A road map for uniform, comprehensive long-term follow-up after curative therapy for sickle cell disease Open Access

Knowledge regarding genetics, pathophysiology, and natural history of sickle cell disease (SCD) has evolved significantly, resulting in improved understanding of complications, morbidity, and mortality and expansion of treatment choices. Curative therapies have expanded in parallel, ranging from HLA-matched sibling transplantation to alternate donor transplantation (allogeneic hematopoietic cell transplant [allo-HCT]) and autologous gene-modified cell transplantation (GT).^1-7 Although results are positive across therapies, outcome analyses are of short duration (restricted by trial guidelines) and highly variable between trials. With increasing pathways to disease eradication, it is important to define treatment efficacy in relation to age, disease, and modality as uniformly as possible to allow for just comparison of advantages and risks. This can be achieved with a combination of clinical and laboratory investigation–based end points. The American Society of Hematology, in collaboration with the US Food and Drug Administration, defines outcomes as a reflection of patient desires integrated with objective measurements to assess disease status, amenable to easy measurement at low cost, providing relevant, interpretable, and comparable information and facilitating complete data collection.⁸ Data collected using comparable methods across therapies at similar time points will help inform families and providers define expectations, provide insights into interventions after therapy, and help choose the best approach of therapy for individual patients. Additional progress is achieved with further research for better end points that are easier or superior. Such research, initially restricted to smaller focused trials, is then adopted for general application if useful. We summarize practical guidelines for long-term follow-up based on existing data and discuss opportunities for further research.

Comparison between treatment approaches is based on objective measures that define positive and negative outcomes. Curative end points should measure the restoration of physical and psychosocial quality of life to levels similar to unaffected peers, correct laboratory parameters, and abrogate medical needs connected to the disease or intervention. The benefit should be stable over the long term, spanning a normal life span. Currently, there are few validated measures, and high variability exists in the description of outcomes between curative therapy trials and in comparisons with conservative SCD management protocols. Thus, the recommendations included here are provided by experts in the field as a working summary of long-term follow-up assessments and associated parameters, along with timing guidelines whenever possible, with a goal to practice harmony. The summary is organized to include individual organ functions, graft function, health-related quality of life (HRQOL), pain perception, patient-related outcomes, and transition of care from childhood to adulthood to encompass lifetime care and monitoring for individuals with SCD treated with curative intention and provide timelines for monitoring to allow for comparison.

The risk of overt cerebrovascular disease is often a reason to seek allo-HCT/GT in SCD. It is important to prevent new pathology and stabilize established injury. By age 30 years, 50% of adults with hemoglobin SS and Sβ⁰ will have a silent cerebral infarct,⁹ and without transcranial Doppler velocity (TCD) screening and transfusion, 5% to 10% will suffer an overt stroke.¹⁰ Cognitive deficits are common with and without visible cerebrovascular pathology on imaging. The etiology is multifactorial, but medical risk factors include hypoxia,¹¹ covert cerebrovascular disease,^12,13 reduced arterial oxygen content,¹⁴ and a compensatory increase in cerebral blood flow.^15,16 Allo-HCT/GT results in higher recipient hemoglobin levels and decreased sickling parameters, which should result in improved oxygen-carrying capacity. In keeping with this, allo-HCT survivors have demonstrated reduced cerebral blood flow^17,18 and improved oxygen extraction^18-21 after intervention. The risk of progressive cerebrovascular injury visible by magnetic resonance imaging (MRI) is lower after HCT^22-27 than after chronic transfusion therapy. In parallel with the above-mentioned observations, stabilization in intelligence quotient and some fluid neurocognitive domains such as processing speed are described.^22,23,28-31 The effects of GT on cerebrovascular outcomes are unknown because only a small number of patients with stroke have undergone the procedure. As more patients with SCD undergo allo-HCT/GT, systematic assessments of cerebrovascular outcomes are essential for comparison and determination of stability as described in Table 1. Modalities of assessment include MRI and TCD measurements. TCD, however, requires bone windows (limited to <16 years) and is operator expertise dependent.

Cardiopulmonary complications are a significant cause of morbidity³² and early mortality^33,34 and manifest as acute chest syndrome, pulmonary hypertension, and cardiopulmonary hypofunction, all predictors of mortality.^35-39 Cardiopulmonary pathology is influenced negatively by advancing age, disease progression, allergens and asthma, and external pathogens such as infections and toxins. Along with symptom improvement (such as abrogation of acute chest syndrome), stabilization with or without improvement of pulmonary functions (forced expiratory volume in 1 second and forced vital capacity) has been demonstrated after HCT.^27,40-48 Improvement in assessments such as diffusing capacity of the lungs for carbon monoxide, although largely limited to children, has also shown stabilization in some adults.^{27,41,44,46,47} Descriptions of cardiac function are traditionally limited to tricuspid regurgitant jet (TRJ) velocity in adolescence and adulthood.^{27,42,43,45,47,49,50} Decrease in TRJ velocity has been demonstrated after HCT, in even higher magnitude in adults than in children. In contrast, recently, an asymptomatic drop in shortening fraction and ejection fractions (EFs) have been detected after HCT, drawing attention to potential cardiotoxicity of conditioning agents, especially after disease-related cardiac involvement.^27,42,43,47 A cardiopulmonary review and meta-analysis⁵¹ that examined pulmonary (forced expiratory volume in 1 second, forced vital capacity, and diffusing capacity of the lungs for carbon monoxide) and cardiac (TRJ velocity, shortening fraction, and EF) functions described stability after HCT on all parameters except for a significant decrease in EF. These standard measures have been supplanted by measures of cardiac stress (high brain natriuretic peptide and cardiac MRI changes) as more sensitive measures of change. A decrease in myocardial fibrosis after HCT can be detected by cardiac MRI.^52,53 Such myocardial fibrosis may not be preventable with supportive care and supplants evaluation in adolescent/young adults with evidence of left heart dilation or prominent trabeculations on echocardiogram.³⁹ Recommended assessments are listed in Table 2.

Chronic kidney disease manifests as defective urine concentration, glomerular hyperfiltration (increased renal perfusion), electrolyte imbalance (tubular dysfunction), and albuminuria.⁵⁴ Hyperfiltration is detected as early as age 2.5 years. As glomerular damage progresses, the glomerular filtration rate declines into adulthood, signaling worsening nephropathy. Microinfarcts and ischemic injury upregulate endothelin-1 and reactive oxygen species, resulting in medullary hypoxia and papillary necrosis. Free hemoglobin, caused by ongoing hemolysis, is toxic to the tubules. Decreased hemolysis (such as coinherited α-thalassemia) can be protective to this effect. Microalbuminuria worsens with age, affecting >60% of patients aged >45 years. Microalbuminuria >100 mg/g before allo-HCT/GT may not be reversible.⁵⁵ Risk factors for acute kidney injury in SCD include anti-inflammatory medications, heart failure, dehydration, sepsis, thrombosis, and rhabdomyolysis.⁵⁶ 

Allo-HCT/GT can affect already compromised kidneys via medications used for conditioning, graft-versus-host disease (GVHD) prophylaxis, hypertension, infections, and thrombotic microangiopathy.⁵⁶ Serial monitoring and supportive care are essential to maintain renal function and combat hypertension to promote healing. In children, diminished glomerular filtration rate (assessment formulas include CKiD U25 for children and young adults) has been described after myeloablative chemotherapy; correction of hyperfiltration and normalization of renal volume and structure have been described after nonmyeloablative transplants. Long-term renal outcomes after allo-HCT/GT in adults with established chronic kidney disease is unknown.

Functional parameters of renal function should be tracked after allo-HCT/GT. Pathologic albuminuria (albumin-to-creatinine ratio of >30 mg/g) can be exacerbated by complications such as hypertension, infection, and GVHD. Proteinuria (albumin-to-creatinine ratio of >300 mg/g) is predictive of increased mortality at 1 year after HCT.⁵⁵ Novel biomarkers of renal dysfunction, such as Kidney Injury Molecule 1 (KIM-1), Neutrophil Gelatinase–Associated Lipocalin, Monocyte Chemoattractant Protein 1, and urine elafin, are under investigation for early detection of renal injury and sensitivity of the rate of change.^57,58 Recommended assessments are listed in Table 2.

At baseline, SCD complications and medications may result in low ovarian reserve, reduced sperm counts, and infertility.^59,60 These risks are compounded by gonadotoxic agents and irradiation used in allo-HCT/GT protocols. Gonadal outcomes should be discussed before embarking on intervention. Fertility preservation is indicated for all individuals who have not completed their families and wish to do so.³⁴ Ensuring safe³⁵ and accessible care,³⁶ including assistance with collection of sperm, ova or gonadal tissue (needs planning around hydroxyurea discontinuation for 2-3 months if applicable), and storage cost planning, is essential. Ovarian tissue cryopreservation is considered standard of care before considering gonadotoxic therapy. Testicular tissue cryopreservation is undertaken under research protocols when sperm collection is not feasible due to age. Access to in vitro fertilization after intervention is an area of active advocacy.³⁷ 

Although limited fertility preservation outcomes are described, anecdotal pregnancy outcomes are described and expected to increase with accessibility.^61-63 Follow-up care for reproductive organs after intervention also require additional multispecialty involvement. The best follow-up care is provided by synergy between endocrinologists, urologists, reproductive endocrinology-infertility physicians, and maternal-fetal medicine specialists.

After allo-HCT/GT, patients require gonadal function monitoring.⁵⁹ For people with ovaries, annual testing with anti-Müllerian hormone, luteinizing hormone, estradiol, and follicle-stimulating hormone is indicated. Adolescent and adult females should be screened for clinical symptoms of stalled puberty and premature ovarian insufficiency.⁵⁹ Hormone induction or replacement therapy may be required. For people with testicles, annual screening also includes testosterone level; semen analysis should be offered when appropriate (Table 2). Although oocyte recovery does not significantly improve after HCT, sperm production can.

During follow-up, individuals should be queried for pregnancy intention.⁶⁰ Individuals attempting unassisted conception for over 6 months warrant referral for infertility care. Individuals who have cryopreserved gonadal tissue, gametes, or embryos and wish to pursue pregnancy with assistance also need referral to reproductive endocrinology and infertility specialists. Conversely, posttherapy patients of reproductive age require counseling regarding limitations of fertility testing and the possibility of unassisted pregnancy. Individuals undergoing allo-HCT/GT should be counseled that their gametes contain a hemoglobinopathy trait that is heritable. A discussion of in vitro fertilization with preimplantation testing may be applicable to some.⁶⁴ 

Growth parameters and thyroid and adrenal function monitoring are essential after allo-HCT/GT because all interventions currently use chemotherapy ± radiation to achieve desired goals. Exposure can invoke toxicities based on age, physiology, and disease status. Toxicities compound preexisting pathology or commence de novo. GVHD is a risk with allo-HCT. The risk of disorders of glucose regulation, lipid metabolism, and metabolic syndromes, which are genetic/environmental, may exacerbate after allo-HCT/GT and consequent lifestyle change during the recovery period. Comprehensive care also includes bone care, dental and visual health, and management of iron overload if present (Table 3).

Infection is a major cause of morbidity and mortality in SCD, contributing to 20% to 50% of deaths.⁶⁵ Vulnerability to infection results from hyposplenism or asplenia.⁶⁶ Additional genetic etiologies such as defective complement activation,⁶⁷ micronutrient zinc deficiency,⁶⁸ HLA-II subtype polymorphism,⁶⁹ dysfunctional T/B cells and Fc receptors, and transforming growth factor β/bone morphogenetic protein pathways have been associated with an increased risk of bacteremia.⁷⁰ Impairment in alternative complement pathways⁶⁷ and abnormal disease macro and microenvironments contribute to this predisposition.⁷¹ 

Allo-HCT–mediated immunosuppression prevails until immune reconstitution (IR).⁷² IR is inversely proportional to age and influenced by graft source, HLA match, conditioning, engraftment kinetics, and GVHD prophylaxis/treatment.^73,74 Infection risks are highest before cellular IR (before day +100) and then recede unless systemic immunosuppression is intensified.⁷⁵ Within this framework, variability is noted due to variations in transplant parameters, such as donor source, age, and disease severity.^1-5,24,76,77 

T-cell recovery is most efficient in young recipients with preserved thymic function undergoing sibling HCT. Function is more impaired after cord blood transplant, immunoablative conditioning, advanced age, mismatched HCT, and prolonged GVHD-related immunosuppression.^78,79 Initial T-cell recovery occurs with peripheral expansion of donor memory CD8⁺ T cells and subsequently with thymus-generated donor T cells from hematopoietic precursors.^80,81 Thymic involution (age related) impairs CD4⁺ T-cell repertoire recovery.⁸² B-cell counts recover by 9 months after HCT; antibody repertoire recovery is aided by CD4⁺ T cells.⁸² Haploidentical HCT using posttransplant cyclophosphamide GVHD prophylaxis results in preferential accumulation of regulatory T cells; de novo donor T-cell recovery takes a year, rendering patients susceptible to viral infections.^75,83-86 In GT patients, IR should commence with the recovery of the cellular immune system after myeloablation and is expected within 3 to 6 months of product reinfusion.

Assessment of IR includes absolute lymphocyte counts, lymphocyte subsets (CD4⁺ and CD8⁺ T cells, natural killer cells, and B cells), and antibody titers. Lymphocyte recovery, notably the CD4⁺ T-cell compartment, correlates with survival and decreased opportunistic infections.^87-91 Functional assays, including polyfunctional T cells and virus-specific responses (such as cytomegalovirus and Epstein-Barr virus) can provide important information on immune recovery.⁹² Molecular assessments including T-cell receptor repertoire, B-cell receptor diversity, T-cell receptor excision circles, and kappa-deleting recombination excision circles can assess thymopoiesis better to evaluate opportunistic infection risks.^93,94 Tests for IR are listed in Table 4.

Delayed IR adds to mortality risk even after correction of SCD pathology.^80,95 Allo-HCT/GT is undertaken in the context of functional or surgical asplenia and increased susceptibility to bacterial infections.⁶⁵ After allo-HCT, B-cell counts typically recover between 3 and 12 months and CD4⁺ T cells between 6 and 9 months in children and later in adults, impairing vaccine response. Without revaccination, antibody titers to vaccine-preventable diseases decline during the first decade after HCT. Hence, revaccination after allo-HCT/GT should be commenced at partial recovery. Patients exposed to nonlymphodepleting busulfan may retain vaccine memory, but long-term data on persistence of titers are lacking.⁹⁶ Inactivated or cell-free vaccination can be resumed at 3 to 6 months; live-attenuated vaccines are administered 24 months after HCT (supplemental Table 1) and are avoided in patients on systemic immunosuppression for GVHD control.⁹⁷ Postexposure prophylaxis can prevent morbidity after potential or documented exposure in immunocompromised patients (supplemental Table 2). Recently, the US Food and Drug Administration approved pemivibart, an anti-COVID monoclonal antibody, for immunocompromised patients as preexposure prophylaxis.

Psychologic changes follow physical manifestations in SCD, increase with age and disease progression, and affect activities of daily living and consequently HRQOL.⁹⁸ HRQOL is a multidimensional concept representing the general perception of physical, psychological, and social aspects of life.^99,100 It is a subjective rating that allows for a general assessment of well-being.⁹⁸ 

HRQOL assessments after allo-HCT/GT are important tools for assessing treatment benefit in disorders that are not imminently life threatening.¹⁰¹ These assessments can quantify the impacts of a disease-free state while considering transplant complications, such as infections, organ damage, or chronic GVHD. HRQL may represent the most clinically relevant measure of treatment toxicity.¹⁰² 

Studies evaluating HRQOL after allo-HCT have shown variable results. Pediatric studies have shown an initial decline in the peri-transplant period, followed by an improvement in HRQOL by 1 year after HCT.^102,103 In adults, after nonablative conditioning, there was no decline in HRQOL at day +30.¹⁰⁴ This variability may be due to effects of donor source, conditioning regimens, and transplant complications. More pediatric patients are now choosing curative treatment before significant complications have affected HRQOL.

Numerous HRQOL evaluations now provide extensive insight into SCD and GVHD variables. Although these are informative, they are time consuming. Less-specific but easier tools such as the Child Health Questionnaire or the Pediatric Quality of Life Inventory are more feasible for completion, allowing for comparisons across clinical trials.^102,105,106 The PedsQL SCD module focuses specifically on the complications of the disease.¹⁰⁷ A pediatric evaluation should include both child and parent reports in an age-dependent fashion.¹⁰⁸ Other HRQOL measures include the Patient Reported Outcomes Measures Information System, a set of person-centered measures that evaluates physical, mental, and social health in adults and children.¹⁰⁹ A comparison of HRQOL parameters with age-matched external controls helps identify the rate of change over time, where patients function as their own internal controls.

Assessing HRQOL before intervention, 6 months, 12 months, 2 years, and yearly thereafter if continued morbidity persists provides a longitudinal assessment that helps compare benefits from a patient perspective and informs decision-making.¹¹⁰ 

Vaso-occlusive pain episodes are the hallmark of SCD, contributing to impaired HRQOL and predicting premature mortality. Vaso-occlusive pain episodes are, hence, an indication for allo-HCT/GT. Pain symptoms (except avascular necrosis or structural bone damage) resolve over time in most cases after the establishment of nonsickle erythropoiesis.^{6,7,49,111-114} Acute or chronic pain persistence even after successful curative interventions in a minority remains a vexing paradox. Graft failure, older age, history of recurrent pain crisis in the 2 years before intervention, and chronic opioid use are predictors of residual pain. Patients with pain episodes after HCT were more likely to have had chronic pain without SCD complications, opioid-induced hyperalgesia, central sensitization, or genetic predisposition.^114,115 The persistent pain is of complex neurobiology, in which SCD pain complexes with prolonged opioid exposure and other mechanisms, especially with age progression.¹¹⁶ A higher rate of pain crises in older patients with more disease complications should inform pain-focused rehabilitation after intervention. Patients are typically not screened in detail for chronic pain before intervention; pain data are not captured by transplant registries such as the Center for International Blood and Marrow Transplant Research (CIBMTR).¹¹³ 

Patient Reported Outcomes Measures Information System measures with pain-focused segments capture intensity, interference, mobility, and quality of pain depending on patient age. The maintenance of a pain diary records patient-experienced pain. Patients must be screened for chronic pain and pain-related domains before intervention and subsequently tracked.¹¹⁷ Pain domains can be tracked qualitatively and quantitatively serially with the PhenX Toolkit (phenxtoolkit.org). This will enhance multidisciplinary interventions for ameliorating chronic pain. Ideally, pain-mitigating interventions are best instituted before allo-HCT/GT and continued afterward until the pain pathway is subdued. This requires recognition of this entity by medical and family caregivers and the patient.

The absence of acute pain episodes over a consecutive 12-month period after intervention has been considered pain-free success in clinical trials.¹¹⁸ An issue with comparing pain parameters after allo-HCT/GT are the variations in defining and measuring pain that does not allow for intertrial comparison. Validated measures of pain burden are likely to elicit a more accurate picture but add to the burden of data collection. However, understanding pain domains and documenting measures of pain burden, including emergency room visits, hospitalizations, opioid use, pain dairies, and pain-related HRQOL questionnaires, are important objective ways of tracking pain (Table 5) and allow for intervention and counseling.

Although it is ideal to have full donor chimerism, mixed chimerism after allo-HCT if stable can be adequate to control SCD manifestations and may even offset immunologic complications, such as GVHD. Mixed donor/recipient chimerism allows for reduced conditioning intensity and opens future possibilities for using nonchemoradiation-based agents such as depleting antibodies. Red blood cell modeling studies based on red cell survival as well as patient-derived mixed chimerism data have indicated that myeloid engraftment levels of 20% to 25% are necessary to achieve normal hemoglobin levels and eradicate hemolysis and pain symptoms.^120,121 Similarly, tracking genetic edits (transduction efficiency, vector copy numbers, double-stranded DNA edits, and base edits) after GT has demonstrated that mixed engraftment with a threshold level of genetically modified cells (especially those with efficient gene correction) can correct anemia and control SCD symptoms, such as pain, adequately.

It is important to evaluate the stability and effect of donor myeloid chimerism or percent gene-modified cells and organ functions long term to determine the adequacy of reversal of vascular pathophysiology. These, combined with measures of hemoglobin S levels and hemolysis, determine the adequacy of engraftment. Studying more sensitive measures of hemolysis and targeted red cell engraftment add to the standard measures of chimerism determination.^45,122-124 Rheologic assessments of red blood cells can help quantify the difference between red cells with sufficient antisickling hemoglobin and those with insufficient modification.¹²⁵ Novel biomarkers may help predict engraftment.¹²⁶ Increased early myeloid-derived suppressor cells at day 60 showed positive correlation with myeloid donor cell engraftment after haploidentical HSCT for SCD.¹²⁷ A similar observation was made with immunoregulatory cytokines and chemokines, such as interleukin-17A, interleukin-10, and VEGF (vascular endothelial growth factor), in predicting engraftment/rejection. Table 6 lists tracking methods for assessing the adequacy of chimerism or the presence of gene-modified cells.

Two large studies have reported an increased (3.6× to 11× higher) prevalence of acute myeloid leukemia (AML) in individuals with SCD.^130,131 However, with >27 years of follow-up, 6 patients with SCD were diagnosed with AML vs 1.67 expected cases controlled for age, race, ethnicity, and sex.¹³¹ Thus, the absolute risk of leukemia is low for the general population of individuals with SCD.

Myelodysplastic syndrome (MDS) and AML have been reported after allo-HCT/GT interventions.¹³² An increased risk of MDS and AML in adults with SCD after conditioning with alemtuzumab and low-dose radiation is described in the setting of graft failure and mixed chimerism.¹³³ The incidence of AML was similarly increased in the first group of adults who received myeloablative busulfan and GT with Lovo-cel (Lovotibeglogene Autotemcel). This group received cells with a lower vector copy number and a lower dose of hematopoietic progenitor cells, and subsequent optimization of manufacture, intensity of myeloablation, and infusion of higher cell doses have resulted in successful engraftment with no malignant evolution to date.

The reasons for susceptibility to MDS and AML remain unclear. Four of 5 patients who developed MDS or AML after allo-HCT and graft failure had different pathogenic TP53 mutations, with variant allele frequencies (VAFs) ranging from 2.9% to 78.8% in the peripheral blood on next-generation sequencing.¹³⁴ The same mutations were present with lower VAFs (0.06%-0.36%) before allo-HCT in 3 patients. No mutation was detected until 1.5 years after HCT in the fourth. The mutation was identified 4 years after HCT (VAF, 0.06%) and increased to 0.34% at 5 years and 78.8% at 5.5 years when AML was diagnosed. There were no TP53 mutations identified in 15 other patients (7 with graft failure), with no MDS or AML 4 to 12 years after HSCT.

The prevalence of somatic mutations identified with high sensitivity (VAF <1%) in patients with SCD is unknown. When whole-genome sequencing data were analyzed (VAF 5%-10%), there was no increased incidence noted.¹³⁵ When whole-exome sequencing data were evaluated (VAF 2.5%), the prevalence of clonal hematopoiesis (CH) was higher in patients with SCD.¹³⁶ Low-level CH may be precipitated by inflammation and erythropoietic stress.¹³⁷ Exposure to genotoxic chemoradiation may promote further proliferation of autologous cells, leading to MDS or AML.^132,138 These events underscore the need for tracking blood for CH before and after intervention to determine risk, with efforts ongoing. Sample retention before and after allo-HCT/GT to analyze retrospectively in the event of MDS or AML development is worth a consideration.

Successfully transitioning from pediatric to adult care is necessary after allo-HCT/GT. Transition involves a comprehensive approach to ensure sustained health and well-being after therapy and includes monitoring for GVHD and associated complications, infection prevention, and management of residual SCD-related complications. The kinetics of change in individual organs affected by SCD (improvement, stabilization, and progression) are unknown, especially after newer therapies. Tracking patients as described will be crucial for understanding the disease course and other effects/complications. Pediatric SCD/transplant teams will need to identify adult care providers who can continue to provide relevant aspects of care. Putting the onus of the follow-up on the young patient is likely to limit the success of the transition. It is also important that an adult SCD provider follows the patient long term to recognize disease-related events if any. This effort in individuals who do not have immediate pressing medical needs of established SCD will need additional effort to accomplish.

Coordination between pediatric and adult care providers, a transition document that provides relevant details, and follow-through on care necessities ensure a smooth transition. In addition, psychosocial care is vital. Young adults who are navigating significant life changes at the time of transition tend to neglect their health, especially after undergoing curative therapy with discernible change in the clinical course of their disease. Although clinically desired hematologic parameters are achieved, residual issues such as established vascular endothelial damage, chronic pain, and late effects of the intervention may continue and require specific medical, educational, and psychosocial adaptations during schooling or vocational decision-making. A well-structured transition plan that includes HCT-related follow-up,¹³⁹ education on medication adherence, symptom monitoring, organ function tracking, and lifestyle adjustments can improve long-term outcomes and enhance quality of life after allo-HCT/GT (Table 7).

Planned efforts at collecting measured outcome details are underway within specific research groups. Some recently developed networks work alongside standard measures collected by the CIBMTR after HCT or GT; for example, the Globin Research Network for Data and Discovery maintained registry that has been adopted by the National Alliance of Sickle Cell Centers to track intervention efficacy, engraftment, transduction assessments, and fertility outcomes,¹⁴⁰ the Cooperative Assessment of Late Effects for SCD Curative Therapies evaluates long-term effects on the heart, lungs, and kidneys, Project Sickle Cure tracks outcomes on patients who received HCT from matched sibling donors. The Sickle Cell Clinical Research and Intervention Program¹⁴¹ and the Sickle Cell Disease Implementation Consortium¹⁴² evaluate longitudinal clinical, neurocognitive, geospatial, psychosocial, and health outcome data across patient lifetimes, assess transition to adulthood, and maintain specimen banks.

The expansion of HCT- and GT-derived hematopoietic manipulations in SCD bodes well for an increasing number of patients with SCD. The functional ability of these interventions will depend on the efficacy of the modality used, disease status at intervention, age, comorbidities, longevity of correction, and the side effects encountered. This makes it important to monitor outcomes uniformly between treatment modalities to determine the scale of advantage gained, delineate disadvantages to combat them better, and predict the duration over which to expect change. It also helps identify which treatment modality could serve individual patients better. This insight is applicable to medical personnel as well as patients and families and is critical for joint decision-making. Comparable outcome analyses maintained with registries can also help comparison with advancing conservative therapies, anticipating pitfalls to combat, and promote additional research effort. HCT and GT registries, such as the CIBMTR, and smaller collaborative efforts from institutions active in providing HCT/GT interventions focusing on in-depth monitoring and documentation can enhance knowledge regarding treatment efforts and provide comparison. A world with manageable SCD care with longevity that parallels the unaffected is work in progress, medically, socially, and economically.¹⁴³ 

Contribution: S.S. coordinated this invited review and wrote the manuscript; J.K., A.K., C.F., E.S., M.B., L.P., L.K., and A.A.K. wrote parts of the manuscript and edited the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Shalini Shenoy, Pediatric Hematology/Oncology, Washington University School of Medicine, 660 S Euclid Ave, Box 8116, St Louis, MO 63110; email: shalinishenoy@wustl.edu.