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Hematopoietic stem cell transplantation in sickle cell disease

Hematopoietic stem cell transplantation in sickle cell disease
Literature review current through: Sep 2023.
This topic last updated: Feb 22, 2023.

INTRODUCTION — Hematopoietic stem cell transplantation (HSCT) is an accepted form of treatment for certain malignant and nonmalignant hematologic disorders. The use of HSCT in sickle cell disease (SCD) is evolving.

This topic review discusses the use of HSCT in SCD, including indications, clinical outcomes, and transplant techniques specific to this population.

Other therapies for SCD are discussed in detail separately.

Hydroxyurea – (See "Hydroxyurea use in sickle cell disease".)

Other pharmacologic therapies – (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Options if hydroxyurea is not tolerated or ineffective in individuals with HbSS or HbS-Beta(0)-thalassemia'.)

Transfusions – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Investigational approaches – (See "Investigational therapies for sickle cell disease".)

Routine care for the general pediatrician – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

Comprehensive specialist care – (See "Overview of the management and prognosis of sickle cell disease".)

TERMINOLOGY

SCD – Sickle cell disease (SCD) is an umbrella term that includes the sickle variant plus a second beta globin gene variant, the combination of which causes moderate to severe symptoms, including vaso-occlusion and hemolytic anemia. The other beta globin mutation could be the sickle mutation or a different mutation in the beta globin gene (eg, one associated with beta thalassemia, hemoglobin C disease, or others). Patients with SCD exhibit a clinical phenotype, anemia, and laboratory evidence of sickling. (See "Overview of the clinical manifestations of sickle cell disease" and "Overview of compound sickle cell syndromes".)

HSCT – Hematopoietic stem cell transplant (HSCT, also called hematopoietic cell transplant [HCT]) is used to refer to transplantation of hematopoietic stem and progenitor cells from any source (bone marrow, peripheral blood, or umbilical cord blood).

Allogeneic – Allogeneic HSCT refers to HSCT using hematopoietic stem cells (HSCs) from a donor. The donor may be related (eg, sibling) or unrelated. Related donors can be human leukocyte antigen (HLA)-matched (typically, matched at eight of eight HLA loci) or haploidentical (matched at half of their HLA loci).

Autologous – Autologous HSCT refers to HSCT using the patient's own HSCs. This is not useful for individuals with SCD unless the autologous cells have been modified (eg, by gene therapy, which is experimental). (See "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing'.)

Conditioning – Conditioning regimens (also called preparative regimens) for HSCT can be myeloablative, nonmyeloablative, or reduced-intensity. These are defined as follows, with additional details presented separately (see "Preparative regimens for hematopoietic cell transplantation"):

-Myeloablative – These regimens destroy the recipient's bone marrow, causing aplasia and pancytopenia that is usually long-lasting and irreversible. Infusion of HSCs is required to reconstitute hematopoiesis.

-Nonmyeloablative – These regimens do not destroy the recipient's bone marrow or cause significant cytopenias; however, engrafting donor T cells usually eliminate host hematopoietic cells.

-RIC – Reduced-intensity conditioning (RIC) regimens are intermediate between myeloablative and nonmyeloablative. These regimens cause cytopenias and suppress the host's immune system to allow engraftment.

Sources of HSCs – These include bone marrow, mobilized peripheral blood, and umbilical cord blood (referred to as cord blood). Bone marrow is generally preferred for nonmalignant disorders because it contains a lower dose of T cells and confers a lower risk of graft-versus-host disease (GVHD). (See 'Optimal source of HSCs' below.)

INDICATIONS FOR TRANSPLANT EVALUATION — Patients with SCD should have the opportunity to discuss risks and benefits of HSCT with their primary hematologist in order to better understand whether to pursue an HSCT evaluation. The evaluation does not necessarily imply that HSCT is indicated. It is a consultation and opportunity to understand the procedure, expected outcomes, and in some cases, to determine whether a sibling is a potential donor or whether there are other donor options that can be pursued.

The most common indications for HSCT evaluation are vaso-occlusive complications of SCD that are not well controlled with medical therapy (hydroxyurea or chronic transfusions). These may include frequent pain episodes, acute chest syndrome, stroke, or silent cerebral ischemia. (See "Overview of the management and prognosis of sickle cell disease", section on 'Curative treatments'.)

Allogeneic HSCT and autologous transplant using gene therapy/gene editing are the only potentially curative options in clinical use for individuals with SCD. However, the morbidity and mortality associated with HSCT are not insignificant. Thus, HSCT is only appropriate for individuals for whom the potential for cure outweighs the potential risks of early death, graft-versus-host disease (GVHD), and other potential toxicities such as organ injury from the conditioning regimen.

In some cases, parents or guardians of children with SCD, children with SCD, and health care providers may consider poor quality of life due to multiple vaso-occlusive pain events as the only indication for HSCT. However, in high-income settings, children with SCD have a 99 percent probability of survival until 18 years of age. Thus, the decision to consider HSCT must consider that SCD in a child is no longer associated with a shortened lifespan. For adults, the median survival of 48 years has not changed considerably, and the risk-benefit ratio favors HSCT in adults with SCD; this should be considered when evaluating curative therapy in this population. (See "Overview of the management and prognosis of sickle cell disease", section on 'Survival and prognosis'.)

DECISION TO PURSUE TRANSPLANT

Overview of decision-making — The decision to pursue HSCT is a challenging one. HSCT is most likely to benefit individuals at risk for severe vaso-occlusive manifestations such as stroke, acute chest syndrome, and pain, especially when performed during childhood. However, it may not be possible to predict which children are most likely to develop these complications, due to clinical variability of the disease and the absence of validated biomarkers for disease severity or mortality.

Also, it is possible that additional disease-modifying therapies may become available. (See "Investigational therapies for sickle cell disease".)

HSCT has not been directly compared with optimally administered medical therapy (hydroxyurea and/or transfusions) in a clinical trial or even in contemporaneous cohorts, and comparisons with historical controls are problematic because improvements in both HSCT and medical therapy continue to accrue. (See 'Clinical experience/transplant outcomes' below.)

Thus, the decision to pursue HSCT is highly individualized. HSCT is more likely to be appropriate for those who place a high value on cure of the disease and on avoiding chronic therapies such as hydroxyurea or transfusions.

The use of HSCT is limited in SCD for a number of reasons [1]:

Improved outcomes with intensive medical therapy (eg, hydroxyurea, chronic transfusions, other disease-modifying therapies), reducing the need for HSCT

Concerns about transplant-related morbidity and mortality

Possible effects of end-organ damage from SCD (eg, pulmonary, renal dysfunction) that may interfere with HSCT protocols

Extensive red blood cell (RBC) alloimmunization that complicates transfusion support in the peri-HSCT period

Concern about effects on fertility

Limited availability of matched sibling donors

Limited experience in transplanting adults with SCD

Limited knowledge about late health effects after HSCT on preexisting heart, lung, or kidney disease, which are the major causes of mortality in adults with SCD

Based on these concerns and other data, a 2014 evidence-based guideline from the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) in the United States, which was endorsed by other societies including the American Academy of Pediatrics and the American Society of Hematology, stated that "Additional research regarding patient and donor selection and the specific transplantation procedure is required before this potentially curative therapy will become more widely available" [2,3].

Experts have presented views in favor of and against HSCT for children with symptomatic disease in a 2017 point-counterpoint discussion [4,5].

Pro – Some of the main points in support of HSCT include [5]:

Medical therapy (hydroxyurea, transfusions) is associated with risks and burdens that may interfere with their use, whereas HSCT offers an option for cure. However, children do well with hydroxyurea and are often started at age 9 months.

Success rates continue to improve with HSCT, and modifications such as less intensive conditioning regimens may further reduce HSCT complications. (See 'Clinical experience/transplant outcomes' below.)

Donor availability has increased with greater use of haploidentical donors. (See 'Haploidentical related donor' below.)

Con – Some of the major points against HSCT include [4]:

Children cannot make informed decisions regarding their best interests.

Prognosis continues to improve for individuals who receive high-quality supportive care and hydroxyurea, and those with frequent vaso-occlusive episodes or episodes of acute chest syndrome do not have reduced mortality compared with other individuals with SCD. (See "Overview of the management and prognosis of sickle cell disease", section on 'Survival and prognosis'.)

Compared with HSCT, long-term survival with hydroxyurea therapy may be superior, although this conclusion is mostly based on small cohort studies [6-8].

Sufficient data for randomized trials are lacking to support the use of HSCT, and follow-up is short in many transplant studies.

Experts generally agree that HSCT may be appropriate for children who continue to have progressive organ dysfunction (strokes, silent cerebral infarcts, recurrent major priapism lasting for at least four hours within the last 12 months, worsening kidney, cardiac, or pulmonary function) despite optimal medical therapy, as well as fully informed older adolescents and adults who can weigh the risks and benefits, provided they have a suitable donor (ideally, a fully matched sibling) [4,5,9].

Some experts would offer alternative-donor HSCT to selected children with severe SCD manifestations [10]. When possible, HSCT is performed as part of a clinical trial with a Data and Safety Monitoring Board and formal stopping rules, especially if nonstandard approaches are used. (See 'Clinical experience/transplant outcomes' below and 'Modifications of the standard protocol (investigational)' below.)

Some adolescents and young adults may be willing to accept the risks associated with the HSCT procedure, and HSCT may be a reasonable choice for these individuals. (See 'Experience in older adolescents and adults' below.)

However, because less toxic therapies are available, mortality from HSCT may be as high as 5 to 10 percent, parents (or individuals with SCD) may reasonably choose not to pursue HSCT even if they have a suitable related donor. Further, several new medical approaches are under investigation, and some individuals may prefer to wait and see how these therapies perform in clinical trials. (See "Investigational therapies for sickle cell disease".)

For individuals who wish to pursue HSCT but lack an HLA-matched related donor, alternative donors or alternative approaches may be appropriate, although these are best pursued in the setting of a clinical trial. (See 'Modifications of the standard protocol (investigational)' below.)

Optimal age for transplant

Children versus adults – In a 2017 retrospective series of 1000 individuals with SCD who underwent allogenic HSCT, the five-year overall survival for those transplanted when <16 years of age was 95 percent (95% CI 93-97 percent); the five-year overall survival for those transplanted when 16 years or older was 81 percent (95% CI 74-88 percent) [11].

Older children versus younger children – A 2017 report retrospectively evaluated outcomes in 161 children treated with HSCT for SCD in the United States following transplant [12]. This represented 90 percent of the children transplanted for SCD in two databases (the Center for International Blood and Marrow Transplant Research [CIBMTR] and the Pediatric Health Information System [PHIS]). The children were divided into cohorts based on age at transplantation (<10 years or 10 to 21 years). Overall survival at two years was 90 percent. Compared with those <10 years, children transplanted from age 10 to 21 years had an increased mortality (hazard ratio [HR] 21.2, 95% CI 2.8-160.8).

Optimal donor — Siblings (or other HLA-matched first-degree relatives such as parents or children) are always preferable as HSCT donors for individuals with SCD. These donors are associated with the greatest survival, lowest rates of graft failure/rejection, and reduced transplant morbidities, especially lower risks of GVHD. Siblings without SCD and siblings with sickle cell trait are both acceptable as donors; inclusion of siblings with sickle cell trait as potential donors expands the donor pool to approximately three-quarters of the patient's HLA-matched siblings, although the proportion of individuals with suitable donors remains small.

Experience using cord blood from a sibling donor is limited [11,13]. (See 'Optimal source of HSCs' below.)

The possibility of using alternative donors (eg, haploidentical siblings, matched unrelated donors, matched unrelated cord blood units) has also been raised but is considered investigational. These alternative donors are best pursued on a clinical trial, as discussed below. (See 'Alternative donors' below.)

Other aspects of donor selection and the effect of donor characteristics (cytomegalovirus [CMV] status, age, parity) on transfusion outcomes are discussed separately. (See "Donor selection for hematopoietic cell transplantation".)

Optimal source of HSCs — Hematopoietic stem cells (HSCs) can be derived from umbilical cord blood, bone marrow, or mobilized peripheral blood. These sources have not been directly compared or extensively analyzed in individuals with SCD. However, it is reasonable to extrapolate from other nonmalignant disorders.

Although data are limited in SCD, data from individuals treated with HSCT for other nonmalignant disorders suggests that bone marrow or umbilical cord blood is likely to be associated with the best outcomes. This is because bone marrow- and cord blood-derived HSCs have a lower risk of causing GVHD than peripheral blood-derived HSCs. In nonmalignant disorders, a graft-versus-tumor effect is not needed and thus peripheral blood stem cells do not provide any advantage. (See "Hematopoietic cell transplantation for aplastic anemia in adults", section on 'Preferred stem cell source' and "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Stem cell source'.)

Of interest, in a series of 1000 individuals who underwent HSCT for SCD, the use of hematopoietic cells from bone marrow or cord blood rather than peripheral blood did not reduce the incidence of GVHD, but it was associated with improved overall survival [11]. (See 'Survival' below.)

Although bone marrow is preferred as the stem cell source, peripheral blood may be used. If peripheral blood is used, individuals with sickle cell trait can safely donate hematopoietic stem and progenitor cells that are mobilized from peripheral blood with filgrastim (granulocyte-colony stimulating factor [G-CSF]) [14]. (See "Sickle cell trait", section on 'Hematopoietic stem cell donation'.)

PREPARATION FOR TRANSPLANT

Testing and interventions prior to transplant — Initial testing of donors and recipients focuses on infectious disease history. (See "Evaluation for infection before hematopoietic cell transplantation".)

Recipients are also evaluated to ensure good organ function and lack of comorbid conditions such as renal or pulmonary disease that might adversely affect transplant outcomes.

Hydroxyurea is discontinued prior to starting the conditioning regimen, and exchange transfusions may be performed prior to transplant to reduce potential complications. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

Data are limited regarding iron chelation prior to transplant in those with iron overload. In individuals undergoing HSCT for thalassemia, outcomes are significantly better when the individual has been treated with lifelong iron chelation to prevent organ damage from iron overload. This subject is discussed separately. (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Impact of iron overload (Pesaro prognostic system)'.)

Optimal conditioning regimen — The optimal conditioning regimen for individuals with SCD is unknown. The majority of studies have used myeloablative conditioning (MAC) with cytotoxic chemotherapy and/or total body irradiation (TBI) at doses sufficient to ablate the recipient's bone marrow (eg, busulfan >8 mg/kg and/or TBI >6 Gy) [11]. Example regimens have included busulfan and cyclophosphamide, busulfan and fludarabine, fludarabine with or without other agents, or TBI with or without cytotoxic agents. Busulfan, cyclophosphamide, and antithymocyte globulin (ATG) is a commonly used combination [9].

Fludarabine is used in some centers as a means of reducing doses of alkylating agents, although autologous reconstitution may be a concern with this approach [15]. (See 'Reduced-intensity and nonmyeloablative conditioning regimens' below.)

Treosulfan has been introduced as a lower-toxicity substitute for busulfan in some centers. In a series of 15 children with SCD who received an allogenic HSCT, the conditioning regimen of treosulfan/thiotepa/fludarabine was well tolerated, with no cases of grade III to IV regimen-related toxicity and a seven-year overall survival of 100 percent [16].

General details about conditioning regimens are presented separately. (See "Preparative regimens for hematopoietic cell transplantation".)

GVHD and infection prophylaxis — Interventions to reduce the risk of graft-versus-host disease (GVHD) and infections are important for increasing the chances of the best outcome.

GVHD prophylaxis – There are a number of immunosuppressive agents available for GVHD prophylaxis. Unlike HSCT for malignant diseases, in which the GVHD regimen is tapered more rapidly to facilitate a graft-versus-tumor effect, in SCD the immunosuppression is typically continued for a longer period (eg, approximately six months) before tapering. (See "Prevention of graft-versus-host disease" and "Prevention of graft-versus-host disease", section on 'Introduction'.)

Infection prophylaxis – Prophylactic antibiotics are similar to those used in other populations. These are discussed separately. (See "Overview of infections following hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Prevention of viral infections in hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)

CLINICAL EXPERIENCE/TRANSPLANT OUTCOMES — The first patient with SCD to be treated with HSCT was an eight-year-old who had recurrent vaso-occlusive pain episodes and developed acute myeloid leukemia (AML). She was treated with allogeneic HSCT using bone marrow from her human leukocyte antigen (HLA)-matched four-year-old brother, who had sickle cell trait [17]. In addition to curing the AML, HSCT led to resolution of vaso-occlusive pain episodes, with full donor chimerism; she remained alive decades later [17,18].

Experience with HSCT has continued to accrue in the ensuing years. However, there are no randomized trials comparing HSCT with medical therapy or evaluating different HSCT protocols. Randomized trials comparing HSCT with medical therapy may be especially challenging to conduct since the two approaches differ dramatically in their short- and long-term risks and benefits.

Survival — There are no randomized trials that compare survival rates in people with SCD who are treated with HSCT versus standard medical treatment (hydroxyurea, regular transfusions, and/or supportive care). Observational studies have demonstrated overall survival of over 90 percent using matched sibling donors in children and adolescents with SCD. When discussing transplant with families, we typically review the outcomes of the specific HSCT platform they are considering rather than reviewing results of trials using other platforms.

Event-free survival (EFS) has improved in those transplanted after 2006. A report from 2017 described outcomes in 1000 recipients of matched sibling donor HSCT from 1986 through 2013 that were reported to three major registries (European Society for Blood and Marrow Transportation [EBMT], Eurocord, and the Center for International Blood and Marrow Transplant Research [CIBMTR]) [11]. Participants were mostly children (85 percent children; median age for the entire cohort, nine years; age range, 0 to 54 years) and median follow-up was 55 months (4.6 years).

The unadjusted five-year overall survival was 93 percent [11]. Multivariate analysis showed better survival for younger patients (10 percent increase in the hazard ratio [HR] for death for every one-year increment in age) and better survival for recipients of bone marrow or cord blood rather than peripheral blood. There was a trend towards improved survival for those transplanted more recently (after 2006) that did not reach statistical significance.

The experience for haploidentical transplant with post-transplant cyclophosphamide continues to demonstrate promising results, particularly for adults with SCD [19]. Despite the success of this approach, we continue to encourage all children and adults with SCD who wish to receive curative therapy be enrolled in a clinical trial, with appropriate stopping rules and a Data Safety Monitoring Board (DSMB) oversight to ensure that appropriate research governance is enforced. We are not supportive of single center curative trials without a strong research governance oversight and without the ability to ask and answer a research question that will advance care. (See 'Modifications of the standard protocol (investigational)' below.)

Engraftment and survival — Rates of engraftment, event-free survival (EFS), and disease-free survival (DFS) are slightly less than rates of overall survival. Typical rates of EFS are in the range of 91 percent (slightly higher for those <16 years of age [approximately 93 percent] and somewhat lower for those 16 years or older [approximately 81 percent]) [11].

Data from two sources indicates that a low intensity HSCT regimen that relies on stable mixed chimerism as the therapeutic goal is associated with increased risk for leukemia malignancy:

In a 2023 study 1096 transplants for SCD between 1991 and 2016, the 10 year incidence of leukemia/myelodysplastic syndrome (MDS) was 1.7 percent (adjusted hazard ratio [HR] 22.69, 95% CI 2.34-118.66) [20]. The rate of any secondary neoplasm was 2.4 percent (HR 7.78, 95% CI 2.20-27.53). These risks were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens.

In a 2022 study from the National Institutes of Health (NIH) involving 120 individuals with SCD who underwent allogenic HSCT using nonmyeloablative conditioning, five individuals (4.2 percent) developed hematologic malignancies.  

These results along with other theoretical concerns have compelled the NIH group to focus on full donor chimerism as the therapeutic goal (rather than mixed chimerism). The field continues to evolve as it seeks to determine the optimal strategy for allogenic HSCT. All children and adults who pursue allogenic HSCT should receive balanced informed consent and should be enrolled on a trial that has stopping rules with a DSMB to monitor the safety and efficacy of therapy. (See 'Assessing engraftment' below.)

Unlike overall survival, which has remained relatively stable for the preceding decades, EFS has continued to improve:

Reports from the 1990s to the early 2000s found EFS in the range of 79 to 86 percent [21-23]

Reports from the mid-2000s onward found EFS in the range of 95 percent [23]

A 2017 series of 1000 patients found better EFS in those transplanted in 2007 or later versus 2006 or earlier (HR 0.95, 95% CI 0.90-0.99) [11]

These outcomes are likely due to improvements in supportive care.

Hematopoietic recovery is fastest with hematopoietic cells from bone marrow and peripheral blood, with a median time to neutrophil engraftment of 18 and 15 days, respectively, in the 2017 series [11]. In comparison, median time to recovery with hematopoietic cells from cord blood was 27 days.

Assessment of engraftment and the degree of chimerism needed for clinical cure is discussed below. (See 'Assessing engraftment' below.)

Vaso-occlusive events — Many studies that report on HSCT outcomes in SCD do not focus on rates of vaso-occlusive events, because it is well accepted that these events no longer occur in individuals who have been cured of the disease.

A 2023 study compared vaso-occlusive events during the two years before transplant versus the two years after transplant in 163 children and adults with SCD, most with a matched sibling donor [24]. The rate of events was reduced from 5.6 (range 0 to 52) to 0.9 (range, 0 to 12), with progressive reduction from post-transplant year 1 to year 2. Although pain is a reasonable clinical outcome after curative therapy, pain should not be the sole determinant of a successful curative therapy in SCD. Other patient-important outcomes include quality of life, mental health, reproductive health, sexual health, brain health, and cessation of progressive disease affecting the heart, lung and kidneys, the major organs associated with premature death in adults with SCD. Multiinstitutional and prospective data are lacking regarding outcomes.

Previous studies have shown reduction in various types of vaso-occlusive phenomena including painful events, acute chest syndrome, and stroke [25]. Reductions in transcranial Doppler (TCD) velocities have also been described [26]. These observations affirm the mechanistic understanding of the disease, in which the primary triggering event for vascular changes is circulation of red cells with abundant sickle hemoglobin. (See "Pathophysiology of sickle cell disease".)

What is perhaps more germane is the reversibility of organ damage related to vaso-occlusion. Fixed deficits related to organ infarction (eg, stroke, avascular necrosis of joints) are generally not reversible; however, some studies have documented a degree of resolution of certain manifestations during the years following transplantation, including improved pulmonary function and improved findings on brain magnetic resonance imaging (MRI) in the individuals with full donor chimerism [21-23,25].

Fertility — Fertility is a great concern, especially since most individuals are transplanted in childhood, precluding sperm banking or oocyte or embryo preservation prior to the transplant.

Hydroxyurea is considered an embryonic and fetal toxin. If an older individual with an adequate sperm count wanted to try sperm banking prior to HSCT, they would have to discontinue the therapy for a period of months before sperm banking. This is not a routine scenario but may be appropriate for selected individuals. (See "Hydroxyurea use in sickle cell disease", section on 'Pregnancy and breastfeeding'.)

Gonadal dysfunction is common after HSCT (eg, hypogonadotropic hypogonadism with androgen deficiency in males, primary ovarian failure in females) [25]. These effects are presumed to be caused by the cytotoxic agents used for myeloablation (eg, busulfan) [27,28]. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Gonadal dysfunction'.)

Despite these findings, some individuals (male and female) have had children following transplant [25,28].

We discuss potential effects on fertility with patients, caregivers, and families. In some cases, clinical trials of fertility preservation (eg, ovarian tissue preservation) may be available.

GVHD — Graft-versus-host disease (GVHD) is one of the major adverse effects of allogeneic HSCT, related to the immune attack of recipient tissues (gastrointestinal, respiratory, skin, liver) by donor lymphocytes. All individuals who undergo allogeneic HSCT are treated with immunosuppression for GVHD prophylaxis (see 'Care after transplant' below); however, severe GVHD can be fatal.

GVHD is divided into acute disease, which is graded according to severity (table 1), and chronic manifestations, which can affect multiple organs (table 2), as discussed separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

In the 2017 retrospective series of 1000 patients (median follow-up, 4.6 years), rates of GVHD following HSCT for SCD were approximately 15 percent for grade II to IV acute GVHD and 14 percent for chronic GVHD [11]. The greatest risk factor for GVHD was age (4 percent increase in the HR for chronic GVHD for every one-year increment in age at the time of transplant). Studies in other populations such as patients with thalassemia have documented a greater risk for GVHD when the source of hematopoietic cells is peripheral blood rather than bone marrow or cord blood (see "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Bone marrow versus peripheral blood'). In this large SCD series, the stem cell source did not affect rates of GVHD, but the numbers of patients who received peripheral blood was very small (7 percent) [11].

Experience in older adolescents and adults — Experience from larger case series includes the following:

A large series from 2017 included 154 adults who underwent related-donor HSCT [11]. Most were treated with a myeloablative conditioning regimen and most received hematopoietic cells from bone marrow (approximately three-fourths in both cases). Five-year overall survival and EFS were both 81 percent. For every one-year increment in age there was a 10 percent increase in the HR for death.

A study from 2014 reported outcomes with related-donor HSCT in 30 individuals with severe SCD who were between 16 and 65 years of age [29]. A reduced-intensity, nonmyeloablative conditioning regimen was used (alemtuzumab and 300 cGy total body irradiation [TBI]), and hematopoietic cells were mobilized from peripheral blood. At a median of 3.4 years, overall survival was 97 percent and EFS was 87 percent; one patient with a history of stroke and Moyamoya disease died of intracerebral hemorrhage after experiencing graft failure with autologous reconstitution.

Smaller series of adults (<20 patients), often using reduced-intensity conditioning regimens, have also been reported [30-36].

Selected older adolescents and adults may choose to pursue HSCT if they place an especially high value on cure of their disease and are willing to accept the risks of organ toxicity, graft failure, and death related to the transplant.

MODIFICATIONS OF THE STANDARD PROTOCOL (INVESTIGATIONAL)

Plerixafor for mobilization — The use of plerixafor for mobilizing CD34-positive cells (stem and progenitor cells) in SCD remains investigational. In a study from 2020 involving 15 patients from two clinical sites who underwent autologous hematopoietic stem cell (HSC) collection for gene therapy, 13 had adequate numbers of CD34-positive cells after a single subcutaneous dose of plerixafor (240 mg/kg) followed by apheresis, while two patients required a second dose [37]. Eleven of these patients experienced pain, with three requiring hospitalization. Plerixafor-mobilized HSCs were enriched for an engrafting population, suggesting relative superiority over other mobilization methods. (See "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing'.)

Alternative donors — Several options are available for individuals who do not have a matched sibling donor. Alternative donors include umbilical cord blood units from cord blood banks, matched unrelated donors, and mismatched (haploidentical) related donors. Experience with alternative donors is limited in SCD, but these approaches may be appropriate for selected individuals as part of a clinical trial.

Matched unrelated umbilical cord blood units — The role of unrelated umbilical cord blood (UCB) transplants in patients with SCD remains experimental [38]. Most transplant centers do not favor this strategy. Potential advantages associated with UCB grafts include [39]:

Lower risk of graft-versus-host disease (GVHD)

Reduced time to prepare for transplant versus transplant with matched unrelated donors (MUD)

Easy availability

No donor morbidity

Possibility of directed sibling banking

Decreased risk of transmitting viral infections

Higher frequency of rare human leukocyte antigen (HLA) haplotypes in the donor pool than in MUD registries

While the efficacy of related UCB transplantation is similar to HLA-matched sibling bone marrow transplantation but with little to no chronic GVHD, related UCB transplantation is also limited due to a paucity of HLA-matched sibling donors.

The first multicenter unrelated UCB transplant trial, the Sickle Cell Unrelated Donor Transplant (SCURT) trial, was discontinued early due to a high incidence of graft rejection [40]. The first report included eight children transplanted with MUD UCB and reported engraftment in only three of the eight (38 percent); the remaining five had graft failure with recovery of autologous hematopoiesis. One of the three who engrafted with full donor chimerism died of chronic GVHD. Based on these results, the cord blood arm of the study was suspended.

However, efficacy was improved in a study that added thiotepa to the conditioning regimen, with an overall survival of 100 percent and SCD-free survival of 78 percent [41]. Additional studies, including studies of ex-vivo expansion of the UCB graft, are ongoing. One study that used ex-vivo expanded UCB units reported a high rate of GVHD, but 11 of 13 patients were off immunosuppression at a median of 14 months posttransplant [42].

Matched unrelated donor (bone marrow) — The first pediatric multicenter MUD HSCT trial was published in 2016 and included a high rate of mortality and chronic GVHD [43]. A pilot study that used the same conditioning plus abatacept in seven patients reported a two-year overall survival of 100 percent and SCD-free survival of 93 percent, with a low incidence of moderate to severe GVHD [44].

Results from the bone marrow arm of the SCURT trial are pending [40]. Additional trials are ongoing, although a trial comparing transplant (HLA-matched related or MUD) was halted due to slow accrual.

Haploidentical related donor — Haploidentical donors are related donors (typically, parents or siblings) who share half of their HLA loci with the recipient. Haploidentical platforms differ; the Johns Hopkins platform has shown remarkable outcomes and is the basis for the National Institutes of Health (NIH) BMT-CTN protocol.

Use of haploidentical donors has been proposed as a means of expanding the donor pool. Haploidentical donors are the most common alternative donor source, and with haploidentical donors, repeat collections are feasible and large cell doses are possible.

The recipient should not have donor-specific red blood cell alloantibodies. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

A series of adults with SCD who underwent HSCT with a reduced-intensity conditioning regimen included 14 recipients of haploidentical bone marrow [45]. By one year, approximately half of the patients who received a haploidentical transplant had experienced graft failure. There was no GVHD. Additional studies using this approach are underway, and additional general information about haploidentical HSCT is presented separately. (See "HLA-haploidentical hematopoietic cell transplantation".)

Most haploidentical regimens for SCD include post-transplant cyclophosphamide (PT-Cy), which decreases the risk of GVHD. While PT-Cy was shown to improve engraftment rates and SCD-free survival, additional myelosuppression, immunosuppression, or both is required to overcome the engraftment barrier and maintain graft survival [46]. Pilot data from a large trial that included thiotepa in the conditioning regimen were encouraging [47]. Small series reported that increasing the dose of total body irradiation and using peripheral blood stem cells as the donor source instead of bone marrow reduced graft failure [48,49]. The most extensive experience is based on the Hopkins regimen mentioned above.

Another approach instead of PT-Cy to decrease GVHD is to perform ex-vivo T- and B-cell depletion of peripheral blood stem cells. One group reported 25 patients transplanted with either CD3/CD19- or T-cell receptor αβ/CD19 depleted cells [50]. At a median follow-up of 22 months, 88 percent were alive and free of SCD with no severe GVHD. A large number of trials evaluating haploidentical transplant for patients with SCD are planned or ongoing.

Reduced-intensity and nonmyeloablative conditioning regimens — Reduced-intensity conditioning (RIC) regimens use lower doses of cytotoxic therapy and/or noncytotoxic agents to ablate or partially ablate the bone marrow.

These approaches are considered experimental. In general, we are not in favor of single center HSCT trials that do not have an opportunity to advance the field. Instead, we favor trials performed in a consortium with formal stopping rules for safety and futility along with a DSMB. The original research team that pioneered the goal of stable mixed chimerism to cure SCD and has the largest cohort with the longest follow-up with this approach has abandoned this strategy [51].

Based on their experience, we would not pursue mixed chimerism as a therapeutic goal of allogeneic HSCT, unless in a setting of a clinical trial with stopping rules for safety and futility with an independent DSMB.

Nonmyeloablative (NMA) regimens typically do not ablate the recipient's bone marrow, but donor T cells do so following transplant. (See 'Terminology' above and "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)

Rare case reports in individuals with severe organ damage prior to HSCT have described an approach involving simultaneous HSCT and solid organ transplantation [52].

Donor lymphocyte infusion — Donor lymphocyte infusion (DLI) is used in hematologic malignancies as a means of increasing graft-versus-tumor effect. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

Experience with DLI to improve engraftment in nonmalignant diseases is extremely limited. A single report described the use of DLI in a child with SCD who underwent HSCT from an HLA-matched sister and subsequently developed mixed chimerism suggestive of imminent disease recurrence [53]. He received two DLI infusions that resulted in easily treated acute GVHD, followed by complete donor chimerism. Two years after the second DLI, he had a normal hemoglobin concentration and excellent growth and development. This intriguing report indicates that DLI can displace residual host hematopoietic cells and suggests that this procedure might be used in other patients with recurrence of SCD following allogeneic HSCT.

Autologous transplant with modified HSCs — The use of autologous transplant would eliminate morbidity and mortality from GVHD, which is one of the greatest concerns with the transplant approach; it would also greatly broaden access beyond those who have an available sibling donor. To be effective in reconstituting hematopoiesis with non-sickled red cells, autologous HSCs would have to be modified to no longer express predominantly sickle hemoglobin. Approaches may include the use of gene therapy, gene silencing, or gene editing to reduce beta globin expression, increase gamma globin expression, and/or to express an antisickling construct. These approaches are discussed separately. (See "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing' and "Overview of gene therapy, gene editing, and gene silencing", section on 'Clinical investigation of gene editing'.)

CARE AFTER TRANSPLANT

Assessing engraftment — Engraftment of the transplanted cells is assessed according to the degree of donor chimerism (percentage of hematopoietic cells derived from the donor rather than the recipient). This may be assessed by chromosomal analysis (eg, if donor and recipient are of opposite sex) or by DNA testing. Further details are discussed separately. (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Engraftment'.)

Donor chimerism of at least 20 percent donor myeloid cells is considered sufficient for clinical cure as it provides sufficient hemoglobin A (non-sickle hemoglobin) to prevent sickling [9].

Supportive care — Care is provided according to institutional protocols. Important aspects soon after transplant include the following:

Transfusions are given during the early engraftment period. Thresholds and special modifications related to ABO blood type discrepancies are discussed separately. (See "Hematopoietic support after hematopoietic cell transplantation".)

We avoid growth factor support such as granulocyte-colony stimulating factor (G-CSF) after transplant for SCD. G-CSF is not used in individuals with SCD, but it can be used in those with sickle cell trait (for stem cell mobilization or treatment of chemotherapy-induced neutropenia). (See "Overview of the management and prognosis of sickle cell disease", section on 'Avoidance of G-CSF'.)

Immunizations after transplantation are discussed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Infections are treated with appropriate antibiotics. (See "Overview of infections following hematopoietic cell transplantation".)

Immunosuppressive therapy for graft-versus-host disease (GVHD) prophylaxis is gradually weaned after six months. (See 'GVHD and infection prophylaxis' above.)

Iron overload, if present, is treated with phlebotomy, provided the individual has a sufficient hemoglobin level. The approach is similar to that used in individuals with thalassemia (eg, magnetic resonance imaging [MRI] to assess iron burden and ferritin monitoring to assess iron removal). (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores'.)

Monitoring — Long-term follow-up is similar to that used in individuals with thalassemia, and includes a multidisciplinary review of growth and development, endocrinology, cardiology, pulmonary function, ophthalmology, and others. This is discussed in detail separately. (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Long-term management'.)

Approach to graft failure — Options in this setting include a second transplant or medical care, depending on the patient's clinical status and donor availability.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Allogeneic bone marrow transplant (The Basics)")

Beyond the Basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

Potential uses of allogeneic HSCT – Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option in patients with sickle cell disease (SCD). The most common indications are vaso-occlusive complications of SCD not well controlled with medical therapy (frequent pain, acute chest syndrome, stroke, or silent cerebral ischemia). (See 'Terminology' above and 'Indications for transplant evaluation' above.)

Decision-making – The decision to pursue transplant is challenging due to significant risks, even in optimal settings. Transplant has not been directly compared with optimally administered medical therapy. Decisions must be individualized. Transplant is typically pursued for progressive organ dysfunction (strokes; osteonecrosis; worsening renal, cardiac, or pulmonary function) or continued vaso-occlusive complications. (See 'Overview of decision-making' above.)

Optimal conditions – Optimal conditions include transplantation in early childhood using a matched related (usually sibling) donor and hematopoietic stem cells (HSCs) harvested from bone marrow rather than from peripheral blood. (See 'Optimal age for transplant' above and 'Optimal donor' above and 'Optimal source of HSCs' above.)

Planning – The pretransplant evaluation includes infectious disease screening and testing for comorbidities. Standard myeloablative conditioning, GVHD prophylaxis, and infection prevention measures are used; however, immunosuppression is given for a longer period of time than used in individuals with malignant disease indications (typical duration of six months before tapering). (See 'Preparation for transplant' above.)

Efficacy and safety – Children who receive a related donor transplant have an overall survival of 91 to 96 percent. Increasing age appears to confer lower survival and higher toxicity. Those with good engraftment (donor chimerism of ≥20 percent) can expect to be cured. Infertility is common but not universal. The risk of acute and chronic GVHD is approximately 15 percent. (See 'Clinical experience/transplant outcomes' above and 'Assessing engraftment' above.)

Alternative donors and other curative approaches – Alternative donors include unrelated cord blood (UCB) units, matched unrelated donors (MUD), and haploidentical donors. Alternative regimens include reduced-intensity conditioning (RIC) and nonmyeloablative (NMA). Gene therapy using modified autologous stem cells is under investigation. These approaches are experimental and should be pursued only in the context of a clinical study. (See 'Modifications of the standard protocol (investigational)' above and "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing'.)

Post-transplant care – Engraftment is assessed and supportive care provided, including transfusions if needed and a number of infection-prevention and treatment interventions. (See 'Care after transplant' above.)

Alternatives to transplant (pharmacologic therapies and transfusions) – (See "Hydroxyurea use in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques" and "Investigational therapies for sickle cell disease".)

ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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Topic 5929 Version 42.0

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