Poor graft function - causes and potential solutions

European Journal of Haematology, 2003

Transplantation and Cellular Therapy, 2021

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.

Biol Blood Marrow Transplant, 2009

The utility of routine chimerism analysis as a prognostic indicator of subsequent outcomes after allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning regimens remains controversial. To address this controversy, routine chimerism test results at 2 -6 months after HCT with myeloablative conditioning regimens were evaluated for association with subsequent risks of chronic graft versus host disease (GVHD), non-relapse mortality (NRM), relapse and overall mortality. Only 70 (5%) of 1304 patients had <95% donor-derived cells in the marrow. Low donor chimerism in the marrow occurred predominantly among patients with low risk disease as compared to higher risk diseases and was significantly associated with a reduced risk of chronic GVHD. Among 673 patients tested, 164 (24%) had <85% donor-derived T cells in the blood. Low donor T cell chimerism occurred predominantly among patients with low risk disease as compared to higher risk diseases, among those who had conditioning with busulfan as compared to TBI, and among those with lower grades of acute GVHD. Low donor T cell chimerism in the blood was significantly associated with a reduced risk of chronic GVHD, but not with the risks of relapse, NRM or overall mortality. Routine testing of chimerism in the marrow and blood at 2 -6 months after HCT with myeloablative conditioning regimens may be helpful in documenting engraftment in clinical trials but provides only limited prognostic information in clinical practice.

Biology of Blood and Marrow Transplantation, 2009

The utility of routine chimerism analysis as a prognostic indicator of subsequent outcomes after allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning regimens remains controversial. To address this controversy, routine chimerism test results at 2 -6 months after HCT with myeloablative conditioning regimens were evaluated for association with subsequent risks of chronic graft versus host disease (GVHD), non-relapse mortality (NRM), relapse and overall mortality. Only 70 (5%) of 1304 patients had <95% donor-derived cells in the marrow. Low donor chimerism in the marrow occurred predominantly among patients with low risk disease as compared to higher risk diseases and was significantly associated with a reduced risk of chronic GVHD. Among 673 patients tested, 164 (24%) had <85% donor-derived T cells in the blood. Low donor T cell chimerism occurred predominantly among patients with low risk disease as compared to higher risk diseases, among those who had conditioning with busulfan as compared to TBI, and among those with lower grades of acute GVHD. Low donor T cell chimerism in the blood was significantly associated with a reduced risk of chronic GVHD, but not with the risks of relapse, NRM or overall mortality. Routine testing of chimerism in the marrow and blood at 2 -6 months after HCT with myeloablative conditioning regimens may be helpful in documenting engraftment in clinical trials but provides only limited prognostic information in clinical practice.

Blood, 1989

Persistent thrombocytopenia after allogeneic marrow transplantation is associated with poor patient survival. To identify the mechanisms of the thrombocytopenia, we studied platelet and fibrinogen kinetics and antiplatelet antibodies in 20 patients between 60 and 649 days (median 90) after transplantation. Seventeen patients had isolated thrombocytopenia (less than 100 X 10(9) platelets/L): the marrow cellularity was normal in five patients and slightly reduced in 12, and there was no discrepancy between thrombopoiesis and myeloerythropoiesis. Three patients had pancytopenia following marrow graft rejection (two) and relapse of leukemia (one). Only three patients had evidence of increased platelet production, indicating that in most cases there is a poor marrow response to thrombocytopenia early after marrow grafting. There was no correlation between platelet count and splenic pooling, suggesting that hypersplenism was an unlikely mechanism of the thrombocytopenia. Although there wa...

Bone Marrow Transplantation, 2005

Bone Marrow Transplantation, 2012

Primary graft failure after allogeneic hematopoietic cell transplantation is a life-threatening complication. A shortened conditioning regimen may reduce the risk of infection and increase the chance of survival. Here, we report the outcome of 11 patients with hematologic diseases (median age, 44; range, 25-67 years, 7 males) who received a 1-day reduced-intensity preparative regimen given as a re-transplantation for primary graft failure. The salvage regimen consisted of fludarabine, cyclophosphamide, alemtuzumab, and total-body irradiation, all administered 1 day before re-transplantation. All patients received T-cell replete peripheral blood stem cells from the same or different haploidentical donor (n = 10) or from the same matched sibling donor (n = 1). Neutrophil counts promptly increased to >500/µL for 10 of the 11 patients at a median of 13 days. Of these, none developed Grade III/IV acute graft-versus-host disease. At present, 8 of the 11 patients are alive with a median follow-up of 11.2 months from re-transplantation and 5 of the 8 are in remission. In conclusion, this series suggests that our 1-day preparative regimen is feasible, leads to successful engraftment in a high proportion of patients, and is appropriate for patients requiring immediate re-transplantation after primary graft failure following reduced-intensity transplantation.

Haematologica

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recov...

Blood, 1989

Risk factors for graft failure were analyzed in 122 recipients of an allogeneic T-cell-depleted human leukocyte antigen (HLA)-identical sibling marrow transplant as treatment for leukemia. In each case pretransplant immunosuppression included 1 .375 to 1 ,500 cGy hyperfractionated total body irradiation and cyclophosphamide (60 mg/kg/ d x 2). No patient received immunosuppression posttransplant for graft-versus-host disease (GVHD) prophylaxis. Nineteen patients in this group experienced graft failure. The major factors associated with graft failure were transplants from male donors and the age of the patient (or donor). Among male recipients of male donor derived grafts a low dose per kilogram of nucleated cells. progenitor cells (colony forming unit-GM) and T cells was also associated with graft failure. Additional irradiation to 1.500 G RAFT-VERSUS-HOST disease (GVHD) is a major limitation to the success of bone marrow transplants (BMT) for the treatment of leukemia.'2 This complication occurs in 50% to 70% of leukemic recipients of human leukocyte antigen (HLA)-identical sibling marrow transplants and is sufficiently severe (grades II to IV) to warrant treatment in 30% to 55% of patients, depending on the selection of pretransplant and posttransplant immunosuppressive agents.' 3 Several clinical trials with bone marrow depleted of donor T-lymphocytes indicate that both the incidence and severity of GVHD in engrafted patients are greatly reduced. 8 Associated with these encouraging results in the reduction of GVHD, however, there has been an increased incidence of graft failure or graft rejection in recipients of T-celldepleted transplants from either HLA-identical or HLAnonidentical donors.'8 In contrast to leukemic recipients of unmodified HLA identical marrow grafts, in which there is a 0. 1% incidence of graft rejection9 and only 7% of the recipients require secondary transplants for poor graft function,'#{176}the reported incidence of graft failure among recipients of T-cell-depleted HLA-identical transplants ranges from 10% to 30%. 8 For patients transplanted with Tcell-depleted marrow from HLA-nonidentical donors, the incidence of rejection has been even higher.7" Previous analyses of T-cell-depleted marrow transplants have mdicated that graft failure correlates with both the degree of HLA mismatch7 and the intensity of the pretransplant immunosuppression.5' 2.13 In this report we have analyzed characteristics of the donor and recipient, including the cellular composition of the bone marrow graft, and the intensity of the pretransplant cytoreduction regimen used for their impact on the incidence of primary graft failure in recipients of T-cell-depleted HLA-identical marrow grafts. We have analyzed 122 patients with leukemia who received marrow grafts depleted

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...

Bone Marrow Transplantation, 1997

Graft failure is a serious complication of allogeneic BMT and occurs in 1-20% of allografted patients depending mainly upon the relationship of the patient and donor, the Allograft recipients are often unwell with significant organ dysfunction by the time delayed or failed extent of HLA identity, the underlying disease, and manipulation (usually T cell depletion) of the infused engraftment is diagnosed. We attempted to identify factors associated with graft failure, or death due to infec-cells. 1-11 Death due to complications of pancytopenia is common in patients experiencing graft failure. Primary tion, hemorrhage or graft failure in 712 patients undergoing allogeneic BMT. Low leukocyte counts graft failure is variously defined as Ͻ0.1-0.5 × 10 9 /l neutrophils on day 28 or Ͻ0.1 × 10 9 /l neutrophils on day 21. 1-11 between days 12 and 22 were strongly associated with subsequent graft failure or death. In multivariate analy-The clinical condition of allografted patients who are persistently pancytopenic usually deteriorates whether they sis, a leukocyte count of р0.2 × 10 9 /l on day 16 was the most powerful predictor of graft failure or death. ultimately experience graft failure or not. The usual course of action once 'delayed engraftment' or graft failure are Transplants from HLA-mismatched and unrelated donors were also associated with increased risk of both, diagnosed is administration of a growth factor such as granulocyte colony-stimulating factor (G-CSF) or granulo-and T cell depletion with increased risk of graft failure. On the basis of these findings, it may be possible to cyte-macrophage colony-stimulating factor (GM-CSF) and/or infusion of more allogeneic or autologous stem define graft failure in functional terms as early as 2 weeks after BMT rather than at 3 or 4 weeks. The use cells. 6,8,11-16 These are not always successful, and morbidity and mortality in this group of patients is high. of growth factors can then be limited to patients most likely to benefit from them, and it may be possible to It is logical to assume that if patients at risk of graft failure, or death as a result of infection or hemorrhage in salvage patients at risk of complications of low counts early before their clinical condition deteriorates. We the early post-transplant stage could be identified sooner, rescue measures such as infusion of more cells and growth suggest that patients with leukocyte counts of 0.2 x 10 9 /l or less 14-16 days after BMT should be started on G-factors may have a better chance of being successful. The present analysis was undertaken to see if serial leu-CSF or GM-CSF even if they are clinically well, and consideration should be given to a second infusion of kocyte counts in the early stages after BMT were predictive of death due to infection, hemorrhage, or graft failure cells.

Journal of Hematotherapy &amp; 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.

British Journal of Haematology, 2005

Bone Marrow Transplantation, 2003

2003

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