HLA Matching and Conditioning for Sickle Cell Transplant

HLA matching for a sickle cell transplant follows a hierarchy. A brother or sister who matches on all ten HLA markers is the best donor; a fully matched unrelated volunteer from a registry comes next; and a half-match relative, usually a parent, is the option almost every patient has, provided the patient carries no antibodies against the donor's tissue type. A sibling with sickle cell trait can donate safely.

This article covers the decisions made before the transplant: choosing the donor, collecting the stem cells, the conditioning chemotherapy and protecting fertility. It draws on the September 2026 masterclass by Dr. Arun Singh Danewa, Senior Consultant – Pediatric-Haemato-Oncology & Bone Marrow Transplant (Unit II), Artemis Hospitals, Gurugram, India. The full sequence of a transplant is set out in the complete guide to the sickle cell bone marrow transplant process, and what happens after the cells are infused in the article on engraftment and chimerism.

How HLA matching for a sickle cell transplant works

HLA (human leukocyte antigen) typing reads the genetic markers the immune system uses to tell self from non-self. Every person's HLA is different, and a transplant needs donor and patient to share enough of it for the new cells to be accepted. The first test before any sickle cell transplant is therefore a high-resolution HLA test on the patient and on every potential donor.

The report lists five genes, HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1, each inherited once from the mother and once from the father, giving ten markers in all. Some reports also include DPB1. A patient and donor who match on all ten markers are a 100% match. Because each child inherits half of each parent's genes, a parent always matches at least half.

The donor hierarchy: sibling, unrelated and half-match

Dr. Danewa described three types of transplant, in order of preference.

1. Matched sibling donor

A fully matched brother or sister is the best donor. The chance that any one sibling is a full match is 25%, and it is purely random: a patient with a single sibling may have a match, while a patient with six or seven siblings may have none. With a matched sibling, graft-versus-host disease and graft failure are least likely and easiest to manage.

2. Matched unrelated donor

If no sibling matches, the next step is a matched unrelated donor. Volunteers around the world register their HLA type with organisations such as DKMS, DATRI in India and NMDP in the United States, and the registries search for a patient's match. An unrelated donor who matches on all ten markers shares the patient's HLA type, although differences in other, minor tissue antigens mean the risk of graft-versus-host disease remains somewhat higher than with a matched sibling.

3. Half-match (haploidentical) donor

If neither search succeeds, almost everyone still has a donor: a half-match, or haploidentical, relative, usually the mother or father. For a transplant physician, any match from 5 out of 10 to 9 out of 10 counts as half-match. Mathematically these look like 50%, 60% or 90% matches, but Dr. Danewa was emphatic that the distinction does not change the outcome: a donor is either a full match or a half match, and anything below 5 out of 10 does not qualify. Results with half-match donors have improved steadily with new techniques and drugs and are moving closer to those with other donors.

The donor-specific antibody test

Half-match transplants need one extra test. Repeated blood transfusions can lead the patient to make antibodies against HLA markers they have been exposed to. If these donor-specific antibodies (DSA) target the mismatched markers of the chosen donor and the level is high, the patient will reject the donor's stem cells. A half-match donor therefore needs two conditions: an HLA match between 5 and 9 out of 10, and a negative DSA test. In the session's discussion of graft rejection, Dr. Danewa said that transplanting into a patient with high DSA without first lowering the antibodies (desensitisation) leads to rejection: the neutrophils never engraft.

Can a sickle cell carrier sibling be a donor?

Yes. This is one of the questions Dr. Danewa hears most often: one child has sickle cell disease, another has sickle cell trait (AS), and the two are a full match. The carrier sibling can donate, and a successful transplant can be done without difficulty. The patient's blood will then behave like the donor's, as sickle cell trait, without disease-related symptoms.

Who can donate: donor age and size

Anyone older than one year, or heavier than about 10 kg, can practically donate stem cells. The constraint is the cell dose. The minimum dose is 3 million stem cells per kilogram of the recipient's weight, so a very small donor may not yield enough for a much larger patient. Dr. Danewa gave the example of a 12 kg donor for a patient weighing 60 to 65 kg. In that situation the team may need to collect twice, which is the maximum, but with a fully matched donor they still proceed and usually reach the required dose.

How stem cells are collected

There are three sources of stem cells, and the choice has shifted sharply.

• Peripheral blood, the source for most transplants today. The donor is admitted in the morning, a line is placed in the neck or the groin (femoral region), and an apheresis machine, the same machine used to collect single-donor platelets on a different setting, separates out the stem cells over three to four hours. The donor sits comfortably, often watching a mobile phone. It is a day-care procedure with no cut, no surgery and no anaesthesia.
• Bone marrow taken from the hip bone, the traditional source.
• Umbilical cord blood, now almost obsolete in Dr. Danewa's view, because of variable quality and because cord blood takes a long time to start working.

Is bone marrow donation safe for the donor?

Dr. Danewa describes donation as a very safe procedure for the donor, with no cut and no surgery. He listed donor safety among the five conclusions of his lecture. The idea that a bone marrow transplant is an operation is a misconception: the stem cells are collected from the blood and given to the patient like a transfusion.

How often can someone donate?

Rules vary from country to country, according to blood bank regulations, but a donor can usually donate a maximum of two times in their lifetime. The gap between donations should be at least six months, and six months to a year is preferred; in a life-threatening situation, a second donation can very rarely be made after three or four months. Most Indian settings do not permit a third donation.

One donor for two siblings

Families with two affected children and one matched donor are a practical reality, and Dr. Danewa has transplanted both children from a single donor. Because the minimum dose is fixed per kilogram of the recipient, the team collects a larger harvest, helped by special injections that raise the stem cell yield, and divides it in two. Often the family prefers to complete the first transplant before starting the second. In that case half the cells are used immediately and the rest are cryopreserved for the second transplant once the first has succeeded and the family has arranged the funds.

Why stem cells are cryopreserved

Collected stem cells survive only about 72 hours at refrigerator temperature (2 to 8 degrees Celsius) before they die. Cryopreservation, the same technique used in sperm banking and egg (oocyte) preservation, stores them frozen at minus 80 to minus 90 degrees Celsius, where Dr. Danewa said they remain viable for about a year. A single donation is therefore enough when the dose collected is sufficient, and an international donor does not need to travel back for a second transplant planned months later.

Conditioning: clearing the sickle marrow

Conditioning is about seven days of chemotherapy that wipe out the patient's sickle-producing marrow so that the donor cells can take over. Several drug combinations exist. For years the standard was busulfan with cyclophosphamide. Busulfan is effective, but a sufficient dose leaves virtually every patient, boy or girl, infertile. Dr. Danewa's team now uses treosulfan, thiotepa and fludarabine.

Conditioning strength also protects the graft. If the chemotherapy fails to clear the patient's own marrow completely, the surviving cells can attack and reject the donor's stem cells. A well-designed conditioning regimen, together with a negative DSA test, is the main defence against rejection, as the article on engraftment and chimerism explains.

Fertility after a sickle cell transplant

Fertility is one of the questions families ask most, and Dr. Danewa regards fertility counselling as an integral part of transplant counselling: it is the right of the patient and the family to know.

With the newer regimen, the risk is lower but not gone. In his estimate, around half of patients may not achieve natural fertility, which means about half will be able to have children, a clear improvement on the near-certain infertility after busulfan-based conditioning.

Fertility preservation before transplant

Where the patient has reached puberty, fertility should be preserved before the transplant:

• Boys: sperm banking is straightforward once a boy is an adolescent who has reached puberty.
• Girls: oocyte preservation is more demanding, because retrieving the eggs requires a procedure.

Dr. Danewa advises families of adolescents to consider sperm or egg preservation before travelling for the transplant.

Sexual function and puberty

Infertility and sexual dysfunction are different problems, and the session addressed both. Busulfan damages not only the cells that make sperm and eggs but also the hormone-producing tissue of the gonads: ovarian failure is common in girls, and testosterone production can be impaired in boys, so a child transplanted young may need hormone support to go through puberty normally. With the newer drugs, Dr. Danewa said, the chance of this is very low, but sexual dysfunction after transplant can occur.

He set this against the disease itself. Sickle cell disease is a double-edged sword: untreated, it also damages the reproductive organs, through priapism leading to erectile dysfunction in boys and men, and through repeated sickling in the ovaries causing infertility in girls and women. The reproductive risks of transplant have to be weighed against the reproductive damage of living with the disease.

Special situation: sickle cell disease with HIV

HIV infection is not a contraindication to a sickle cell transplant. The donor must be HIV-negative, and viral markers are part of the pre-transplant evaluation. Dr. Danewa noted that HIV resides in the CD4 lymphocytes, which conditioning removes, and that case reports describe patients transplanted for another disease who were also cleared of HIV. This is not the standard of care, and transplant is not performed for HIV alone. The documented cures have generally involved donors carrying the CCR5-delta32 mutation, which makes their cells resistant to HIV, so clearance is a possible incidental benefit rather than an expected result.

The donor hierarchy, conditioning choices and fertility steps described here are the foundation of the transplant journey outlined in the complete guide. Indicative costs by donor type are listed for matched sibling, matched unrelated donor and half-match transplants. The session's questions on donation limits, carrier donors and cryopreservation are collected on the Live Discussion page for this masterclass. For a different perspective on donor choice for patients from Africa, see Dr. Vikas Dua's article on bone marrow donors for sickle cell patients.