7. Progenitor cells trapped in marrow filters can reduce GvHD and transplant mortality. Vicente D, Podestà M, Pitto A, Pozzi S, Lucchetti S, Lamparelli T, Tedone E, Ibatici A, Figari O, Frassoni F, Van Lint MT, Piaggio G, Sacchi N, Bacigalupo A. Bone Marrow Transplant. 2006;38:111-7.

This is a novel study. The investigators changed their protocol for the administration of stem cells for HSCT. Previously the stem cell products were filtered at the bedside and the filters discarded after infusion. More recently, in order not to lose progenitor cells that were trapped in the filter, the authors washed the marrow filters after infusion, counted the progenitor cell colonies from cells trapped in the filters and then added back the cells that were recovered.

The aim of the study was to evaluate HPC content in the filters and to assess the outcome of transplants with filter-discarded or filter-recovered cells. Haemopoietic progenitors were grown from filters of 19 marrow transplants. The authors then compared the outcome of 39 filter-recovered transplants from HLA-identical siblings (years 2001-2004) with a matched cohort of 43 filter-discarded marrow grafts (years 1997-2000). Filters contained on average 21% long-term culture-initiating cells (LTC-IC) and 15% fibroblasts colony-forming units (CFU-F) of the total progenitor cell content. Filter-discarded transplants had significantly more grade II-IV graft-versus-host disease (GvHD) (42 vs 15%, P=0.008) as compared to filter-recovered transplants, and more transplant-related mortality (TRM) (20 vs 3%, P=0.04). The actuarial survival at 5 years is 69 vs 87%, respectively (P=0.15).

This study suggests that a significant proportion of LTC-IC is lost in the filters together with CFU-F. Recovery and add back of progenitors trapped in the filters may reduce GvHD and TRM.

8. Additional quite recent articles of note about GVHD:

Incidence and outcome of chronic graft-versus-host disease using National Institutes of Health consensus criteria. Jagasia M, Giglia J, Chinratanalab W, Dixon S, Chen H, Frangoul H, Engelhardt B, Goodman S, Greer J, Kassim A, Morgan D, Ruffner K, Schuening F. Biol Blood Marrow Transplant. 2007;13:1207-15.

The clinical spectrum of acute graft-versus-host disease. Deeg HJ, Antin JH. Semin Hematol. 2006;43:24-31.

Update on the management of acute graft-versus-host disease. Bolaños-Meade J. Curr Opin Oncol. 2006;18:120-5.

Diagnosis and treatment of chronic graft-versus-host disease. Gilman AL, Serody J. Semin Hematol. 2006;43:70-80.

Chronic graft-versus-host disease. Cutler C, Antin JH. Curr Opin Oncol. 2006;18:126-31.

9. Rituximab responsive refractory acute graft-versus-host disease. Kamble R, Oholendt M, Carrum G. Biol Blood Marrow Transplant. 2006; 12:1201-2.

The authors describe 3 patients who received rituximab with complete improvement in acute GVHD.

The first patient developed grade III aGVHD after a PBSCT for refractory diffuse large B cell lymphoma. On day +12, she developed grade III aGVHD and on day +27 she developed severe transplant-associated TTP manifesting as seizure, encephalopathy, brain edema, renal failure, fever, and thrombocytopenia that failed to respond to methyl prednisone and 26 sessions of plasmapheresis. Rituximab was initiated for refractory TTP on day +58 while plasma exchange was continued. After 3 doses of weekly rituximab, there was resolution of TTP. At the time of rituximab, the patient also had active grade III aGVHD (skin grade IIII, biopsy-proved gut aGVHD with ≥2.0 L/day of diarrhea) that was refractory to steroids. Decreased GVHD was noted from day+79 with complete resolution on day+95. Steroids were progressively tapered and beyond 100 days she had limited cGVHD involving the skin that was well controlled on oral prednisone at 10 mg/day.

Incidental improvement in aGVHD with rituximab prompted its use in 2 additional patients with aGVHD that was refractory to multiple immunosuppressants. Complete resolution of aGVHD occurred on 16 and 15 days.

The decrease in aGVHD after B cell depletion is intriguing and raises questions concerning its pathogenic role.

10. How I Treat Refractory Acute GVHD. H Joachim Deeg. Blood First Edition Paper, prepublished online January 18, 2007; DOI 10.1182/blood-2006-12-041889.

The author provides a comprehensive discussion of Acute GVHD with emphasis on the management of refractory cases. The manuscript includes a discussion of (1) Pathology and Risk Factors, (2) Incidence of Acute GVHD, (3) Classification of GVHD and (4) Primary Therapy.

However, most of the article consists of a detailed discussion of Secondary Therapy (Steroid-Refractory GVHD). A table provides a summary of available agents and their preferred use for secondary therapy. The author provides an extensive discussion of the pros and cons of the various possible therapies including ATG; monoclonal antibodies including anti-CD-2, anti-CD3, anti-CD5; HuM291 (visilizumab); anti-CD52 (alemtuzumab); immunotoxins, anti-TNFα (infliximab), chemotherapeutic/immunomodulatory drugs; pentostatin; sirolimus (rapamycin); tacrolimus or cyclosporine; phototherapy, extracorporeal photopheresis and mesenchymal stem cells. Detailed results of trials are provided as is a figure summarizing the Management of Acute GVHD.

The author summarizes by stating that, while many pilot studies have yielded encouraging response rates, in most of these studies long-term survival was not improved in comparison to that seen with the use of steroids alone. A major reason for failure has been the high rate of infections, including invasive fungal, bacterial and viral infections. It is difficult to conduct controlled prospective trials in the setting of steroid-refractory GVHD, and a custom-tailored therapy dependent upon the time after HCT, specific organ manifestations of GVHD and severity is appropriate. All patients being treated for GVHD should also receive intensive prophylaxis against infectious complications.

11. Chronic graft-versus-host disease (cGVHD) is more frequent due to changes in the practice of stem cell transplantation (ACT). Vogelsang GB Blood 2003;102:1149-1150.

The low incidence of GVHD following cord blood transplants takes on added significance as a result of a recent report emphasizing that chronic GVHD (cGVHD) is becoming more frequent after other approaches to hematopoietic cell transplantation. This is due to changes in transplantation practices with the use of peripheral blood instead of bone marrow, the use of donor lymphocyte infusions (DLIs) and the use of nonmyeloablative transplants (where DLI is frequently given). cGVHD is associated with decreased quality of life, impaired function status, and increased risk of non-relapse mortality and morbidity.

12. Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Mats Remberger, Dietrich W Beelen, Axel Fauser, Nadezda Basara, Oliver Basu, and Olle Ringden. Blood 2005;105:548-51.

The authors indicate that previously published reports have indicated a higher incidence of cGVHD after sibling PBSC, and that they have previously reported the initial results comparing PBSC with BM from unrelated donors at three centers. In this article, they report the long-term follow-up of a study including 214 patients receiving either peripheral blood stem cells (PBSC) or bone marrow from an HLA-A, -B and -DR-compatible unrelated donor. Median follow-up were 4.4 (2.3-7.3) and 5.0 (0.7-8.4) years in the two groups, respectively. The cumulative incidence of overall cGVHD was similar in the two groups (78% vs. 71%), while extensive cGVHD was significantly more common in the PBSC group compared to the BM group (39% vs. 24%, p=0.03). The five-year transplant-related mortality (TRM) was 37% in the PBSC group and 35% in the BM controls (p=0.7), and overall survival was 42% in both groups. The relapse incidences were 26% and 27% in the two groups, respectively, resulting in a disease-free survival of 41% in both groups. The authors conclude that PBSC from HLA-compatible unrelated donors results in similar outcome compared to BM, but an increased risk for extensive cGVHD.

13. Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved survival. Eapen M, Logan BR, Confer DL, Haagenson M, Wagner JE, Weisdorf DJ, et al. Biol Blood and Marrow Transplantation 2007;13:1461-1468.

The authors compared outcomes after 331 PBSC and 586 BM transplants in adults with leukemia and myelodysplastic syndrome who were followed for a median of 3 years after transplantation. The results of the study indicated that transplantation of PBSC was associated with higher rates of grade II-IV aGVHD and cGVHD than transplantation of BM. Mortality rates were higher in recipients with cGVHD regardless of the type of graft used for transplantation.

The presumed protective effect of GVHD in preventing recurrent leukemia was not observed in this study and in that of others even though rates of aGVHD and cGVHD were significantly higher after PBSC transplants. Unlike results after HLA-matched sibling donor PBSC transplants, the authors did not identify a survival advantage with PBSC grafts in patients receiving unrelated donor transplants for advanced leukemia.

The higher rate of cGVHD after PBSC transplants and, consequently, more frequent late adverse events warrant extended follow up of PBSC recipients.

14. Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Remberger M, Beelen DW, Fauser A, Basara N, Basu O, Ringdén O. Blood. 2005;105:548-51.

This is a report of a the long-term follow-up of 214 patients receiving either peripheral blood stem cells (PBSCs) or bone marrow (BM) from an HLA-A, -B, and -DR-compatible unrelated donor. Median follow-up was 4.4 (2.3-7.3) and 5.0 (0.7-8.4) years in the 2 groups, respectively. Cumulative incidence of overall chronic graft-versus-host disease (cGVHD) was similar in the 2 groups (78% vs 71%), while extensive cGVHD was significantly more common in the PBSC group compared with the BM group (39% vs 24%, P = .03). The 5-year transplant-related mortality was 37% in the PBSC group and 35% in the BM controls, and overall survival was 42% in both groups. The relapse incidences were 26% and 27% in the 2 groups, respectively, resulting in a disease-free survival of 41% in both groups.

The authors concluded that PBSCs from HLA-compatible unrelated donors results in similar outcome compared to BM but implies an increased risk for extensive chronic GVHD.

15. Chronic graft-versus-host disease: Pathogenesis and clinical management. Perez-Simon JA, Sanchez-Abarca I, Diez-Campelo M, Caballero D, San Miguel J. Drugs. 2006; 66:1041-1057.

This is a detailed review of chronic GVHD, the most common and severe complication among patients surviving >100 days after allogeneic transplantation. In a 16 page manuscript, the authors review the Pathogenesis, Clinical Management (Risk factors, Classification and When to treat) and Treatment (Current standard treatment, Current rescue therapy, Potential future strategies).

Among their conclusions are that clinical management of cGVHD requires the development and standardization of new grading systems that allow better classification and treatment of patients according to prognosis, and a comparison of the results of newer strategies.

The use of prednisone together with a calcineurin inhibitor, such as ciclosporin or tacrolimus, can be considered the standard regimen as primary treatment. To date, there is no standard salvage regimen for cGVHD and, accordingly, the best choice is to enter the patient into a clinical trial. Immunosuppressive drugs that decrease T cell activation or survival such as MMF, daclizumab, sirolimus and pentostatin have been used with promising results. In addition, the effect of anti-cytokine or anti-B cell agents such as etanercept or rituximab has also been explored. Newer strategies based on the selective depletion of alloreactive T cells and the use of immature dendritic cells and mesenchymal stem cells are being developed in order to generate immunotolerance.

16. Chronic graft-versus-host disease. Lee SJ, Vogelsang G, Flowers ME. Biol Blood Marrow Transplant 2003; 9:215-233.

This extensive review describes current concepts of the pathogenesis, clinical risk factors, classification systems, organ manifestations, and available treatments for cGVHD. Chronic GVHD remains a vexing and dangerous complication of allogeneic stem cell transplantation. Mild forms of cGVHD are often manageable with local or low-dose systemic immunosuppression and do not affect long-term survival. In contrast, more severe forms of cGVHD require intensive medical management and adversely affect survival. The authors also provide a comprehensive listing of the published clinical trials aimed at prevention and primary treatment of cGVHD.

17. 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.

18. 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).

19. 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.

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