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Setbacks and hopes for patients with Fanconi's anaemia
NEWS Setbacks and hopes for patients with Fanconi’s anaemia he European Group for Blood and Marrow Transplantation reports this month that the outcome in patients with Fanconi’s anaemia who undergo allogeneic stem-cell transplantation from HLA-matched unrelated donors is worse in patients with extensive congenital malformations than in those with limited malformations. More positively, other researchers report that gene therapy for the disorder may be possible. Fanconi’s anaemia is an autosomal disorder characterised by developmental abnormalities, bone-marrow failure, and cancer predisposition; it is usually lethal by age 20. Stem-cell reconstitution via HLA-matched bone-marrow transplantation is the only way to restore normal haematopoiesis in many patients. If a HLAmatched sibling donor is available, 5-year survival can be more than 70%; with unrelated donors, transplantations rarely succeed. Eliane Gluckman (Hôpital St Louis, Paris, France) and co-workers studied 69 patients who received bone-marrow transplants from unrelated HLA-matched donors. The overall 3-year survival rate was 33%. But although 3-year survival for
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patients with limited congenital malformations was 44%, for those with extensive malformations, it was only 14%. Positive cytomegalovirus serology in recipients, use of androgens before transplantation, and use of a female donor were also associated with worse survival (Blood 2000; 95: 422–29). The results, says Gluckman, indicate “a correlation between some gene mutations and the sensitivity of the patient’s cells to graft-versus-host disease, and to agents used for conditioning”. The investigators also report that although T-cell depletion of the donor bone marrow lessens the risk of graft-versus-host disease, patients given depleted grafts had no greater 3-year survival than patients given non-depleted grafts. This, the investigators say, is because “primary and secondary graft failures became the predominant cause of death” with Tcell-depleted grafts. However, the number of CD34-positive haematopoietic progenitor cells infused was significantly associated with neutrophil recovery in patients who received T-cell-depleted grafts. “Our finding argues in favour of trying to obtain as many CD34+ haematopoietic stem
cells as possible before the graft is processed”, they conclude. In separate study, Christopher Walsh (Gene Therapy Center, University of North Carolina at Chapel Hill, NC, USA) and colleagues report phenotypic correction of Fanconi’s anaemia by means of gene transfer. Human FANCC cDNA was introduced into bone-marrow cells harvested from mice nullizygous for FANCC, which have many of the features of Fanconi’s anaemia. The engineered cells were injected into wild-type mice whose marrow had been destroyed by irradiation and the transplanted mice were challenged with mitomycin C, an agent that causes pancytopenia in patients with Fanconi’s anaemia. Mice given FANCC-transduced cells maintained normal blood counts after mitomycin C administration, but the nullizygous control animals developed pancytopenia (Blood 2000; 95: 700–04). The researchers claim that their study is “relevant for the treatment of patients with Fanconi’s anaemia who do not have an HLA-matched donor for bone marrow transplantation”. Xavier Bosch
Long-term hepatitis C virus infection may not always cause liver disease ealthy individuals who are positive for hepatitis C virus (HCV) may be at less risk of progressive liver diseases than is generally thought, report Leonard Seeff (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA) and colleagues. These findings, says Seeff, suggest that many HCV-positive people, perhaps the majority, may “live out their days without serious liver disease” and ultimately die from other causes. In addition, he says, “our study provides the earliest recognition of HCV in the USA and suggests that the virus was around during World War II”. In their study, the researchers looked at the natural history of HCV infection in 8568 healthy
THE LANCET • Vol 355 • January 22, 2000
young military recruits by testing people died of liver diseases (Ann serum samples, collected between Intern Med 2000; 132: 105–11). 1948 and 1954, for antibodies to Donald Jensen (Rush-PresbyHCV and for HCV RNA. terian–St Luke’s Medical Center, 17 (0·2%) of Chicago, IL, USA) the samples were says that although positive for HCV. the study confirms During 45 years the observation of follow-up, liver that HCV may diseases occurred have a less aggresin two (11·8%) of sive natural histhe HCV-positive tory in healthy recruits and in 205 young individuals, (2·4%) of HCVit is perhaps “too negative recruits. Hepatitis C virus—not always deadly great a leap to Seven virus-posiimply that all tive and 2226 negative recruits had healthy HCV-infected persons may died by the end of 1996. One (5·9%) be at less risk for progressive dispositive recruit died of liver disease ease than is currently thought”. 42 years after the original phleKhabir Ahmad botomy; 119 (1·4%) HCV-negative Science Photo Library
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patients with limited congenital malformations was 44%, for those with extensive malformations, it was only 14%. Positive cytomegalovirus serology in recipients, use of androgens before transplantation, and use of a female donor were also associated with worse survival (Blood 2000; 95: 422–29). The results, says Gluckman, indicate “a correlation between some gene mutations and the sensitivity of the patient’s cells to graft-versus-host disease, and to agents used for conditioning”. The investigators also report that although T-cell depletion of the donor bone marrow lessens the risk of graft-versus-host disease, patients given depleted grafts had no greater 3-year survival than patients given non-depleted grafts. This, the investigators say, is because “primary and secondary graft failures became the predominant cause of death” with Tcell-depleted grafts. However, the number of CD34-positive haematopoietic progenitor cells infused was significantly associated with neutrophil recovery in patients who received T-cell-depleted grafts. “Our finding argues in favour of trying to obtain as many CD34+ haematopoietic stem
cells as possible before the graft is processed”, they conclude. In separate study, Christopher Walsh (Gene Therapy Center, University of North Carolina at Chapel Hill, NC, USA) and colleagues report phenotypic correction of Fanconi’s anaemia by means of gene transfer. Human FANCC cDNA was introduced into bone-marrow cells harvested from mice nullizygous for FANCC, which have many of the features of Fanconi’s anaemia. The engineered cells were injected into wild-type mice whose marrow had been destroyed by irradiation and the transplanted mice were challenged with mitomycin C, an agent that causes pancytopenia in patients with Fanconi’s anaemia. Mice given FANCC-transduced cells maintained normal blood counts after mitomycin C administration, but the nullizygous control animals developed pancytopenia (Blood 2000; 95: 700–04). The researchers claim that their study is “relevant for the treatment of patients with Fanconi’s anaemia who do not have an HLA-matched donor for bone marrow transplantation”. Xavier Bosch
Long-term hepatitis C virus infection may not always cause liver disease ealthy individuals who are positive for hepatitis C virus (HCV) may be at less risk of progressive liver diseases than is generally thought, report Leonard Seeff (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA) and colleagues. These findings, says Seeff, suggest that many HCV-positive people, perhaps the majority, may “live out their days without serious liver disease” and ultimately die from other causes. In addition, he says, “our study provides the earliest recognition of HCV in the USA and suggests that the virus was around during World War II”. In their study, the researchers looked at the natural history of HCV infection in 8568 healthy
THE LANCET • Vol 355 • January 22, 2000
young military recruits by testing people died of liver diseases (Ann serum samples, collected between Intern Med 2000; 132: 105–11). 1948 and 1954, for antibodies to Donald Jensen (Rush-PresbyHCV and for HCV RNA. terian–St Luke’s Medical Center, 17 (0·2%) of Chicago, IL, USA) the samples were says that although positive for HCV. the study confirms During 45 years the observation of follow-up, liver that HCV may diseases occurred have a less aggresin two (11·8%) of sive natural histhe HCV-positive tory in healthy recruits and in 205 young individuals, (2·4%) of HCVit is perhaps “too negative recruits. Hepatitis C virus—not always deadly great a leap to Seven virus-posiimply that all tive and 2226 negative recruits had healthy HCV-infected persons may died by the end of 1996. One (5·9%) be at less risk for progressive dispositive recruit died of liver disease ease than is currently thought”. 42 years after the original phleKhabir Ahmad botomy; 119 (1·4%) HCV-negative Science Photo Library
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