CBF

Also see VIII. GRAFT-VERSUS-HOST DISEASE (GVHD); i. GVHD IN BMT AND PBSC HEMATOPOIETIC CELL TRANSPLANTS

  1. A protective gene for graft-versus-host disease. (Perspective) Cooke KR, Ferrara JLM.  New Eng J Med 2003;349;2183-2184.Extract

  2. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. Lin M-T, Storer B, Martin PJ, Tseng L-H, Gooley T, Chen P-J, Hansen JA. New Eng J Med 2003;349:2201-2210. Abstract

Lin et al analyzed nearly 1000 recipients of allogeneic hematopoietic stem cell transplants and their HLA-identical sibling donors for genetic variants of several cytokine genes. They show that a simple genetic test for a common variant in the promoter region of the interleukin-10 (IL10) gene can identify patients who are homozygous at this locus and are therefore at low risk for GVHD after stem-cell transplantation. These important findings are likely to change clinical practice. Knowledge of the IL10 genotype will help physicians to inform their patients about the relative risks after stem cell transplantation and will help to prioritize transplantation as a therapeutic option.

It is not yet clear whether IL10 genotypes will be important among recipients of transplants from unrelated donors. The relatively low rate of GVHD in Japan may be due to the fact that the frequency of the favorable IL10 allele is approximately 70 percent among Japanese people, as compared with 23-24 percent among North Americans.

Cooke and Ferrera envision a time in the near future when the genotyping of patients with respect to a panel of cytokines, chemokines, and adhesion molecules will complement traditional histocompatibility typing and increase our ability to predict the risk of transplant-related toxicity.

  1. Outbreaks of infectious diseases in stem cell transplant units: a silent cause of death for patients and transplant programmes. McCann S, Byrne JL, Rovira M, Shaw P, Ribaud P, Sica S, Volin L, Olavarria E, Mackinnon S, Trabasso P, VanLint MT, Ljungman P, Ward K, Browne P, Gratwohl A, Widmer AF, Cordonnier C; Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant. 2004;33:519-29. Abstract

The EBMT carried out a survey to investigate the occurrence of outbreaks of infection in stem cell transplant units and the impact on patient morbidity, mortality and the administration of the program over a 10-year period from 1991 to 2001. A questionnaire was sent to 505 EBMT stem cell transplant centers, but only thirteen centers responded. These centers reported 23 outbreaks of infection involving 231 patients: 10 bacterial, eight viral and five fungal outbreaks were reported and 56 deaths were attributed to infection. In all outbreaks, the infection was reported to be hospital acquired and in all the viral, and half the bacterial infections, cross-infection was a major factor. All viral, four of 10 bacterial and three of five fungal outbreaks occurred in HEPA filtered rooms. A total of 12 transplant units reported a partial or total closure. The authors suggested that the low number of responses to the questionnaire is most probably due to reluctance on the part of the transplant physicians to report such instances or failure to recognize infectious outbreaks in transplant units. They commented that it is clear from these limited data that hospital-acquired infection is still a problem and that cross-infection remains in issue, especially in viral outbreaks. They concluded that a specific, comprehensive approach to all infections in transplantation units should be implemented, reports of such events should occur in a standardized manner and prospective studies should be conducted to assess the efficacy of measures taken.

  1. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission. Kiehl MG, Kraut L, Schwerdtfeger R, et al. J Clin Oncol. 2004;22:2816-25.Abstract

The authors state that the role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. Accordingly, they analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor. Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). There was an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). They concluded that either a myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.

  1. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR Jr, Ringden O, Wagner JE. J Clin Oncol. 200415;22:4872-80.

The authors point out that, despite lack of data on PBSC transplantation in children, there has been a change in clinical practice, with increasing numbers of children receiving PBSC allografts. The investigators compared the results of 143 PBSC and 630 BM transplants from human leukocyte antigen-identical sibling donors in children aged 8 to 20 years with acute leukemia. PBSC transplant recipients were older, and were more likely to have advanced leukemia, receive growth factors post-transplantation, and have undergone transplantation more recently. Risks of acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, treatment failure (relapse or death), and overall mortality were compared using Cox proportional hazards regression to adjust for potentially confounding factors.

Results indicated that hematopoietic recovery was faster after PBSC transplantation. Risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSC transplantation. In contrast to reports in adults, treatment-related mortality, treatment failure, and mortality were higher after PBSC transplantation. Risks of relapse were similar.

The authors concluded that their data suggest poorer outcomes after PBSC compared with BM transplantation in children after adjusting for relevant risk factors.

  1. Allogeneic peripheral blood versus bone marrow transplantation: children are small adults and more. Wall DA. J Clin Oncol. 2004;22:4865-6.

The author comments on the above citation (#5) by Eapen et al that indicated that there was a higher rate of cGVHD and treatment-related mortality (with similar relapse risk) in children receiving PBSC compared with BM. Overall, there was poorer survival when PBSC were used as the donor source, even after adjusting for relative risks. She states that this is an unsettling finding, given that in 2003, close to 30% of pediatric matched sibling transplants reported to the IBMTR used PBSC as the donor source.

Dr. Wall states that the report by Eapen et al captures the early experience in pediatrics with the use of PBSC in the allogeneic setting. Some risk factors are difficult to define in retrospective surveys so that it will be important to repeat the analysis in the current practice setting an a prospective study, as is now under way in the Blood and Marrow Transplant Clinical Trials Network. To date, there is only a limited set of pediatric data and, based on the retrospective review by Eapen et al, the benefit of PBSC is in question.

A secondary observation in the Eapen article is the negative impact of early post-transplantation G-CSF administration on transplant outcome, as has been reported recently by Ringden et al (see citation #7, below). Patients who received G-CSF during the first 2 weeks post-transplantation to stimulate early neutrophil recovery had inferior outcome. This is another clinical practice that became established with limited prospective comparison trials and needs to be explored further.

  1. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Ringden O, Labopin M, Gorin NC, Le Blanc K, Rocha V, Gluckman E, Reiffers J, Arcese W, Vossen JM, Jouet JP, Cordonnier C, Frassoni F. J Clin Oncol. 2004;22:416-23.

The investigators studied 1,789 patients with acute leukemia receiving BMT and 434 patients receiving peripheral-blood stem cells (PBSCs) from HLA-identical siblings from 1992 to 2002. Among the BMT and PBSC patients, 501 (28%) and 175 (40%), respectively, were treated with G-CSF during the first 14 days after the transplantation. The outcome variables were entered into a Cox proportional hazards model.

The analysis indicated that BMT and PBSC patients treated with G-CSF had a faster engraftment of absolute neutrophils (P <.01), but platelet engraftment was slower (P <.001). In the BMT patients, acute graft-versus-host disease (GVHD) grades II to IV was 50% +/- 5% in the G-CSF group versus 39% +/- 3% in the controls (relative risk [RR], 1.33; P =.007, in the multivariate analysis). The incidence of chronic GVHD was also increased (RR, 1.29; P =.03).

G-CSF was associated with an increase in transplantation-related mortality (TRM; RR, 1.73; P =.00016). The data also indicated reduced survival (RR, 0.59; P <.0001) and leukemia-free survival rates (LFS; RR, 0.64; P =.0003), but no effect on relapse rate. No such effects of G-CSF were seen in patients receiving PBSC.

The authors concluded that, after BMT, platelet engraftment was delayed, and GVHD and TRM were increased. Survival and LFS were reduced. This suggests that G-CSF should not be given shortly after BMT.

  1. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bacigalupo A. Bone Marrow Transplant. 2005;35:225-31.

Antilymphocyte/thymocyte globulins (ALGs/ATGs) have now been used for over 30 years in the setting of hemopoietic stem cell transplants (HSCT), with the aim of preventing graft-versus-host disease (GvHD). This is true especially for transplants from alternative donors. The author reviewed published and unpublished data on the advantages and disadvantages of using ALG/ATG before or after an allogeneic HSCT. These studies show that ALG/ATG significantly reduces the incidence and severity of acute and chronic GvHD. Unfortunately, they also show that immune deficiency is more prolonged and infectious complication more frequent in patients receiving ALG/ATG. These data suggest the importance of aggressive monitoring of viral and fungal infections, in particular, the emerging problem of Epstein-Barr virus (EBV) infections and EBV-related lymphoproliferative disorders. The author suggests that ALG/ATG has an important role in allogeneic HSCT, especially today with the increasing use of peripheral blood transplants and the consequent high risk of chronic GvHD. However, ALG/ATG should be used with caution, and the negative consequences must be understood and possibly prevented.

  1. Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Hanash AM, Levy RB. Blood. 2005;105:1828-36.

The authors indicate that efforts to reduce GVHD by removing donor T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic hematopoietic stem/progenitor cell engraftment without inducing GVHD could increase numbers of potential recipients while broadening the pool of acceptable donors. CD4(+)CD25(+) regulatory cells (T-reg's) were examined for their capacity to support allogeneic hematopoietic engraftment. In a murine fully major histocompatibility complex (MHC)-mismatched BMT model, cotransplantation of donor B6 T-reg's into sublethally conditioned BALB/c recipients supported significantly greater lineage-committed and multipotential donor progenitors in recipient spleens 1 week after transplantation and significantly increased long-term multilineage donor chimerism. Donor engraftment occurred without GVHD-related weight loss or lethality and was associated with tolerance to donor and host antigens by in vitro and in vivo analyses.

The authors conclude that donor CD4(+)CD25(+) T cells may represent a potential alternative to unfractionated T cells for promotion of allogeneic engraftment in clinical hematopoietic cell transplantation

  1. Life-threatening neurological complications after bone marrow transplantation in children. Uckan D, Cetin M, Yigitkanli I, Tezcan I, Tuncer M, Karasimav D, Oguz KK, Topcu M. Bone Marrow Transplant. 2005;35:71-6.

The reported incidence of neurological complications in transplant patients varies greatly among different centers, ranging from 11 to 59%. They are reported to be the main causes of death in 10-15%. The authors point out that, in patients with sickle cell disease with a previous history of stroke, neurological complications have been reported to occur in 50% of patients during the transplant period.

In this study, life-threatening neurological complications were seen in 11 out of 113 (9.7%) children who underwent BMT from HLA-matched family (n=7) or mismatched donors (n=4). Eight of the 11 patients developed the neurological complication when critically ill with a non-neurological condition, and the neurological event probably contributed to death. In the remaining three patients, the neurological events were followed by worsening of the patient's clinical status. Events occurred between days +13 and +85 after transplantation. Minor symptoms including reversible, nonrepetitive seizures were excluded. Cyclosporine A toxicity was diagnosed in six children. The rest of the complications were brain abscess/meningo-encephalitis (two), severe hypomagnesemia (one), busulfan toxicity (one), sustained hypertension (three), and intracranial hemorrhage (three). Six patients with neurological complications suffered from >grade II graft-versus-host disease (GvHD), and all were high risk for transplant-related complications.

Important adverse factors for the development of severe life-threatening neurological complications were status of the underlying disease, mismatched transplantation, a diagnosis of AML (advanced stage), older age and >grade II GvHD.

  1. Progressive neurological dysfunctions twenty years after allogeneic bone-marrow transplantation for Chediak-Higashi syndrome. Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, Fischer A. Blood  2005;106:40-42.

The authors reported three patients with Chediak-Higashi syndrome who underwent allogeneic bone marrow transplantation between the ages of 2 9/12 and 7 years. The outcome was uneventful, with sustained mixed chimerism. However, at the age of 22 to 24 years, these three patients developed a neurological deficit combining difficulty walking, loss of balance and tremor. Neurological evaluation demonstrated cerebellar ataxia and signs of peripheral neuropathy. Moderate axon loss and rarefaction of large myelinated fibers were observed on semi-thin sections of peripheral nerve. Cerebellar atrophy was detected by cerebral magnetic resonance imaging in two patients.

The authors also reviewed the very long-term outcome of the other 11 patients with Chediak-Higashi syndrome who had received bone-marrow transplants at their center since 1981. All displayed neurological deficits or low cognitive abilities.

  1. Parasitic central nervous system infections in immunocompromised hosts. Walker M, Zunt JR. Clin Infect Dis. 2005;40:1005-15.

Immunosuppression due to therapy after transplantation or associated with HIV infection increases susceptibility to various central nervous system (CNS) infections. This article discusses how immunosuppression modifies the presentation, diagnosis, and treatment of selected parasitic CNS infections, with a focus on toxoplasmosis, Chagas disease, neurocysticercosis, schistosomiasis, and strongyloidiasis.

  1. Post-transplant lymphoproliferative disorders. Gottschalk S, Rooney CM, Heslop HE. Annu Rev Med. 2005;56:29-44.

This is a detailed review of an important complication following transplantation. Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after hematopoietic stem cell or solid organ transplantation. Ninety percent of PTLDs are Epstein-Barr virus (EBV) positive (EBV-PTLD). The development of PTLD is linked to a deficient EBV-specific cellular immune response. The authors review the pathogenesis of EBV-PTLD, the incidence and risk factors, clinical presentation, pathology, the identification of patients at high risk, and treatment including novel immunotherapies using monoclonal antibodies and adoptive transfer of EBV-specific T cells. They conclude that PTLD remains a life-threatening disease, and early diagnosis and treatment are essential to assure good clinical outcome.