17. Peripheral blood progenitor cell or bone marrow transplantation: controversy remains. Koca E, Champlin RE. Curr Opin Oncol. 2008;20:220-6.

The paper compares bone marrow and peripheral blood progenitor cell transplantations in the allogeneic setting.

Peripheral blood progenitor cell (PBPC) use has emerged as an international standard of care for hematopoietic transplantation. These cells have a different cellular composition including higher numbers of CD34 cells and markedly higher numbers of T lymphocytes. Current data support the general safety of this approach for normal transplant donors.

Results consistently indicate more rapid hematopoietic recovery compared with bone marrow transplantation. This may result in improved early survival in adults with high-risk leukemias, but longer follow-up has demonstrated an increased rate of chronic graft-versus-host disease morbidity and mortality which may obviate the long-term benefit.

Most studies report a comparable rate of acute GVHD with allogeneic BMT and PBPC transplants, although an EBMT randomized study showed a significantly higher frequency of acute GVHD in allogeneic PBPC transplantation compared with BMT.

The majority of studies show a higher risk of chronic GVHD with PBPC transplantation and there remains uncertainty whether this will impact the rate of late mortality or affect the risk of leukemia relapse, because graft-versus-malignancy effects correlate with the presence of chronic GVHD. A survival advantage of PBPC transplantation was reported in some studies in patients with advanced leukemias. However, this advantage was not well documented in early leukemias.

[Comment: This article adds to the growing concern about the increased rate of chronic GVHD morbidity and mortality when using PBSCs for HSCT. For further information see Annotated Bibliography, Category 0, Top Ten articles, VIII Graft-Versus-Host Disease.]

18. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Przepiorka D, Anderlini P, Saliba R, Cleary K, Mehra R, Khouri I et al. Blood 2001; 98:1695-1700.

The incidence, characteristics, risk factors for, and impact of cGVHD were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited cGVHD occurred in 6% (95% confidence interval (CI), 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). When adjusted for disease status at the time of transplantation, high-risk cGVHD had an adverse impact on overall mortality (hazard ratio (HR), 6.6; P <.001) and treatment failure (HR, 5.2; P <.001) at 18 months. It was concluded that there is a substantial rate of cGVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk cGVHD adversely affects outcome.

19. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Mohty M, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L et al. Blood 2002; 100:3128-3134.

The authors analyzed the evolution of cGVHD in 101 patients. At a median follow-up of 45 months (range, 31-57 months), the 3-year cumulative incidence of cGVHD was 65% (95% confidence interval (CI) 51%-78%) in the PBSC group and 36% (95% CI 23%-49%) in the BM group (P =.004). Extensive cGVHD was more frequent in the PBSC group (44% (95% CI 30%-58%) vs 17% (95% CI 7%-27%); P =.004). The prevalence of cGVHD was always higher in the PBSC arm. Chronic GVHD required multiple courses of immunosuppressive therapy in addition to cyclosporine and corticosteroids during longer periods (P =.03). Altogether, this translated into longer periods of hospitalization after transplantation in the PBSC group (P =.04).

20. Chronic graft-versus-host disease: where do we go from here? Farag SS. Bone Marrow Transplant. 2004;33:569-77.

This is a review of the clinical manifestations, staging and risk stratification, and management of chronic graft-versus-host disease (cGVHD). The emphasis is on the details of management, including a list of agents with reported activity in "high-risk" and refractory cGVHD. Corticosteroids remain the most effective primary treatment of this condition, but for patients failing initial therapy, no standard therapy is available. A plethora of drugs have been reported to have activity and promise in this disease. However, the majority of reports are small retrospective studies, with few prospective trials. The author points out that cGVHD remains a significant cause of late morbidity and mortality following allogeneic stem cell transplantation.

21. New approaches for preventing and treating chronic graft-versus-host disease. Stephanie J. Lee, MD, MPH. Blood. 2005 Jun;105:4200-6.

This is a comprehensive yet succinct review (8 typed pages of text) that is notable for providing an extensive reference list (103 citations). The author repeats the gloomy comments made by others who have reviewed chronic graft-versus-host disease (cGVHD) following bone marrow or PBSC transplantation, i.e., despite improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over the last 25 years, cGVHD remains a substantial problem with little change in the incidence, morbidity, and mortality. In fact, with increased use of peripheral blood, transplantation of older patients, and less immediate transplant-related mortality, the prevalence of cGVHD may increase.

The review discusses rodent models, human pathophysiology, approaches to cGVHD prevention (choice of donor, graft source, and GVHD prophylaxis; prevention of acute GVHD; cGVHD prophylaxis; and pre-emptive treatment of minimal cGVHD). The author next discusses new approaches to treatment (elimination or inhibition of pathogenic T cells through pharmacologic therapy; inhibition of pathogenic T cells through cellular therapy; interventions to induce tolerance, cytokine therapy; elimination of B cells; and minimizing effects on target tissues).

(Comment: There is little discussion of cord blood transplantation in this review (one sentence and one reference citation). For information about GVHD following cord blood transplantation, see Annotated Bibliography, VIII. GRAFT-VERSUS-HOST DISEASE (GVHD), citation #6: "Various reports of unrelated cord blood transplants indicate an incidence of grades II-IV acute GVHD of 33%-44%, and an incidence of grades III-IV acute GVHD of 11%-22%. The incidence of chronic GVHD has ranged from 0% to 25%. These results are particularly notable since the majority of unrelated umbilical cord blood transplants were performed using 1 to 2 HLA-mismatched grafts. Although a majority of patients were young in these reports, the incidence of severe GVHD in adults receiving mismatched umbilical cord blood grafts has also been low.")

22. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Couriel D, Caldera H, Champlin R, Komanduri K. Cancer. 2004101:1936-46.

Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality in the hematopoietic stem cell transplantation setting, even in patients who receive human leukemic antigen (HLA) identical sibling grafts. Up to 30% of the recipients of stem cells or bone marrow transplantation from HLA-identical related donors, and most patients who receive cells from other sources will develop >Grade 2 aGVHD despite immunosuppressive prophylaxis.

In this review, the authors summarize the most current knowledge on the pathophysiology, clinical manifestations, and management of this potentially life-threatening transplantation complication.

They state that, in patients who survive aGVHD, the chronic form of this disease will cause significant morbidity and even death over months and years after transplantation. Once established, aGVHD is difficult to treat, and the best primary treatments have shown responses of approximately 50%. Once aGVHD becomes steroid-refractory the chances of survival are slim, whereas the possibility of further long-term complications from chronic GVHD is almost always the rule. Although a number of newer approaches are under intense investigation in murine models and in limited human preclinical and clinical trials, none are close to emerging as standard methods that may be used routinely to decrease the incidence of GVHD. Therefore, GVHD is the major barrier to successful allogeneic stem cell transplantation. Additional research efforts should be directed toward prevention, because, once established, the outcome of aGVHD is dismal.

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