1. Chronic graft-versus-host disease (cGVHD) following unrelated donor hematopoietic stem cell transplantation (HSCT): higher response rate in recipients of unrelated donor (URD) umbilical cord blood (UCB). Arora M, Nagaraj S, Wagner JE, Barker JN, Brunstein CG, Burns LJ, Defor TE, McMillan ML, Miller JS, Weisdorf DJ. Biol Blood Marrow Transplant. 2007;13:1145-52.

Patients who underwent HLA matched or mismatched volunteer adult unrelated donor (URD) or unrelated UCB HSCT were evaluated; all consecutive patients who developed cGVHD were included. Adult URD transplants were performed in 123 patients and results were compared to those of 47 unrelated UCB transplants. The URD transplant recipients were significantly younger (median age 25 versus 39 years, P = .002), and the URD grafts were mostly HLA matched whereas the UCB transplants were not (67% versus 10%, P < .0001).

UCB recipients had more frequent responses to therapy (complete remission [CR] + partial remission [PR]) to treatment (URD 48% versus UCB 74% at 2 months [P = .005]; 49% versus 78% at 6 months [P = .001] and 51% versus 72% at 1 year [P = .03] in the URD and UCB groups, respectively). Nonrelapse mortality (NRM) after diagnosis of cGVHD was worse after URD grafts (1 year NRM 27% [19%-35%] URD versus 11% [2%-20%] UCB, P = .055). Separate multivariate analyses were performed in each cohort. In both, thrombocytopenia and no CR or PR at 2 months were independently associated with increased mortality. In addition, progressive onset of cGVHD was a significant predictor of increased mortality in URD cohort.

These data suggest that cGVHD following UCB transplant may be more responsive to therapy and also lead to a lower NRM.

2.Cutaneous manifestations of chronic graft-versus-host disease. Hymes SR, Turner ML, Champlin RE, Couriel DR. Biol Blood Marrow Transplant. 2006; 12:1101-13.

This is an article that, among other things, displays the cutaneous manifestations of cGVHD in 14 excellent color photographs. It is very informative and should be seen in the original. The authors use the lesional morphology of cGVHD to develop a classification system that may prove useful in early diagnosis. In addition, this approach may help to facilitate the correlation of different morphologic entities with outcome and response to therapy.

Traditionally, cGVHD has been defined as developing >100 days post-transplant. However, since the availability of new, less intensive preparative regimens and the use of donor lymphocyte infusions, it is not uncommon to see a delayed or late aGVHD (i. e., aGVHD >100 days) and, in some cases, overlapping aGVHD and cGVHD, or other “atypical” forms of cGVHD. Acute GVHD and cGVHD in the skin are more accurately diagnosed by clinical and, less frequently, histopathologic features. The authors describe, illustrate and summarize the diversity of cutaneous manifestations of cGVHD.

Cutaneous chronic graft versus host disease has traditionally been classified into lichenoid and scleroderma-like forms. However, the initial presentation is sometimes subtle and a variety of less common cutaneous manifestations may be prevalent. This clinical review lists 16 Clinical Patterns of cGVHD, such as xerotic, lichen planus-like, lichen sclerosus-like, papulosquamous/psoriasiform, poikiloderma, etc.

3. Umbilical cord blood transplantation: where do we stand? Wadlow RC, Porter DL. Biol Blood Marrow Transplant 2002; 8:637-647.

In both related and unrelated umbilical cord blood transplantation, as well as in cases of HLA-matched and –mismatched grafts, the incidence and severity of acute and chronic GVHD appear to be less than in conventional hematopoietic stem cell transplants. There are a number of studies that suggest that cord blood transplantation results in less GVHD compared to transplantation of cells from other sources, and no trial results have suggested that cord blood transplants increase the risk of GVHD.

4. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Grewal SS, Barker JN, Davies SM, Wagner JE. Blood 2003; 101:4233-4244.

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.

HLA mismatch has been the strongest risk factor for GVHD in recipients of marrow transplants. This association is less clear in cord blood transplants. Many series have failed to observe an influence of 0- to 3- antigen mismatch on the risk of acute or chronic GVHD. However, some authors have reported higher rates of acute GVHD with mismatched grafts, although not with chronic GVHD.

5. Hematopoietic stem-cell transplantation using umbilical-cord blood. Cohen Y, Nagler A. Leukemia & Lymphoma 2003; 44:1287-1299.

In pediatric patients, despite the frequent use of HLA mismatched grafts, incidence of grade III-IV acute GVHD (11-24% in the groups reviewed) was comparable to that reported for (well-matched) unrelated donor BMT. The influence of HLA disparity on incidence and severity of acute GVHD was controversial. In the Japanese and New York Blood Center (NYBC) studies, a higher degree of HLA-disparity was associated with an increased incidence of severe GVHD. These results conflict with other studies in which no correlation between GVHD and HLA disparity was apparent. Chronic GVHD rates varied between 9 (University of MN) and 31% (NYBC), compared to 42% at two years in unrelated donor BMT, and it was limited in extent in most cord blood transplants.

In adults, the probability of grade III-IV GVHD using cord bloods (ranging between 9 and 38%) was comparable to that reported in HLA-matched unrelated donor BMT despite the extensive use of HLA disparate grafts with cord bloods, There was no association between incidence of acute GVHD and the degree of HLA disparity. Chronic GVHD developed in about 30% of patients at risk in two large series.

6. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. Rocha V, Wagner JE, Jr., Sobocinski KA, Klein JP , Zhang MJ, Horowitz MM et al. N Engl J Med 2000; 342:1846-1854.

The authors studied the records of 113 recipients of cord blood from HLA-identical siblings and compared them with the records of 2052 recipients of bone marrow from HLA-identical siblings during the same period. The study population consisted of children 15 years of age or younger. They compared the rates of GVHD, hematopoietic recovery, and survival using Cox proportional-hazards regression to adjust for potentially confounding factors. Multivariate analysis demonstrated a lower risk of acute GVHD (relative risk, 0.41; P=0.001) and chronic GVHD (relative risk, 0.35; P=0.02) among recipients of cord-blood transplants. As compared with recovery after bone marrow transplantation, the likelihood of recovery of the neutrophil count and the platelet count was significantly lower in the first month after cord-blood transplantation (relative risk, 0.40 (P<0.001), and relative risk, 0.20 (P<0.001)), respectively. Mortality was similar in the two groups (relative risk of death in the recipients of cord blood, 1.15; P=0.43). The conclusion reached was that recipients of cord-blood transplants from HLA-identical siblings have a lower incidence of acute and chronic GVHD than recipients of bone marrow transplants from HLA-identical siblings.

i. GVHD IN BMT AND PBSC HEMATOPOIETIC CELL TRANSPLANTS

1. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E, Camitta BM, Champlin RE, Gale RP, Fuhrer M, Klein JP, Locasciulli A, Oneto R, Schattenberg AV, Socie G, Eapen M. Blood. 2007;110:1397-400.

We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation. In patients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P = .002) and overall mortality (RR 2.04; P = .024) were higher after transplantation of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM transplantations, respectively. Corresponding probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA-matched sibling donor transplantation for SAA.

2. Management of acute graft-versus-host disease. Bacigalupo A. Br J Haematol. 2007;137:87-98.

This is an authoritative and well-referenced review of acute GVHD. It includes discussion of pathogenesis and grading. A detailed review of preventative approaches includes discussion of HLA matching, T-cell depletion ex-vivo, T-cell depletion in vivo, expanding regulatory T cells, post-transplant immunosuppressive therapy, mesenchymal stem cells, inactivation of antigen presenting cells, reduced-intensity conditioning regimens, and anti-IL2 anti-TNF antibodies), Aspects of treatment that are reviewed include first-line treatment, second-line treatment, interleukin 2 receptor antibodies, anti-CD147 monoclonal antibody, RNF antibodies, pre-emptive treatment, cellular therapy of GVHD, and extracorporeal photopheresis.

The authors conclude that treatment of established GVHD is complex and has not made major advances in the last decade. It is possible that patients are treated too late, when tissue damage has already taken place and cytokine production by activated donor T cells and autologous macrophages can proceed undisturbed. It would seem that acute GVHD is, to a certain extent, self-programmed, since very early treatment with high dose corticosteroids and/pr ATG does not modify the natural course of the disease. Over the last three decades the risk of acute GVHD has been considerably reduced and by modifying the transplant program and the stem cell source. Now the need is to improve our ability to predict GVHD and develop new strategies of early treatment.

3. The management and outcome of chronic graft-versus-host disease. Fraser CJ, Scott Baker K. Br J Haematol. 2007;138:131-45.

This review focuses on therapeutic options for prevention, primary treatment, salvage therapy and supportive care. Issues pertaining to relevant outcome measures including impact on transplant-related mortality, relapse rates, quality of life, functional impairment and complications related to therapy are also reviewed. Numerous reference citations are included.

The authors point out that chronic GVHD is the leading cause of non-relapse mortality in transplant survivors and has a significant impact upon their functional status and quality of life. Despite significant advances being made in the field of HCT over the past 25 years, there has been little change in the incidence, morbidity and mortality of cGVHD. This is partly because of a lack of understanding about the pathogenesis of the disorder but also because a lack of well validated grading systems and outcome measures has hindered clinical research.

Standard primary treatment remains a combination of corticosteroids and calcineurin inhibitors. There is no standard therapy for those who fail to respond to corticosteroids. Many agents have been studied but there is an urgent need for systematic research to compare the efficacy of different approaches. Infection is the leading cause of death among patients with cGVHD so antimicrobial prophylaxis is mandatory. A multidisciplinary approach to the care of patients with cGVHD is essential to adequately address its effects on both physical and psychological functioning.

4. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, Smith V, Khouri I, Giralt S, de Lima M, Hsu Y, Ghosh S, Neumann J, Andersson B, Qazilbash M, Hymes S, Kim S, Champlin R, Donato M. Blood. 2006;107:3074-80.

Extracorporeal photochemotherapy (ECP) has been tested extensively in small cohorts of patients with chronic GVHD. This is a report of a retrospective study of 71 patients with severe chronic GVHD treated with ECP.

Response rate was 61% (n = 43), and 14 patients had complete responses (CRs). The best responses were observed in skin, liver, oral mucosa, and eye. Factors affecting outcomes were assessed in the less heavily pretreated subgroup (n = 63). Thrombocytopenia was associated with a lower response rate (P = .04), and there was a trend toward a higher response rate in de novo chronic GVHD.

At 6 months, a total of 27 (69%) of 39 patients who were alive continued to have a sustained response (CR 4 [10%] of 39, and partial response [PR] 23 [59%] of 39). The cumulative incidence of steroid discontinuation at 1 year was 22%. The overall survival since initiation of therapy was 53% at 1 year.

Response to ECP and platelet count at initiation of therapy were the strongest predictors of nonrelapse mortality (NRM) on univariate analysis. Objective responses were observed in a substantial number of patients with both skin and visceral chronic GVHD failing corticosteroids and other immunosuppression.

The authors also discuss previous reports of successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease (Greinix HT, et al., Blood 1998;92:3098-3104; Apisarnthanarax N, et al., Bone Marrow Transplant. 2003;31:459-65.)

5. Rituximab for steroid-refractory chronic graft-versus-host disease. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, Klickstein LB, Levin J, Miller K, Reynolds C, Macdonell R, Pasek M, Lee SJ, Ho V, Soiffer R, Antin JH, Ritz J, Alyea E. Blood 2006;108:756-62.

This is a report of a phase 1/2 study of anti-B-cell therapy with rituximab in steroid-refractory chronic GVHD. Twenty-one patients were treated with 38 cycles of rituximab. Rituximab was tolerated well, and toxicity was limited to infectious events.

The clinical response rate was 70%, including 2 patients with complete responses. Responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy. The median dose of prednisone among treated subjects fell from 40 mg/day to 10 mg/day, 1 year after rituximab therapy (P < .001). A chronic GVHD symptom score improved in the majority of treated patients. Antibody titers against Y chromosome-encoded minor HLA antigens fell and remained low, whereas titers against infectious antigens (EBV, tetanus) remained stable or rose during the treatment period.

The authors concludec that specific anti-B-cell therapy with rituximab may be beneficial for patients with steroid-refractory chronic GVHD.

6. Rituximab is effective for extensive steroid-refractory chronic graft-vs.-host-disease. Carella AM, Biasco S, Nati S, Congiu A, Lerma E. Leuk Lymphoma. 2007;48:623-4.

The authors describe a 28-year-old-male patient with extensive liver and GI cGVHD combined with severe thrombocytopenia. The GVHD was refractory to cyclosporine, high-dose prednisolone (secondary to which he developed severe steroid myopathy) and high-dose immunoglobulins. He obtained a complete resolution after rituximab which was used at a dose of 375 mg/m² per week for four consecutive weeks. A gradual but sustained increase in the platelet count was noted after three doses of rituximab. Diarrhea, skin and mouth GVHD resolved. Bilirubin levels reduced from 7.8 to 0.7 mg/dl and ALP/GTP from 847/345 to 227/111. Other immunosuppressive therapy was stopped when rituximab was started. The patient had been followed for 3 months at the time of this report and the platelet count was normal and there were no clinically significant signs or symptoms of cGVHD.

Page 1 | 2 | 3