Baseline TP53 mutations in Adults with SCD developing Myeloid Malignancy following Hematopoietic Cell Transplantation

Ghannam, Jack; Xu, Xin; Marić, Irina; Dillon, Laura W.; Li, Yuesheng; Hsieh, Matthew M.; Hourigan, Christopher S.; Fitzhugh, Courtney D.

doi:10.1182/blood.2019004001

Cited by 34 publications

(38 citation statements)

References 22 publications

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“…One patient had two HPCTs, and the other patient had a very slow autologous recovery after graft failure. This low frequency of pre‐malignant and malignant conditions post transplant is consistent with the current literature 34–36 …”

Section: Discussionsupporting

confidence: 91%

Non‐myeloablative human leukocyte antigen‐matched related donor transplantation in sickle cell disease: outcomes from three independent centres

et al. 2021

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Summary Non‐myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim‐mobilized peripheral blood HPC and sirolimus. The median follow‐up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle‐free survival at one and five years were 93% and 85% respectively. Age, sex, pre‐HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft‐versus‐host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle‐related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well‐tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.

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Section: Discussionsupporting

confidence: 91%

Non‐myeloablative human leukocyte antigen‐matched related donor transplantation in sickle cell disease: outcomes from three independent centres

et al. 2021

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“…In 1 report, 86 there were no late malignancies described among 30 patients with SCD conditioned with low-dose TBI; however, the follow-up was brief. Additionally, there were case reports describing malignancies (eg, myelodysplastic syndrome and acute leukemia) in patients with SCD after undergoing allogeneic transplantation with chemotherapy-based regimens 87 and low-dose TBI-based regimens 88,89 and in the absence of transplantation, 87,90 making attribution difficult. Only 1 report described the assessment of fertility after low-dose TBI in 31 patients and noted no effect on the hypothalamuspituitary-adrenal axis and no effect on male gonadal function (male participants underwent testicular shielding).…”

Section: Recommendationmentioning

confidence: 99%

American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation

et al. 2021

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Background: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. Methods: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. Conclusions: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

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“…A recent report found that TP53 mutant clones can be present at low frequency in SCD patients and may be associated with risk of myeloid malignancy in the context of allogeneic HSCT. 157 Both the WGS and WES studies were unable to detect low-frequency somatic clones, had limited clinical annotation, and did not include prospectively defined age-and ancestry-matched controls. The frequency of clonal hematopoiesis in SCD (and TDT) subjects based on highly sensitive detection methods (such as prospective targeted sequencing), identification of its risk factors, and evaluation of possible associations with clinical outcomes in non-transplant, allogeneic transplant, and autologous transplant settings will require future study.…”

Section: Risk For Malignancymentioning

confidence: 99%

“…The frequency of clonal hematopoiesis in SCD (and TDT) subjects based on highly sensitive detection methods (such as prospective targeted sequencing), identification of its risk factors, and evaluation of possible associations with clinical outcomes in non-transplant, allogeneic transplant, and autologous transplant settings will require future study. 157 The two recent cases of myeloid malignancy in SCD subjects who had received autologous hematopoietic transplant with lentiviral globin gene addition following myeloablative therapy may be instructive. In one case the malignant clone lacked a viral insertion, while in the other case a viral insertion was present but not adjacent to known oncogenes or tumor suppressors and without evidence of adjacent gene expression changes.…”

Section: Risk For Malignancymentioning

confidence: 99%

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy

Rosanwo

Bauer

2021

Molecular Therapy

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Baseline TP53 mutations in Adults with SCD developing Myeloid Malignancy following Hematopoietic Cell Transplantation

Cited by 34 publications

References 22 publications

Non‐myeloablative human leukocyte antigen‐matched related donor transplantation in sickle cell disease: outcomes from three independent centres

Non‐myeloablative human leukocyte antigen‐matched related donor transplantation in sickle cell disease: outcomes from three independent centres

American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy

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