting more than 24 hours.
• Impaired neuropsychological function with an abnormal brain MRI and angiography.
• Elevated TCD velocity that does not respond to hydroxyurea or chronic transfusion therapy.
• Recurrent acute chest syndrome despite hydroxyurea.
• Recurrent severe pain episodes.
• Red cell alloimmunisation, which makes further transfusion difficult.
• Pulmonary arterial hypertension.
• Recurrent priapism (a painful, prolonged erection caused by sickling).
• Sickle nephropathy, bone or joint involvement, or sickle retinopathy.

When only an alternative donor is available

The criteria for partially mismatched related (haploidentical) or unrelated donors were set more narrowly: recurrent stroke despite adequate chronic transfusion, or severe symptoms unresponsive to hydroxyurea.

Dr. Choudhary's update to this framework is important. Those recommendations were written between about 2010 and 2015. Since then, haploidentical results have improved to the point where they are almost equal to matched sibling transplant. His current position is that a patient with serious disease (repeated hospitalisation, recurrent infection, avascular necrosis) should be considered for transplant whatever the donor. The comparison of donor types is covered in haploidentical versus sibling donor transplant.

Neurological injury: transplant after the first event

ASH suggests HLA-matched related transplant over standard care for patients who have had an overt stroke or an abnormal TCD. When transplant is considered for neurological injury, children younger than 16 who receive a matched sibling transplant do better than those who are older.

Chronic transfusion is useful for preventing primary and secondary stroke, but it is not curative, and years of transfusion bring alloimmunisation and iron overload. That is why, Dr. Choudhary explained, efforts to prevent stroke increasingly focus on the curative option. Most patients do well neurologically after transplant, but some, because of the infarcted brain tissue already present, go on to have recurrent stroke, haemorrhage or seizures.

His recommendation is unambiguous: a patient should be taken up front for transplant whenever there has been a single neurological complication.

Severe symptoms and chronic pain

Patients with recurrent painful crises, particularly recurrent acute chest syndrome, should also be considered for transplant, and the absence of a matched sibling is no longer a reason to wait. Dr. Choudhary cited data presented in 2019 showing that with newer conditioning regimens, outcomes are now above 80% whether the donor is a matched sibling or haploidentical.

Patient-reported pain intensity and pain impact improve after transplant in patients who had intermittent pain beforehand. Referring doctors should, however, set expectations: some patients continue to experience pain after transplant, particularly where nerve injury is already established, and chronic pain can remain a problem even once the disease itself is cured.

Is there an age limit for sickle cell transplant?

The lower limit: two years

Dr. Choudhary advises that the youngest patients should be more than two years old. A child of six months or a year has usually had only one 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 he advises offering it after two years of age.

No upper limit

There is no upper age limit. Every patient has the right to live, he argued, and whether the expected result is 70% or 80% does not change that for the individual. The decision to proceed rests with the patient and family. In leukaemia, transplant is offered even when the cure rate is 30%, because there is no alternative; equally, if recurrent sickling crises are making life miserable, transplant should be considered at any age, with the conditioning chosen to suit the patient. The oldest sickle cell patient Dr. Choudhary has transplanted was around 36 or 37 years old.

How the risks change with age

Age does change the risk profile, and the referring doctor's counselling should reflect it:

• In young children, the main problems are viral infections and sinusoidal obstruction syndrome (veno-occlusive disease of the liver).
• In older patients, transplant-related mortality rises, largely because vascular damage is already widespread. Neurotoxicity, including posterior reversible encephalopathy syndrome (PRES), veno-occlusive disease and graft-versus-host disease are more frequent. Many older patients are already alloimmunised from transfusions, which delays immune reconstitution and raises the risk of graft rejection.

Early transplant gives better outcomes with fewer complications. But, as Dr. Choudhary acknowledged, the transplant team cannot control when a patient presents: whenever a patient arrives with serious symptoms, the best available treatment has to be offered at that point. For adults in their thirties with complications such as avascular necrosis or priapism, reduced-intensity or non-myeloablative conditioning is preferred over full-intensity regimens, as explained in the conditioning section.

Who is not a candidate

The patients Dr. Choudhary does not transplant are those with established organ failure:

• Liver failure.
• Kidney failure.
• Paralysis after a very severe stroke.
• Lung failure, defined in his practice as a diffusing capacity of the lung below 70%.
• Cardiac compromise or heart failure.

Outside these organ-system failures, he said, age has nothing to do with whether a transplant can be done. Lung-function cut-offs vary between centres and with conditioning intensity, so a patient near this threshold should be discussed with the transplant team rather than ruled out.

He also distinguishes patients who are not ill enough to need one. Asymptomatic patients and mild "sicklers" who reach adulthood without serious complications need no treatment, because every treatment, transplant included, carries a risk of morbidity and mortality.

Counselling families before referral

Referral is as much a conversation as a clinical decision. Families need to hear two things plainly. First, the outcome does not depend on race: African patients usually have more severe disease than Indian patients, but in Dr. Choudhary's experience their transplant outcomes are the same, and what matters is disease stage, comorbidity, donor match and the quality of treatment. How he explains success rates to families is set out in the pillar guide.

Second, the risk to life is real. Every transplant, whether full match, half match or mismatch, carries a risk to life, which ranges from about 5% with a matched sibling in childhood to 10% or more with alternative donors or in older patients. It is reduced, not removed, by the right treatment, close follow-up and long-term reporting between doctors. A family that understands both the chance of cure and the risk is better placed to decide, and the decision, as he stresses, belongs to the patient and family.

The referral itself

Most patients reach a transplant centre late: Dr. Choudhary's sickle cell transplant series was dominated by patients with comorbidities, late referral and prior alloimmunisation. Earlier referral is the single change most within a referring doctor's control.

Two practical steps shorten the path. First, HLA typing of the patient and full siblings tells the family at once whether a matched sibling exists; where local typing is unavailable, samples can be sent to the transplant centre, as described in the HLA typing section. Second, a doctor-to-doctor note describing the patient's history, crises, transfusion burden and organ function allows the transplant team to advise on candidacy before the family commits to travel. Questions raised by referring doctors during the session are collected in the masterclass Live Discussion.

The role of the referring doctor does not end at referral. Once the patient returns home, the local physician becomes central to the outcome, as explained in complications and follow-up after a sickle cell transplant.