Death by Graft-Versus-Host Disease Associated With Hla Mismatch, High Recipient Age, Low Marrow Cell Dose, and Splenectomy

Summary:We compared the occurrence of severe infections following 71 reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplants (PBSCT) and 123 standard myeloablative PBSCT (MINI and STAND groups, respectively) from HLA-identical siblings. The probability of 1-year infection-related mortality (IRM) was 19% in the STAND group and 10% in the MINI group (log-rank, P = 0.3). On multivariate analysis the only significant variable associated with a higher risk of IRM was the development of moderate-to-severe GVHD (P = 0.005). The probability of developing CMV infection was 39% in the STAND group and 21% in the MINI group (P = 0.03) (43% and 21%, respectively, in seropositive donor/recipient pairs, P = 0.01), and the probability of developing CMV disease was 9.5% and 1%, respectively (P = 0.05) (11% and 1%, respectively, in seropositive donor/recipient pairs, P = 0.03). Multivariate analysis of CMV infection identified four variables associated with a higher risk: CMV positive serostatus (P = 0.05), STAND transplant group (P = 0.02), the development of moderate-to-severe GVHD (P Ͻ 0.001) and a dose of CD34 + cells infused below 6 × 10 6 /kg (P = 0.01). Invasive fungal infections and pneumonias of unknown origin did not differ between groups, and neither did other severe non-CMV viral infections and bacterial infections. Our results suggest that RIC allogeneic PBSCT may decrease the risk of dying from an opportunistic infection and reduces the occurrence of CMV infection and disease. Overall, the development of GVHD (acute or chronic) is an important risk factor for these complications. Other infections continue to pose a significant threat to recipients of RIC allografts, stressing that prophylactic and supportive measures are an Following conventional allogeneic hematopoietic stem cell transplantation (HSCT) all patients experience a period of profound neutropenia and immunodeficiency that are significantly responsible for the serious infectious complications that ensue post transplant. Standard conditioning regimens for HSCT involve high-dose chemoradiotherapy given in doses that are myeloablative or at least severely myelotoxic. However, over the past years several groups of investigators have developed reduced-intensity conditioning (RIC) or non-myeloablative regimens, which lead to engraftment of donor lymphoid and hematopoietic stem cells without the extrahematologic toxicities of traditional myeloablative transplants. [1][2][3][4][5][6][7] This reduced extrahematologic toxicity may lead to a reduction in infectious complications post transplant, since disruption of the gastrointestinal mucosa and/or damage to other key organs is a significant triggering mechanism of many of the infections that occur post transplant. 8,9 On the other hand, graft-versus-host disease (GVHD) and its treatment has a profound negative impact on immune reconstitution following HSCT, 10 and the impact of RIC regimens on the risk of acute and chronic GVHD is currently uncertain. The potential benefit on the ri...

Section: Discussionmentioning

confidence: 56%

Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation

Martino

Caballero

Canals

et al. 2001

“…[79][80][81] We were the first group to use MSCs for the treatment of life-threatening acute GVHD, and we reported dramatic responses in some patients, but unfortunately not all. 8,9 These results encouraged a multi-centre phase-II study involving five centres and 55 patients.…”

Section: Clinical Use Of Bm-derived Mscsmentioning

confidence: 99%

Stromal cells–are they really useful for GVHD?

Kaipe

Erkers

Sadeghi

et al. 2014

Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal-BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD.

“…1,2 Major obstacles to success include graft-versus-host disease (GVHD), infections, toxic effects of treatment, and recurrence of disease. 3,4 While only onethird of the patients have an HLA-identical sibling, the use of unrelated donors has increased over the last 15 years. [5][6][7][8][9] However, marrow transplantation from unrelated donors confers an increased risk of complications compared to HLA-identical sibling donors, presumably because of undetected HLA mismatches.…”

mentioning

confidence: 99%

Association between pretransplant Thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors

Remberger

Storer

Ringdén

et al. 2002

Summary:A matched cohort study was designed to test the efficacy of polyclonal rabbit antiserum specific for human T cells (Thymoglobulin), administered in vivo on days 1-5 (2 mg/kg/day) before T cell-replete unrelated donor marrow transplantation. Thymoglobulin was given to 52 leukemic patients at Huddinge Hospital. Control patients matched for diagnosis, disease stage, age and treated with a similar regimen, apart from the omission of Thymoglobulin, were selected in Seattle during the same period (n ‫؍‬ 104). All received conditioning with cyclophosphamide and TBI. In the study group all patients received 10 Gy single dose TBI, while the controls were given 12-14.4 Gy fractionated TBI. GVHD prophylaxis was cyclosporine and methotrexate. Patients were treated for grade I acute GVHD in the study group, and for grade II GVHD in the control group. Multivariable analyses were adjusted for patient and donor age and CMV serology, HLA matching, donor gender and marrow cell dose. Non-relapse mortality was lower in the study patients (hazard ratio ‫؍‬ 0.30, 95% CI 0.12-0.75, P value ‫؍‬ 0.005). The 5-year cumulative incidence of non-relapse mortality was 19% in the study cohort, and 35% in the control cohort. Overall mortality was also lower in study patients (hazard ratio 0.51, 95% CI 0.27-0.97, P value ‫؍‬ 0.03). No significant difference in the risk of relapse was seen (P ‫؍‬ 0.63). This suggests that Thymoglobulin during conditioning may reduce non-relapse mortality after unrelated donor marrow transplantation.