Feb. 5, 2025 – On January 30, 2025, the American Society of Hematology (ASH) published a report that found no evidence to support that physical activity can cause sudden death for individuals with sickle cell trait (SCT) without rhabdomyolysis (muscle breakdown) or heat injury. The article also found that there is not a high-level of evidence that sickle cell trait causes acute pain crises.

The ASH report, No Scientific Link Found Between Sickle Cell Trait and Sudden Death, brought together expert hematologists and forensic pathologists to take a closer look at the existing available research to answer two primary questions:

• Do uncomplicated acute pain crises occur in people with SCT?
• Can higher levels of physical activity result in sudden death in individuals with SCT?

The group conducted a multi-database search, identifying 1,474 citations. Only seven of those studies reported original data, included laboratory testing for SCT in individuals and addressed the two primary research questions.

Of these studies, none assessed acute pain crises in individuals with SCT compared to those with SCD and only one citation described death in individuals reported to have SCT, and this study of active-duty U.S. soldiers found that SCT was associated with a higher risk of heat-related-exertional rhabdomyolysis but not a higher risk of death. After the U.S. military made changes to its exercise policies, the risk of death was no different in individuals with SCT compared to individuals without SCT. There was no direct evidence of acute painful episodes in people with sickle cell trait.

The review had some limitations including a lack of high-quality, peer-reviewed direct evidence. Following the results of this study, ASH revised its position statement on SCT, which states that listing “sickle cell crisis” or “sickle cell trait” as a cause of death on an autopsy report for an individual with sickle cell trait is medically inaccurate and without medical evidence of causation.

WHY IS THIS IMPORTANT?

Some lawyers and medical examiners have attempted to use sickle cell trait as a reason for death in, for example, college athletes who have died after rigorous training, or for individuals who have died while in police custody. This ASH statement is clear that judges should no longer accept this argument in court. This thoughtful evaluation represents a systematic review of the scientific evidence by hematologists convened by ASH (Weeks et al. 2025).

SCDAA’s Medical and Research Advisory Committee (MARAC) supports these findings and reports but recognizes that more research is needed. MARAC will continue to work with our experts as well as with our partners at ASH to provide clear guidance to the sickle cell community about sickle cell trait and how it relates to exercise and pain crisis. SCDAA continues to recommend that all athletes practice universal precautions to avoid the risk of rhabdomyolysis or heat injury.

REFERENCES:

Weeks LD, Wilson AM, Naik RP, Efebera YA, Murad MH, Mahajan A, McGann PT, Verhovsek M, Weyand AC, Zaidi AU, DeBaun MR, Donald C, Mitchell RA Jr. Sickle Cell Trait Does Not Cause “Sickle Cell Crisis” Leading to Exertion-Related Death: A Systematic Review. Blood. 2025 Jan 30:blood.2024026899. doi: 10.1182/blood.2024026899. Epub ahead of print. PMID: 39882975.

Lichtsinn, H. S., Weyand, A. C., McKinney, Z. J., & Wilson, A. M. (2021). Sickle Cell Trait: An Unsound Cause of Death. The Lancet, 398(10306), 1128-1129.

Mack AK, Bercovitz RS, Lust H. edited by Lemonick MD. Some Medical Examiners Say Sickle Cell Trait Causes Sudden Death—They’re Wrong. Scientific American June 20, 2021.

LaForgia M, Valentino-DeVries J. How a Genetic Trait in Black People Can Give the Police Cover. New York Times. May 15, 2021.

Thogmartin JR et al. Sickle Cell Trait-Associated Deaths: A Case Series with a Review of the Literature. J Forensic Sci. 2011 Sep; 56(5):1352

Click here for a printable version of this statement.

SCDAA Medical and Research Advisory Committee (MARAC) Statement: Pfizer’s Voxelotor (Oxbryta®) Withdrawal

9/27/24

What is the news?

Pfizer announced the withdrawal of voxelotor (Oxbryta®) from national and global markets on September 25, 2024.  Clinical research was also stopped. “Pfizer’s decision is based on the totality of clinical data that now indicate the overall benefit of OXBRYTA no longer outweighs the risk in the approved sickle cell patient population. The data suggest an imbalance in vaso-occlusive crises and fatal events, which require further assessment.” [1].

What is the reason?

The Pfizer statement mentions that worrisome new information came from three reports that link voxelotor with more pain and deaths:

1. A clinical research study of children with sickle cell disease and with higher risk of stroke (GBT440-032) had eight deaths in the voxelotor group compared to two deaths in the group without voxelotor. The study recruited 236 children (2y-15y) from Egypt, Ghana, Kenya, Nigeria, Oman, Saudi Arabia, USA and the United Kingdom.
2. Another clinical research study of adolescents and adults with sickle cell disease and leg ulcers (GBT440-042) had eight deaths on voxelotor. Eighty-eight patients at least 12 years of age were enrolled in Brazil, Kenya and Nigeria.
3. Monitoring reports from people taking voxelotor as a prescribed medication, not on a clinical research study. No numbers were listed.

Following standard rules when new risks are found, Pfizer voluntarily withdrew voxelotor from use worldwide, while further investigation is conducted. Pfizer also reports that they are halting manufacturing production and clinical research.

What if I have been doing well on voxelotor (Oxbryta®)?

The FDA has received questions about whether to allow some individuals living with sickle cell disease to continue voxelotor on a “compassionate use” basis. However, for now we cannot assume that “compassionate use” will be allowed.

Do I just throw away the voxelotor?

For people with sickle cell disease who have been on voxelotor and doing well, MARAC does not have evidence on what will happen when you stop taking the medication. There is a report that going from full-dose voxelotor to completely stopping taking the drug led to intense hemolysis (breakdown of red blood cells) and severe sickle cell problems within three days that injured the kidneys and other organs and required hospital care. Thus, many doctors are suggesting that people taper off voxelotor over a period of about two weeks. However, tapering is optional and not based on strong clinical evidence. We strongly urge individuals to discuss their options and next steps with their sickle cell health care professional.

What if I have unusual problems as I discontinue voxelotor?

Contact your sickle cell health care provider. Voxelotor acts by slowing down the breakage of red blood cells (hemolysis) and blocking the red cells from changing to the sickle shape. A possible problem is that if the hemolysis suddenly increases it may damage the kidneys. Your eyes will probably become more yellow (jaundiced), and your urine will be darker yellow-orange. Tell your doctor if you have brown urine (the color of cola). You will probably need to come in for lab tests and treatment. Immediately seek medical attention if you stop making urine even when you are drinking a lot of water. Comprehensive sickle cell centers and sickle cell health care providers are collecting reports from patients about any new problems experienced when they come off voxelotor.

What about my other sickle cell medicines?

This news is only about voxelotor.  Continue taking other medications as prescribed.

What are the alternatives to voxelotor?

In the USA, sickle cell disease severity can be reduced by three other medications approved by FDA:

• hydroxyurea (Droxia®, Siklos®),
• glutamine (Endari®), and
• crizanlizumab (Adakveo®)

Blood transfusions are used for selected problems in sickle cell disease, especially to prevent stroke.

• “top-off transfusions” or simple transfusions
• “exchange transfusions” or erythrocytapheresis

Hematopoietic stem cell transplant (also known as bone marrow transplant) is a cure that requires an:

• HLA-identical (fully-matched) sibling donor, or
• haploidentical (half-matched) related donor, or
• unrelated HLA-matched donor

Two gene therapy approaches can potentially cure sickle cell disease without having to find a donor.

• Casgevy^TM (CRISPR/Vertex) or
• Lyfgenia^TM (bluebird bio)

MARAC recommends making an appointment to discuss your sickle cell treatment plan with your sickle cell health care provider.

Is this the first time a medication has been withdrawn?

No. Other situations of medication withdrawal from the market have occurred.

• 2004: Merck withdrew rofecoxib (Vioxx) as an arthritis drug.
• 1997: FDA ordered Wyeth to remove the weight-loss medications fenfluramine (Pondimin) and a related drug, dexfenfluramine (Redux) from the market.
• 1961: Chemie withdrew thalidomide as an antinausea drug. 2006 thalidomide was approved for the treatment of plasma cell myeloma.

When will there be more updates?

We do not know. MARAC is following the news as it unfolds. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulations control some of the timing for release of information. SCDAA MARAC is continuing to monitor the situation and will update the community as soon as new information is released.

Additional Information — 9/30/24 Update

What details are publicly available about the deaths?
A document posted online by the European Medicines Agency has the most details that MARAC was able to find. “Notification to the CHMP/EMA Secretariat of a referral under Article 20 of Regulation (EC) 726/2004” electronically signed July 30, 2024, accessed Sept. 29, 2024. https://www.ema.europa.eu/en/documents/referral/oxbryta-article-20-procedure-notification_en.pdf The rules of EMA and FDA control release of information.

• Of the 8 deaths in the GBT440-032 randomized study of children with abnormal stroke risk: “Most of the fatal cases in the voxelotor group describe incidence of infection, including 3/8 who developed fatal malaria and 2/8 patients with sepsis.”
• Of the 8 deaths in the open-label GBT440-042 of voxelotor for leg ulcers: “In 4 cases, malaria was identified either the cause or contributing factor.”
• “The investigator and sponsor considered that none of the fatal cases were related to voxelotor in these studies.”

What information is still missing?
Quoting from the same EMA document from July 30, 2024:

• Some of the “case narratives” from GBT440-032 and GBT440-042 “are still not available, … and overall information provided to date is limited. However, given the fact that concerns due to possible immunosuppressive effects of voxelotor were raised at the time of the MA (with immunosuppressive effects observed in animal studies and decrease in WBC in clinical studies), and the study population in those studies partially overlap with the intended population based on the authorized indication, the findings from these emerging safety data need to be further reviewed, taking into account all available data, to determine whether there is an impact on the benefit-risk balance of Oxbryta in the authorized indication.”
• It is unclear how these deaths compare with the known vulnerability to infection and early death of sickle cell disease without treatment.

References

Pfizer statement, 9/25/24: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-voluntarily-withdraws-all-lots-sickle-cell-disease

Pfizer letter to Health Care Providers, 9/26/24: https://webfiles.pfizer.com/dear-hcp-letter-oxbryta-us-final-092524?cmp=US-21234&campaign=US-21234&identitytype=account&tpn=1532773&LNK=GL_BD3-C2&mkt_tok=MTk1LVVMQy0yMDAAAAGV1F26wnPvgN6fKRyyOgU-kt_3Pa-xaL9I_wa6yP1ROToTo85YnZaSQ98g2cAj9j-cf9xvsubH4Rvs50AWKcAMrA4qw1nLMAsCEbu8-c6PeXuPhg

European Medicines Agency, July 2024: https://www.ema.europa.eu/en/medicines/human/referrals/oxbryta

FDA statement, 9/26/24: https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerting-patients-and-health-care-professionals-about-voluntary-withdrawal-oxbryta-market-due

MARAC Statement: Parvovirus B19, Fever and Urgent Care

Aug. 13, 2024 – More infections with parvovirus B19, also known as “fifth disease” or “slapped-cheek disease,” are showing up in 2024 [1,2].

WHY IS THIS IMPORTANT FOR SICKLE CELL DISEASE?

• Parvovirus B19 causes a special problem in sickle cell disease called aplastic crisis [3,4,5], and infects the bone marrow and stops production red blood cells for about 10 days. Reticulocyte counts (number of young red blood cells) drop to zero. Hemoglobin can drop to dangerously low levels in people with sickle cell disease and other conditions with short- lived red blood cells (hemolytic anemias). A red blood cell transfusion is often needed.
• Parvovirus can cause other SCD problems like acute chest syndrome, enlarged spleen and damage to many parts of the body. These problems can also require hospital treatment.

HOW DO YOU DETECT PARVOVIRUS B19 INFECTION?

• Checking for parvovirus B19 infection requires blood tests: reticulocyte count and parvovirus testing by PCR.
• Symptoms of parvovirus infection overlap with the symptoms of many other respiratory infections: fever, headache, respiratory symptoms, fatigue.
• A facial rash that looks like “slapped cheeks” is seen in some children, but not always. Pregnant women usually do not get this rash.

HOW DOES PARVOVIRUS B19 SPREAD?

• Parvovirus spreads in the air from one child to another.
• Avoiding people with respiratory symptoms, wearing masks and washing hands can help to reduce the spread of parvovirus B19.
• Most adults have had parvovirus B19. The previous infection protects them from getting it again.
• Because parvovirus B19 and COVID-19 are both respiratory viruses, their spread can be prevented in similar ways. Widespread use of COVID-19 precautions likely lowered the number of people with parvovirus exposure in the past few years. However, the larger vulnerable group who were not exposed to parvovirus B19 can now catch it.

WHO IS VULNERABLE TO PARVOVIRUS B19?

• Children.
• People with sickle cell disease, thalassemia and other hemolytic anemias. They might need blood transfusion.
• People with severe immunocompromise (such as AIDS, cancer chemotherapy or transplant immunosuppression). They might need to have antibody treatment to clear the parvovirus infection.
• Pregnant women. Catching parvovirus B19 during pregnancy means a higher risk of miscarriage. Pregnant women should avoid children with parvovirus B19.

CAN A CHILD WITH SCD BE EVALUATED FOR PARVOVIRUS IN AN URGENT CARE OR PRIMARY CARE CLINIC?
Although they seem convenient, most urgent care centers and primary care clinics cannot do immediate (STAT) reticulocyte count. Emergency departments have the capacity to perform these steps in the appropriate medical evaluation of a child with SCD and fever above 101.3 F:

• Blood counts including reticulocyte count, with results within an hour or two (STAT)
• Blood culture
• Physical exam including spleen
• Pulse oximetry, blood pressure and other vital signs
• Antibiotic injection (usually ceftriaxone) to clear bacteria
• Possible chest X-ray to rule out acute chest syndrome

DON’T DOGS GET PARVOVIRUS?

Dogs get other kinds of parvovirus (CPV-1 or CPV-2), not parvovirus B19. You cannot get the infection from your pet, and you cannot infect your pet.

RECOMMENDATIONS:

1. Children with SCD and fever should be evaluated promptly in emergency departments, and families should clearly state at the intake desk (triage) that the child has sickle cell disease immunocompromise with fever.
2. Medical evaluation of a child with SCD and fever should include CBC and reticulocyte count, with STAT results. Low reticulocyte count (absolute reticulocytes below 10,000 per microliter) should raise concern about aplastic crisis from parvovirus B19, and the child should not be discharged home without a plan for possible blood transfusion.
3. Families of children with SCD and fever should not go to urgent care centers and clinics that lack the capability to do STAT labs. These types of centers and clinics should not delay sending a child with SCD and fever to a medical facility that can provide appropriate care, usually an emergency department.

REFERENCES:

1. Increase in human parvovirus activity in the United States. CDC Health Alert Network CDCHAN-00514. August 13, 2024 https://emergency.cdc.gov/han/2024/han00514.asp
2. Risks posed by reported increased circulation of human parvovirus B19 in the European Union / EEA. June 5, 2024 https://www.ecdc.europa.eu/sites/default/files/documents/Risks%20posed%20by%20reported%20increased%20circulation%20of%20human%20parvovirus%20B19%20FINAL.pdf
3. Sickle cell aplastic crisis. Texas Department of Health https://www.dshs.texas.gov/newborn-screening-program/sickle-cell-disease/more-about-sickle-cell/aplastic-crisis
4. Sickle Cell aplastic crisis. Childrens Healthcare of Atlanta. https://www.choa.org/-/media/Files/Childrens/teaching-sheets/sickle-cell—aplastic-crisis.pdf
5. Sickle cell aplastic crisis. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/24557-aplastic-crisis

Download and print this statement.