Children who received a stem cell transplant for sickle cell disease (SCD) experienced better health-related Quality of Life (hrQoL) outcomes and cognitive performance 10 years after their transplant compared with children who received chronic blood transfusion therapy and the SCD drug hydroxyurea but did not undergo a stem cell transplant.
Overall, transplant recipients show better physical, school, and social functioning than those receiving blood transfusions and medications alone.
This conclusion is based on study results presented during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7 – 10, 2024, in San Diego, CA, and online.[1]
The study was sponsored by the Centre Hospitalier Intercommunal de Créteil (CHIC Hospital) in France and funded by the Agence de Biomédecine and Pfizer.
Ten-year outcomes
The findings reflect 10-year outcomes from the DREPAGREFFE-1 trial (NCT01340404), a multicenter, prospective study that ran from 2010 to 2013 in France and was the first head-to-head comparison of allogeneic stem cell transplantation versus standard of care (transplantation vs. transfusion) for children with SCD
Combined with the study’s one-year and three-year outcomes, the 10-year findings further strengthen the evidence in favor of stem cell transplantation for reducing complications and improving the overall outlook for people living with SCD, according to the researchers.
“This trial demonstrated that following stem cell transplantation, patients had a better quality of life, not only for physical functioning but also for social and school functioning,” said the study’s lead author, Françoise Bernaudin, MD, a physician at Hôpital Intercommunal de Créteil, Université Paris-Est, in France.
“We found that these patients can have a greater ability to do sports and run, attained higher academic degrees, are not anxious about their future, and experience less anger and less difficulty with memory compared with those who received chronic transfusions and hydroxyurea,” Bernaudin said.
Sickle cell disease
Sickle cell disease or SCD is an inherited blood disorder that causes red blood cells to become hard, sticky, and sickle-shaped. These damaged blood cells generally clump together, impeding the flow of blood and reducing the ability for blood to carry oxygen to tissues and organs. This results in episodes of acute pain as well as long-term damage, causing a range of complications throughout life and increasing the risk of premature death.
One common complication of SCD is abnormally high cerebral arterial velocities, an indicator of stenosis presence or reduced oxygen delivery to the brain, which can be associated with a greater risk of strokes and cognitive problems.
SCD is the most common inherited genetic disease in France, but generally affects people from the Mediterranean, Southern Europe, Africa, Central America, South America, the Middle East, Asia, and India. In the United States, SCD affects more than 100,000 people, and worldwide 8 million people are affected. In the United States, 9 of 10 people who have sickle cell disease are of African ancestry or identify as Black with 1 in 13 Black babies carrying the sickle cell gene.[2]
When the first-line treatment with hydroxyurea (Hydrea®; Bristol-Myers Squibb), a myelosuppressive agent, is insufficient or in the case of organic damage(s) (in particular cerebral vasculopathy), a therapeutic intensification must be considered.[3][4]
Treatment options
New therapeutics, including L-glutamine (Endari®; Emmaus Medical), voxelotor (Oxbryta®; Pfizer)*, and crizanlizumab (Adakveo®; Novartis) are available, but only a hematopoietic stem cell transplant (HSCT) is known to be potentially curative. HSCT is generally considered for children with severe sickle cell disease who have minimal organ damage. However, to be successful, the donor must be a close relative, usually a sibling. Widespread use of HSCT in older patients is limited due to donor availability and morbidity and mortality risks.
Allogeneic HSCT during childhood with a sibling donor is the reference but it is now possible to perform this procedure in adults with reduced pre-transplant conditioning. Furthermore, gene therapy, which consists of an autograft of genetically modified HSCs, has demonstrated promising results but has not yet shown a complete cure for the disease. The toxicity of myeloablative conditioning, which is used in pediatrics or for gene therapy, particularly the sterility induced, and the risk of graft-versus-host disease, for allogeneic transplantation, remain limiting factors of these treatments.
In addition to HSCT, two novel gene therapies are available and may be potentially curative for patients diagnosed with SCD. In December 2023 the FDA approved exagamglogene autotemcel (Casgevy®; Vertex/Crisper Therapeutics), [5][6] and lovotibeglogene autotemcel (Lyfgenia™; Bluebird Bio) for the treatment of SCD in patients who are 12 years and older. In both therapies, adverse events were mostly limited to the myeloablative conditioning (MAC), the treatment regimen that uses high doses of chemotherapy and/or radiation to prepare patients for a stem cell transplant. However, while these novel gene therapy products seem very promising, access remains limited due to availability and (high) costs.
Study
DREPAGREFFE-1 enrolled 67 children between the ages of five to 15 who were receiving chronic blood transfusions to prevent complications from abnormal cerebral arterial velocities. Those with a matched sibling donor (n=32) were transplanted while those without a matched sibling donor (n=35) continued their transfusions and then switched to hydroxyurea in the absence of stenosis and if their cerebral arterial velocities normalized. At one and three years, those who received a stem cell transplant showed significant improvements in several measures compared with those who did not receive a transplant, but at those time points, there was no difference in the presence of ischemic lesions (blood clots that block blood flow in the brain) or cognitive performance.
In the subsequent years, researchers continued to follow up with study participants, including through clinical evaluations, brain scans, and tools for assessing quality of life and cognitive functioning.
At 10 years, health-related Quality of Life (hrQoL) scores related to physical, school, and social functioning were significantly higher among those who received a stem cell transplant. For cognitive performance, participants who received a stem cell transplant showed significantly better performance on tests used to assess working memory and processing speed.
There was no difference between groups in terms of verbal comprehension, perceptual reasoning, or emotional quality of life scores.
The researchers also assessed trends in the rate of silent cerebral infarcts (SCIs) – a type of small stroke that is visible on a brain scan but causes no obvious symptoms. While it is unclear whether SCIs influence cognitive functioning, they are considered to be a sign of increased SCD severity and complications. SCIs were found in 18 participants at the time of enrollment; at 10 years, five additional patients had developed silent cerebral infarcts in the standard-of-care arm compared to zero in the stem cell transplant arm.
Better outcomes
Taken together, researchers said that the study findings suggest that undergoing stem cell transplantation results in better outcomes for children with SCD compared with chronic transfusions and hydroxyurea. While this can offer additional reassurance for patients, families, and physicians who are considering the procedure, Bernaudin noted that families should also be aware of the risks of undergoing a stem cell transplant, including infertility, which is a common side effect of the conditioning regimen used to clear the bone marrow in preparation to receive a transplant.
She said that fertility preservation procedures are available in France for all patients undergoing stem cell transplantation for SCD at no charge to the families, adding, “with this technique, we hope that the patients will be able to have children after the transplantation.”
What’s next
Looking ahead, Bernaudin said that it would be useful to compare outcomes from haplo-identical stem cell transplant to gene therapy, a type of treatment that has become more widely available since DREPAGREFFE-1 was conducted. She also noted that additional work is needed to further improve transplantation techniques to minimize the risk of complications or treatment failure particularly after haplo-identical transplants in children.
An observational study (NCT05053932) to remotely reevaluate the cohort of 67 sickle cell patients with transcranial Doppler-detected cerebral vasculopathy included in the national “Sickle Cell Transplant” protocol is ongoing.
__
Note:* On November 25, 2024 Pfizer announced today that it is voluntarily withdrawing all lots of voxelotor, an oral, once-daily therapeutic for the treatment of sickle cell disease (SCD) at this time, in all markets where it is approved. Pfizer has also discontinued all active voxelotor clinical trials and expanded access programs worldwide. The company said that the decision is based on the totality of clinical data that suggests that the overall benefit of voxelotor no longer outweighs the risk in the approved sickle cell patient population. The data also indicated an imbalance in vaso-occlusive crises and fatal events, which require further assessment. Pfizer has notified regulatory authorities about these findings and its decision to voluntarily withdraw voxelotor from the market and discontinue distribution and clinical studies while further reviewing the available data and investigating the findings. In 2019, the United States Food and Drug Administration granted accelerated approval for voxelotor for the treatment of SCD in adults and children ages 12 years and older. In December 2021, the FDA expanded the approval of the drug for the treatment of SCD in patients 4 years of age and older in the USA. Voxelotor was granted Priority Medicines (PRIME) designation by the European Medicines Agency (EMA) and designated an orphan medicinal product for the treatment of patients with SCD by the European Commission (EC). In February 2022, the EC granted Marketing Authorization for voxelotor for the treatment of hemolytic anemia due to SCD in adult and pediatric patients 12 years of age and older as monotherapy or in combination with hydroxycarbamide (hydroxyurea). Since its first approval in 2019, OXBRYTA has been approved in over 35 countries globally.
Clinical trials
Allogeneic Genoidentical Stem Cell Transplantation in Children With Sickle-cell Anemia and Cerebral Vasculopathy (DREPAGREFFE) – ClinicalTrials.gov ID NCT01340404
Long-term Comparative Cerebrovascular Outcome After Transplantation vs Standard Care in Sickle Cell Anemia (DREPAGREFFE2) – ClinicalTrials.gov ID NCT05053932
Highlights of prescribing information
Hydroxyurea (Hydrea®; Bristol-Myers Squibb) [Prescribing Information]
L-glutamine (Endari®; Emmaus Medical)[Prescribing Information]
Crizanlizumab (Adakveo®; Novartis) [Prescribing Information]
Voxelotor (Oxbryta®; Pfizer) [Prescribing Information]
Exagamglogene autotemcel (Casgevy®; Vertex)[Prescribing Information]
Lovotibeglogene autotemcel (Lyfgenia™; Bluebird Bio)[Prescribing Information]
Reference
[1] Bernaudin F, Verlhac S, Ducros-Miralles E, Arnaud C, Genty I, Petras M, Paillard C, Isabelle T, Kamdem A, et all. Outcome of Cerebral Vasculopathy and Cognitive Performances 10 Years Post-Enrollment in the Drepagreffe Trial Comparing Allogeneic Stem Cell Transplantation to Standard-Care in Children with Sickle Cell Anemia and History of Abnormal Cerebral Velocities. LBA-5: presented on Tuesday, December 10, 2024, during a late-breaking abstracts session at the 66th American Society of Hematology Annual Meeting and Exposition.
[2] What Is Sickle Cell Disease? National Heart, Lung and Blood Institute. Online. Last accessed on December 4, 2024.
[3] Agrawal RK, Patel RK, Shah V, Nainiwal L, Trivedi B. Hydroxyurea in sickle cell disease: drug review. Indian J Hematol Blood Transfus. 2014 Jun;30(2):91-6. doi: 10.1007/s12288-013-0261-4. Epub 2013 May 24. PMID: 24839362; PMCID: PMC4022916.
[4] Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, James AH, Laraque D, Mendez M, Montoya CJ, Pollock BH, Robinson L, Scholnik AP, Schori M. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008 Jun 17;148(12):932-8. doi: 10.7326/0003-4819-148-12-200806170-00220. Epub 2008 May 5. PMID: 18458271.
[5] Hoy SM. Exagamglogene Autotemcel: First Approval. Mol Diagn Ther. 2024 Mar;28(2):133-139. doi: 10.1007/s40291-024-00696-z. Epub 2024 Jan 17. PMID: 38228954.
[6] Frangoul H, Locatelli F, Sharma A, Bhatia M, Mapara M, Molinari L, Wall D, Liem RI, Telfer P, Shah AJ, Cavazzana M, Corbacioglu S, Rondelli D, Meisel R, Dedeken L, Lobitz S, de Montalembert M, Steinberg MH, Walters MC, Eckrich MJ, Imren S, Bower L, Simard C, Zhou W, Xuan F, Morrow PK, Hobbs WE, Grupp SA; CLIMB SCD-121 Study Group. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med. 2024 May 9;390(18):1649-1662. doi: 10.1056/NEJMoa2309676. Epub 2024 Apr 24. PMID: 38661449.
Featured image: General Views of attendees during the day at the American Society of Hematology 59th Annual Meeting at the San Diego Center. Photo courtesy: 2018 – 2024 © ASH/Scott Morgan. Used with permission.
DOI
