Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II–III trial

The Lancet ◽  
2005 ◽  
Vol 366 (9487) ◽  
pp. 733-741 ◽  
Author(s):  
John E Wagner ◽  
John S Thompson ◽  
Shelly L Carter ◽  
Nancy A Kernan
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Phase Ii ◽  
Graft Versus Host Disease ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Graft Versus Host ◽  
Donor Bone Marrow ◽  
Disease Free

scholarly journals Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases [published erratum appears in Blood 1990 Aug 1;76(3):654]

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1728-1732 ◽  
Author(s):  
PB McGlave ◽  
P Beatty ◽  
R Ash ◽  
JM Hows
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Acute Gvhd ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Free Survival ◽  
Donor Bone Marrow ◽  
Grade Ii ◽  
Disease Free

Abstract From April, 1985, to February, 1989, 102 consecutive patients received unrelated donor bone marrow transplantation therapy for chronic myelogenous leukemia (CML) at four centers. Median age of the group was 31 years (range, 4.5 to 51 years). Fifty-four patients were in first chronic phase (CP) at time of transplantation, and 48 had evidence of more advanced disease (AD) (accelerated phase, 32; blast crisis, 9; second CP, 7). In 44 cases, the donor and recipient were identical at the HLA A, B, and DR loci and were nonreactive in bidirectional mixed leukocyte culture (MLC) (“matched”). In 58 cases, nonidentity between donor and recipient could be determined at at least one HLA locus or in bidirectional MLC (“mismatche”). Fifty-eight patients were prepared for transplantation with a combination of cyclophosphamide and fractionated total body irradiation (FTBI) and received acute graft- versus-host disease (GVHD) prophylaxis consisting of methotrexate alone or in combination with cyclosporine, prednisone, or antithymocyte globulin (ATG). In 44 cases, patients received preparative agents in addition to cyclophosphamide and FTBI, and marrow depleted of mature T lymphocytes by ex vivo incubation with either anti-CD3 antibody plus complement (n = 24) or Campath-1 (n = 20). Engraftment defined by a peripheral blood neutrophil count greater than 0.5 X 10(9)/L was demonstrated in 92 cases and occurred at a median of 22 days (range, 11 to 46 days). In 10 cases, peripheral blood evidence of engraftment did not occur, and in one case, engraftment was followed by aplasia. Hematologic relapse was seen in four cases. Recurrence or persistence of the Ph1 chromosome without evidence of hematologic relapse occurred in four additional cases. The incidence of grade II to IV acute GVHD is 65% (95% confidence interval [CI], +/- 10%). After adjustment for recipient age and donor matching status, recipients of T lymphocyte- depleted donor marrow had a significantly lower incidence of grade II to IV acute GVHD (P less than .01); however, T depletion was not significantly associated with improved survival (P = .34), disease-free survival (P = .51), or increased incidence of relapse (P = .39). Of 102 patients, 46 are alive, with a median survival of 12 months (range, 3 to 46 months), and the Kaplan-Meier estimate of disease-free survival is 29% (95% CI, +/- 9%) for the entire group at 2 1/2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

No difference in graft-versus-host disease, relapse, and survival comparing peripheral stem cells to bone marrow using unrelated donors

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1739-1745 ◽  
Author(s):  
Mats Remberger ◽  
Oolle Ringdén ◽  
Igor-Wolfgang Blau ◽  
Hellmut Ottinger ◽  
Bernhard Kremens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Free Survival ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Disease Free

Abstract The clinical results in 107 patients receiving a peripheral blood stem cell (PBSC) graft mobilized by granulocyte colony-stimulating factor (G-CSF) from HLA-A, -B, and -DR–compatible unrelated donors were compared to 107 matched controls receiving unrelated bone marrow (BM) transplants. Engraftment was achieved in 94% of the patients in both groups. The PBSC graft contained significantly more nucleated cells, CD34+, CD3+, and CD56+ cells (P < .001), and resulted in a significantly shorter time-to-neutrophil (15 versus 19 days) and platelet engraftment (20 versus 27 days), compared to the BM control group (P < .001). Probabilities of acute graft-versus-host disease (GVHD) grades II to IV were 35% and 32% (not significant [NS]) and of chronic GVHD 61% and 76% (NS) in the PBSC and BM groups, respectively. There was no difference between the 2 groups in bacteremia, cytomegalovirus reactivation or disease, and fungal infection. The 3-year transplant-related mortality (TRM) rates were 42% in the PBSC group and 31% in the BM controls (P = .7) and the survival rates were 46% and 51%, respectively. The probability of relapse was 25% and 31% in both groups (NS), resulting in disease-free survival rates of 43% in the PBSC group and 46% in the BM controls (NS). In the multivariate analysis, early disease, acute GVHD grade 0 to I, and presence of chronic GVHD were independent factors associated with a better disease-free survival in this study. PBSC from HLA-compatible unrelated donors can be used safely as an alternative to BM for stem cell transplantation.

Impact of Chronic Graft Versus Host Disease in the Overall Survival and Disease Free Survival of Patients with Hematologic Disorders Submitted to Allogeneic Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4305-4305
Author(s):  
Emmerson de Sousa Eulalio ◽  
Elizabeth Schulz ◽  
José Salvador Rodrigues de Oliveira
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Graft Versus Host Disease ◽  
De Novo ◽  
Disease Free Survival ◽  
Extensive Form ◽  
Free Survival ◽  
Graft Versus Host ◽  
The Mean ◽  
Disease Free

Abstract The management of the chronic graft versus host disease (C-GVHD) in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still challenging and does not follow a consensus. This disease can manifest as auto-immune phenomena, often affecting multiple organs, and it is considered as a determinant factor for higher post transplant mortality and detrimental quality of life, although conversely associated with a strong graft versus tumor effect which determines a beneficial biological response in patients with haematological pathologies. The aim of this study was to determine the impact of the C-GVHD in the overall survival (OS) and disease free survival (DFS) in patients with hematologic pathologies who underwent allo-HSCT with HLA identical donors in the BMT Hospitals Sao Paulo and Santa Marcelina, in Sao Paulo, Brazil. We performed a retrospective study of historical cohort including 233 allo-HSC transplants, 151 patients aged 9 to 63 years old (median 31) with survival superior to 100 days, from August 1993 to December 2004. The classification of DECH-C followed the criteria of Seattle (Shulman et al. 1980) revised by Lee et al (2003). Our series was composed of 97 patients with chronic myeloid leukemia (CML), 54 with acute leukemias (AL), 42 with marrow failure (MF) and 40 with lymphoproliferative diseases (LPD). Forty one percent of the patients exhibited the advanced disease at HSCT time and the main source of HSC was bone marrow (n=174, 74.7%). The diagnosis of C-GVHD was performed in 166 procedures (71.2%). Seventy one patients (42.8%) were classified as C-GVHD quiescent, 69 (41.6%) as de novo, and 25 (15.1%) as progressive. The extensive form occurred in 95 cases (57.2%) and the limited form in 70 cases (42.2%). The mean OS for our cohort was 34.5 months (m) and the mean DFS was 29.5 m. The mean OS of patients with C-GVHD was 42 m, significantly higher than than 33.8m OS of patients without C-GVHD (p=0.05). Similarly, the DFS was 38.6m for C-GVHD patients, against 22.6m of DFS for patients without C-GVHD (p=0.0001). The OS of those patients with C-GVHD de novo (47m) and quiescent (44.8m) were superior than the OS of patients without C-GVHD (33.8%) or with the progressive form of C-GVHD (20.8m), p=0.002. The same effect was observed for the DFS in the de novo form (42.6m) and quiescent form (41.4m) of C-GVHD, with a DFS twice superior than the progressive form (19.8m) and than the C-GVHD absent (22.6m), p=0.001. When compared with cases without C-GVHD, the clinical severity of the C-GVHD (limited or extensive) showed a strong correlation with a higher DFS. Patients with limited C-GVHD had a DFS of 38.3m and the extensive form a DFS of 38.9m, significantly superior than the DFS of patients without C-GVHD with a DFS of 22.6m (p=0.002). Hence, this study shows the existence of a correlation between the presence of C-GVHD and higher OS and DFS in patients with haematological disorders submitted to allo-HCT. The diagnosis of progressive C-GVHD was associated to a deleterious effect over the outcome of allo-HCT, therefore inactivating the benefits of the graft versus tumour effect observed in the clinical presentations de novo and quiescent of C-GVHD.

scholarly journals Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases [published erratum appears in Blood 1990 Aug 1;76(3):654]

Blood ◽  
1990 ◽  
Vol 75 (8) ◽  
pp. 1728-1732 ◽  
Author(s):  
PB McGlave ◽  
P Beatty ◽  
R Ash ◽  
JM Hows
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Acute Gvhd ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Free Survival ◽  
Donor Bone Marrow ◽  
Grade Ii ◽  
Disease Free

From April, 1985, to February, 1989, 102 consecutive patients received unrelated donor bone marrow transplantation therapy for chronic myelogenous leukemia (CML) at four centers. Median age of the group was 31 years (range, 4.5 to 51 years). Fifty-four patients were in first chronic phase (CP) at time of transplantation, and 48 had evidence of more advanced disease (AD) (accelerated phase, 32; blast crisis, 9; second CP, 7). In 44 cases, the donor and recipient were identical at the HLA A, B, and DR loci and were nonreactive in bidirectional mixed leukocyte culture (MLC) (“matched”). In 58 cases, nonidentity between donor and recipient could be determined at at least one HLA locus or in bidirectional MLC (“mismatche”). Fifty-eight patients were prepared for transplantation with a combination of cyclophosphamide and fractionated total body irradiation (FTBI) and received acute graft- versus-host disease (GVHD) prophylaxis consisting of methotrexate alone or in combination with cyclosporine, prednisone, or antithymocyte globulin (ATG). In 44 cases, patients received preparative agents in addition to cyclophosphamide and FTBI, and marrow depleted of mature T lymphocytes by ex vivo incubation with either anti-CD3 antibody plus complement (n = 24) or Campath-1 (n = 20). Engraftment defined by a peripheral blood neutrophil count greater than 0.5 X 10(9)/L was demonstrated in 92 cases and occurred at a median of 22 days (range, 11 to 46 days). In 10 cases, peripheral blood evidence of engraftment did not occur, and in one case, engraftment was followed by aplasia. Hematologic relapse was seen in four cases. Recurrence or persistence of the Ph1 chromosome without evidence of hematologic relapse occurred in four additional cases. The incidence of grade II to IV acute GVHD is 65% (95% confidence interval [CI], +/- 10%). After adjustment for recipient age and donor matching status, recipients of T lymphocyte- depleted donor marrow had a significantly lower incidence of grade II to IV acute GVHD (P less than .01); however, T depletion was not significantly associated with improved survival (P = .34), disease-free survival (P = .51), or increased incidence of relapse (P = .39). Of 102 patients, 46 are alive, with a median survival of 12 months (range, 3 to 46 months), and the Kaplan-Meier estimate of disease-free survival is 29% (95% CI, +/- 9%) for the entire group at 2 1/2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1980-1987 ◽  
Author(s):  
WR Drobyski ◽  
RC Ash ◽  
JT Casper ◽  
T McAuliffe ◽  
MM Horowitz ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Gvhd ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Free Survival ◽  
Entire Cohort ◽  
Graft Versus Host ◽  
Disease Free

Abstract Between January 1988 and March 1993, 48 patients received T-cell- depleted marrow grafts from unrelated donors as treatment for chronic myelogenous leukemia (CML). The median age of the population was 31.7 years (range 5.4 to 53) with 17 of 48 patients greater than 40 years of age. Twenty-seven patients were transplanted in chronic phase, 17 in accelerated phase, and 4 in blast crisis. All patients received a standardized preparative regimen of cyclophosphamide, high-dose cytosine arabinoside, methylprednisolone, and total body irradiation. Marrow grafts were depleted of mature T cells with the alpha beta T- cell receptor antibody T10B9 as graft-versus-host disease (GVHD) prophylaxis. All patients also received posttransplant cyclosporine therapy. Twenty-eight of 48 patients were mismatched with their donors for one or more HLA-A, B, DR, or DQ loci by either serology or high- resolution oligonucleotide genotyping. Nine of 28 were mismatched at multiple HLA loci. Durable engraftment was achieved in 94% (45/48) of patients. The actuarial probability of developing grades II to IV and grades III to IV acute GVHD were 39.6% (95% confidence interval (CI) 26.9 to 53.0) and 8.3% (95% CI 6.1 to 10.9) for the entire cohort. There was no difference in the incidence of grades II to IV acute GVHD between patients receiving matched (36.8%) or mismatched (41.4%) marrow grafts (P = .77). The actuarial probability of relapse at 2 years was 8.8% (95% CI 2.1 to 21.6) for the entire cohort and 18% (95% CI 4 to 41) for patients transplanted in either the accelerated or blast crisis phase (advanced disease). One cytogenetic relapse has occurred among patients transplanted in the chronic phase. The probability of disease- free survival at 2 years was 52% (95% CI 24 to 70) for patients transplanted in chronic phase and 46% (95% CI 25 to 73) for patients transplanted with advanced disease. No difference in disease-free survival was observed between patients receiving matched (49%) or mismatched (51%) marrow grafts (P = .90). This study shows that patients receiving unrelated T-cell-depleted marrow grafts for CML can achieve durable engraftment with a low incidence of severe GVHD and apparent preservation of graft-versus-leukemia reactivity. These data also suggest that T-cell depletion may allow patients who might otherwise experience unacceptable toxicity from GVHD-related complications caused by older age or increased HLA disparity to benefit from unrelated marrow grafts.

Quadruple Therapy with CsA, MTX, MMF and ATG and Triple Therapy with CsA, MTX and ATG for Preventing Graft-Versus-Host Disease in Unrelated Donor Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5296-5296 ◽  
Author(s):  
Zhiping Fan ◽  
Zhengshan Yi ◽  
Qifa Liu ◽  
Jing Sun ◽  
Dan Xu ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Genetic Loci ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Disease Free

Abstract Objective To explore the effective protocol for graft-versus-host disease (GVHD) prophylaxis in unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Methods 31 patients with leukemia received URD-HSCT, of whom 16 received quadruple therapy (quadruple group) with CsA, MTX, MMF and ATG for GVHD prophylaxis and 15 received triple therapy (triple group) with CsA, MTX and ATG. 22 patients were matched in all HLA genetic loci with donors, seven were mismatched in one HLA genetic locus, 1 in two HLA genetic loci, and 1 in three HLA genetic loci. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 17 cases and modified BuCY conditioning regimen (hydroxyurea, busulfan, Ara-C, Cyclophosphamide) in the other 14 cases. Immune reconstitution of quadruple group and triple group at 1,3, 6, 9,12 month after transplantation were examined by flow cytometer, and the diference of the two group were estimated with Independent-Samples T test. The incidence of GVHD of the two group was esitimated with Mann-Whitney Test. Kaplan-Meier survival analysis model was used to estimate the overall survival and the disease-free survival (DFS). Results Immune reconstitution after transplantation of quadruple group and triple group have no significant difference (P>0.05). Acute GVHD (aGVHD) occurred in 9 patients (56.25%) of the quadruple group and in 11 (73.33%) of the triple group, respectively. The incidence of acute GVHD (aGVHD) differed little between the two group (P=0.238). The incidence ofIII~IV°aGVHD in the two group were 6.30% and 26.67%, respectively, and there was no significant difference (P=0.122). 6 patients had chronic GVHD (cGVHD), in the16 cases who could be followed up in quadruple group, 3 of the 11 patients who could be followed up in triple group developed cGVHD postoperatively (P=0.580). Four patients of quadruple group died of hemorrhagic cystitis, mycotic pneumonia, tuberculosis and relapse, respectively. 3 patients of triple group died of GVHD, and the other 3 died of GVHD associated interstitial pneumonia, cytomegalovirus (CMV) pneumonia and pneumocystis carinii infection. The lethality of GVHD of quadruple group and triple group were 0%,26.7%, respectively, and there was significant difference(P=0.027). The one-year disease-free survival rate was 75% and 60% in patients of the quadruple and the triple group, respectively, and significant difference was not noted (P= P=0.188). Conclusion Compared with triple therapy with CsA, MTX and ATG, CsA+MTX+MMF+ATG procedure dose not worsen the immune reconsititution after transplantation. It can’t decrease the incidence and severity of aGVHD, but can lower the lethality of GVHD in URD-HSCT. The quadruple procedure may lead to higher relapse rate after URD-HSCT.

Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3034-3034
Author(s):  
Andrea P Bacigalupo ◽  
Anna Maria Raiola ◽  
Alida Dominietto ◽  
Maria Teresa Van Lint ◽  
Francesca Gualandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Active Disease ◽  
Related Mortality

Abstract Abstract 3034 Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7). In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival. Disclosures: No relevant conflicts of interest to declare.

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