Transformative therapies for sickle cell disease

Key points

• Sickle cell disease (SCD) is associated with major morbidity, reduced life expectancy, and impaired quality of life.

• Transformative therapies for SCD include allogeneic hematopoietic stem cell transplant and gene therapy.

• After successful transformative therapy, people with SCD no longer demonstrate an SCD phenotype and experience a reduction in SCD-related morbidities and improvement in quality of life.

• Transformative therapies for SCD can be associated with major adverse events, including death.

• The decision to proceed with a transformative therapy must take into careful consideration the severity of the SCD, the risk of future SCD complications, and the risks of available transformative therapies.

• The expertise and infrastructure to deliver transformative therapies lies within existing Canadian cancer care programs.

Sickle cell disease (SCD) occurs when a DNA base pair substitution in the β-globin gene results in the formation of hemoglobin S, which polymerizes when deoxygenated, leading to deformation (“sickling”) and hemolysis of red blood cells. Sickle cell disease results in recurrent acute complications like pain crises, acute chest syndrome, and stroke, as well as chronic end-organ injury affecting the heart, lungs, kidneys, bones, and retina.¹ Canadian data are unavailable, but recent American data indicate that the life expectancy of people with SCD is 52.6 years.² However, life expectancy varies considerably depending on disease-related factors and access to health care, among other factors. Additionally, SCD is associated with high health care utilization, impairment in quality of life, and employment loss among patients and caregivers.^1,3

An estimated 6000 people live with SCD in Canada, with increasing prevalence owing to immigration.⁴ Thus, clinicians in Canada should be aware of novel therapies that aim to optimize health outcomes for individuals with SCD.

What are transformative therapies in SCD, and what are their benefits?

Transformative therapies encompass allogeneic hematopoietic stem cell transplant and gene therapy (Table 1 and Figure 1). Both therapies address the mutated β-globin gene in bone marrow stem cells, but with differing mechanisms.

Table 1:

Comparison of transformative therapies in sickle cell disease

Characteristic	Matched sibling transplant	Haploidentical transplant	Gene therapy
Donor	HLA-matched sibling‡	Haploidentical relative‡,§	Self
Mechanism	Replace sickle cell–producing bone marrow stem cells	Replace sickle cell–producing bone marrow stem cells	Modification of bone marrow stem cells via: CRISPR-Cas9 to deactivate BCL11A, leading to increased Hb F Lentiviral transduction to produce an antisickling Hb
Conditioning*	Nonmyeloablative or myeloablative¶	Nonmyeloablative or myeloablative¶	Myeloablative
Age range of patients treated in trials or real-world studies, yr	3–65	8–43	12–38
Risk of GVHD or rejection of donor stem cells†	Yes	Yes	No
Need for immunosuppressive therapy	Yes	Yes	No
Duration of follow-up or clinical experience, approximate, yr	40	10	3–4
Real-world evidence available	Yes	Yes	No
Reduction in acute complications of SCD	Yes	Yes	Yes
Improvement in quality of life	Yes	Yes	Yes
Improvement or stability in end-organ function	Yes	Yes	Not yet demonstrated

Note: GVHD = graft-versus-host disease, Hb = hemoglobin, HLA = human leukocyte antigen, SCD = sickle cell disease.

^*Conditioning refers to the preparative chemotherapy or total body irradiation required to ablate or impair the patient’s bone marrow stem cells.

^†Graft-versus-host disease occurs when donor immune cells attack the patient’s organs, whereas rejection results in resumption of blood cell (i.e., sickle cell) production by the patient’s stem cells.

^‡Donors may be unaffected by SCD or may have sickle cell trait.

^§Haploidentical donor refers to a relative, most often first-degree, sharing 1 HLA haplotype with the patient (sometimes referred to as a 50% match).

^¶In the current era, nonmyeloablative conditioning (less intensive treatment that does not completely ablate the patient’s bone marrow) is increasingly preferred, owing to lower toxicity, versus myeloablative conditioning (highly intensive treatment that leads to permanent ablation of the patient’s bone marrow), although not universally.

Figure 1:

Delivery of transformative therapies for sickle cell disease. Note: HLA = human leukocyte antigen.

Transplant replaces the patient’s stem cells with those of a donor unaffected by SCD or who has sickle cell trait. After successful transplant, the patient’s blood cell production mirrors that of the donor. Transplant requires conditioning (total body irradiation or chemotherapy or both) before the transplant occurs, and immunosuppressive therapy for 1 to 2 years after transplant to prevent rejection of donor stem cells (resulting in resumption of sickle cell production by the patient’s stem cells) and graft-versus-host disease (GVHD; resulting in donor immune cells attacking the patient’s organs). Conditioning can be myeloablative (where the patient’s stem cells are permanently ablated) or nonmyeloablative (where the patient’s stem cells may survive but donor stem cells take over blood cell production). More than 4 decades of experience with transplant from human leukocyte antigen (HLA)–matched sibling donors informs this innovation. In the current era, nonmyeloablative conditioning is increasingly used. About 90% of patients successfully switch to donor blood cell production and no longer demonstrate an SCD phenotype.⁵ These results have since been replicated in real-world settings, including in Canada.^6,7 After successful transplant, patients demonstrate improvements in quality of life, resolution of acute complications of SCD, and stability or improvement in end-organ function.^8,9

Unfortunately, only 18% of people with SCD have a matched sibling donor.¹⁰ Recent studies have established transplant from a haploidentical donor (a first-degree relative sharing 1 HLA haplotype; i.e., 50% matched) as an alternative for those without a matched sibling. More than 90% of people with SCD are expected to have at least 1 haploidentical donor. After nonmyeloablative conditioning, about 90% of adults who undergo transplant from a haploidentical donor successfully switch to donor blood cell production.^11,12 However, 25% of children experience transplant rejection, and further research is needed to determine whether haploidentical transplant is suitable for people younger than 18 years.¹¹

Another transformative therapy for SCD is gene therapy. Currently, 2 gene therapies are marketed worldwide. In contrast to transplant, gene therapies are autologous stem cell products. The patient’s own stem cells are collected via apheresis; shipped to a manufacturing facility, where gene editing is applied; then returned for infusion. One available product deactivates BCL11A, a suppressor of fetal hemoglobin (Hb F) production, thereby reconstituting erythropoiesis with about 40% Hb F. Fetal hemoglobin prevents sickling and reduces morbidity and mortality in SCD. Another product introduces a novel β-globin gene, which leads to production of an antisickling hemoglobin. In contrast to transplant, myeloablative conditioning is required to replace the patient’s stem cells with the gene-edited stem cells, but immunosuppressive therapy is not required. In phase 3 industry-sponsored trials (each with fewer than 100 patients treated), about 90% of patients are free of pain crises and have experienced improvement in quality of life, with median follow-up of 3 to 4 years.¹³ Real-world data are not yet available, follow-up is relatively short, and it is not yet known whether gene therapies stabilize or improve end-organ function.

What are the harms of transformative therapies for SCD?

Despite promising outcomes, clinicians and patients must be aware of the possible adverse events associated with transformative therapies, including the risk of death.

Graft-versus-host disease may occur on a spectrum of severity, typically in the first year after transplant. Common symptoms of GVHD include rash (often maculopapular erythema), diarrhea, oral ulcers, and dry eyes. Clinical manifestations include hepatitis, cholestatic liver disease, lichen planus, and keratoconjunctivitis. Moderate-to-severe forms require prolonged courses of immunosuppressive therapies and result in impaired quality of life and an increased risk of death.¹⁴ With a matched sibling donor and nonmyeloablative conditioning, moderate-to-severe GVHD was seen in 1 of 91 patients in the largest prospective studies to date, and in none of the first 31 patients transplanted in Canada.^6,7,15 Graft-versus-host disease occurs more frequently after haploidentical transplant: 25% experience a moderate-to-severe form. Rejection of donor stem cells, leading to recurrence of SCD, occurs in 10% to 20% of patients with either donor type.^12,15

Infection and bleeding are also important risks in the first 3 to 5 weeks after transplant, given that neutropenia and thrombocytopenia are expected during this time. Patients remain at increased risk of infection while on immunosuppressive therapy after transplant and must be investigated and treated promptly for fever or infectious symptoms. Infertility is possible, owing to gonadal toxicity of conditioning therapies; however, this is not universal after nonmyeloablative conditioning. The baseline risk of hematologic malignancy is also elevated in people with SCD, which may be further increased after transplant. After transplant, the 10-year incidence of hematologic malignancy is 2%; however, direct comparisons of those receiving and not receiving transplant are not available.¹⁶ In contemporary trials, 7% of patients died after a median follow-up of 10 years after matched sibling transplant, whereas 7% of patients died at 3 years after haploidentical transplant. The higher risk of death after haploidentical transplant is due to the more intensive immunosuppression and higher risk of GVHD in the setting of HLA mismatch.

Toxicities are most prevalent in the first 3 months after gene therapy and relate to the use of myeloablative conditioning leading to febrile neutropenia, infection, thrombocytopenia, bleeding, nausea, stomatitis, and organ dysfunction.¹³ In the first cohort (n = 7) treated with 1 gene therapy product and followed for a median of 5 years, 2 patients developed acute myeloid leukemia at 3 and 5.5 years after treatment.¹⁷ No further cases of hematologic malignancy have been reported after gene therapy, with subsequent cohorts reaching 3 to 4 years of follow-up. Infertility is expected in most patients who are treated with myeloablative conditioning, and fertility preservation options should be discussed as part of the decision-making process.¹⁸ At 3 to 4 years’ follow-up, 2% to 4% of patients enrolled in clinical trials of the marketed gene therapy products died. As such, longer follow-up and real-world data are awaited.¹³

Who is eligible for transformative therapies for SCD?

When deciding whether to proceed with a transformative therapy, the severity of the SCD, the risk of future SCD complications, and the risks of available transformative therapies must be considered carefully.

No universally agreed-upon eligibility criteria for transplant exist. Typical indications in trials and real-world studies include end-organ complications or frequent acute complications of SCD despite treatment with hydroxyurea. Haploidentical transplant is typically reserved for more severe SCD, given the higher risk of complications versus matched sibling transplant.^12,19 Inclusion criteria for gene therapy trials have focused solely on acute complications, such as pain crises, acute chest syndrome, and stroke. People with at least 2 to 4 acute complications per year in the preceding 2 years were eligible for these trials.¹³

Transplant from a matched sibling donor, when available, is strongly considered as the transformative therapy of choice, given the established experience with this approach. Gene therapy clinical trials have, thus, largely excluded those with an available matched sibling donor. The decision to pursue gene therapy or haploidentical transplant for those without a matched sibling donor must be individualized, based on disease characteristics and patient preference.

Currently, transplant for SCD is offered at all Canadian pediatric transplant centres (in Vancouver, Calgary, Winnipeg, and Toronto, and 2 sites in Montréal) and at 3 adult centres (Ottawa, Toronto, and Calgary), with referral typically from the treating SCD physician. No Canadian centres currently offer gene therapy, pending price negotiations for 1 Health Canada–approved product, and clinical trials for these products are no longer accruing in Canada. Presently, collaborative efforts between patient groups and SCD and transplant clinicians are being undertaken with the goals of establishing referral pathways for transformative therapies and identifying barriers to access.

What are the resource implications?

The expertise and infrastructure to deliver transformative therapies lie within existing cancer care programs. Disparities in access exist (greater pediatric than adult capacity and lack of availability in some provinces). Incorporating SCD care into more Canadian cancer care programs is logical, but may stress existing capacity challenges. Expanding the capacity of current cancer programs to include SCD transformative therapies will require more health care professionals with the knowledge, skills, and training to care for patients receiving these novel therapies and expanded capacity in cancer programs to treat patients with SCD.

What can be expected in the foreseeable future?

Transformative therapies for SCD have the potential to decrease the morbidity and mortality associated with SCD. As these therapies become more available, more patients with SCD in Canada will be offered these therapies earlier in the disease course. Further advances in the delivery of transformative therapies — for example, in vivo gene therapy and novel, less toxic conditioning regimens — are actively being studied and could make transformative therapies more accessible and palatable to patients and providers.