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

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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. 

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Dr. Lewis Hsu, chief medical officer of the Sickle Cell Disease Association of America Inc. said:

We at the Sickle Cell Disease Association of America Inc. celebrate that two gene therapies are approved for sickle cell disease by the FDA today, Dec. 8. This double milestone was a long time coming, and sickle cell disease now joins the ranks of other genetic diseases with gene therapy treatments. Sickle cell disease was called “the first molecular disease” about 70 years ago, and a gene therapy treatment was predicted for sickle cell disease in the 1950s when DNA was first described.

These two gene therapies mark a big step forward for sickle cell disease research and treatment. The results of the clinical trials are very impressive. The patients selected had a lot of pain (two or more vaso-occlusive crisis pain hospitalizations per year for two years). The data show that, after gene therapy was administered, nearly all patients were free of hospitalizations for vaso-occlusive crises for at least nine consecutive months. The patients’ health-related quality of life also improved in every way: physically, emotionally, socially and functionally with both gene therapies.

Regina Hartfield, president and CEO of the Sickle Cell Disease Association of America Inc. said:

Gene therapy is an exciting and potentially curative addition to the treatments available to sickle
cell warriors. This is a historic milestone, but everyone may not be eligible for gene therapy.
We must continue to move forward with research to ensure that there is a solution for every member of our community.

Is gene therapy a cure for sickle cell disease?
The Sickle Cell Disease Association of America Inc. recognizes gene therapy as a “potentially curative” therapy. The treatment is so new that more data is needed to understand its impact and patient prognosis. Additionally, the word “cure” suggests a simple solution that does not reflect the reality of these therapies. Even after completing treatment, the FDA recommends 15 years of patient monitoring for health issues.

What is the treatment like?
The patient journey will be similar for both Casgevy and Lyfgenia. Gene therapy is administered during a one-time infusion; however, there are steps that patients must take to prepare for the treatment. First, the patient’s care team will collect stem cells, which are the progenitors of red blood cells, from their body. Then, those cells will be treated in a lab. The patient will undergo chemotherapy to remove the original, abnormal stem cells from the bone marrow. After this process is complete, the treated stem cells are injected back into the patient through an intravenous process like a transfusion (not surgery). The whole procedure takes about a year. It is similar to autologous bone marrow transplantation, as there is no need to find a donor of stem cells.

What is the difference between the two therapies?
The two gene therapy strategies are scientifically different. Casgevy is gene editing, the first of its kind, and Lyfgenia uses gene addition. Both gene therapy strategies have about the same patient journey and potential issues: access, cost, infertility, unknown possibility of organ damage and unknown long-term effects.

How effective is it?
Gene therapy provides a significant reduction in acute episodes of sickle cell pain within a few years of administration. More years of follow-up will be needed to determine whether it will also reduce the organ damage of sickle cell disease and if the stem cells treated with continue to produce non-sickling red blood cells for the rest of the person’s life, or if the stem cells die off over a certain number of years. Currently the treatment requires chemotherapy, which means there are also concerns about chemotherapy-associated complications, such as infertility or secondary cancer.

When will gene therapy be available for use?
Gene therapy will likely be available in early 2024.

Who is eligible?
Casgevy and Lyfgenia are approved for people ages 12 and up. Sickle cell disease SS and S-beta-zero-thalassemia are eligible. The FDA indicates that sickle cell disease SC is not included. Additionally, individuals may also not be able to receive gene therapy if they have:

• A recurring viral infection
• Significant organ damage

Where is gene therapy administered?
Individuals with SCD can receive gene therapy at existing bone marrow treatment facilities with sickle cell expertise, which may pose accessibility issues to patients. SCDAA encourages gene therapy centers to partner with sickle cell centers, such as in the National Alliance of Sickle Centers, so that there is expertise to monitor for sickle cell organ damage.

How much will it cost? Will insurance cover gene therapy?
Gene therapy treatments are produced through expensive, highly technical processes. Casgevy is estimated to cost $2.2 million, and Lyfgenia is estimated to cost $3.1 million. However, the high price should be worthwhile as the savings in lifelong care may exceed the one-time cost of gene therapy. FDA-approved high-cost medications come with insurance barriers and rules that are not evidence-based.

What do these approvals mean for people living with sickle cell?
These approvals are expected to be life-changing for many and usher in a new age of treatment for sickle cell disease. Until now, the only way to cure sickle cell disease was through a bone marrow transplant, which is not a widely accessible option because it requires a matched bone marrow donor. Gene therapy does not require a donor; therefore, it has the potential to be a more widely available treatment.

What does it mean for sickle cell treatment in the future?
Casgevy and Lyfgenia are the first gene therapy treatments approved by the FDA for sickle cell disease. They open the door for other gene therapies to gain approval and help advance research into other potentially curative treatments. At the same time, there are concerns that these approvals will create an increase in competition for health care resources that could make it difficult to access other forms of treatment outside of gene therapy. Many people will not be eligible to receive gene therapy. To provide the highest quality of care to these individuals, we need to continue research into a variety of treatment options beyond gene therapy.

What are the implications for the medical community at large?
More broadly, Casgevy is the first FDA-approved CRISPR gene editing therapy for a genetic disease. This could have wide-reaching impacts for individuals with other conditions like cystic fibrosis, Tay-Sachs disease and others.

Where can I find more information?
Research into Casgevy and Lyfgenia specifically is ongoing; however, there is a wide variety of information about gene therapy for sickle cell disease available as it relates to clinical trials.

• The Democratizing Education for Sickle Cell Gene Therapy Project created materials with input from individuals with SCD and their families. Read their FAQs and visit their website.
• SCDAA has produced several videos on gene therapy. Watch the gene therapy masterclass and this webinar to learn more.
• OneSCDVoice hosts gene therapy resources on their Gene Therapy 101 page.
• The Dec. 8 FDA approval statement for Casgevy and Lyfgenia.

To learn more about Vertex’s Casgevy, visit casgevy.com. To learn more about bluebird bio’s Lyfgenia, visit my bluebird support.

Updated Dec. 14, 2023, 11:12 a.m. EST

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MARAC Statement: Health Insurance Coverage for Hematopoietic Stem Cell Transplant for Sickle Cell Disease from HLA-matched Sibling Donor (MSD HCT)

Sept. 16, 2023

BACKGROUND
Hematopoietic stem cell transplant for sickle cell disease from HLA-matched sibling donor (MSD) after myeloablative conditioning has been proven as curative therapy for sickle cell disease for over 25 years. It is no longer considered an experimental procedure. Over 2,000 transplants have been performed successfully across the world from HLA-matched sibling donors. Pooled Overall Survival rates for children and adults are high at 97% and 98%, respectively (meta-analysis by Iqbal 2021). The outcomes in sickle cell disease are much better for younger ages, but outcomes can still be good for selected adults. MSD HCT is expensive, but multiple analyses have shown that long-term health care costs go down, quality of life improves and organ damage is usually slowed or stopped. This means that MSD HCT is very cost-effective for the family, the health care system and society in general (less than $50k per QALY). Therefore, it is logical for MSD HCT to be covered by health insurance.

PROBLEM
Refusals of coverage for MSD HCT are concerning to SCDAA. Some of the publicly available insurers’ guidelines (REFERENCES below) appear to be based upon older datasets. The success of MSD HCT and a number of other therapies for SCD make the ethical implementation of a randomized trial of MSD HCT vs. a “control group” very difficult, and insurance companies should not expect such a large randomized controlled trial data to emerge. Similarly, federal agencies are no longer writing guidelines for sickle cell disease care, leaving guidelines to the professional societies like the American Society of Hematology.
The core mission of SCDAA is to work toward a universal cure for sickle cell disease. MSD HCT is well established as potentially curative therapy (although not universal because of the limitation of finding an MSD). SCDAA Medical Advisory and Research Committee (MARAC) offers to help health insurance payers gain an accurate picture of the stratification of risks and benefits of MSD HCT.

RECOMMENDATIONS
MARAC recommends MSD HCT for sickle cell disease should be covered by health insurance policies. Broad eligibility for MSD HCT would be an indicator of insurance coverage that understands the modern cost-effective management of sickle cell disease. Barriers to eligibility would indicate a low-quality policy that perpetuates health system barriers to care and adds to the health disparities in sickle cell disease.
MARAC recommends that modern datasets and the latest analyses should be used in consideration of insurance coverage policies for sickle cell disease, because HCT procedures and eligibility have moved forward since the first landmark studies and progressed even further in the past 10 years. Outcomes are best for individuals below age 5.

The current evidence base includes:

1. American Society of Hematology guidelines (Kanter et al. Blood Adv 2021)
2. Cost-effectiveness analysis (Arnold et al. Biol Blood Marrow Transplant. 2015)
3. Pediatric Bone Marrow Transplant Consortium late-effects guidelines (Shenoy et al. Biol Blood Marrow
   Transplant. 2018).
4. Large review. (Iqbal et al. Transplant Cell Ther. 2021).
5. Risk stratification by age. (Brazauskas et al. Blood. 2020).
6. Risk stratification by donor and conditioning regimen. (Eapen et al. Lancet Haematol. 2019).

MARAC endorses a patient-centered shared-decision-making process about MSD HCT. The risks and benefits of sickle cell disease are very individualized. However, the insurance payer should not be the gatekeeper for the decision for potentially curative therapy, because cost-effectiveness is already established.
MARAC offers assistance to insurance payers as “content experts” in sickle cell disease. MARAC could provide input on accurate information for insurance policies. MARAC is considering mobilizing a panel of sickle cell experts to provide an evidence-based review of denials of insurance coverage for MSD HCT. We also invite insurers to join the numerous educational sessions conducted by SCDAA and its member organizations.

REFERENCES
Current information about Hematopoietic Stem Cell Transplant for sickle cell disease.

1. Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, Murad MH, Panepinto JA, Rondelli D, Shenoy S, Wagner J, Walters MC, Woolford T, Meerpohl JJ, Tisdale J. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021 Sep 28;5(18):3668-3689. doi: 10.1182/bloodadvances.2021004394C. PMID: 34581773; PMCID: PMC8945587
2. Cost-effectiveness analysis Arnold SD, Jin Z, Sands S, Bhatia M, Kung AL, Satwani P. Allogeneic Hematopoietic Cell Transplantation for Children with Sickle Cell Disease Is Beneficial and Cost- Effective: A Single-Center Analysis. Biol Blood Marrow Transplant. 2015 Jul;21(7):1258-65. doi: 10.1016/j.
   bHCT.2015.01.010. Epub 2015 Jan 20. PMID: 25615608; PMCID: PMC5605133.
3. Pediatric Bone Marrow Transplant Consortium late-effects guidelines Shenoy S, Gaziev J, Angelucci E, King A, Bhatia M, Smith A, Bresters D, Haight AE, Duncan CN, de la Fuente J, Dietz AC, Baker KS, Pulsipher MA, Walters MC. Late Effects Screening Guidelines after Hematopoietic Cell Transplantation (HCT) for Hemoglobinopathy: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT. Biol Blood Marrow Transplant. 2018 Jul;24(7):1313-1321. doi: 10.1016/bbmt.2018.04.002. Epub 2018 Apr 10. PMID: 29653206.

The latest evidence.

• Large review. Iqbal M, Reljic T, Corbacioglu S, de la Fuente J, Gluckman E, Kumar A, Yassine F, Ayala E, El-Jawahri A, Murthy H, Almohareb F, Hashmi SK, Cappelli B, Alahmari A, Scigliuolo GM, Kassim A, Aljurf M, Kharfan-Dabaja MA. Systematic Review/Meta-Analysis on Efficacy of Allogeneic
  Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium. Transplant Cell Ther. 2021 Feb;27(2):167.e1-167.e12. doi: 10.1016/j.jtct.2020.10.007. Epub 2020 Dec 10. PMID: 33830027.
• Risk stratification by age. Brazauskas R, Scigliuolo GM, Wang HL, Cappelli B, Ruggeri A, Fitzhugh CD, Hankins JS, Kanter J, Meerpohl JJ, Panepinto JA, Rondelli D, Shenoy S, Walters MC, Wagner JE, Tisdale JF, Gluckman E, Eapen M. Risk score to predict event-free survival after hematopoietic cell transplant for sickle cell disease. Blood. 2020 Jul 30;136(5):623-626. Doi: 10.1182/blood.2020005687. PMID: 32518950; PMCID: PMC7393258.
• Risk stratification by donor and conditioning regimen. Eapen M, Brazauskas R, Walters MC, Bernaudin F, Bo-Subait K, Fitzhugh CD, Hankins JS, Kanter J, Meerpohl JJ, Bolaños-Meade J, Panepinto JA, Rondelli D, Shenoy S, Williamson J, Woolford TL, Gluckman E, Wagner JE, Tisdale JF. Effect of donor
  type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study. Lancet Haematol. 2019 Nov;6(11):e585-e596. doi: 10.1016/S2352-3026(19)30154-1. Epub 2019 Sep 5. PMID: 31495699; PMCID: PMC6813907.

Insurance Coverage Policies about transplant for hemoglobinopathies and/or genetic diseases

1. AmeriGroup (November 2021) https://medpol.providers.amerigroup.com/docs/gpp/AGP_HistoricalMedPol_TRANS_00029.pdf?v=202301052014 Accessed 9/15/2023
2. NC Medicaid. (August 2023) https://medicaid.ncdhhs.gov/11a-5-allogeneic-hematopoietic-transplant-genetic-diseases-and-acquired-anemias/download?attachment Accessed 9/15/2023
3. Premera Blue Cross (Jan 2023) https://www.premera.com/medicalpolicies/8.01.538.pdf Accessed 9/15/2023

Download this statement.

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Sept. 16, 2023 – The worldwide pandemic of COVID-19 (SARS-CoV2) infections seem to have settled down, and we are now seeing waves of infections with new variants. As facemasks come off and isolation rules end, everybody has higher chances of catching other respiratory infections, such as RSV (respiratory syncytial virus) and influenza (flu). SCDAA’s Medical and Research Advisory Committee (MARAC) endorses a shared-decision-making process about vaccines and treatments but would like to offer unbiased information to help in the decision-making process.

1. MARAC recommends that individuals with sickle cell disease and members of their households get all immunizations as they become available. Immunizations generally reduce the risks of severe infection and hospitalization, both for the individual receiving the immunization and for the people around them.

MARAC has specifically monitored news about COVID vaccines over the past 3 years to determine the side effect and benefits of immunization. The global experience with COVID immunizations spans hundreds of thousands of individuals with sickle cell disease, and we have only heard about side effects that are temporary and medically mild. Rare exceptions would be individuals with unusual allergies to vaccine ingredients.

2. If an individual with sickle cell disease catches COVID and has symptoms, we recommend that they strongly consider seeking anti-COVID treatment to reduce the chances of severe acute chest syndrome or other sickle cell problems. Individuals with sickle cell disease have a higher risk of hospitalization with COVID than the general population, especially when matched for the
same age.

3. MARAC highlights that giving corticosteroids (oral or IV) can often trigger a “rebound” pattern of sickle cell pain or sickle acute chest syndrome a couple days after the steroids stop. Steroids are widely used in general medical practice for symptoms of many kinds, including COVID and RSV. However, MARAC recommends that steroids should only be given to individuals with sickle cell disease under the advice of a sickle cell expert* who can carefully consider whether the scenario is worth the risk of steroid rebound sickle cell pain or acute chest syndrome.

MARAC is continuing to monitor the situation. Click here to download this statement.

None of the MARAC members receive funding for any COVID treatments or vaccines.

*To connect with a sickle cell expert, MARAC suggests the listings in the National Alliance of Sickle
Cell Centers. SCDAA MARAC and the National Alliance of Sickle Cell Centers are developing phone consultation resources.

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July 7, 2023 – SCDAA’s Medical and Research Advisory Committee (MARAC) notes that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended on May 26, 2023, that the conditional marketing authorization for crizanlizumab (Adakveo) be revoked. The EMA stated that this revocation was triggered by the findings of the Novartis STAND multinational clinical trial showing no significant benefit of crizanlizumab over placebo in reducing pain or hospitalizations. Novartis reports that there were no safety problems in STAND. Abstract PB2512 submitted to the 2023 European Hematology Association reports no new safety issues in Novartis’ post-marketing surveillance of over 5,000 patient-treatment-years.

Crizanlizumab was given United States Food and Drug Administration (FDA) approval in November 2019 and remains on the market in the U.S. Americans with sickle cell disease are still receiving this treatment. MARAC urges the FDA to keep crizanlizumab available for use in the U.S. while it awaits more detailed examination of the data so that individuals with sickle cell disease can benefit from this treatment.

Read the full statement here.

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Penicillin VK solution is suffering from intermittent supply shortages. This can affect children with sickle cell disease. Penicillin VK in liquid form is prescribed for babies and young children with sickle cell disease who are unable to swallow pills as standard care, twice a day, starting as early as 6-8 weeks of age. Children less than 3 years of age should receive oral penicillin 125 mg twice daily, and the dose should be increased to 250 mg twice daily for children older than 3 years.

WHY DO CHILDREN WITH SICKLE CELL DISEASE NEED PENICILLIN?

The strategy of using an antibiotic daily to prevent infection in people with lower immune defense is called prophylaxis. Without medical care, young children with sickle cell disease have extremely high risk of hospitalizations and death from infection. Strong scientific evidence shows that penicillin twice a day helps young children with sickle cell disease avoid an overwhelming bacterial infection, especially the bacteria called pneumococcus. Newborn screening diagnosis of sickle cell disease leading to penicillin prophylaxis are the two fundamental starting points of sickle cell comprehensive care.

WHAT CAN THE HEALTH CARE TEAM DO ABOUT PENICILLIN SHORTAGES?

• Urge the manufacturers and distributors to improve the supply of penicillin so that we do not lose out on this effective, evidence-based standard of care.
• Prioritize sickle cell disease as an immune-compromised condition that has specific guidelines stating the necessity for penicillin prophylaxis.

WHAT DO FAMILIES DO ABOUT PENICILLIN SHORTAGES?

• Alternatives to penicillin liquid exist, although all are suboptimal. Discuss with your doctor:
  • Penicillin VK tablets, crushed (Miss out on residual uncrushed portions, takes time twice a day while the family is already busy with parenting a young child)
  • Penicillin G injection, once a month (Cannot be administered at home/requires visiting a medical facility, needle stick)
  • Other alternative antibiotics: Amoxicillin 20mg/kg/day or Erythromycin (Broader effects on normal bacteria than penicillin, supply shortages might also be a problem)
• Make sure your child has all immunizations as recommended for sickle cell disease. SCDAA MARAC strongly encourages full immunization, especially pneumococcal vaccines PCV and PPSV-23.
• Fever needs prompt attention in individuals with SCD. Go to the Emergency Department (not urgent care) for blood counts, blood cultures and injection of a strong antibiotic like ceftriaxone.

HOW STRONG ARE THE RECOMMENDATIONS FOR PENICILLIN PROPHYLAXIS?

In the United States, penicillin prophylaxis is written into public health policy, National Institutes of Health guidelines and even state laws. Brazil, Canada, France, Italy, Jamaica, Ghana, Nigeria, Tanzania, Uganda, the United Kingdom and other countries have penicillin prophylaxis in their national guidelines for sickle cell disease.

IS IT SAFE TO GIVE ANTIBIOTICS DAILY?

Penicillin prophylaxis has an excellent track record and has been used to provide safe care to thousands of children for over 30 years. Studies have showed that giving penicillin prophylaxis continuously does not cause harmful bacteria to become antibiotic resistant. On-and-off periods of penicillin prophylaxis could cause antibiotic resistant bacteria to emerge. Penicillin was chosen for prophylaxis because it is focused on the pneumococcal bacteria that can cause problems in sickle cell disease.

IS PENICILLIN EXPENSIVE?

Penicillin is one of the oldest and most affordable antibiotics. Business analysts say that the low prices of penicillin make few companies motivated to manufacture penicillin.

For references and highlight points, download the full statement.

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December 6, 2022 — The Sickle Cell Disease Association of America (SCDAA) Medical and Research Advisory Committee (MARAC) shares the following:

For individuals with sickle cell disease and their caregivers

What is influenza, and why should I worry about it?

Influenza (“flu”) is a contagious viral infection that can cause severe medical problems in anyone. It is worse than a common cold. The problems are potentially bigger for individuals with sickle cell disease. Influenza can trigger sickle cell vaso-occlusive pain or acute chest syndrome. This means that influenza has a high chance

of sending you to the hospital and possibly to the intensive care unit with severe breathing problems. If you already have lung problems from asthma or from repeated acute chest syndrome, then influenza is even more likely to cause you to be severely ill.

What can I do?

Prevention Tip #1: MARAC strongly encourages all individuals with sickle cell disease (and their families) to get their flu shot every year. Although the shot might cause symptoms for a day or two (sore injection site, muscle aches and mild fever), these problems are small compared to the potential problems of influenza infection. To find a flu shot near you, visit vaccines.gov.

Prevention Tip #2: Wash your hands. Stay away from people who are coughing or sneezing or wear a mask around them.

Prevention Tip #3: During flu season, it is very important for individuals with sickle cell disease to take all their medications as prescribed. Hydroxyurea can protect against sickle cell pain or acute chest syndrome. Penicillin can protect against bacterial infection when a person is already weakened by influenza. Asthma medications can keep lungs functioning better.

If you think you have the flu, see your health care team early. If you can be diagnosed with influenza in the first 48 hours of the illness, you will probably be eligible to start a prescription treatment for influenza called oseltamivir (Tamiflu). Oseltamivir can shorten the course of influenza and reduce the risk of severe problems.

For health care providers and policymakers

Sickle cell disease has a high risk for complications and high morbidity from influenza (references 1-6 below). Sickle cell disease has both altered immune response and vulnerability to lung inflammation, triggering hospitalizations for acute chest syndrome, pain or other sickle cell complications. Health care providers should monitor sickle cell patients with influenza for possible acute chest syndrome. Acute chest syndrome is greatly

feared because it is the leading cause of death in sickle cell disease in the United States. Much of the clinical experience regarding sickle cell and the flu was gained from the 2009 H1N1 influenza but some is more recent, including a CDC report from 2021 (ref 2).

SCDAA MARAC notes that there is a national shortage of the treatment for influenza called oseltamivir (Tamiflu) and stewardship of its use is important. Oseltamivir reduces complications in influenza (Lee 2020, Wiemken 2021). MARAC recommends that sickle cell disease should be included in the list of conditions to prioritize for oseltamivir. Sickle cell disease is a rare disease nationally and might be overlooked in national policy because of its rarity. However, the special needs of sickle cell disease should be acknowledged.

For references and highlight points, download the full statement.

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The Sickle Cell Disease Association of America (SCDAA) Medical and Research Advisory Committee (MARAC) believes that progress in sickle cell disease (SCD) is tied to clinical trials and comprehensive care. For this reason, we encourage individuals with SCD to consider participating in research. It’s because thousands of courageous children and adults with sickle cell disease signed up for research that we have improved survival, developed new medicines and found possible cures. Download the full statement. 

I’ve been invited to be in a clinical trial – what should I know before I sign up?

Here are questions to ask if you are invited to be in a clinical trial. Many of these questions are answered in the informed consent papers – it will be lot to read, and it may be confusing, but it is worthwhile to pay attention and ask questions. You should always get a copy of the consent papers for your records.

1. What is the purpose of the study?
   There are many types of clinical research studies, but the goal of research is the same – to improve the lives and treatment of individuals with SCD. Some studies involve the use of new drugs. Others look at existing approved therapies to see whether they can be useful for SCD. Sometimes studies are simply questionnaires, X-rays and blood draws. Make sure to ask your physician about the trial’s purpose.
2. What kind of treatments and tests are involved in the trial?
   As mentioned above, the type and number of treatments differ for each clinical trial. During the trial, a lab technician may need to draw blood or perform an electrocardiogram to ensure that you are reacting well to the treatment. Ask your clinical care team about the treatments and tests you can expect throughout the trial process.
3. What are the possible risks or side effects of this treatment?
   Side effects vary by trial. You will be closely monitored throughout the clinical trial to ensure that any potential side effects are addressed. It is important to understand all the potential risks or side effects of the treatment before the trial begins.
4. How will the trial affect my daily life?
   Asking this question will help you be prepared for your upcoming treatment and plan your personal schedule during the trial. Each trial has a different schedule of care. How often do you have to come to the hospital or clinic? Will you have to stay in the hospital during the clinical trial? If so, how often and for how long? How far will you need to travel to take part in the trial?
5. Do I have to pay for any of the treatments? What costs will my health insurance cover?
   Talking to your health care team, as well as facility staff and your insurance company, will help you answer these questions. Your insurance plan should cover the standard of care or routine care associated with the trial. Research-specific tests and procedures will be paid by the sponsor the trial sponsor. Sometimes transportation assistance is provided and you may receive money to compensate for your time and effort.
6. Who will oversee my care while I am participating in the trial?
   Your care team will consist of a physician overseeing your participation as well as a team of nurses and research personnel assisting with your treatment and day-to-day care.
7. What questions should I ask about my other choices?
   What are my other treatment choices, including standard treatments? How does the treatment I would receive in this trial compare with other treatment options? What will happen to my SCD without treatment?
8. What questions should I ask about my decision process?
   How long do I have to make up my mind about joining this trial? Who can I speak with about questions during and after the trial? Can I talk to who has been in the trial? What if I decide to leave the trial?
9. What questions should I ask about my rights to privacy?
   How will my health information be kept private? What happens to my data if I decide to leave the trial? Be cautious about clinical research organizations that might want to sell your data to others and/or claim that you will pay less to participate in their trial.
10. If I benefit from this therapy, will I be allowed to continue receiving it after the trial ends? If I get a placebo, can I switch to the active drug?
    The design of some clinical trials allows patients to continue using the therapy as long as they are benefitting. Clarifying this question with your care team is important.

WATCH: “I participated in clinical trials. I would do it again.” (Video testimony from the National Institutes of  Health)

My friend was asked to participate in a clinical trial, and I wasn’t – why not?

• Certain kinds of clinical research study new medications with unknown side effects, so they focus on people who are the least likely to be harmed by the new medication. For example, many studies do not accept older people, or individuals who have kidney/liver problems, asthma, are pregnant, heart problems or a high risk for bleeding.
• If you have not come regularly for sickle cell care or had difficulty taking medications on their prescribed schedule, the research investigators will wonder whether you will follow the rigid schedule of a clinical research study. You may have had valid reasons such as medication side effects or transportation issues. Discuss these barriers with the study team. They may be able to help.
• Advocate for Ask your doctor(s) whether you are eligible for any clinical research. Some busy doctors simply need a reminder. Others might not have a research study open for enrollment but could refer you to a nearby clinical research group.
• Go to a specialty sickle cell Clinical research requires a lot of expertise. You might need to find a specialty center with the right level of resources to offer research studies. Consider going at least once a year to an academic, reputable sickle cell center.
• You might seek out clinical research that does not exclude Surveys, questionnaires and registries can help to change health care systems or set the stage for future research.

How do I find more clinical research opportunities?

• Ask your doctor(s) whether you are eligible for any clinical research
• Visit ClinicalTrials.Gov, a government sponsored listing of all approved clinical trials in the U.S. and some abroad.
• Ask your local SCDAA member organization (or the patients’ organization you belong to) whether they have news about SCD clinical research in your region.
• Seek studies using clinical research finders for sickle cell on the SCDAA website and oneSCDvoice.com.
• Many registries study SCD using regular questionnaires. The SCDAA Get Connected Registry is being set up to serve this Registries may also try to relate symptoms with blood tests or genetic tests to lay a foundation for better preventive care in the future.

I’m nervous about participating in clinical research – isn’t it risky?

Clinical research participation today looks very different from the past. Many feel nervous about clinical trials after learning about problems with the Tuskegee syphilis project and the HELA cells from Henrietta Lacks. Know that modern clinical trials are set up with layers of safeguards for patients and opportunities to ask questions. Sponsors of clinical trials keep the interest of patients as a priority. Extra cautions are taken to protect children as research participants. Another new feature of clinical research is the community advisory boards for research studies and SCD research networks. Many individuals with SCD now serve on these boards and you can too.

Can clinical trials replace my regular sickle cell care?

All individuals with SCD should have regular health care appointments, but you should make sure check in with your care team before and after participating in a clinical trial. Comprehensive sickle cell care is available because of those who participated in past research. Honor those who came before you by taking care of yourself.

LEARN MORE:

Questions to ask – adapted from https://www.cancer.gov/about-cancer/treatment/clinical-trials/questions, and from https://sarahcannon.com/blog/entry/7-questions-to-ask-when-considering-a-clinical-trial accessed 9/15/22.

Here are links that describe the features of clinical research studies:

• Find a clinical trial near you SCDAA
• ASH-CTN
• Proudford Foundation
• CURE Sickle (focuses on curative therapies clinical research)
• Cayenne Wellness
• British Health Inequalities Program (requires registration)

G Puppalwar, M Mourya, G Kadhe, A. Mane. Conducting clinical trials in emerging markets of sub-Saharan Africa: review of guidelines and resources for foreign sponsors. Open Access Journal of Clinical Trials, 7 (2015), pp. 23-34

*MARAC is a diverse group of SCD providers who have volunteered to provide SCDAA and the sickle cell community with trustworthy advice. The primary advice of SCDAA MARAC is directed toward the sickle cell population in the United States, but we recognize frequent implications for other countries and recognize there is wisdom to gain from other countries.

**SCDAA is the leader in promoting and advancing initiatives focused on people affected by sickle cell conditions worldwide. SCDAA is the largest national community-based organization for sickle cell disease. For 50 years SCDAA and its more than 50 member organizations have demonstrated how community-based organizations can work as partners with medical facilities and local and state government agencies to pursue national health care objectives.

Who is watching over the study?

• IRB (Institutional Review Board) – A special group at a medical center that watches over clinical research safety.
• DSMB (Data Safety Monitoring Board) – They regularly go over all study data looking for new problems with safety and whether the study should continue.
• DSMC (Data and Safety Monitoring Committee) – Similar responsibilities as the DSMB.
• FDA (Food and Drug Administration) – United States government agency that is responsible for drug safety.

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August is National Immunization Awareness Month. What does that mean for individuals with sickle cell disease (SCD)?

The Big Picture from SCDAA MARAC
Individuals with sickle cell disease are more likely to have complications from many infections and receive a lot of benefit from immunizations. Family members can help protect a child or adult with sickle cell disease by also getting immunizations.

More Information
Immunizations and vaccines protect people from serious disease. The possible risks from a vaccine are much smaller than the possible bad outcomes from the diseases.

Streptococcus Pneumoniae

• Streptococcus pneumoniae bacteria was a leading cause of death for children with SCD.
• Infection with Strep pneumo can move quickly from fever to extremely sick in the intensive care in just a few hours for children with SCD. Losing spleen function due to clogging of the spleen with sickle red blood cells is what makes Strep pneumo bacteria so dangerous for SCD patients.
• Immunizations against Strep pneumo are important for every child, and extra immunizations are recommended for individuals with SCD: Pneumovax-23 and PCV20.

Monkeypox (MPV)

• MARAC monitoring has not found any unusual monkeypox problems in individuals with sickle cell disease. If anybody hears of unusual events with monkeypox and sickle cell disease, please pass along this information to the SCDAA Chief Medical Officer Dr. Lewis Hsu at info@sicklecelldisease.org.
• MARAC encourages anyone with symptoms of monkeypox (MPV) to see a health care provider to get tested. If you do not have access to a provider, visit findhealthcarecenter.hrsa.gov to get connected.
• There is a vaccine available for those who are at highest risk. If you are experiencing any symptoms contact your health care provider, avoid close contact with others and take a break from sex, going out to bars, gyms, clubs and other events. Do not share personal items, wash your hands and clean shared surfaces regularly.

COVID-19

• The latest data continues to show that SCD does have increased vulnerability to severe COVID.
• COVID can trigger SCD symptoms like vaso-occlusive pain or sickle acute chest syndrome.
• MARAC strongly urges everyone with SCD and their families to get vaccinated and get all recommended boosters. In addition, you should consider wearing a mask, avoiding crowds and standing at least six feet away from other people.
• Do not attend social events if you have symptoms of COVID-19 or tested positive for COVID 5 days prior, even if you’re vaccinated.
• If you do catch COVID, SCD is among the conditions eligible to receive treatments to reduce the risk of getting severe disease and hospitalization. Contact your health care provider.

Influenza (the Flu)

• MARAC encourages everyone to get immunized against influenza, especially individuals with SCD and their family members.
• Influenza can lead to severe illness in individuals with SCD. Influenza can trigger a vaso-occlusive painful event or acute chest syndrome. The risks of the immunizations are less than the risks of severe influenza disease.

Other diseases

• Immunizations against meningitis are very important in all individuals living with sickle cell disease.
• Children with sickle cell should all be immunized following the recommendations of the CDC and American Academy of Pediatrics. Childhood immunizations can help protect against diseases that are deadly or disabling, like measles, polio, mumps, whooping cough or rubella.
• There is currently an outbreak of Polio in communities with low rates of polio immunizations. Polio can cause permanent paralysis.
• In tropical areas with malaria, avoid mosquito bites and take anti-malarial medicines, especially young children with SCD. Malaria immunizations began to be offered in 2021.
• The risks of the immunizations are much smaller than the risks of these severe diseases.

Click here to download this MARAC statement.

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