Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy

INTRODUCTION — 

Allogeneic hematopoietic stem cell transplantation with a matched sibling donor (MSD) is an established treatment of sickle cell disease (SCD), while transplantation using alternative donors (haploidentical, matched unrelated) is becoming a viable treatment option. The use of gene therapy in SCD is evolving.

This topic discusses these potentially curative therapies for patients with SCD, including indications, clinical outcomes, and transplant strategies specific to this population.

Other therapies for SCD are discussed separately.

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

●Other medical therapies – (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

●Transfusions – (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications".)

●Investigational non-curative approaches – (See "Investigational pharmacologic therapies for sickle cell disease".)

●Routine pediatric care – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

●Comprehensive specialist care – (See "Overview of preventive/outpatient care in sickle cell disease".)

TERMINOLOGY

●SCD – Sickle cell disease (SCD) includes homozygosity for the sickle cell variant in the beta globin gene or compound heterozygous inheritance of the sickle cell variant and another variant in the beta globin gene such as hemoglobin C, a thalassemia variant (beta⁰-thalassemia or beta⁺-thalassemia), or others. (See "Overview of compound sickle cell syndromes", section on 'Specific compound sickle cell syndromes'.)

Patients with SCD exhibit a clinical phenotype mainly characterized by hemolytic anemia, microvascular occlusion, and laboratory evidence of red blood cell sickling. (See "Overview of the clinical manifestations of sickle cell disease" and "Overview of compound sickle cell syndromes".)

●Transplantation – Hematopoietic stem cell (HSC) transplantation (HCT, also called HSCT) refers to transplantation of hematopoietic stem and progenitor cells (HSPCs) from any source (bone marrow, peripheral blood, or umbilical cord blood).

•Allogeneic – Allogeneic transplantation uses HSCs from a donor. The donor may be related (eg, sibling) or unrelated.

-HLA matched or haploidentical – Related donors can be human leukocyte antigen (HLA)-matched (typically, matched at 10 out of 10 HLA loci) or haploidentical (matched at least 5 out of 10 or 50 percent of their HLA loci with the donor having one haplotype in common with the recipient).

-Matched unrelated – Matched unrelated HSCs can come from an unrelated donor or stored cord blood unit.

•Autologous – Autologous transplantation uses the patient's own HSCs. This is not useful for individuals with SCD unless the autologous cells have been modified (eg, by gene therapy). (See 'Gene therapies' below.)

•Conditioning – Conditioning regimens (also called preparative regimens) 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. HSCs are required to reconstitute hematopoiesis.

-Nonmyeloablative (NMA) – These regimens do not destroy the recipient's bone marrow or cause persistent cytopenias; however, engrafting donor T cells usually eliminate host hematopoietic cells following transplantation. These may also be referred to as immunoablative regimens, and transplantation with these regimens is mostly used in adults with SCD who have an increased risk of transplant-related toxicity/mortality with the myeloablative regimens.

-Reduced-intensity conditioning (RIC) – This category consists of a range of regimens that are usually intermediate between myeloablative and nonmyeloablative and use lower doses of cytotoxic and/or noncytotoxic agents to ablate or partially ablate the bone marrow. These regimens cause cytopenias and suppress the host's immune system to allow engraftment.

●Gene therapy and gene editing – Gene therapies for SCD involve the delivery of genetically modified autologous HSCs, most commonly after busulfan myeloablative conditioning. Genetic modification of HSCs can be achieved by gene addition (eg, using a lentiviral vector) or gene editing (manipulation of an endogenous globin or regulatory gene). (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene therapy' and "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

DECISION TO CONSIDER CURATIVE THERAPY — 

There is a wide range of professional opinions on whether children and adults with SCD should receive curative therapy.

Various considerations contribute to the lack of consensus:

●Continued evolution of overall improvement in care for children with SCD, with progressively reduced mortality.

●Increased number of curative therapy options, particularly in the early 2020s.

●Short lifespan in adults (median, 48 years).

●Lack of randomized controlled trials to identify short-term and long-term benefits and risks of curative therapy.

For children, opinions may vary widely and may include only offering curative therapy for children with strokes or progressive organ disease despite maximum medical management to providing curative therapy to children as young as two years of age with no evidence of irreversible organ disease [1]. There is a range of opinions about what constitutes standard care for using curative treatment, with very little consensus.

Even though the outcomes of matched sibling donor transplantation in children with SCD are excellent, there is still a risk of transplant-related mortality and a significant risk of late health effects due to the myeloablative conditioning regimen. On the other hand, improvements in supportive care and disease-modifying therapies have resulted in almost 100 percent survival of children with SCD into adulthood. Therefore, reserving transplantation for children with severe manifestations of SCD (recurrent pain, acute chest syndrome, stroke, or progressive organ damage) might improve outcomes without exposing asymptomatic children to the risks of transplant-related mortality.

However, while the majority of patients with SCD undergoing transplantation have severe disease, some children with SCD who do not have severe manifestations and have an HLA-identical sibling donor available may have reasons to consider transplantation, such as a very high risk of developing severe manifestations. The nuances of these viewpoints are discussed in a pair of point and counterpoint articles from 2017 and a review from 2019 [2-4].

Opportunity for discussion and shared decision-making — Decision-making for transplantation includes the consideration of complex risk-benefit tradeoffs; the decision to consider (and/or to pursue) transplantation is highly individualized. Mere consideration or consultation regarding curative therapy does not necessarily imply that the patient must proceed to transplantation.

Patients with SCD should have the opportunity to learn about possible therapies within a rapidly changing therapeutic landscape, and to discuss risks and benefits of hematopoietic stem cell transplantation (HCT) with their primary hematologist as well as experts at a center that treats patients with SCD (including transplantation/curative therapies as well as pharmacologic therapies).

The primary hematologist should inform patients with SCD about the possibility of HCT as a curative treatment option early in their care. The hematologist should discuss general risks and benefits of curative therapy. Perhaps the best way to ensure that all individuals interested in pursuing these therapies can reasonably weigh their options, after discussion with the primary hematologist and decision to move to the next step, is to refer to a center where experts in both SCD and in transplantation are present. Ideally a psychologist with expertise in SCD can also provide consultation and guidance.

In our practice, the hematologists and the transplant physicians work together and review candidates before or immediately after the patient and/or family asks about the possibility of curative therapy.

●We discuss the disease severity, the different curative therapy approaches, and any open clinical trials.

●The patient and family/caregivers visit with the hematologists first, followed by the transplant physician (with the hematologist present if possible).

●For those considering transplantation, HLA typing is offered for the patient and any full siblings early in childhood.

●Ultimately, we provide a joint recommendation, based on disease severity, donor availability (matched sibling or haploidentical) and patient and family/caregivers preferences.

Indications and eligibility — We are most likely to consider curative therapy in children and adults with complications of SCD associated with early mortality or severe morbidity.

The decision to pursue transplantation must assess the benefits and risks related to standard care, which is challenging as both transplant techniques and standard care are rapidly and continuously evolving. The table summarizes benefits and risks of curative versus medical therapies (table 1).

The following complications are common reasons to prompt evaluation of transplantation when disease manifestations are not responding well to standard therapies:

●Recurrent vaso-occlusive pain episodes (>2 per year, recognizing that some pain episodes may be managed at home without hospitalization)

●Life-threatening or recurrent acute chest syndrome

●Strokes [5]

●Need for chronic blood transfusions

Indications for transplantation might be different for children versus adults [6].

●In children, recurrent pain episodes, acute chest syndrome, and the risk or history of stroke and silent cerebral infarcts are the most common reasons for pursuing transplantation.

●In adults, recurrent pain episodes and progressive organ dysfunction might be the reason for considering transplantation.

Additional complications that may less commonly be indications for pursuing transplantation apply primarily to adults, in whom these comorbidities are associated with a shortened lifespan. These include:

●Cardiac dysfunction due to pulmonary hypertension as suggested by elevated tricuspid regurgitant jet velocity, diastolic dysfunction, or both, and confirmed by right heart catheterization [7,8].

●Progressive lung disease [9].

●Progressive kidney disease [10-13].

●Recurrent major priapism despite medical therapy.

●Progressive avascular osteonecrosis (AVN), especially at a relatively young age, as this tends to predict future episodes of AVN affecting other joints; however, there is also a possibility that transplantation might worsen AVN, especially if glucocorticoids are used for graft versus host disease (GvHD).

●Progressive hepatopathy, with the indications for transplantation considered in a multidisciplinary team, since advanced chronic liver injury can significantly increase transplantation-related toxicity, especially when using busulfan-containing myeloablative conditioning regimens. Mild SCD-related liver fibrosis can be an indication for transplantation [14].

●Alloimmunization of a severity that precludes transfusion when necessary. Patients with severe alloimmunization need special preparation in collaboration with transfusion specialists, and units with compatible blood type need to be reserved for the patient.

Patients or their parents and caregivers may also seek consultation regarding transplantation due to diminished quality of life, recent complications, an imminent major medical decision, or anxiety about future severe complications [15].

Conversely, some chronic complications, including kidney and liver dysfunction and alloimmunization that interferes with transfusions, may adversely affect transplant outcomes [16].

Indication for transplantation in patients with less severe disease has been a matter of debate, but transplantation is increasingly being pursued by patients or their families/caregivers. A careful and thorough discussion of the risks and benefits is needed in offering transplantation to these patients, since there may be substantial transplant-related morbidity, even if the eventual outcome remains favorable, and even the small risk of severe complications or mortality may not be acceptable in these patients.

Exclusion criteria based on adverse organ function — Patients undergoing allogeneic transplantation must have adequate heart, lung, kidney, and liver function to be able to withstand the anticipated treatment-related morbidities. Thus, some individuals with impaired organ function due to SCD or its treatments may not be able to undergo allogeneic transplantation with myeloablative conditioning.

Examples include:

●Left ventricular ejection fraction (LVEF) <45 percent

●Carbon monoxide diffusion capacity (DLCO) <50 percent of predicted

●Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²

●SCD-related hepatopathy

Patients undergoing allogeneic transplantation will receive chemotherapy and/or radiation, serotherapy with antithymocyte globulin or alemtuzumab and GVHD prophylaxis with calcineurin inhibitors such as tacrolimus or cyclosporine or mTOR inhibitors such as sirolimus. They also are at risk for sepsis during the aplastic phase and may undergo unique cardiopulmonary stress. They also require red blood cell and platelet transfusions.

Patients with SCD may have disease related organ function, such as chronic kidney, liver, or heart dysfunction or chronic lung disease. They may also have organ dysfunction due to transfusional hemosiderosis. They may have allosensitization or severe delayed hemolytic transfusion reaction, rendering it challenging to safely administer red blood cell transfusions.

Similar restrictions may apply to autologous transplantation with gene therapy. (See 'Gene therapies' below.)

Unique considerations for children — For children with SCD, the proposed transplantation approach must have the potential to improve survival, besides improving health-related quality of life, which is especially challenging since the likelihood of survival to adulthood is very high. In addition, this metric (survival to adulthood) fails to capture many nuances of quality of life [3]. Further, it may not be possible to predict which children are most likely to develop life-threatening or severe SCD complications, due to clinical variability of the disease and the absence of validated biomarkers for disease severity or mortality. The reduced life expectancy and diminished quality-adjusted life expectancy of SCD patients are also important considerations [17,18]. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Survival and prognosis'.)

Given the 2 to 5 percent risk of transplantation-related mortality and the relatively low (<2 percent) risk of mortality in children receiving maximum medical therapy, we recommend consideration of HCT only in children with severe recurrent painful events and/or an organ complication such as those listed above, until specific guidelines and recommendations for other scenarios can be made. However, age is a continuous variable, and the mortality rate may be higher in older children than in younger children [19]. (See 'Indications and eligibility' above.)

Unique considerations for adults — There has been debate in the scientific community about risk benefit tradeoffs in older children and adults, due to the higher prevalence of organ complications and the higher risk of transplantation-related toxicities.

Life-expectancy is shortened in adults with SCD; the lifespan of approximately 48 years has not improved in recent decades [20]. Given this, we believe that adults wanting a cure for SCD should receive a formal consult with a hematologist and a transplant physician familiar with allogeneic transplantation in SCD.

In general, we would consider transplantation from a matched sibling donor or haploidentical donor; at least 90 percent of older children and adults have a related donor when haploidentical donors are included [6].

In contrast, unrelated donor transplant was shown to be associated with increased toxicity, including GvHD and mortality [21]. However, it remains to be seen whether these unfavorable results were due to the donor type (higher risk of mismatches in minor histocompatibility complexes) or the conditioning regimen used. We therefore recommend unrelated donor transplants to be considered only as part of clinical trials.

Considerations for people without a matched related donor — Most patients with SCD do not have an available HLA-matched sibling donor.

For individuals who lack an HLA-matched related donor, options include an alternative donor such as haploidentical donor (including a parent, child, or sibling), 10/10 matched or 9/10 mismatched unrelated donor, matched related umbilical cord blood, or gene therapy/gene editing approaches. (See 'Terminology' above.)

●Haploidentical donor – Studies show encouraging outcomes for haploidentical transplantation using nonmyeloablative conditioning, with outcomes in adults comparable to those of myeloablative HLA-matched sibling donor transplantation in children with SCD [6,22-24]. An ongoing study in the EU is examining the merits of a myeloablative haploidentical transplant with graft manipulation as GVHD prophylaxis [22]. (See 'Haploidentical related donor' below.)

●Unrelated donor – The safety and efficacy of matched unrelated donors (including cord blood donors) is still a subject of active investigation. Major and life-threatening toxicities have been reported with matched unrelated donors and unrelated umbilical cord blood in patients with SCD, including graft rejection and acute and chronic GvHD when used in the context of a reduced intensity conditioning regimen. Few patients having received myeloablative conditioning similar to that used in matched sibling donor HCT have been reported [21,25,26]. (See 'Matched unrelated donor (bone marrow or umbilical cord blood)' below.)

●Gene therapies – Gene therapy approaches using myeloablative conditioning and autologous modified hematopoietic cell transplantation are another option that has the potential to provide access to transformative therapies to most patients with SCD. Two approaches to gene therapy were approved in December 2023, but information is limited about the long term safety and efficacy of these therapies. (See 'Gene therapies' below.)

PLANNING AND PREPARATION

Decisions regarding age, donor, stem cell source, and conditioning regimen — The preeminent timing of transplantation (patient age), donor selection (when an HLA-identical sibling donor is unavailable), conditioning regimen, and post-transplant immunosuppression remains unknown and continues to be studied.

In a 2019 retrospective cohort of 910 allogeneic transplant recipients, the best outcomes occurred in patients <13 years who underwent HLA-matched sibling donor transplantation [27]. While myeloablative conditioning was associated with a higher rate of disease-free survival, mortality was higher with myeloablative and reduced intensity conditioning regimens as compared with nonmyeloablative regimens, suggesting increased toxicity of more intensive conditioning regimens, especially in patients >12 years old. (See 'Survival' below.)

●Patient age – Transplantation should be considered in patients of all ages with severe disease who have an HLA-identical sibling. Transplantation in children with SCD is most likely to be successful when using a myeloablative conditioning regimen, but it may not be possible to predict which children are most likely to benefit. (See 'Opportunity for discussion and shared decision-making' above.)

●Donor – An HLA-matched sibling donor provides the greatest chance of successful cure but is limited in application due to lack of an available HLA-matched sibling [28]. (See 'Survival' below.)

Siblings or other relatives with sickle cell trait can donate; after successful transplantation, the recipient will have sickle cell trait, a benign carrier condition. (See "Sickle cell trait".)

For individuals who lack a matched sibling donor, another feasible option is to use a related haploidentical donor (including a parent, child, or sibling) [6,23]. (See 'Haploidentical related donor' below.)

The odds of finding a matched unrelated donor (MUD) differ based on ethnic background and are as low as <20 percent for patients with ancestry from African countries [28].

MUD transplant with reduced intensity conditioning is associated with an unacceptably high risk of GvHD, and unrelated umbilical cord donors are associated with an unacceptably high risk of graft failure. A matched unrelated donor transplant should only be pursued in the context of a clinical trial [1]. (See 'Matched unrelated donor (bone marrow or umbilical cord blood)' below.)

●Stem cell source – There are no direct comparisons between bone marrow and peripheral blood stem cells. Our approach is to endorse the source of hematopoietic stem cells used in multicenter peer reviewed clinical trials. Bone marrow-derived stem cells (as opposed to peripheral blood-derived stem cells) have been the preferred stem cell source for collection of unmanipulated grafts, especially in children using myeloablative conditioning regimens, as peripheral blood-derived stem cells have been associated with an increased risk of GvHD [19]. However, using peripheral blood derived stem cells in combination with a nonmyeloablative conditioning regimen has resulted in excellent outcomes and is increasingly being applied, especially in adults [29]. Furthermore, the risk of GvHD has significantly decreased in the era of double lymphodepletion with pre-transplant ATG and post-transplant cyclophosphamide.

Often there is an assumption that the identical conditioning regimen from a successful multicenter trial can be modified to include a different stem cell source with limited prior evidence of the clinical utility. If such adjustments are made at a local site, we encourage the transplant team to acknowledge that there is a major departure from previous protocols, to register their protocol in clinicaltrials.gov, and to have appropriate research oversight with appropriate stopping rules for futility and safety.

●Conditioning regimen – Studies have shown that full donor chimerism can be achieved with reduced intensity conditioning, especially in adults with SCD [6].

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

Testing and interventions prior to transplant — Considerations include the following, which are summarized in the table (table 2) and discussed in separate topic reviews:

●Detailed organ evaluation with special consideration of SCD-related comorbidities including neurologic, lung, kidney, and heart disease, as well as chronic pain and iron overload [30,31]

●Infectious disease evaluation of donor and recipient. (See "Evaluation for infection before hematopoietic cell transplantation".)

●Consultation regarding fertility preservation, with cryopreservation of tissues or embryos as appropriate. (See "Fertility preservation: Cryopreservation options" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

●Attention to pre-transplantation percent Hb S and SCD-directed medication management.

●Evaluation and optimization of psychosocial conditions.

CLINICAL EXPERIENCE/TRANSPLANT OUTCOMES — 

The first patient with SCD to be treated with an allogeneic hematopoietic stem cell transplant (HCT) was an eight-year-old who had recurrent vaso-occlusive pain episodes and developed acute myeloid leukemia (AML); her case history was published in 1984 [32]. She received bone marrow from her matched related four-year-old brother, who had sickle cell trait. In addition to curing the AML, the transplant led to resolution of vaso-occlusive pain episodes, with full donor chimerism; she remained alive decades later [32,33].

Experience with allogeneic HCT has continued to accrue in the ensuing years. However, there are no randomized trials comparing HCT with medical therapy or directly comparing different transplantation protocols or stem cell sources. Randomized trials comparing transplantation with medical therapy may be especially challenging to conduct since the two approaches differ dramatically in their short- and long-term risks and benefits [34]. The preferred approach may differ in adults and children.

Survival — Outcomes with HLA-identical sibling donors are excellent in children and even in adults with SCD. The use of less toxic nonmyeloablative and reduced intensity conditioning regimens has significantly reduced transplantation-related mortality while achieving good rates of disease-free survival [6,29,35,36].

Observational studies have demonstrated overall survival of ≥95 percent using matched sibling donors in children and adolescents with SCD [19,37]. Rates of event-free survival (with events defined as death or graft failure) and disease-free survival (with disease defined as persistent vaso-occlusive complications or recurrent strokes) are slightly lower than rates of overall survival.

A general overview can be obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, which provides data on large numbers of patients [19,27]. However, these data have accumulated over multiple decades during which there have been some changes and variability in conditioning regimens, supportive care, graft-versus-host disease prophylaxis, and other aspects of transplantation, making comparisons challenging.

Graft failure — Unlike overall survival, which has remained relatively stable, freedom from graft failure (which correlates with event-free survival) has continued to improve, likely due to improvements in HLA matching, conditioning regimens, GvHD prophylaxis, and supportive care for HCT over time [23,27,38-40].

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

GvHD — Risk factors for graft-versus-host disease (GvHD) include patient age, donor type and age, stem cell source, conditioning regimen, GvHD prophylaxis, and recipient characteristics (inflammatory environment) [6,19,23,27,35,37,41-43]. Robust lymphodepletion (eg, using pre-transplant anti-thymocyte globulin [ATG] and post-transplant cyclophosphamide) has led to a significant decrease in the incidence of severe GvHD and graft rejection [22,44-47]. (See "Pathogenesis of graft-versus-host disease (GVHD)".)

SCD-related complications — Results are summarized as follows:

●Acute vaso-occlusive pain events are eliminated after successful engraftment. However, some patients might continue to have chronic pain, especially those with a greater history of pain prior to transplant and older age [48,49].

●Organ dysfunction seems to improve, although systematic evaluations are lacking, and fixed deficits often are not reversible [30,31,38-40,50-53]. Some organ dysfunctions may be worsened due to transplantation-related toxicities.

●Ovarian and testicular function are impaired [35,54-58]; all patients should be offered age-appropriate fertility preservation strategies [58,59].

●Quality of life improves, although research is limited [60-62].

●Myeloid malignancy has been reported, particularly in adults following graft failure or with very low donor myeloid chimerism [27,63-67]. A mechanism involving oxidative stress and inflammation coupled with cytotoxic therapy leading to expansion of clonal hematopoiesis has been suggested [68].

Infertility — This is discussed separately. (See "Hydroxyurea use in sickle cell disease", section on 'Fertility' and "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults", section on 'Hypogonadism and fertility issues'.)

Alternative donors — Several options are available for individuals who do not have a matched sibling donor.

Alternative donors include haploidentical related donors, matched unrelated donors, mismatched unrelated donors, and unrelated umbilical cord blood units from cord blood banks.

●Experience with haploidentical transplantations is increasing rapidly with promising results being reported [6,23]. (See 'Haploidentical related donor' below.)

●Experience with matched unrelated donors and unrelated cord blood units is limited, mainly due to the very low donor availability, but these approaches may be appropriate for selected individuals as part of a clinical trial. (See 'Matched unrelated donor (bone marrow or umbilical cord blood)' below.)

Haploidentical related donor — Haploidentical donors are related donors (typically parents, siblings, or children) who share at least one haplotype (50 percent of their HLA loci) with the recipient. Use of haploidentical donors is a means of expanding the donor pool as haploidentical donors are the most common alternative donor source.

Another benefit of haploidentical donors is that repeat collections and large cell dose collections are possible. The experience for haploidentical transplant with nonmyeloablative conditioning and post-transplant cyclophosphamide continues to demonstrate promising results, particularly for adults with SCD [6,23]. (See "HLA-haploidentical hematopoietic cell transplantation".)

Haploidentical platforms differ; the Johns Hopkins platform has shown remarkable outcomes and is the basis for the National Institutes of Health (NIH) Blood & Marrow Transplant Clinical Trials Network (BMT CTN) protocol [42,43].

●A 2024 multicenter study involving 70 children and adults with SCD who underwent haploidentical transplantation using nonmyeloablative conditioning reported overall survival of 96 percent at one year and 94 percent at two years [6]. Participants received antithymocyte globulin, thiotepa, fludarabine, cyclophosphamide and 200 cGy total body irradiation, with post-transplant cyclophosphamide as GvHD prophylaxis. There were five deaths, all due to infections. Graft failure occurred in eight individuals (11 percent), all of whom were <18 years. Addition of thiotepa to the conditioning regimen was reported to dramatically reduce the risk of graft failure.

●A 2025 multicenter observational study of 42 adolescents and adults who underwent haploidentical related donor transplantation using the same conditioning regimen as the above study reported a 2-year event-free survival of 88 percent and overall survival of 95 percent [24]. The rate of acute grade 3 to 4 GVHD at 100 days was 5 percent and chronic GVHD at 2 years was 22 percent. Three individuals had graft failure. In this study, preconditioning with hydroxyurea 30 mg/kg during 60 days preceding the conditioning regimen was used. However, the similar outcomes between these two studies suggest a lack of additional effect of the hydroxyurea preconditioning on transplantation outcomes.

●Another approach for haploidentical transplantation in SCD uses in vitro lymphodepletion (TCRαβ/CD19 depleted peripheral blood derived stem cells) in combination with a myeloablative conditioning regimen [69]. A prospective phase 2 study evaluating this approach for both MSD and haploidentical transplantations is ongoing [70]. Preliminary outcomes are encouraging, though infectious complications remain a concern [71].

For haploidentical transplant, the recipient should not have donor-specific HLA antibodies for the mismatching HLA loci of the potential donor, as these are associated with an increased risk of graft rejection, especially when the mean fluorescence intensity (MFI) level is >5000 [6].

Patients with donor-specific HLA antibodies have been successfully transplanted following lowering the antibody titers with a desensitization protocol [72]. However, this is considered experimental, and using alternative donors to whom the recipient has no donor-specific antibodies is preferred. (See "Donor selection for hematopoietic cell transplantation", section on 'Donor-specific HLA antibodies'.)

Most haploidentical regimens for SCD include post-transplant cyclophosphamide, which decreases the risk of GvHD. While post-transplant cyclophosphamide reduced GvHD, additional myelosuppression, immunosuppression, or both are required to improve engraftment and SCD-free survival [23].

While further improvements are needed in haploidentical transplantation protocols in children with SCD, results in adults appear comparable with those in myeloablative MSD transplantations in children [6]. Many trials evaluating haploidentical transplant for patients with SCD are planned or ongoing.

Matched unrelated donor (bone marrow or umbilical cord blood) — The first pediatric multicenter matched unrelated donor (MUD) trial was published in 2016 and included a high rate of mortality and chronic GvHD [21]. A pilot study that used the same reduced intensity 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 [73].

Additional trials are ongoing.

The role of unrelated umbilical cord blood (UCB) transplants in patients with SCD remains experimental [74]. Most transplant centers do not favor this strategy, as it is associated with a significant risk of GvHD and graft failure [75].

POST-TRANSPLANTATION CARE

Slow weaning of GvHD prophylaxis — In contrast to hematologic malignancies, graft-versus-malignancy effect is not required in transplantation protocols for SCD. Furthermore, the risk of graft rejection is higher in SCD patients than in patients with hematologic malignancies.

Therefore, to further limit the risk of graft-versus-host disease (GvHD) and graft rejection, immunosuppressive therapy is used for longer periods than in transplantations for hematologic malignancies [76]. As an example, while immunosuppression for malignant disease is tapered starting between two to three months following transplantation, in SCD the taper starts at least six months after transplantation. In haploidentical transplantations, the immunosuppression may continue up to 12 months post-transplantation [6].

Immune ablative therapies with lymphodepleting agents pre-transplant and/or post-transplant cyclophosphamide serve as rejection and GvHD prophylaxis in transplantations for non-malignant diseases and have facilitated the successful use of less toxic chemotherapy in the conditioning regimens [45].

However, immune ablative practices may render patients more susceptible to viral reactivation and infections following transplantation. (See "Overview of infections following hematopoietic cell transplantation".)

The immunosuppressive medications most commonly used as GvHD prophylaxis in matched sibling donor transplantation are:

●A calcineurin inhibitor

●Methotrexate or mycophenolate mofetil (MMF)

The immunosuppressive medications most commonly used as GvHD prophylaxis, in addition to lymphodepletion with ATG and post-transplant cyclophosphamide, are:

●Sirolimus (mTOR inhibitor).

●Cyclosporine (calcineurin inhibitor).

●Tacrolimus (calcineurin inhibitor).

●Mycophenolate mofetil (MMF, inhibits DNA synthesis in lymphocytes) is often used as a second prophylactic drug until day +35, especially in haploidentical transplantations [43].

●Methotrexate.

Cyclosporine and tacrolimus have been associated with increased risk of neurotoxicity (particularly posterior reversible encephalopathy syndrome [PRES]) in children with SCD undergoing myeloablative HCT [77]. While sirolimus seems to be less neurotoxic, it is associated with a higher incidence of bone aches in patients transplanted for SCD [36].

General details of GvHD prevention and treatment in hematologic malignancies are presented separately. (See "Prevention of graft-versus-host disease" and "Treatment of acute graft-versus-host disease".)

Assessing engraftment and donor chimerism — 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 is generally done by DNA testing, most commonly with short tandem repeat (STR) testing by polymerase chain reaction (PCR) and next generation sequencing (NGS) [78]. Details are similar to testing in thalassemia. (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Engraftment'.)

●Donor chimerism of >95 percent is considered full donor chimerism.

●Donor chimerism of <5 percent is considered graft rejection.

●Donor chimerism between 5 and 95 percent is called mixed chimerism.

•Donor myeloid chimerism of ≥20 percent appears sufficient to prevent acute SCD-related vaso-occlusive episodes as it provides sufficient hemoglobin A (non-sickle hemoglobin) to prevent significant sickling, but there may be varying degrees of SCD-related hemolytic anemia and its potential downstream complications [79].

•Donor T-cell chimerism of >50 percent is considered essential to maintain a stable mixed donor chimerism [35].

Methods of donor chimerism assessment that use red blood cell phenotyping and/or cytogenetic differences (eg, Y chromosome when donor and recipient are of different sex) are considered insufficient to accurately monitor donor chimerism.

Post-transplant immunosuppression (GvHD and rejection prophylaxis) is mostly discontinued based on chimerism assessments [6,35].

Options for individuals with graft failure include a second transplant or medical therapy, depending on the patient's clinical status and donor availability.

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

●Hematologic support

•Transfusions – 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".)

•G-CSF – While granulocyte-colony stimulating factor (G-CSF) should be avoided in non-transplant patients with SCD, G-CSF stimulation has been shown to be safe and well tolerated after allogeneic HCT in patients with SCD [80]. Stimulation with G-CSF can be used to enhance neutrophil recovery following transplantation. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Avoid G-CSF'.)

●Iron stores – Iron overload, if present, is treated with phlebotomy given its low risk of adverse events and low costs, provided the individual has a sufficient hemoglobin level to tolerate removal of a unit of blood. Iron chelation may also be used if phlebotomy cannot be performed. 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'.)

●Infection prevention and treatment – Immunizations after transplantation are discussed separately; these are typically provided 6 to 12 months or longer after transplantation. (See "Immunizations in hematopoietic cell transplant candidates, recipients, and donors".)

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

●Psychosocial support – Adults with SCD mostly need psychological and/or occupational support following transplantation, as being cured after a life-long disease brings new challenges [61]. Children may require school support and/or accommodations.

●Rehabilitation and management of chronic and recurrent pain – Health care utilization for painful episodes decreases significantly, but patients with severe chronic pain continue to experience pain [48,49,81]. These individuals require multidisciplinary rehabilitation focused on chronic disabling pain.

Long-term follow-up is similar to that used in individuals with thalassemia, with multidisciplinary review of growth and development (for children), endocrinology, cardiology, pulmonary and kidney function, ophthalmology, and others. (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Long-term management'.)

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. DLI to treat ongoing graft rejection is associated with a risk of GvHD and is of unknown efficacy.

However, given the risks of graft failure (delayed or absent autologous regeneration and myeloid malignancies), application of low dose DLI might be a useful addition that needs to be evaluated in the setting of a well-designed clinical trial, especially when using nonmyeloablative or reduced intensity conditioning regimens [82].

GENE THERAPIES

Overview of gene therapy approaches including gene silencing/editing — Gene addition therapy (introducing a new gene) and gene editing (altering the sequence of an endogenous gene) have the potential to abrogate the clinical features of SCD [83,84]. Unlike transplantation of allogeneic hematopoietic stem cells (HSCs) from a donor, these approaches modify the person's own HSCs, and concerns about GvHD (and the need for immunosuppression) do not apply. Unlike allogeneic transplantation, these therapies have not met the same standards for curative therapy.

Typically, the autologous HSCs are harvested from peripheral blood via mobilization (with plerixafor) and an apheresis procedure, manipulations are done in the laboratory, myeloablative chemotherapy (busulfan) is delivered, and the modified autologous HSCs are reinfused as part of an autologous transplant.

CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 is one of the most studied tools for gene silencing/editing. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

In December of 2023, the US Food and Drug Administration (FDA) approved two autologous cell-based therapies, one using gene addition and one using gene silencing/editing [85-88]. Gene therapy is approved by the FDA for patients 12 years and above with a history of severe vaso-occlusive complications.

●Lovotibeglogene autotemcel (lovo-cel, Lyfgenia) is a gene therapy construct that introduces an anti-sickling beta globin variant into autologous HSCs (the T87Q variant, which blocks Hb S polymerization). (See 'Anti-sickling beta globin gene addition (lovo-cel, Lyfgenia)' below.)

●Exagamglogene autotemcel (exa-cel, Casgevy) is a gene silencing/editing construct that disrupts the BCL11A gene and subsequent production of the transcription factor BCL11A in autologous HSCs. This results in downstream Hb F upregulation. (See 'Gamma globin upregulation (including exa-cel, Casgevy)' below.)

Other general conceptual strategies include:

●Correction of an abnormal allele at the beta globin gene locus (HBB^S) to the wild-type HBB^A allele using CRISPR-Cas9 and homologous directed repair (resembling a "cut and paste" mechanism). (See 'Beta globin gene correction' below.)

●Other genetic methods of increasing Hb F expression targeting various components affecting gamma globin activity. (See 'Gamma globin upregulation (including exa-cel, Casgevy)' below.)

●Expressing delta globin, which lacks the Hb S mutation. (See 'Delta globin gene' below.)

In vitro studies and animal models have provided evidence for the feasibility of these approaches [89-94]. However, issues remain related to the safety and efficacy of the delivery viruses as well as the precision of editing. Myeloid malignancy is a particularly concerning outcome that is incompletely understood. (See 'Concern about myeloid malignancy in gene therapy studies' below.)

Other areas of active research include whether alternatives to myeloablative therapy can be used to prepare the individual for infusion of the autologous HSCs, or whether the gene therapy or gene editing construct can be delivered directly to the patient (ex vivo gene therapy) rather than to their HSCs in the laboratory (in vitro gene therapy) [95-97]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'In vitro versus in vivo transduction'.)

As with other autosomal recessive conditions, it is not necessary to completely eliminate expression of the disease gene. For example, induction of 40 to 50 percent Hb F can be sufficient to eliminate SCD-related vaso-occlusive pain episodes. However, the effects of gene therapies on the rheologic behavior of modified red blood cells and on chronic SCD-related organ complications are not known.

Gene therapy adds substantial cost of care in the short term, while potentially reducing long-term costs. Government-funded programs may have access to gene therapy products at substantially discounted prices, which may be closer to the "fair price" at which these products have been found to be cost-effective. Additional issues related to health equity, disparities in care, and adequate funding for care must be considered.

The increased and as yet unspecified risk of myeloid malignancy post gene therapy must be taken into consideration in risk benefit tradeoffs in the course of shared decision making about gene therapy. (See 'Concern about myeloid malignancy in gene therapy studies' below.)

Specific gene therapy approaches

Beta globin gene correction — The sickle cell variant is a single point mutation, and reversion to the wild-type sequence at one or both alleles of the beta globin gene (HBB) locus could convert SCD to sickle cell trait, a benign carrier condition, or to normal adult hemoglobin (Hb A).

Gene correction takes advantage of gene editing and homology directed repair to allow endonucleases to "repair" a pathogenic variant using a wild-type beta globin sequence as a template. (See "Genetics: Glossary of terms", section on 'Gene editing'.)

A preclinical model using this approach was able to correct the sickle mutation in cultured bone marrow cells from patients with SCD, and cells manipulated in this manner could differentiate and restore hematopoiesis in a mouse model [98].

Nulabeglogene autogedtemcel (nula-cel, formerly GPH101) is a CRISPR-Cas9 gene editing system used to correct the sickle cell mutation. In January 2023, a clinical trial was voluntarily paused due to unexpected cytopenias that were attributed to the therapy [99,100].

Anti-sickling beta globin gene addition (lovo-cel, Lyfgenia) — A manufactured version of the beta globin gene has been developed that creates an amino acid substitution of glutamine for threonine at position 87 (beta globin T87Q) [89]. This amino acid switch replicates the region of the gamma globin sequence that is thought to block polymerization of sickle hemoglobin.

Gene therapy with lovotibeglogene autotemcel (lovo-cel, Lyfgenia, previously called LentiGlobin) consists of autologous CD34-enriched hematopoietic stem and progenitor cells transduced with the lentiviral vector BB305 that expresses Hb A^T87Q. Clinical experience includes the following:

●In a 2017 case report, a 13-year-old boy with SCD who had multiple vaso-occlusive pain episodes and other SCD complications that did not improve with hydroxyurea or chronic transfusions was treated with an autologous transplantation using this construct [101]. Following engraftment, he had increasing expression of the modified beta globin until it reached stable levels of approximately 50 percent of total hemoglobin at nine months, with a reciprocal decline in Hb S expression. He had no vaso-occlusive events and required no further analgesics during the post-transplant observation period of more than 15 months. There were no major adverse events other than the expected cytotoxicity of the conditioning regimen.

●In individuals in group A of a study using this construct, two of seven patients developed acute myeloid leukemia (AML) that could not be directly related to the gene therapy construct and was attributed to the increased risk of myeloid malignancy due to the underlying SCD, exposure to cytotoxic chemotherapy, and a suboptimal treatment protocol with insufficient number of transduced hematopoietic stem and progenitor cells [102,103]. Details are discussed below. (See 'Concern about myeloid malignancy in gene therapy studies' below.)

●In a 2021 report describing outcomes in 35 individuals who underwent gene therapy with this construct using the more optimized protocol in group C of this study, using plerixafor-mobilized peripheral blood stem cells and myeloablative conditioning, all 35 had engraftment, with a median follow-up of 17.3 months (range 3.7 to 37.6) [104]. The following post-transplant outcomes were reported:

•Vaso-occlusive events decreased from a mean of 3.5 per year to a mean of 0 (in 25 evaluable patients).

•Median hemoglobin increased from 8.5 g/dL to ≥11 g/dL.

•Hb A^T87Q accounted for ≥40 percent of hemoglobin and was present in 85 percent of RBCs.

•Hb S decreased to approximately 50 percent.

•Two patients developed anemia related to subsequent alpha and beta globin chain imbalances (both with concurrent alpha thalassemia minor), without evidence of MDS.

•There was one death, 20 months after transplant, in an individual with pulmonary hypertension, left ventricular hypertrophy, and cardiac interstitial fibrosis.

Gamma globin upregulation (including exa-cel, Casgevy) — The gamma globin gene is the source of gamma chains (beta-like chains) for fetal hemoglobin (Hb F), the predominant hemoglobin expressed in late gestation and early infancy. It is a separate gene from beta globin and thus does not contain the Hb S mutation (figure 1). (See "Structure and function of normal hemoglobins", section on 'Hb F'.)

The switch from gamma globin to beta globin expression leads to a reduction in Hb F and an increase in Hb A in early infancy. This switch is controlled in large part by the BCL11A gene, which encodes a transcriptional repressor of gamma globin expression. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'BCL11A'.)

Manipulations that block the function of BCL11A reverse the switch and can dramatically increase Hb F levels, in turn reducing sickling and vaso-occlusive complications. These genetic manipulations have the potential to raise Hb F levels (and decrease Hb S) to a much greater extent than hydroxyurea. (See "Hydroxyurea use in sickle cell disease".)

Studies have validated the approach of targeting BCL11A using different methods:

●Gene editing using CRISPR-Cas9 – Gene editing has been used to increase Hb F expression via targeting the BCL11A gene or the gamma globin promotor.

•BCL11A gene silencing/editing – Exagamglogene autotemcel (exa-cel, Casgevy) is a gene editing construct that uses the CRISPR-Cas9 system to disrupt the BCL11A gene (and BCL11A expression) in autologous HSCs followed by myeloablative conditioning (busulfan) and autologous transplantation. A 2024 report described 44 patients with SCD ages 12 to 35 years who had at least two vaso-occlusive episodes per year in the previous two years (eg, pain, acute chest syndrome, priapism) who were treated with this therapy [105]. Of the 30 participants who had a follow-up duration of at least 12 months, 29 (97 percent) had no vaso-occlusive episodes and none were hospitalized for vaso-occlusive events during the year following therapy. Among all 44 patients, the mean Hb was 11.9 g/dL at month 3 and 12.5 g/dL at month 6. The mean percent Hb F was 37 percent at month 3 and 44 percent at month 6. Toxicities were as expected with myeloablative conditioning regimens, and no cancers occurred. One patient who had preexisting lung disease and busulfan-induced lung injury died of COVID-19 at day 268.

•Gamma globin promotor editing – OTQ923 is a CRISPR-Cas9-based system for disrupting the gamma globin promotor region (HBG1/HBG2). In a mouse model, targeting this region led to induction of Hb F [106]. Follow-up of the first three patients with SCD treated with OTQ923 (using myeloablative busulfan conditioning and autologous HSCs treated with OTQ923) demonstrated clinical improvements (substantial reduction in vaso-occlusive episodes, discontinuation of transfusions) as well as marked increases in Hb (range, 10 to 12 g/dL), Hb F (range, 19 to 27 percent), and F cells (range, 70 to 88 percent) [107,108]. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Gamma globin genes (HBG2 and HBG1)'.)

●Gene editing using zinc finger nucleases – Zinc finger nucleases (ZFN) are also used for gene editing. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

BIVV003 uses ZFN to target BCL11A. In a study of four patients with SCD treated with BIVV003, Hb F increased from 12 to 41 percent, and three had complete resolution of vaso-occlusive events [109].

Since patients received myeloablative chemotherapy prior to transplantation of genetically modified hematopoietic cells, transplant-related complications attributable to the myeloablative conditioning regimen were observed.

●RNA interference – One approach used RNA interference (RNAi) from a lentiviral vector encoding a short hairpin RNA (shRNA) targeting BCL11A mRNA [110,111]. The shRNA was embedded in a microRNA to promote erythroid-specific knockdown in autologous HSCs followed by autologous HCT using the transfected construct. Gene therapy was ineffective in one individual; in the remaining patients, Hb F was increased from 21 to 42 percent. Five patients with >6 months of follow-up had a median of 6 (3 to 13) vaso-occlusive events prior to gene therapy and a median of 1 (0 to 1) vaso-occlusive events following gene therapy.

Details of Hb F regulation, gene editing techniques, and RNAi are discussed separately [112]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'RNA interference' and "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing' and "Fetal hemoglobin (Hb F) in health and disease", section on 'Hemoglobin switching and downregulation of Hb F expression'.)

Delta globin gene — The delta globin gene is the source of beta globin-like chains for Hb A2, a minor adult hemoglobin that typically accounts for only 2 to 3 percent of total hemoglobin in children and adults. It is a separate gene from beta globin and thus does not contain the Hb S mutation. Like Hb F, Hb A2 inhibits the polymerization of Hb S [113,114]. (See "Structure and function of normal hemoglobins", section on 'Hb A2'.)

Studies in transgenic SCD mice highlight the possible value of increasing delta globin gene expression [115,116].

Preclinical models using gene therapy to introduce a delta globin gene have not been reported, but patients with SCD who have especially high Hb A2 levels appear to have a milder clinical phenotype, suggesting that approaches to increase delta globin expression might be worthwhile [113].

Choice among gene therapy/gene editing approaches — Individuals considering gene therapy must consider the risk-benefit tradeoffs as well as which therapy to pursue. General decision-making about gene therapy is discussed above. (See 'Overview of gene therapy approaches including gene silencing/editing' above.)

For those who do wish to pursue one of these approaches, the contemporaneous availability of two different therapies, lovotibeglogene autotemcel (Lyfgenia) and exagamglogene autotemcel (exa-cel, Casgevy) poses a therapeutic dilemma. In the absence of side-to-side comparison of the two approaches, no conclusions can be drawn regarding their comparative safety or efficacy [117].

●Following treatment with Lyfgenia, patients with alpha thalassemia trait may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. Lyfgenia has not been studied in patients with more than two alpha globin gene deletions. (See 'Anti-sickling beta globin gene addition (lovo-cel, Lyfgenia)' above.)

●Patients with high baseline Hb F expression prior to the initiation of optimal hydroxyurea therapy should be carefully evaluated to exclude a prior gene variant affecting the target therapeutic pathway of Casgevy. (See 'Gamma globin upregulation (including exa-cel, Casgevy)' above.)

Autologous HSC mobilization with plerixafor — Plerixafor is FDA approved for autologous hematopoietic stem cell (HSC) mobilization for some cancers. It has been evaluated in small studies as a single agent for stem cell mobilization in individuals with SCD and was included in the pivotal studies leading to the FDA approvals of Lyfgenia and Casgevy [97,105].

In a study from 2020 involving 15 patients from two clinical sites who underwent autologous 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 [118]. 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.

An analysis of 23 participants with SCD undergoing plerixafor mobilization and apheresis in a phase I safety and efficacy study found that severity of SCD, the number of medications used against chronic pain, and the period of hydroxyurea being held prior to the mobilization influenced the CD34 positive yields following plerixafor mobilization [119].

Avoid G-CSF for autologous HSC mobilization — For autologous hematopoietic stem cell mobilization for gene therapy or gene editing in patients with SCD, G-CSF must be avoided, since these individuals continue to produce sickle hemoglobin and may be at higher risk of severe and potentially fatal vaso-occlusive episodes [120,121]. Plerixafor is used for stem cell mobilization in these individuals. (See 'Autologous HSC mobilization with plerixafor' above.)

This contrasts with allogeneic hematopoietic stem cell donors with sickle cell trait, for whom G-CSF can be used. (See "Sickle cell trait", section on 'Hematopoietic stem cell donation'.)

Concern about myeloid malignancy in gene therapy studies — In early 2021, gene therapy studies using lentiviral vectors were suspended temporarily after 2 of 47 individuals with SCD who were participating in a study using the BB305 lentiviral vector subsequently developed myeloid malignancies (myelodysplastic syndrome [MDS] that later transformed to acute myeloid leukemia [AML] in one participant, AML in another participant) [102,103].

●For the first participant, the investigative team concluded that MDS/AML was not related to the viral vector but was a result of the conditioning regimen in combination with a higher risk of mutational burden due to the underlying SCD [102].

●Evaluation of the second patient, who had very limited engraftment of the modified HSCs and developed AML more than five years later, also determined that the gene therapy construct was unlikely to be responsible [103]. The insertion site was in a gene not known to be associated with oncogenesis and was present in most patients with SCD who received the same construct and did not develop AML, and several somatic mutations were present in the leukemic blasts unrelated to the vector but commonly seen in monosomy 7, which is known to complicate alkylating agent therapy. Low transgene expression, insufficient therapeutic response, and persistent hematopoietic stress may have contributed to somatic mutation evolution.

●Two other patients who were originally suspected of having MDS had transfusion-dependent anemia and trisomy 8, but there was no evidence of dysplasia or blasts on bone marrow evaluation. Both patients had concurrent alpha thalassemia trait (-α3.7, -α3.7) [104,122,123].

Studies may be indicated to assess for genetic risk factors for MDS and AML development after gene therapy for SCD. Hypotheses for the mechanism of leukemogenesis include insertional mutagenesis, transplant conditioning regimens, and expansion of preexisting premalignant clonal populations driven by regeneration stress of autologous hematopoiesis [124]. The observation of increased risk of myeloid malignancy after graft failure following allogeneic HCT suggests a higher prevalence of preexisting clonal hematopoiesis in SCD patients that might expand following exposure to the toxic conditioning regimen [64].

The optimal strategy to identify individuals with SCD who are at increased risk for transplant-related malignancy is unknown. Several strategies have been suggested but not proven to have clinical utility. Screening for clonal hematopoiesis with sensitive deep sequencing methods might detect patients who are at increased risk for transplant-related myeloid malignancy. The gene(s) and variant allele frequencies associated with an increased risk of MDS/AML following any curative therapy in SCD are unknown.

Individuals with thalassemia treated with the same lentiviral construct have not shown evidence of AML or MDS. However, no conclusive evidence exists to determine which features of disease or therapy predispose to myeloid malignancy, from among myeloablative therapy, the lentiviral vector, SCD-related genetic predisposition, stress erythropoiesis, or some combination of these factors. MDS and AML have been observed in allogeneic transplant studies in SCD that did not involve gene therapy, especially after graft failure [27,64,125]. The cause(s) in individuals with SCD are under investigation.

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 5^th to 6^th 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 10^th to 12^th 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)" and "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (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

●Definitions – Definitions used in curative therapies for sickle cell disease (SCD), including types of hematopoietic stem cell (HSC) donors, conditioning regimens, and gene therapies, are discussed above and separately. (See 'Terminology' above and "Overview of gene therapy, gene editing, and gene silencing".)

●Decision to consider curative therapy – The decision to consider or pursue transplantation is highly individualized. Consultation for transplantation does not necessarily imply that transplantation is imminent or must be inevitably pursued; it is an opportunity for discussion and shared decision-making. (See 'Decision to consider curative therapy' above and 'Opportunity for discussion and shared decision-making' above.)

We are most likely to consider curative therapy in individuals with SCD complications associated with risk of premature mortality or severe morbidity, such as stroke, frequent pain, or acute chest syndrome (table 1). Pain interfering with activities or resulting in disability is the most common indication. For children, the approach should have the potential to improve long-term survival, organ function, and quality of life. For adults, the lifespan of approximately 48 years has not improved, and we believe adults wanting a cure should receive a formal consultation with a hematologist and transplant physician. (See 'Indications and eligibility' above and 'Unique considerations for children' above and 'Unique considerations for adults' above.)

Transplantation is most likely to be successful in children using myeloablative conditioning and an HLA-matched sibling donor, but such donors are frequently unavailable. Alternate donor options include a haploidentical related donor (parent, child, sibling), unrelated donor, or umbilical cord blood. Haploidentical related donors are most promising. Gene therapies have been approved and appear promising, although long-term outcomes need further study. (See 'Considerations for people without a matched related donor' above and 'Haploidentical related donor' above.)

●Preparation – Relatives with sickle cell trait can donate. Bone marrow and peripheral blood stem cells have not been directly compared; we endorse the HSC source used in multicenter peer reviewed trials. Other considerations include detailed organ evaluation understanding SCD-related comorbidities, infectious disease evaluation (donor and recipient), fertility preservation, and graft-versus-host disease (GvHD) prophylaxis (table 2). (See 'Planning and preparation' above and "Sickle cell trait" and "Evaluation for infection before hematopoietic cell transplantation" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Fertility preservation: Cryopreservation options" and "Prevention of graft-versus-host disease".)

●Survival – Overall survival in children and adolescents with matched sibling donors is ≥95 percent. Disease-free survival is impacted by donor type, conditioning, and patient age. Center for International Blood and Marrow Transplant Research (CIBMTR) is a rich source of outcome information but is subject to the limitations of registry data. (See 'Survival' above.)

●Other outcomes – Rates of graft failure continue to decrease. Severe GvHD has decreased due to robust lymphodepletion (pre-transplant lymphodepleting serotherapy and/or post-transplant cyclophosphamide). Rates of pain episodes are dramatically reduced. SCD-related organ damage stabilizes, and complications improve. Myeloid malignancy has been reported, particularly in adults with graft failure or low donor chimerism. (See 'Graft failure' above and 'GvHD' above and 'SCD-related complications' above.)

●Post-transplantation care – Graft-versus-malignancy effect is not required, and the risk of graft rejection is higher in SCD. Therefore, immunosuppressive therapy is used for longer periods than with transplant for hematologic malignancies. Engraftment and percent donor chimerism is generally assessed by DNA testing. Support must be provided (hematologic, infection, psychosocial) along with multidisciplinary care for chronic pain. Excess iron stores can generally be treated with phlebotomy. (See 'Post-transplantation care' above.)

●Gene therapies – Several approaches using genetic material to modify the person's own HSCs are under study. Two gene therapies, one gene addition and one gene editing approach, were approved by the FDA in late 2023. Long-term studies of safety and efficacy including the risk of myeloid malignancy are ongoing. (See 'Gene therapies' above.)

●Medical therapies – Separate topics discuss approved and investigational medical therapies. (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, RBC matching, and modifications" and "Investigational pharmacologic therapies for sickle cell disease".)

ACKNOWLEDGMENTS — 

UpToDate gratefully acknowledges Stanley L Schrier, MD, 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, Shakila Khan, MD, and Griffin P Rodgers, MD, to earlier versions of this topic review.