Sickle Cell Transplant Donor Options and Conditioning

The main sickle cell transplant donor options are a matched sibling, still the preferred donor, and a haploidentical (half-matched) parent or relative, now a near-equal alternative. Dr. Dharma Choudhary, Chairman - Haemato Oncology & BMT, BLK-Max Super Speciality Hospital, New Delhi, India, puts haploidentical rejection at around 5 to 10% and survival at around 80 to 90%. More than half of his sickle cell transplants used haploidentical donors.

For families, this changes the first question from "is there a donor?" to "which donor, and which conditioning?". This article covers donor options, HLA typing (including how to send samples from countries without local testing), the choice of stem cell source, conditioning regimens and the three phases of the transplant itself. Why transplant is worth pursuing is covered in bone marrow transplant as a cure for sickle cell disease; who should be referred, and when, in the referral article.

What an allogeneic transplant requires

A transplant cures sickle cell disease only when the stem cells come from another person (allogeneic). The patient's own unmodified stem cells carry the defect, so a conventional autologous transplant has no role; gene therapy is the exception, because it corrects the patient's cells before they are returned. An allogeneic transplant needs a suitable HLA-matched donor.

HLA (human leukocyte antigen) molecules are the tissue markers the immune system uses to tell self from non-self. The closer the match between donor and recipient, the lower the risks of the two immune conflicts that define transplant: rejection, in which the recipient's remaining immune cells destroy the graft, and graft-versus-host disease (GVHD), in which donor immune cells attack the recipient's tissues.

Dr. Choudhary summarised the historic trade-off. An allogeneic transplant brings more GVHD, more infection and a risk of rejection. Two things have changed that balance. Infection rates have fallen with better antibiotics, antifungal treatment and immunosuppression. And graft rejection has become much less common because high-resolution HLA typing identifies the best donor with far greater precision.

Sickle cell transplant donor options, in order of preference

The order of preference is a matched sibling, then a haploidentical relative, then a matched unrelated donor from a registry.

Matched sibling donor

A full sibling who shares both HLA sets with the patient remains the benchmark donor, and Dr. Choudhary was clear that the best results are always with matched sibling transplant. The survival figures he presented for matched sibling transplant are set out in the pillar guide.

Each full sibling has a 25% chance of being a full match. The chance of finding a donor rises with family size, and is higher in genetically homogeneous populations, particularly where consanguineous marriage is common.

A sibling who carries the sickle cell trait can generally donate. Carriers are healthy and their stem cells produce normal adult haemoglobin alongside sickle haemoglobin, so the transplanted patient ends up with the carrier's blood picture, not the disease.

Haploidentical donor

A haploidentical donor shares exactly one of the two HLA sets with the patient. Every biological parent and every child is a half match, and each sibling has a 50% chance of being one, so almost every patient has a potential haploidentical donor.

The barrier used to be the immune conflict across a half match. A landmark approach, giving cyclophosphamide after the stem cell infusion (post-transplant cyclophosphamide), changed that by selectively eliminating the donor T cells most likely to cause GVHD. In Dr. Choudhary's account, haploidentical transplant with post-transplant cyclophosphamide became the standard of care where no matched donor exists, and the number of haploidentical transplants worldwide has risen exponentially since 2010, for malignant and non-malignant disease alike.

For sickle cell disease specifically, the early haploidentical experience used non-myeloablative regimens and saw more graft rejection. With current platforms, Dr. Choudhary puts rejection at around 5 to 10%, essentially the same as matched sibling transplant, and overall survival at around 80 to 90%. His conclusion was that, today, donor type does not decide the outcome. His programme has performed more than 270 haploidentical transplants across all diseases, and 35 of its 65 sickle cell transplants were haploidentical.

A parent who has sickle cell disease cannot donate; a parent who is a carrier can.

Matched unrelated donor

Where neither a sibling nor a suitable relative is available, an unrelated donor can be sought through international registries. In Dr. Choudhary's series this route played a small part: one of his 65 sickle cell transplants used a matched unrelated donor.

HLA typing: what is tested and how to send samples

HLA typing is a blood test on the patient and potential donors. For a sibling match, HLA-A, HLA-B and HLA-DRB1 are the minimum loci tested. For unrelated and haploidentical donors, Dr. Choudhary explained, ten antigens are typed (two copies each of HLA-A, B, C, DRB1 and DQB1), and the more loci are typed, the better the donor can be identified.

High-resolution typing is a major reason rejection has become less common.

When HLA typing is not available locally

In several countries HLA typing is not available at all, a problem raised directly in the masterclass Live Discussion: how should a physician collect samples from a patient and siblings, what precautions apply, and how should the samples travel to a transplant centre?

Dr. Choudhary's answer was practical. The receiving laboratory specifies the prerequisites for an HLA sample sent to India: the temperature at which it must travel, how many hours it can be in transit, the volume of blood needed, and whether a buccal (cheek) swab can be used instead of blood. He undertook to circulate these requirements from his laboratory team. The discussion also noted that regional laboratory networks now operate in several African countries, though not in all, which can make collection and dispatch simpler. Referring doctors should obtain the transplant laboratory's current instructions before collecting, because sample handling requirements are specific to each laboratory.

Choosing the stem cell source

Bone marrow is the preferred stem cell source for young patients with a matched sibling, because peripheral blood carries more GVHD risk. Allogeneic stem cells can come from the donor's bone marrow, from peripheral blood or, less often, from umbilical cord blood. The choice matters more in sickle cell disease than in most transplants.

• Bone marrow is the preferred source for young patients with a matched sibling. The five-year survival above 95% that Eliane Gluckman described for early matched sibling transplant was achieved using bone marrow as the stem cell source.
• Peripheral blood stem cells carry a higher risk of GVHD than marrow, Dr. Choudhary explained. A higher stem cell dose, sometimes given out of fear of graft rejection, also increases chronic GVHD.

Collecting stem cells from the blood requires mobilisation, which in sickle cell disease is a problem in itself. Growth factor, the standard mobilising drug, can provoke a sickle crisis. Plerixafor, which mobilises stem cells by a different mechanism, is now, in Dr. Choudhary's words, a very good alternative for mobilisation.

Conditioning choices: preparing the marrow

Conditioning is the preparation given before the stem cell infusion: chemotherapy drugs, with or without radiation. It has two jobs. It destroys the patient's own marrow to create space for donor cells to populate, and it suppresses the recipient's immune system enough to prevent rejection. The central rule, as Dr. Choudhary put it, is that as intensity increases, toxicity increases too.

Three intensities

• Myeloablative (full-intensity) conditioning destroys the recipient's marrow completely. Dr. Choudhary recommends it for young, fit patients, under about 15 years of age, because the affected marrow has to be eliminated and these patients have the best outcomes with full myeloablation.
• Reduced-intensity conditioning uses lower doses and suits patients who are less fit.
• Non-myeloablative conditioning is gentler still, for older or medically compromised patients. Low-dose total body irradiation (TBI) forms part of non-myeloablative regimens.

Older patients often already have pulmonary hypertension, nephropathy, neuropathy and other comorbidities, which is why they are not chosen for myeloablative conditioning. The haematopoietic cell transplantation comorbidity index (HCT-CI), a score of the patient's comorbidities, is weighed together with age to guide the choice.

How regimens have evolved

When Dr. Choudhary's programme began transplanting in the early 2000s, the standard conditioning combined busulfan, cyclophosphamide and anti-thymocyte globulin (ATG), an antibody preparation that depletes T cells. Since then, intravenous busulfan and refinements in the use of ATG have improved engraftment, while high-resolution HLA typing has improved donor selection. Graft failure has fallen, and overall survival now exceeds 90% for myeloablative matched sibling transplant.

For older and compromised patients, fludarabine-based conditioning with ATG is used. Overall survival with these regimens is also high, but non-myeloablative and reduced-intensity transplants can leave mixed chimerism, a state in which donor and recipient blood cells coexist, and disease-free survival ranges from 80 to 90%.

The regimen Dr. Choudhary's programme most commonly follows is fludarabine-based conditioning with ATG. Haploidentical platforms add further measures to prevent rejection; established haploidentical regimens for sickle cell disease use agents such as thiotepa and low-dose total body irradiation alongside post-transplant cyclophosphamide.

The three phases of a sickle cell transplant

Dr. Choudhary describes every transplant in three phases.

1. Pre-BMT: work-up and conditioning. Donor and recipient both undergo a detailed work-up. The patient receives secure central venous access, then the conditioning regimen. GVHD prophylaxis, the immunosuppression that prevents the fight between donor and recipient T cells, begins around this time.
2. BMT day: the infusion. The transplant itself is simply an infusion of stem cells through a vein, much like a blood transfusion. There is no operation on the recipient.
3. Post-BMT: waiting for engraftment. Engraftment means the donor cells settle in the marrow and begin producing blood. Until then, the patient has very low blood counts and is at risk of infection and bleeding.

Patients need close monitoring for the first 30 to 100 days and long-term follow-up for about five years to watch for late complications. Immunosuppression usually continues for six months to one year, unlike liver and kidney transplant recipients, who need it for life.

What happens after engraftment, including the complications of the early weeks, GVHD, fertility and the follow-up that continues at home, is set out in complications and follow-up after a sickle cell transplant. Indicative package costs for each donor type are listed on the treatment-cost pages for matched sibling donor BMT, haploidentical BMT and matched unrelated donor BMT.