Poor graft function - causes and potential solutions

Bone Marrow Transplantation, 2005

Bone Marrow Transplantation, 1999

, 30 patients with hematological malignancies (12 ANLL, 10 CML, four ALL and four multiple myeloma) received HLA-identical allogeneic bone marrow transplants with the marrow graft selectively depleted of CD4 ؉ lymphocytes and the CD8 ؉ cell content adjusted to 1 ؋ 10 6 /kg. Total depletion of CD4 ؉ and partial depletion of CD8 ؉ lymphocytes was carried out by an immunomagnetical method. All patients were considered as having high risk for developing GVHD by at least one of the following criteria: patient age Ͼ35 years; donor age Ͼ35 years; donor multiparity or marrow from an unrelated donor. Twenty-four cases received marrow from an identical sibling and six from an unrelated donor. In order to assess the role of methotrexate (MTX) in addition to cyclosporin A (CsA) after transplant, patients were randomly assigned to received either CsA alone (n = 15) or CsA plus a short course of MTX (n = 15). No case of primary graft failure was observed, but two patients developed late graft failure. Six patients presented grade II acute GVHD and no case of severe III-IV GVHD was seen. The actuarial probability of developing grade II-IV acute GVHD was 25.9 ؎ 9.6% for the entire population. Patients receiving post-transplant CsA ؉ MTX had significantly less probability of acute GVHD than those receiving CsA exclusively (6.7 ؎ 6.4% vs 50.5 ؎ 17.8%, P = 0.03) and the schedule of post-transplant immunosuppression was the only factor associated with the incidence of acute GVHD in a multivariate analysis. The actuarial incidence of chronic GVHD for the entire population was 31.8 ؎ 12.5, and there was no significant difference between both groups with additional prophylaxis. Four patients with CML and three with ANLL relapsed: the actuarial probability of remaining in complete remission for all patients was 53.6 ؎ 17.3%. For patients with acute leukemia, the probability of remaining in complete remission did not differ significantly between those transplanted in first complete remission and those

European Journal of Haematology, 2003

PubMed, 1998

Primary graft failure, secondary to either host-vs.-graft reaction or delayed engraftment, and graft-vs.-host disease (GVHD) are among the most difficult clinical problems to manage in the field of allogeneic bone marrow transplantation (BMT). Early diagnosis of both conditions would greatly improve their outcome. Using fluorescence in situ hybridization (FISH) with an X- and Y-probe mixture, we sequentially monitored chimerism of neutrophils and lymphoid cells from day 1 to 100 in 28 consecutive recipients of sex-mismatched unmanipulated bone marrow grafts. The objective was to quantitatively assess the evolution of chimerism during this crucial time interval and to determine whether chimerism patterns would be predictive of engraftment and GVHD. In recipients with primary graft failure (n=7), the presence of donor-type neutrophils and NK cells as well as the predominance of donor-type T cells distinguished patients who responded to G-CSF (n=5) from nonresponders (n=2). Furthermore, the clearance of host CD3+CD56- cells during days 5-10 posttransplantation was significantly hastened in patients who subsequently developed acute (delta=80%) or chronic (delta=81%) GVHD compared with patients without GVHD (delta=17%). Thus, our data suggest that molecular monitoring of the fate of host/donor hematopoietic cells in the early posttransplantation period could be useful in differentiating patients with delayed engraftment from those with irreversible rejection and in predicting the occurrence of GVHD as soon as day 10. This investigational approach may provide an appropriate basis on which to select adequate treatment for primary graft failure and high-risk candidates that could benefit from novel preemptive therapies for GVHD.

Transplant International, 2008

Various factors determine the graft-and patient survival after transplantation. HLA-matching and immunological factors are of importance for the short-and long-term survival. Apart from these obvious determinants, nonimmunological factors play an important role in defining the baseline organ quality as well as the recipients' status. The influence of these parameters on graft-and patient survival is still underestimated and is a topic of debate. On account of the increasing acceptance of marginal-donor organs these events are of increasing importance for graft survival and long-term function. We review nonimmunological causes for deteriorated graft function and graft loss after solid organ transplantation.

Cancer Research, 1986

Grufi-wnu.v-host disease (GVHD) remains a major cause of morbidity and mortality following bone marrow transplantation. The in vitro re moval of the GVIID-causing T-lymphocytes from donor marrow is one approach which could control this complication. Treatment of the donor bone marrow with lectins and erythrocyte-forming rosette depletion, anti-T-cell antisera or monoclonal antibodies are methods currently being tested to accomplish this. CT-2 is an immunoglobulin monoclonal antibody specific for the Tcell erythrocyte-forming rosette receptor. Bone marrow from 23 consec utive donors was treated in vitro with CT-2 and complement, prior to infusion, as a potential means of controlling GVHD. Surface marker analysis using erythrocyte-forming resetting, and OKT-3 and OKT-11 monoclonal antibodies on paired samples of treated and untreated marrow demonstrated a mean depletion to 1% of the original number of 'I'-cells. Proliferarne responses to alloantigens and mitogens as well as cytotoxic and natural killer cell function were tested and found to be markedly reduced. Despite these effects on T-lymphocytes, viable hematopoietic stem cell colonies were retained. Clinical results following the in vitro T-lymphocyte depletion of donor bone marrow for the 8 histocompatible and 15 nonhistocompatible bone marrow transplantation are reported. Prompt engraftment with minimal GVHD, despite no posttransplant GVHD prophylaxis, was seen in seven of the matched patients. In the nonhistocompatible bone marrow trans plantation, failure of engraftment occurred in 11 patients. Grades 111-IV GVHD were seen in two of the four patients that engrafted despite good T-lymphocyte depletion. No predictive correlation could be found between the in vitro analysis of marrow following CT-2 treatment and clinical outcome.

Bone Marrow Transplantation, 2004

Graft rejection is a major cause of treatment failure after T-cell-depleted stem cell transplantation (TCD-SCT) and remains a therapeutic challenge. Donor leukocyte infusions (DLIs) have an efficient graft versus host effect, which has been successfully used to treat recipient relapses. We hypothesized that this effect could be exploited to counteract the host versus graft reactions responsible for graft rejection. We report two adult patients with haematological malignancies who underwent sex-mismatched TCD-SCT from HLA-identical sibling donors. Peripheral blood (PB) counts and bone marrow (BM) cellularity were studied on a serial basis. Sequential chimaerism and minimal residual disease analysis were performed by FISH on PB and BM samples as well as on leukocyte lineages (T and B lymphocytes and myeloid cells) purified from PB using immunomagnetic technology. Both patients were diagnosed with incipient graft rejection 2-3 months after engraftment, based on persistently decreasing PB counts and BM cellularity together with the observation of decreasing mixed chimaerism (increasing percentage of recipient cells), mostly in whole PB and T lymphocytes. Both patients were successfully treated with a single DLI (1 Â 10 7 CD3 þ cells/kg), thereafter achieving normal PB counts and BM cellularity as well as complete chimaerism. Interestingly, the only side effect observed was mild graft versus host disease that did not require treatment. In conclusion, provided that an early diagnosis is made, the graft versus host lymphohaemopoietic effect harboured by immunocompetent donor cells can be successfully used for the treatment of incipient graft rejection.

Blood, 1989

Graft failure was analyzed in 625 patients receiving allogeneic bone marrow transplants from HLA-identical sibling donors as treatment for severe aplastic anemia. Sixty-eight (11%) had no or only transient engraftment. Second bone marrow transplants were successful in achieving extended survival in 16 of 27 patients with transient initial engraftment but in none of ten patients with no sign of engraftment after the first transplant. The major factors associated with a reduced risk of graft failure were use of radiation for pretransplant immunosuppression and use of cyclosporine rather than methotrexate or T-cell depletion of the donor bone marrow for prophylaxis against graft-v-host disease (GVHD). Among 266 patients prepared for transplantation with cyclophosphamide alone, the risk of graft failure was increased in patients who received previous transfusions and reduced in those who received corticosteroids for previous therapy. Neither cell dose nor administration of donor buffy c...

Journal of Hematotherapy & Stem Cell Research, 2001

Graft-versus-host disease (GVHD) is currently one of the major obstacles for successful allogeneic bone marrow transplantation (BMT). GVHD results from a complex set of interactions between donor T cells and a variety of target tissues from the host. To gain a better understanding of the biology of the human hematopoietic system in GVHD patients, in the present study we have determined the progenitor cell content in bone marrow (BM) samples from BMT recipients, with and without GVHD, and followed their growth kinetics in Dexter-type long-term marrow cultures (LTMC). We have also assessed some aspects regarding the composition of the hematopoietic microenvironment developed in vitro. As compared to normal subjects, BMT recipients showed decreased numbers of myeloid, erythroid, and multipotent progenitor cells. Interestingly, progenitor levels were significantly lower in GVHD patients (7% of the levels in normal marrow) than in those without GVHD (44% of the levels in normal marrow). When marrow cells from BMT recipients were cultured in LTMC, hematopoiesis was sustained at lower levels and for shorter periods of time, as compared to cultures from normal subjects. The hematopoietic deficiencies observed in this in vitro system were also more pronounced in GVHD patients. In terms of the microenvironment elements, reduced numbers of fibroblastic progenitors and adherent stromal cells were observed in BMT recipients, as compared to normal subjects, who showed 7 colony-forming unit fibroblast (CFU-F)/10 5 marrow cells and 320,000 adherent cells in LTMC. Again, GVHD patients showed more severe deficiencies (0.16 CFU-F/10 5 marrow cells and 34,000 adherent cells in LTMC) than patients without GVHD (2 CFU-F/10 5 marrow cells and 122,000 adherent cells in LTMC). Our results demonstrate that the hematopoietic system of BMT recipients is impaired, both in terms of its in vitro composition and function, and that these deficiencies are clearly more pronounced in patients with GVHD than in those without GVHD. Finally, although the evidence is still preliminary, our results also indicate that the severity of the hematopoietic alterations may be greater in acute GVHD than in chronic GVHD.

Bone Marrow Transplantation, 2005