Bone Marrow Transplantation in Fanconi Anaemia

Gluckman, Éliane; Devergié, A; Schaison, G; Bussel, A; Berger, Roland; Sohier, Jérôme; Bernard, J

doi:10.1111/j.1365-2141.1980.tb07178.x

Cited by 140 publications

(79 citation statements)

References 33 publications

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“…[12][13][14] In other genomic instability syndromes, such as Fanconi anemia (FA), Nijmegen breakage syndrome (NBS) or DNA ligase IV deficiency, BMT has been successfully used. [15][16][17][18] In FA, continuous improvements to the approach to BMT over the last 20 years have resulted in reduced regimen-related toxicity, superior engraftment and less GVHD, leading to improved survival. [19][20][21] However, in contrast to BMT with HLA-identical siblings, using alternate donors has been markedly less successful, due to the high rates of graft failure, regimen-related toxicity, GVHD and opportunistic infection.…”

Section: Introductionmentioning

confidence: 99%

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

Pietzner¹,

Merscher²,

Baer³

et al. 2016

Bone Marrow Transplant

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Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a coconditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host-conditioning regimen together with TBI (0.2-2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose-dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of γ-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atmdeficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model.

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Section: Introductionmentioning

confidence: 99%

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

Pietzner¹,

Merscher²,

Baer³

et al. 2016

Bone Marrow Transplant

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“…It has been difficult to optimize transplant protocols for patients with FA. Standard regimens are too toxic for patients with FA, 6,7 but the graft will fail if the conditioning is too mild. Effective regimens have been developed.…”

Section: Introductionmentioning

confidence: 99%

Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants

Rosenberg

Socié

Alter

et al. 2005

Blood

252

241

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Hematopoietic stem cell transplant (SCT)is currently the only therapy that can restore normal hematopoiesis in patients with Fanconi anemia (FA). Patients with FA have a high baseline risk of squamous cell cancers (SCCs) of the head, neck, and esophagus, and SCT conditioning may increase SCC incidence. We evaluated the risks of SCC and death in 145 patients with FA in the North American Survey (NAS) cohort who did not receive transplants, and 117 patients with FA in the Hô pital Saint Louis (SLH) cohort who did receive transplants. The age-specific hazard of SCC was 4.4-fold higher in patients who received transplants than in those who did not (P ‫؍‬ .003), and SCCs occurred at significantly younger ages in the former (respective medians, 18 and 33 years, P ‫؍‬ .004). Survival after SCC was similarly poor in both cohorts (P ‫؍‬ .135, median, 13 months). The hazard of SCC increased at a greater than linear rate, to 4.4% per year by age 40 in NAS and 4.7% per year by 10 years after transplant in SLH. In SLH, the hazard of non-SCC death was biphasic, declining significantly (P ‫؍‬ .004) from 7.1% per month during the first 6 months after transplant to 0.13% per month (1.6% per year) after the first year. Acute and chronic graft-versushost diseases were significant SCC risk factors. Adverse event rates in these cohorts provide historical control rates to assess emerging therapies for FA. IntroductionFanconi Anemia (FA) is an autosomal recessive genomic instability syndrome 1 associated with congenital abnormalities, progressive pancytopenia, and a predisposition to cancer. 2 Acute myeloid leukemia (AML) is the most frequent cancer of FA, 3 but a number of specific solid tumors occur at remarkably high rates in patients with FA who survive to adulthood, notably squamous cell cancers (SCCs) of the head, neck, and esophagus, and vulvar and cervical cancer in women. 4,5 Hematopoietic stem cell transplant (SCT) is currently the only therapy that can restore normal hematopoiesis in FA. It has been difficult to optimize transplant protocols for patients with FA. Standard regimens are too toxic for patients with FA,6,7 but the graft will fail if the conditioning is too mild. Effective regimens have been developed. 8 However, in non-Fanconi patient populations, conditioning increases the incidence of certain tumors, 9-14 especially SCCs, that occur at high baseline rates in FA. The occurrence of these cancers in Fanconi patients following SCT has been an ongoing concern. [15][16][17][18][19][20] Two methodological issues affect risk assessment in patients with FA who receive transplants. First, SCT protocols for patients with FA are institution-specific, and when protocols are enhanced over time, a number of modifications may be made at once. However, secondary solid tumors and some transplant-related deaths occur years after transplant. Therefore, the ultimate assessment of any new protocol must compare adverse event rates that manifest over time to corresponding rates in the past, for instance, using historical controls. ...

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“…Although many different therapies, including gene therapy, have been tried, the only curative modality for the bone marrow failure is haemopoietic stem cell transplantion (SCT). Conventional doses of alkylating agents used in the conditioning regimen, particularly the use of cyclophosphamide at 200 mg/kg, and irradiation produce high toxicity 6,7 and an increased rate of malignancies (42% by 20 years) 8,9 when compared with patients with idiopathic aplastic anaemia (IAA). The high occurrence of severe graft-versus-host disease (GVHD) is a significant cause of transplant-related mortality and appears in multivariate analysis as one of the most important risk factors for the development of secondary cancers.…”

mentioning

confidence: 99%

Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors

Fuente

Reiss

McCloy

et al. 2003

Bone Marrow Transplant

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Summary:Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m 2 ), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.

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Bone Marrow Transplantation in Fanconi Anaemia

Cited by 140 publications

References 33 publications

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants

Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors

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