scholarly journals Impact of the Presence of HLA 1-Locus Mismatch and the Use of Thymoglobulin in Unrelated Bone Marrow Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4688-4688
Author(s):  
Koji Kawamura ◽  
Junya Kanda ◽  
Shigeo Fuji ◽  
Kosuke Yoshioka ◽  
Yukiyasu Ozawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Total Dose ◽  
Marrow Transplantation ◽  
Low Dose ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Recent Cohort ◽  
Overall Mortality

Abstract Introduction: HLA 1-locus mismatched unrelated donor (1MMUD) has been used in allogeneic hematopoietic stem cell transplantation (HCT) for patients who lack an HLA-matched related or unrelated donor, although its outcome has been shown to be inferior to that of HLA-matched HCT. The use of anti-thymocyte globulin such as thymoglobulin (Thymo) as GVHD prophylaxis may overcome this drawback. The aims of this study were to compare the transplant outcomes between 1MMUD and matched unrelated donor (MUD) and to evaluate the effectiveness of Thymo in unrelated HCT from 1MMUD using the recent cohort. Methods: We retrospectively analyzed 3313 adult patients with acute myeloid leukemia (n=1835), acute lymphoblastic leukemia (n=830), or myelodysplastic syndrome (n=648) who underwent a first bone marrow transplantation from HLA -8/8 allele MUD or 1MMUD between 2009 and 2014. The patients who underwent allo-HCT from MUD with Thymo were excluded in this study. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes of MUD (n=2089) and 1MMUD with Thymo (n=109) with those of 1MMUD without Thymo (n=1115). Results: The median total dose of Thymo was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MMUD with Thymo group. The incidence of grade II-IV and III-IV acute GVHD were 44.5% (95% confidence interval (CI), 41.5- 47.4%) and 13.1% (95% CI, 11.2-15.2%), 33.4% (95% CI, 24.5-42.5%) and 5.8% (95% CI 2.4-11.6%), and 36.1% (95% CI, 34.1-38.2%) and 10.5% (95% CI, 9.2-11.9%) in the 1MMUD without Thymo group, the 1MMUD with Thymo group, and the MUD group, respectively (p<0.001, and p=0.0085). The incidence of non-relapse mortality (NRM) at 3 years was higher in the 1MMUD without Thymo group (26.6%; 95% CI 23.7-29.5%) than that in the 1MMUD with Thymo group (11.9%; 95% CI, 5.9-20.2%) or the MUD group (21.4%; 95% CI 19.5-23.4%, p<0.001, Figure1A), although the incidence of relapse did not differ among 3 groups. The probabilities of GVHD-free, relapse-free survival (GRFS) at 1 year were 38.8% (95% CI, 35.8-41.8%), 48.4% (95% CI, 37.9-58.0%), and 41.8% (95% CI, 39.6-44.0%) in the 1MMUD without Thymo group, the 1MMUD with Thymo group, and the MUD group, respectively (p=0.0012, Figure1B).In multivariate analysis (Table 1), the rates of grade II-IV and III-IV acute GVHD, NRM and overall mortality were significantly lower in the MUD group than in the 1MMUD without Thymo group (hazard ratio (HR) 0.75; 95% CI 0.67-0.84; p<0.001, HR 0.77; 95% CI, 0.63-0.95; p=0.014, HR 0.74; 95% CI, 0.63-0.87; p<0.001, and HR 0.87; 95% CI, 0.78-0.98; p=0.017, respectively). Likewise, the rates of grade II-IV and III-IV acute GVHD and NRM were significantly lower in the 1MMUD with Thymo group than in the 1MMUD without Thymo group (HR 0.69; 95% CI 0.49-0.98; p=0.040, HR 0.42; 95% CI, 0.19-0.94; p=0.035, and HR 0.35; 95% CI, 0.19-0.65; p<0.001, respectively). In addition, the overall mortality rate also tended to be lower in the 1MMUD with Thymo group than in the 1MMUD without Thymo group (HR 0.74; 95% CI 0.53-1.03; p=0.075). On the other hand, there were no statistically significant differences in relapse rates between the 1MMUD without Thymo group and the MUD group (HR 1.09; 95% CI 0.94-1.27; p=0.27), or between the 1MMUD without Thymo group and the 1MMUD with Thymo group (HR 1.28; 95% CI 0.84-1.96; p=0.26). Finally, we divided patients in the 1MMUD with Thymo group into 3 groups according the total dose of Thymo (Thymo<2 mg/kg, 2 mg/kg≤Thymo≤4 mg/kg, Thymo>4 mg/kg), and compared the outcomes of the 3 groups with those of 1MMUD without Thymo. The incidence of NRM at 2 years and the probabilities of GRFS at 1 year were 16.1% (95% CI, 3.7-36.3%) and 33.8% (95% CI, 13.9-55.1%) in the Thymo<2 mg/kg group, 6.4% (95% CI, 1.6-16.0%) and 55.3% (95% CI, 40.6-67.8%) in the 2 mg/kg≤Thymo≤4 mg/kg group, 12.7% (95% CI, 3.0-29.6%) and 44.7% (95% CI, 25.1-62.6%) in the Thymo>4 mg/kg group, and 24.1% (95% CI, 21.5-26.8%) and 38.8% (95% CI, 35.8-41.8%) in the 1MMUD without Thymo group (p=0.014 and p=0.053), respectively. Conclusions: The outcome of HCT from 1MMUD without Thymo was inferior to that of HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared by the use of relatively low dose of Thymo without increasing the risk of relapse. A large prospective study is warranted to confirm the role of low dose of Thymo in HCT from 1MMUD. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

Low-Dose ATG-F Reduces Non-Relapse Mortality after Reduced-Intensity Bone Marrow Transplantation from an Unrelated Donor: A Single-Center Analysis of 65 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5070-5070
Author(s):  
Shigeo Fuji ◽  
Takahiro Fukuda ◽  
Sung-Won Kim ◽  
Eiji Usui ◽  
Saiko Kurosawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Low Dose ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Reduced Intensity

Abstract Background: In Japan, peripheral blood stem cell transplantation from an unrelated donor has not been approved. Therefore, for unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (u-RIST), low-dose TBI has been added to facilitate engraftment. However, non-relapse mortality (NRM), which was mostly related to GVHD, was extremely high (54% at 1 year) after u-RIST with cladribine/busulfan/TBI 4 Gy (Kim et al. ASH 2006). To overcome this problem, we introduced antithymocyte globulin (Fresenius: ATG-F) at a lower dosage of 5–10 mg/kg to replace TBI. This study evaluated the feasibility of this regimen. Patients and Methods :From January 2000 to May 2007, 65 patients with hematological malignancies received u-RIST with a conditioning regimen including fludarabine (Flu 30 mg/m2 x 6 days) or cladribine (2CdA 0.11 mg/kg x 6 days) plus busulfan (oral Bu 4 mg/kg x 2 days, iv Bu 3.2 mg/kg x 2 days) with 4 Gy TBI (n=30), 2 Gy TBI (n=20) or low-dose ATG-F (n=15). The median age of the patients was 57 years (range, 20–65). Their diagnosis included AML/MDS (n=39), lymphoma (n=19) and others (n=7). There were no differences in pretransplant disease status or HLA-disparity among the 3 different groups. Results: The median follow-up of surviving patients was 381 days (range, 64–1832). Although more patients in the ATG-F group experienced graft failure, all 3 patients were rescued with a second transplant or DLI. Compared to low-dose TBI group, the incidences of grade II–IV and III–IV acute GVHD were significantly lower in the ATG-F group, which resulted in significantly lower NRM, better overall survival (OS) and better progression-free survival (PFS) (Figure). However, the incidences of disease relapse and CMV reactivation were not different among the 3 groups. A Cox proportional hazard model showed that low-dose ATG-F was associated with a significantly better PFS. Conclusions: Our study showed that very low-dose ATG-F (5–10 mg/kg) significantly reduced the incidence of acute GVHD without an increase in the relapse rate, which led to a significantly improved PFS rate. A slightly higher rate of graft failure was manageable. The optimal dose of ATG-F needs to be determined according to the source of stem cells and HLA-disparities, including ethnic differences, and our study should help to provide a model to pursue this. TBI 4 Gy (n=30) TBI 2 Gy (n=20) LD ATG-F (n=15) P (TBI vs ATG-F) 2CdA/Flu 11/19 5/15 0/15 0.01 CSP/TAC 28/2 4/16 4/11 0.01 CR/non-CR, pretransplant 10/20 9/11 5/10 0.74 HLA match/mismatch 17/13 13/7 10/5 0.64 Graft failure 3% 0% 20% 0.04 Acute GVHD, grade II–IV 55% 74% 8% <0.01 Acute GVHD, grade III–IV 31% 16% 0% <0.01 1-year NRM 46% 15% 0% 0.01 1-year OS 47% 69% 100% <0.01 1-year Relapse 19% 40% 12% 0.43 1-year PFS 43% 51% 88% <0.01 Figure Figure

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)

Obesity Is Associated with An Increased Risk of Infectious Diseases after Unrelated Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4346-4346
Author(s):  
Shigeo Fuji ◽  
Sung-Won Kim ◽  
Ken-ichi Yoshimura ◽  
Hideki Akiyama ◽  
Shin-ichiro Okamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Clinical Outcome ◽  
Infectious Diseases ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Increased Risk ◽  
Grade Ii ◽  
Low Bmi ◽  
The Impact

Abstract (Background) Both obesity and malnutrition have been considered to be risk factors for complications after bone marrow transplantation (BMT). To elucidate the impact of pre-transplant body mass index (BMI) on the clinical outcome, we performed a retrospective cohort study with registration data from the Japan Marrow Donor Program (JMDP). (Results) From January 1998 to December 2005, 3935 patients received unrelated BMT through JMDP, and 3827 patients for whom pre-transplant height and weight data were available were included. Patients were stratified according to pre-transplant BMI values (low BMI: BMI&lt;18, n=295; normal BMI: 18≤BMI&lt;25, n=2906; overweight: 25≤BMI&lt;30, n=565; obese: 30≤BMI, n=61). In a univariate analysis, pre-transplant BMI was associated with a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD, P=0.03). Other factors which was associated with higher incidence of grade II-IV acute GVHD was HLA allele disparity, GVHD prophylaxis with CSP compared with TAC and donor age (≥40). Multivariate analysis showed that pre-transplant BMI tended to be associated with an increased risk of grade II-IV acute GVHD (P=0.07). Obesity was associated with an increased risk of infectious diseases compared with normal BMI [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.1–3.2; P=0.02]. Progression-free survival was 54%, 52%, 56% and 47% in low BMI, normal BMI, overweight and obese, respectively in 1 year after BMT, and there was a trend that 1-year non-relapse mortality was higher in obese group (low BMI 29%, standard BMI 31%, overweight 32%, obesity 39%). (Conclusions) This study shows the correlation between pre-transplant BMI and posttransplant complications. Although BMI strongly depends on multiple factors, the effect of obesity on clinical outcome, as suggested here, should be evaluated in a prospective study.

Non T-Depleted Bone Marrow Transplantation From Haploidentical Related Donor in Hematological Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2291-2291 ◽  
Author(s):  
Stella Santarone ◽  
Gottardo De Angelis ◽  
Erminia Di Bartolomeo ◽  
Pasqua Bavaro ◽  
Mauro Montanari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Platelet Recovery ◽  
Prognostic Features ◽  
Grade Ii

Abstract Abstract 2291 Poster Board II-268 Haploidentical bone marrow transplantation (BMT) is an alternative treatment to patients with high-risk hematologic malignancy lacking a HLA-matched donor and those urgently need transplantation. We used a haploidentical-BMT protocol without ex vivo T cell depleted based on the knowledge that marrow grafts have 10 times fewer lymphocytes compared to peripheral blood stem cell grafts and granulocyte colony-stimulating factor (G-CSF) donor priming reduce the incidence of acute GvHD. Materials and Methods: 40 patients (median age of 32, 12-63) with advanced disease or leukemia with poor prognostic features underwent unmanipulated haplo-BMT: 22 with AML, 9 with ALL, 3 with CML, 3 with Hodgkin lymphoma and 3 with plasmacell leukemia. Status at disease: 22 early (first or second comple! te remission), 18 advanced (progressive or refractory disease). All pairs of donors and recipients were identical for one HLA haplotype and incompatible at 2 or 3 loci.The myeloablative conditioning regimens used were different; antithymocyte globuline, cyclosporine, metotrexate, mycophenolate mofetil and basiliximab were used for GvHD prophylaxis. Donors were primed with filgrastim at 4 micrograms/Kg/d for 7 consecutive days. Bone marrow cells were harvest on the 8 day and were infused unmanipulated. Results: the median dose of total nucleated, CD34+ and CD3+cells was 7×10e8/Kg (1.01-28.7), 2.3×10e6/Kg (1.17-6.0) and 23.3×10e6/Kg (9.7-66.6) respectively. 1 patients had a primary graft failure and 5 patients died early prior to engraftment. In the remaining 34 patients, engraftment was seen with median time to granulocyte and platelet recovery of 22 and 27 days respectively; acute GvHD was grade 0 in 17 patients (50%), grade I in 9 (26%), grade II in 7 (20%) and grade IV in 1 (3%). In 29 evaluable patients, chronic GvHD was limited in 3 (10%) and extensive in 1 (3%). Transplant-related mortality at 6 months for early and advantage stage was 22% and 35% respectively. After a median follow up of 18 (3-42) months, 8 patients relapsed; 11 patients (50%) in the early stage and 4 (22%) in advanced phase are now living in haematological remission. The 1-year Kaplan-Meyer probability of disease-free survival is 45% for all patients. Conclusion: the high engraftment rate, low incidence of grade II-IV acute GvHD and an acceptable TRM suggest that G-CSF-primed marrow grafting along with sequential immunosuppression could provide an excellent alternative for patients who lack matched donors. Disclosures: No relevant conflicts of interest to declare.

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)

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