Homozygous α‐thalassemia: Challenges surrounding early identification, treatment, and cure

Pecker, Lydia H.; Guerrera, Michael F.; Loechelt, Brett; Massaro, An N.; Abraham, Allistair; Fasano, Ross M.; Meier, Emily Riehm

doi:10.1002/pbc.26163

Cited by 9 publications

(4 citation statements)

References 23 publications

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“…This may be due to multiple variables including the challenges of identifying a suitable donor for postnatal stem cell transplantation. 36 Recognizing the challenges of identifying a donor and the associated morbidity of this treatment, we are currently testing the safety and efficacy of in utero transplantation for ATM. 13 Gene therapy or editing strategies to enable alpha-globin production in red blood cells could also be developed.…”

Section: Discussionmentioning

confidence: 99%

The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry

et al. 2023

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Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally and 11 were diagnosed postnatally: all 11 spontaneous survivors' genotypes had preserved embryonic zeta globin. We compared three groups of patients; Group 1 were prenatally diagnosed and alive at hospital discharge (n=14), Group 2 were prenatally diagnosed and deceased perinatally (n=5), Group 3 were postnatally diagnosed and alive at hospital discharge (n=11). Group 1 had better outcomes than Groups 2 and 3 in resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation correlated with higher neurodevelopmental (Vineland-3) scores (r= -0.72, P=0.02). Preterm delivery after IUT was seen in 3/16 (19%) of patients who continued their pregnancy. When we combined our data with those from two published series, patients who received ≥2 IUTs had better outcomes than those with 0-1 IUT, including resolution of hydrops, delivery ≥34 weeks' gestation, and 5-minute Apgar scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT versus 5/13 of the 0-1 IUT group (OR 2.74; P=0.01). Thus, fetal transfusions enable survival of patients with ATM with normal neurodevelopment even in patients presenting with hydrops. Non-directive prenatal counseling of expectant parents should include the option of IUTs.

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Section: Discussionmentioning

confidence: 99%

The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry

et al. 2023

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“…28 The other patient died of fungal infection and severe graft-versus-host disease after HSC transplantation at the age of 13 y (4 mo after transplantation). 58 and in 26 of 41 patients transfused in utero. Although the proportion of patients suffering from severe growth retardation varies between age groups, 31% (12/39) are severely affected by weight and height; an additional 8% (3/39) have severely affected weight, and an additional 20% (9/44) have severely affected height (weight/height #3rd centile).…”

Section: Long-term Growth Outcomesmentioning

confidence: 97%

“…used for the conditioning regimen, were noted in 3 patients. Of the 4 unsuccessfully treated cases, HSC transplantations resulted in lethality in 1 case 58 and were unsuccessful because of graft rejection in 3 patients, who remain transfusion dependent. A total of 53 of 69 patients (77%, Table 2) are transfusion dependent and the majority of these patients have been regularly transfused starting from a few days to a few weeks after birth.…”

Section: Current Treatmentsmentioning

confidence: 99%

An international registry of survivors with Hb Bart's hydrops fetalis syndrome

Songdej

Babbs

Higgs

2017

Blood

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Hemoglobin (Hb) Bart's hydrops fetalis syndrome (BHFS) resulting from α-thalassemia is considered a universally fatal disorder. However, over the last 3 decades, improvements in intrauterine interventions and perinatal intensive care have resulted in increasing numbers of BHFS survivors. We have initiated an international registry containing information on 69 patients, of which 31 are previously unpublished. In this perspective, we analyze the available clinical information to document the natural history of BHFS. In the future, once we have accrued sufficient cases, we aim to build on this study and provide information to allow counseling of at-risk couples. To date, 39 patients have survived beyond the age of 5 years, 18 of whom are now older than 10 years. Based on the available cases, we find evidence to suggest that intrauterine therapy provides benefits during the perinatal and neonatal period; however, it may not provide additional benefits to long-term growth and neurodevelopmental outcomes. Growth retardation is a major adverse long-term outcome among BHFS patients with ∼40% being severely affected in terms of weight and ∼50% in terms of height. There is also an increased risk of neurodevelopmental delay as we find 20% (11/55) of BHFS survivors suffer from a serious delay of ≥6 months. Most patients in the registry require lifelong transfusion and often have associated congenital abnormalities and comorbidities. This perspective is a first step in gathering information to allow provision of informed counseling on the predicted outcomes of affected babies.

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“…2 Other infants, such as those with a-thalassemia, begin to manifest symptoms of their disease even before birth. 3 Hence, when there is prenatal knowledge that such a disease exists, in utero HCT holds great promise for very early correction of the defect. 4 Unfortunately, clinical application of in utero HCT has been significantly limited by the inability to administer the traditional bone marrow "spacemaking" chemotherapeutics used in most postnatal HCT settings.…”

mentioning

confidence: 99%

Musical chairs: in utero HCT via mobilization

Dvorak

2016

Blood

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Homozygous α‐thalassemia: Challenges surrounding early identification, treatment, and cure

Cited by 9 publications

References 23 publications

The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry

The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry

An international registry of survivors with Hb Bart's hydrops fetalis syndrome

Musical chairs: in utero HCT via mobilization

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