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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2020 Jul 3;2020(7):CD007001. doi: 10.1002/14651858.CD007001.pub5

Hematopoietic stem cell transplantation for people with sickle cell disease

Chioma Oringanje 1,✉, Eneida Nemecek 2, Oluseyi Oniyangi 3
Editor: Cochrane Cystic Fibrosis and Genetic Disorders Group
PMCID: PMC7390490  PMID: 32617981

Abstract

Background

Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review.

Objectives

To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long‐term gain for people with sickle cell disease.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and quarterly searches of MEDLINE. We also searched trial registries for ongoing trials up to April 2020.

Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 December 2019.

Selection criteria

Randomized controlled and quasi‐randomized trials that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting.

Data collection and analysis

No trials were eligible for inclusion in the review.

Main results

We identified 12 potentially‐eligible trials by the searches; we excluded 11 of these and the remaining trial is an ongoing trial that may be eligible for inclusion in a future version of the review.

Authors' conclusions

Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. We did not find any eligible randomized controlled trials assessing the benefit or risk of hematopoietic stem cell transplantations. However, there is an ongoing quasi‐randomized trial comparing hematopoietic stem cell transplantation with standard care, Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease.

Plain language summary

Transplantation of blood‐forming stem cells for children with sickle cell disease

Review question

We reviewed the evidence about the cure rate and risks of hematopoietic stem cell transplantation for people with sickle cell disease.

Background

Sickle cell disease is a genetic disorder mainly characterized by the presence of deformed, sickle‐shaped red blood cells in the blood stream. These cells deprive tissues of blood and oxygen resulting in periodic and recurrent painful attacks. Complications include acute chest syndrome and stroke. Although sickle cell disease is responsive to preventive and supportive measures such as the use of prophylactic antibodies and periodic blood transfusion, these do not provide a cure. The use of hematopoietic (blood forming) stem cell transplantation involves replacing the deformed red blood cells and its stem cells with stem cells from a healthy donor thereby producing normal red blood cells. These stem cells can be derived from either the bone marrow or blood (umbilical cord blood or peripheral blood) of a healthy individual. This is an update of a previously published review.

Search date

The evidence is current to: 09 December 2019.

Study characteristics

There are no trials included in the review. There is one ongoing trial which may, in the future, be eligible for inclusion.

Key results

There are currently no randomized controlled trials assessing the benefits and risks; the most appropriate source of stem cells; or the most eligible participants (those who have experience severe complication or those who have not) of the procedure in people with sickle cell disease.

Background

Description of the condition

Sickle cell disease (SCD) is a genetic hemoglobin disorder caused by a structural abnormality of hemoglobin (Hb) called sickle hemoglobin (Hbs), a structural variant of normal adult hemoglobin (BHbA), which originates from a single nuleotide substitution in the gene encoding beta‐globin (Ware 2017). SCD occurs when the haemoglobin variant Hemoglobin S gene is inherited in an autosomal recessive way and it can also occur due to homozygosity of HbS (HbSS), a condition known as sickle cell anaemia (SCA) (Ware 2017). Individual heterozygous for sickle hemoglobin (HbAS) are generally asymptomatic, whereas most homozygous individuals (HbSS) die before the age of five yeas in low‐income countries. When adults survive, the suffer from lifelong acute and chronic complications (Rees 2010; Serjeant 2001). Other clinically significant types of SCD are compound heterozygous conditions in which the sickle haemoglobin interacts with other abnormal haemoglobins, such as haemoglobin C (HbSC) or β‐thalassaemia (HbSb+ and HbSb0) (Lane 2001). The disease is characterized by the presence of distorted, sickle‐shaped red blood cells in the blood stream. These distorted cells can get trapped in small blood vessels, causing blockages depriving the tissues of blood and oxygen in turn leading to pain episodes known as vaso‐occlusive crises. Blockages may even cause severe damage to major organs such as the brain, liver, kidneys and spleen.

Amongst the haemoglobinopathies, SCD is by far the largest public health concern (Aygun 2012). According to the Center for Disease Control and Prevention, it is estimated that SCD affects approximately 100,000 American; 1 out of every 365 African‐American births and 1 out of every 16,300 Hispanic‐American births (CDC 2020). Globally, it is estimated that 300,000 infants are born annually with SCD, two thirds of these births occurring in low‐income countries, especially in sub‐Saharan Africa, where access to medical care and public health strategies to decrease mortality and morbidity of the disease are not uniformly handled. The global burden is expected to rise by more than 25%, increasing to up to 400,000 individuals annually by 2050 (Piel 2013). Significant morbidity and premature death may result from SS disease with average life expectancy estimated at between 42 years and 53 years for men; and between 48 years and 58 years for women (Platt 1994). However, there has been a reduction in mortality in children with SCD over the past decades, especially in high‐income countries (Yanni 2009). Medial survival estimates have continued to improve from 42 to 48 years of age in 1994 to 58 years of age in 2014 (Elmariah 2014; Platt 1994). This is largely due to increased clinical recognition, universal newborn screening (Vichinsky 1988), and therapeutic and preventive interventions such as the introduction of penicillin prophylaxis in the 1980s (Gaston 1986), and pneumococcal and Haemophilus influenza type b vaccinations in children with SCD (Yanni 2009). The use of transcranial doppler ultrasonography screening makes it possible to identify asymptomatic children at increased risk for stroke (Adams 1992).

Treatment of SCD is usually aimed at avoiding crises, relieving symptoms and preventing complication. Thus, preventive and supportive measures such as periodic blood transfusion and use of prophylactic antibiotics are the main therapeutic interventions used. Long‐term blood transfusion, although shown to be effective in preventing stroke and other complications of SCD (Adams 1998), is also associated with increased risk of iron overload, infection, and alloimmunization (Nietert 2000). Hydroxyurea, which is known to raise foetal haemoglobin and decrease cellular dehydration, has been shown to be both safe and effective in severely affected SS adults, as well as, more recently, in children aged two years and older, in reducing the incidence of vaso‐occlusive pain episodes and acute chest syndrome, but also has recognized side effects such as myelosuppression and nausea (Nevitt 2017). Although, studies have suggested a reduction in mortality after long term use of hydroxyurea, the mortality rate is still high; 25% after nine years and 43.1% after 17 years (Steinberg 2003; Steinberg 2010). In addition, less than 40% showed a reduction in the disease severity, indicated by a rise in fetal hemoglobin.

Description of the intervention

Hematopoietic stem cell transplantation (HSCT) is an accepted form of treatment for various hematologic disorders. Its goal in SCD is to eliminate sickle red blood cells and progenitors (hematopoietic (blood forming) stem cells (HSCs). These are replaced with normal stem cells, to produce cells that expresses total or at least partial correction of the abnormal haemoglobin phenotype (Walters 2001). Sources of stem cells include bone marrow (bone marrow transplantation (BMT)); peripheral blood (peripheral blood cell transplantation (PBCT)); and umbilical cord blood (umbilical cord blood transplantation (UCBT)) (LHSC 2003) from another person, related or unrelated.

Currently, HSCT is the only curative option for SCD (Shenoy 2013). Ideally, the recommended donor is a sibling with an immunologic match (human leucocyte antigen (HLA) type match) (LHSC 2003). After identification of a suitably matched donor, a recipient undergoes extensive evaluations to confirm disease status, major organ functions and general health status. The decision to transplant is based on risk‐benefit ratio depending on the recipient's status and donor availability.

The individual receives the preparative regimen, also called conditioning. For HSCT, the conditioning regimen must provide both myeloablation and effective immunosuppression in the recipient. Myeloblative regimens include busulfan, cytoxan with or without antithymocyte globulin or total lymphoid irradiation (Adamkiewicz 2004; Bernaudin 1993; Locatelli 2003; Vermylen 1998; Walters 2001). There are toxicities associated with myeloablative regimens; such as infertility and gonadal failure, chronic graft versus host disease (GVHD) (an immune reaction of donor cells against recipient tissues and a potential for secondary malignancies). In order to avert these, reduced intensity conditioning regimens were developed, which include a purine analog, an alkylating agent, or low‐dose total‐body irradiation. The purine analogs include fludarabine, cladribine, and pentostatin (Horan 2005; Iannone 2003; Jacobsohn 2004; van Besien 2000). With reduced‐intensity preparative regimens, unfavourable outcomes are frequently reported, especially graft failure (the lack of sustained donor engraftment) (Iannone 2003; van Besien 2000). Immunosuppressants such as cyclosporine and methotrexate have also used to prevent GVHD (Atkins 2003).

Since its first successful use in 1968, HSCT has been used to treat a variety of malignant disorders. In 1984 the first case reported of HSCT for SCD involved an individual with acute myelogenous leukemia who was cured of both disorders after a bone marrow transplantation (Johnson 1984; Milpied 1988). This case illustrated the elimination of SCD upon engraftment of donor hematopoietic stem cells. Since then, several groups have studied HSCT for treating mostly children (under 16 years) with symptomatic SCD, showing severe complications such as stroke, recurrent vaso‐occlusive painful crises, acute chest syndrome, sickle nephropathy and osteonecrosis of multiple joints (Brichard 1996; Jaing 2005; Johnson 1984; Vermylen 2003; Walters 1995; Walters 1996; Walters 2001). This is because of the complications associated with the treatment. There is limited information about the outcome after HSCT amongst adults. However, adults might have a higher risk of death compared to younger people (Lucarelli 1999; van Besien 2000), due in part to the increased frequency of GVHD (Sullivan 1991).

Why it is important to do this review

Despite the use of hydroxyurea, pain medications, and chronic blood transfusion, in managing SCD, some treated patients will show no reduction of thier symptoms. By 2015, according to the Center for International Blood and Marrow Transplant Rsearch and the European Society for Blood Marrow Transplantation, approximately 1200 people have undergone HSCT for SCD, a small number compared to the high prevalence of this disorder (Bhatia 2015). Studies have reported an overall survival rate greater than 90% and event‐free survival rate greater than 80% at two years, four years and further follow‐up, suggesting that HSCT cures SCD (Bernaudin 1997; Locatelli 2003; Vermylen 2000; Walters 1996; Walters 2000; Panepinto 2007). This chance for cure comes at the expense of an increased risk for adverse events, including death, GVHD, post‐transplant neurologic complications, and late effects such as gonadal failure, sterility and reoccurrence of SCD (Bernaudin 1997; Giardini 1993; Vermylen 2000; Walters 2000; Walters 2002; Panepinto 2007).

The use of HSCT in people with SCD is well established in developed countries. Current investigations are targeted at determining what population are best fitted for the procedure and improving conditioning regimens that greatly reduce graft rejection and GVHD. This systematic review aims to assess the cure rate and risks associated with HSCT. This is an update of previously published versions of this review (Oringanje 2009; Oringanje 2013; Oringanje 2016).

Objectives

To determine whether HSCT can improve survival and prevent symptoms and complications associated with SCD. To examine the risks of HSCT against the potential long‐term gain for people with SCD.

Methods

Criteria for considering studies for this review

Types of studies

All randomized controlled and quasi‐randomized trials.

Types of participants

Children and adults with SCD of all phenotypes, either gender and in all settings*.

Post hoc change: the review has been expanded to include adults.

Types of interventions

Methods of stem cell transplantation compared with each other or with supportive care (e.g. periodic transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen).

Types of outcome measures

Primary outcomes

  1. Event‐free survival (individuals alive and free of SCD symptoms)

Secondary outcomes

  1. Mortality (overall and at 100‐days, and one‐year post‐HSCT)

  2. Transplant‐related (non SCD‐related) mortality

  3. Incidence of acute graft versus host disease

  4. Incidence of chronic graft versus host disease

  5. Incidence of neurological complications

  6. Incidence of late complications related to SCD

  7. Quality of life using a validated scale.

  8. Graft rejection with recurrence or persistence of SCD

  9. Other transplant‐related morbidity (e.g. adverse drug reactions)

Search methods for identification of studies

We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register using the terms: (sickle cell OR (haemoglobinopathies AND general)) AND (stem cell* OR bone marrow* OR gene therapy).

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and weekly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Public Health Agency Annual Scientific Meeting (formerly the Caribbean Health Research Council Meeting); and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 December 2019.

We searched the following trials registries (Appendix 1):

Date of last searches: 29 April 2020.

Searching other resources

We searched the Meetings of the American Society for Blood and Marrow Transplantation (1970 to December 2015); Center for the International Blood and Marrow Transplant Research (1972 to December 2015); and European Group for Blood and Marrow Transplantation (1970 to December 2015).

Data collection and analysis

Selection of studies

Two authors (CO and EN) independently screened the 12 trials identified by the searches of all the databases and reference lists to identify papers with potential relevance to the review. We obtained the full text of selected articles. Two authors (CO and EN) independently selected trials for inclusion by applying the inclusion criteria to all potential trials. We excluded 11 trials and have added one trial to 'Ongoing studies' (NCT02766465). We resolved disagreements concerning inclusion by discussion.

Data extraction and management

For future updates, if we find trials eligible for inclusion, two authors (CO and EN) will independently perform data extraction using data extraction forms designed specifically for this review. Information included on this form will include the number, age and gender of participants; type of SCD; type of HSCT; HLA status of the donor and recipient); the trial design; duration of the trial and the interventions; GVHD prophylaxis. We will extract data for all relevant outcome measures including death before transplant; and will resolve any disagreement about extracted data by discussion.

Unless otherwise stated above (Types of outcome measures), where possible, we will group outcome data into those measured at three months, at six months, then six monthly intervals (i.e. one year, 18 months, and so on). If outcome data are recorded at other time periods, then we will consider examining these as well.

Assessment of risk of bias in included studies

Two authors (CO and EN), using a simple form, will independently assess the risk of bias of the included trials and will follow the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.1 (Higgins 2011).

We will assess the following domains as having either a low, unclear or high risk of bias:

  1. randomisation;

  2. concealment of allocation;

  3. blinding (of participants, personnel and outcome assessors);

  4. incomplete outcome data;

  5. selective outcome reporting.

Measures of treatment effect

We will relate dichotomous variables to risk using the risk ratio (RR); we will relate continuous outcomes to risk using the mean difference (MD); we plan, if possible, to extract hazard ratios with their 95% confidence intervals (CIs) for any time‐to‐event data (e.g. event‐free survival and mortality).

Dealing with missing data

If possible, we will extract data by allocation intervention, irrespective of compliance with the allocated intervention, in order to allow an 'intention‐to‐treat' analysis; otherwise we will perform an 'as treated' analysis. We will include these variables in a meta‐analysis using Review Manager 5.1 for the outcomes selected above (Review Manager 2011).

Assessment of heterogeneity

For future updates, if we have enough trials for the respective outcomes, we will assess heterogeneity both by visual inspection of the forest plots and by a formal statistical test for heterogeneity using the Chi² test for interaction (or trend) (DerSimonian 1986). We will assess any detected heterogeneity and investigate reasons for this. If we are not able to explain any heterogeneity found, we will clearly state this in the review and apply appropriate caution in the interpretation of these data. If a cause for heterogeneity is apparent and justifies separate analyses of the studies, we will undertake these analyses and present the results.

Assessment of reporting biases

We will attempt to assess whether the review is subject to publication bias by using a funnel plot to graphically illustrate variability between trials and by using Egger's test (Egger 1997). If asymmetry in the funnel plot is detected, we will explore causes other than publication bias.

Data synthesis

Where meta‐analysis is possible, we plan to use the fixed‐effect model, however, If there is significant heterogeneity (I² > 50%), a random‐effects model will be considered.

Subgroup analysis and investigation of heterogeneity

We will also attempt to perform subgroup analysis by sickle status: 'severe genotypes' (HbSS and Sb0) and 'mild genotypes' (SC and Sb+); severity of disease (if an individual has experienced severe symptoms of the diseases such as stroke, acute chest syndrome, vaso‐occlusive crises etc.); age (children versus adults) and setting (developed versus developing countries). We will attempt to perform analysis by type of HSCT used (comparing BMT, PBCT and UBCT) and conditioning regimen if possible.

Sensitivity analysis

We plan to perform a sensitivity analysis based on the generation of the allocation sequence, including and excluding quasi‐randomised trials.

Results

Description of studies

Results of the search

We identified 12 potentially‐eligible trials; we have excluded 11 trials and listed one in 'Ongoing studies' (NCT02766465).

Included studies

No trials were eligible for inclusion in the review.

Excluded studies

The trials listed as 'Excluded studies' were not eligible for inclusion because they were neither RCTs, quasi‐RCTs nor address the specified intervention (Bernaudin 2007; Hongeng 2004; Horan 2005; Iannone 2003; Locatelli 2003; Vermylen 2000; Walters 1995; Walters 1996; Walters 2001; Weinberg 2001, Yalcin 2017).

Ongoing trials

We have identified one ongoing trial and will assess this within a future update of the review (NCT02766465). Please see the relevant table for further information (Characteristics of ongoing studies).

Risk of bias in included studies

We did not identify any trials eligible for inclusion in this review.

Effects of interventions

We did not identify any trials eligible for inclusion in this review.

Discussion

Decades after the discovery of the use of hematopoietic stem cells to cure SCD, there are no randomized controlled trials to provide concrete evidence for its use in people with SCD. This could be attributed to the complexity of the patient condition (e.g. severity of condition, co‐morbid conditions, and so forth) making it unfeasible to conduct randomized controlled trials in this area (transplant versus no transplantation or transplant versus standard care procedure such as the use of hydroxyurea), as this would be unethical. Therefore, this leaves observational studies to assess these interventions. One of the study explored HLA‐identical HSCT in 50 patients (less than 16 years) and reported 82% and 85% event‐free (EFS) and disease‐free survival (DFS) rates, respectively after 11 years (Vermylen 1998). Survival rates were higher in asymptomatic individuals compared to symptomatic individuals, those that show higher severity of the disease (Vermylen 1998). Another study reported a one‐ and two‐year EFS rate of 76% and 69%, respectively, with corresponding survival rates of 86% and 79% after allogeneic bone marrow transplant from unrelated donor (Shenoy 2016). Higher rates of EFS have been reported in other studies (Panepinto 2007). A review on a 1000 recipients of HLA‐identical siblings transplants performed between 1986 and 2013 showed a five‐year EFS and overall survival of > 90% (Gluckman 2017). These studies report that HSCT does improve survival and prevent symptoms and complications (or both) associated with SCD but there is the issue of risk which is still being investigated. The outcomes are better in HLA‐identical HSCT. Currently, there is a quasi‐randomized trial underway in the USA (NCT02766465), this is comparing bone marrow transplantation versus standard of care (hydroxyurea, and chronic blood transfusions) in adolescents and young adults with SCDs; the trial is expected to be completed in 2023. In the absence of any relevant randomized controlled trial comparing HSCT to standard care or comparing the different methods of HSCT in SCD, this systematic review found no evidence for or against these interventions.

Authors' conclusions

Implications for practice.

Due to lack of randomized controlled trials on hematopoietic stem cell transplantations (HSCTs) for people with sickle cell disease (SCD), we can currently not report on any findings, nor make any conclusions. Although some studies have reported high event‐free survival rate, this research evidence is currently limited to observational and other less robust studies. Clinicians should therefore inform people with SCD about the uncertainty surrounding this clinical procedure if it is to be used. During counseling, it is important to balance the potential benefits of long‐term survival against the risks for mortality from transplant‐related complications and the potential risks for severe graft versus host disease.

Implications for research.

The absence of randomized controlled trials of HSCT in SCD, as shown by this extensive literature search, suggests the need for a well‐designed prospective randomized controlled trial of HSCT in people with SCD in order to make necessary recommendations regarding its use.

While ideally, trials comparing HSCT to supportive standard care could be carried out, the high variability in the clinical course of SCD and characteristics of patient population hinders its feasibility and may be considered unethical. Thus, trials may compare the different types of HSCT with one another with subgroup analyses by sickle status, severity of disease, setting and age groups carried out to provide guidance on the optimal HSCT for each individual with SCD. Outcomes to be included in these trials should address the needs and concerns of patients, care‐givers and health providers, in order to assess the risks and benefits of the procedure. Similar outcomes should be measured across trials to allow comparability of results and future synthesis of data in a meta‐analysis. Long‐term follow up of participants is also necessary.

What's new

Date Event Description
11 June 2020 New search has been performed A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register did not identify any eligible trials.
Further searching identified one trial that has been added to 'Excluded studies' (Yalcin 2017) and a further quasi‐randomized trial that has been added to 'Ongoing studies' (NCT02766465).
11 June 2020 New citation required but conclusions have not changed Minor changes have been made throughout the review; the background and discussion section was updated to reflect current findings.
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History

Protocol first published: Issue 1, 2008
Review first published: Issue 1, 2009

Date Event Description
31 March 2016 New citation required but conclusions have not changed Minor changes have been made throughout the review.
31 March 2016 New search has been performed A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register did not identify any potentially eligible trials.
24 March 2014 Amended Contact details updated.
15 March 2013 New search has been performed A search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register did not identify any potentially eligible trials for inclusion in the review.
15 March 2013 New citation required but conclusions have not changed The review has been expanded to include adults as well as children. Minor changes to the text have been made throughout.
6 October 2010 New search has been performed A search of the Group's Haemoglobinopathies Trials Register did not identify any potentially relevant trials for inclusion in the review.
9 September 2009 New search has been performed A search of the Group's Haemoglobinopathies Trials Register did not identify any references potentially eligible for inclusion in this review.
28 March 2008 Amended Converted to new review format.
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Acknowledgements

Dr. S. Shenoy for his comments.

Appendices

Appendix 1. Search strategy: Clinicaltrials.gov

Trial registry Search terms Date of last search
ClinicalTrials.gov Stem cell transplantation AND sickle cell 29 April 2020
     
WHO ICTRP Stem cell transplantation AND sickle cell 29 April 2020
     
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Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Bernaudin 2007 Not a RCT/quasi‐RCT
Hongeng 2004 Not a RCT/quasi‐RCT
Horan 2005 Not a RCT/quasi‐RCT
Iannone 2003 Not a RCT/quasi‐RCT
Locatelli 2003 Not a RCT/quasi‐RCT
Vermylen 2000 Not a RCT/quasi‐RCT
Walters 1995 Not a RCT/quasi‐RCT
Walters 1996 Not a RCT/quasi‐RCT
Walters 2001 Not a RCT/quasi‐RCT
Weinberg 2001 Not a RCT/quasi‐RCT
Yalcin 2017 Wrong intervention, looking at the effectiveness of defibrotide prophylaxis on acute graft versus host disease
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RCT: randomized controlled trial

Characteristics of ongoing studies [ordered by study ID]

NCT02766465.

Study name Bone Marrow Transplantation vs Standard of Care in Patients with Severe Sickle Cell Disease (BMT CTN 1503) (STRIDE2)
Methods Quazi‐randomized controlled trial
Participants Adolescents and young adults with severe SCD
Interventions Hematopoietic cell transplant versus standard of care
Outcomes Survival, changes in SCD‐related events (pulmonary hypertension, cerebrovascular events, renal function, avascular necrosis, leg ulcer) and functional outcomes (6MWD, health‐related quality of life, cardiac function, pulmonary function, and mean pain intensity)
Additionally for those assigned to the donor arm, the trial will assess hematopoietic recovery, graft rejection, acute and chronic graft‐versus‐host disease, other significant transplant‐related complications and disease‐free survival
Starting date November 2016
Contact information Medical College of Wisconsin
Notes  
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SCD: sickle cell disease
6MWD: 6‐minute walk distance

Differences between protocol and review

The review has been expanded to include adults as well as children. Minor changes to the text have been made throughout.

Contributions of authors

Chioma Oringanje conceived the idea for the review and drafted the original protocol with input on draft versions from Eneida Nemecek and Oluseyi Oniyangi.

Sources of support

Internal sources

  • Institute of Tropical Disease, Research & Prevention, University of Calabar Teaching Hospital, Calabar, Nigeria

External sources

  • No sources of support supplied

Declarations of interest

Chioma Oringanje: none known.
Eneida Nemecek: none known.
Oluseyi Oniyangi: none known.

New search for studies and content updated (no change to conclusions)

References

References to studies excluded from this review

Bernaudin 2007 {published data only}

  1. Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, et al. Long term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood 2007;110(7):2749-56. [DOI] [PubMed] [Google Scholar]

Hongeng 2004 {published data only}

  1. Hongeng S, Pakakasama S, Chaisiripoomkere W, Chuansumrit A, Sirachainan N, Ungkanont A, et al. Outcome of transplantation with unrelated donor bone marrow in children with severe thalassaemia. Bone Marrow Transplantation 2004;33(4):377-9. [DOI] [PubMed] [Google Scholar]

Horan 2005 {published data only}

  1. Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow Transplantation 2005;35(2):171-7. [DOI] [PubMed] [Google Scholar]

Iannone 2003 {published data only}

  1. Iannone R, Casella JF, Fuchs EJ, Chen AR, Jones RJ, Woolfrey A, et al. Results of Minimally Toxic Non-myeloablative Transplanation in Patients with Sickle Cell Anemia and Beta-thalassemia. Biology of Blood and Marrow Transplantaion 2003;9(8):519-28. [DOI] [PubMed] [Google Scholar]

Locatelli 2003 {published data only}

  1. Locatelli F, Vanderson R, Reed W, Bernaudin F, Ertem M, Grafakos S, Brichard B, et al. Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Blood 2003;101(6):2137-43. [DOI] [PubMed] [Google Scholar]

Vermylen 2000 {published data only}

  1. Vermylen C, Cornu G, Ferster A, Brichard B, Ninane J, Ferrant A, et al. Hematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplantation 2000;22(1):1-6. [DOI] [PubMed] [Google Scholar]

Walters 1995 {published data only}

  1. Walters MC, Sullivan KM, Bernaudin F, Souillet G, Vannier JP, Johnson FL, et al. Neurologic complications after allogeneic marrow transplantation for sickle cell anemia. Blood 1995;85(4):879-84. [PubMed] [Google Scholar]

Walters 1996 {published data only}

  1. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, et al. Bone Marrow Transplantation for sickle cell disease. New England Journal of Medicine 1996;335(6):369-76. [DOI] [PubMed] [Google Scholar]

Walters 2001 {published data only}

  1. Walters MC, Patience M, Leisenring W, Rogers ZR, Aquino VM, Buchanan GR, et al. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biology of Blood and Marrow Transplantation 2001;7(12):665-73. [DOI] [PubMed] [Google Scholar]

Weinberg 2001 {published data only}

  1. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, et al. Factors affecting thymic function after allogenic hematopoietic stem cell transplantation. Blood 2001;97(5):1458-63. [DOI] [PubMed] [Google Scholar]

Yalcin 2017 {published data only}

  1. Yalcin K, Guler E, Kupesiz OA. Effectivity of defibrotide prophylaxis on acute graft versus host disease: a single center experience with high risk pediatric patients. Bone Marrow Transplantation 2017;52(Suppl 1):S357-8. [ABSTRACT NO.: P457] [CN-01467247] [Google Scholar]

References to ongoing studies

NCT02766465 {unpublished data only}

  1. NCT02766465. Bone marrow transplantation vs standard of care in patients with severe sickle cell disease (BMT CTN 1503) (STRIDE2). www.clinicaltrials.gov/ct2/show/NCT02766465 (first posted 09 May 2016).

Additional references

Adamkiewicz 2004

  1. Adamkiewicz T, Mehta P, Boyer M, Kedar A, Olson T, Olson E, et al. Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. Bone Marrow Transplant 2004;34(5):405-11. [DOI] [PubMed] [Google Scholar]

Adams 1992

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