Unrelated Donor Marrow Transplantation for Treatment of Childhood Hematologic Malignancies-Effect of HLA Disparity and Cell Dose

1999 ◽  
pp. 25-51 ◽  
Author(s):  
Ann E. Woolfrey ◽  
Claudio Anasetti ◽  
Effie W. Petersdorf ◽  
Paul J. Martin ◽  
Jean E. Sanders ◽  
...  
Keyword(s):  
Marrow Transplantation ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Cell Dose

Reduced-intensity unrelated donor bone marrow transplantation for hematologic malignancies

2008 ◽  
Vol 88 (3) ◽  
pp. 324-330 ◽  
Author(s):  
Sung-Won Kim ◽  
Keitaro Matsuo ◽  
Takahiro Fukuda ◽  
Masamichi Hara ◽  
Kosei Matsue ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Donor Bone Marrow ◽  
Reduced Intensity

Primary Graft Failure (GF) after Unrelated Donor Cord Blood Transplants (UCBT): Risk Factors and Management.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 44-44 ◽  
Author(s):  
Ka Wah Chan ◽  
Michael S. Grimley ◽  
Candace Taylor ◽  
Donna A. Wall
Keyword(s):  
Risk Factors ◽  
Cord Blood ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Viral Reactivation ◽  
Unrelated Donor ◽  
Cell Dose

Abstract Primary GF is recognized as a major risk in UCBT. Both graft (cell dose and quality of the cord blood unit) and recipient (diagnosis of aplastic anemia, prior chemotherapy exposure) characteristics have been reported as being associated with non-engraftment. Here we present a large series of UCBT patients from a single institution and analyze the risk factors and management of this complication. Between 3/2001 and 7/2006, 106 consecutive patients (pts), of median age 5.3 (range 0.1–18.4) years and weight median 22 (range 4–85) kg, received UCBT at Texas Transplant Institute. 13 did not achieve donor engraftment as documented by recovery of ANC< 500/μl by day + 42, and lack of donor cells on ≥2 RFLP analysis of the bone marrow. Failure to attain engraftment occurred in 5/27 with a non-malignant disorders, and 8/79 with hematologic malignancies (p< 033). Non-engraftment was less common in better HLA matched transplants (≥5/6 HLA match: 1/45 vs ≤ 4/6 HLA : 12/61; p< 0.02). Preliminary analysis showed no difference in cord blood TNC/kg, CD34/kg and pre thaw CFU/kg in pts who had primary GF compared to the rest of the cohort. A post thaw CFU/pre-freeze ratio of <20% was more common in primary GF. Among the 79 pts with hematologic malignancies (HM), 8 did not engraft. 4 died early; 1 from persistent leukemia, and 3 from transplant-related complications (TRM). Of the remaining 4 pts with HM, 2 were ALL children in CR1. The other primary GF occurred in 2/5 children with HLH (both with active disease at UCBT), 2/8 the children transplanted for aplastic anemia, and one pt with CD40L deficiency who had primary GF. The 9 pts who had not relapsed or died of TRM went on to second (2nd) UCBT 33 to 95 (median 55) days after first transplant (1st UCBT). Conditioning regimen for 2nd UCBT was fludarabine 175mg/m2, cyclophosphamide 50mg/kg, TBI 2 Gy, ± ATG in 7/9 patients. Median cell dose for 2nd UCBT were 3.6 × 107/kg. HLA matching was similar to 1st UCBT. There was one TRM (respiratory failure) but the rest (8/8) engrafted; with ANC >500/μl at a median of 15 (range 5–64) days, and platelets > 20000/μl at a median of 92 (range 24 to 137) days. All became transfusion-independent, and as of 8/1/2006, 7 of 9 pts are alive. All have complete donor chimerism 164–1616 (median 672) days after 2nd UDCBT. EBV-lymphoproliferatve disorders developed in 2 patients and it was fatal in one. Other viral infections encountered were BKV(1), HHV-6(1), CMV(3) in the blood; adenovirus(1) and enterovirus(1) in the stool; and BKV (1) in the urine. Acute graft-versus-host disease (GVHD) was diagnosed in 2/8 pts. 7/8 pts surviving >100 days had chronic GVHD, and it was extensive in 5 pts. It is important that primary GF be recognized as a risk of UDCBT and a back-up donor source be identified prior to transplant. Children with intact/active immune systems prior to transplant are at greater risk. Early 2nd UCBT, before patient’s condition deteriorates, is a feasible treatment alternative. This immunosuppressive preparative regimen is well tolerated early post first UCBT and can result in reliable engraftment, albeit a greater risk of chronic GVHD and viral reactivation post transplant.

Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4096-4102 ◽  
Author(s):  
Stella M. Davies ◽  
Craig Kollman ◽  
Claudio Anasetti ◽  
Joseph H. Antin ◽  
James Gajewski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Multivariate Logistic Regression Analysis ◽  
Unrelated Donor ◽  
Cell Dose ◽  
Donor Bone Marrow ◽  
Male Donor ◽  
Primary Graft Failure

Abstract We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 × 108/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non–African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell–depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 × 109/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P < .0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.

Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4096-4102 ◽  
Author(s):  
Stella M. Davies ◽  
Craig Kollman ◽  
Claudio Anasetti ◽  
Joseph H. Antin ◽  
James Gajewski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Multivariate Logistic Regression Analysis ◽  
Unrelated Donor ◽  
Cell Dose ◽  
Donor Bone Marrow ◽  
Male Donor ◽  
Primary Graft Failure

We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 × 108/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non–African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell–depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 × 109/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P < .0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.

scholarly journals Improved Outcomes of Haploidentical Blood and Marrow Transplantation in Hematologic Malignancies: A Single Center Study of 514 Cases

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3224-3224 ◽  
Author(s):  
Yan-Li Zhao ◽  
Tong Wu ◽  
Yue Lu ◽  
Xing-Yu Cao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Marrow Transplantation ◽  
Advanced Disease ◽  
Conflicts Of Interest ◽  
Hematologic Malignancies ◽  
Third Party ◽  
Unrelated Donor ◽  
Blood And Marrow Transplantation ◽  
The Third ◽  
The Third Party ◽  
Individualized Chemotherapy

Abstract Introduction: With GIAC regimen, haploidentical blood and marrow transplantation (haplo-BMT) has achieved comparable outcomes with identical sibling transplant (Dao-Pei Lu et al., Blood 2006; 107:3065). Our previous study has shown that the third party cell co-infusion in haplo-BMT (GIAC-3 regimen) could significantly reduce aGVHD and transplant-related mortality (TRM). We have also demonstrated that individualized chemotherapy to decrease leukemia burden followed by conditioning could improve disease-free survival (DFS) in refractory/relapsed AML. Objective: To learn the outcomes of our haplo-BMT with these integrated approaches, all patients who received haplo-BMT for hematologic malignancies in our center were analyzed retrospectively. Methods: Between April 2012 and December 2014, consecutive 514 patients with hematologic malignancies who underwent haplo-BMT were included. The median age was 20 (1.8 to 64) years old. The diagnosis included AML 232 (45.1%), ALL 207 (40.3%), MDS 27(5.3%), CML 14 (2.7%), lymphoma 13 (2.5%) and others 21 (4.1%). Transplants at CR1, ≥CR2 or advanced disease were 216 (42.0%), 114 (22.2%), 184 (35.8%), respectively. All patients received unmanipulated bone marrow (BM) and peripheral blood stem cells as graft after myeloablative conditioning plus ATG. Majority of the patients with AML received BuCy-based conditioning, while most ALL patients received TBICy-based regimen. Fludarabine was substituted for cyclophosphamide in some patients due to impaired organ function or high tumor burden. For refractory/relapsed diseases, individualized chemotherapy followed by conditioning was administered. Cyclosporine/tacrolimus, short-term Methotrexate, and Mycophenolate mofetil were employed for GVHD prophylaxis. Either 1ml/kg (recipient's body weight) haploidentical BM from the second haploidentical donor or one unit of unrelated cord blood was infused right after haplo-BMT as the third party cells. Minimal residual disease (MRD) was monitored routinely by quantitative PCR or flow cytometry. The patients with persistent MRD were interfered by immunosuppressant withdrew, adoptive immunotherapy with cytokine induced killer or NK cells or donor lymphocyte infusion. Results: All patients but 5 achieved durable engraftment. The cumulative incidences of grade II to IV aGVHD and grade III to IV aGVHD were 32.2%, 19.8%, respectively. The cumulative incidences of cGVHD and extensive cGVHD were 48.3%, 18.4%, respectively. 100-day TRM and 2-year TRM were 4.1%, 14.9%, respectively. Two-year relapse rate was 22.8%. With the median follow up 17 (6 to 38) months, overall 2-year DFS rates in CR1, ≥CR2 and advanced disease were 75.6%, 70.9%, 49.2%, respectively. For AML, two-year DFS rates in CR1, ≥CR2 and advanced disease were 74.1%, 76.9%, 48.2% (CR1 vs. ≥CR2, p=0.84; CR vs. advanced disease, p=0.000). For ALL, two-year DFS rates in CR1, ≥CR2 and advanced disease were 78.9%, 56.6%, 38%, respectively (CR1 vs. ≥CR2, p=0.018; CR1 vs. NR, p=0.000; ≥CR2 vs. NR P=0.02 ). Conclusions: With our strategies, overall outcomes of haplo-BMT have been improved remarkably and very encouraging. Therefore, haplo-BMT should be an important way to save life for the patients with hematologic malignancies who need urgent BMT but without matched either sibling or unrelated donor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome

Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4894-4902 ◽  
Author(s):  
C Peters ◽  
M Balthazor ◽  
EG Shapiro ◽  
RJ King ◽  
C Kollman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Rejection ◽  
Marrow Transplantation ◽  
Unrelated Donor ◽  
Hurler Syndrome ◽  
Cell Dose ◽  
The Impact ◽  
Mps I

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bons marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

Effects of Recipients’ Body Weight and Total Nucleated Cell Dose on Outcomes of Unrelated Bone Marrow Transplantation: Analysis of Clinical Data of 3,114 Leukemia Patients from the Database of the Japan Marrow Donor Program

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3010-3010
Author(s):  
Takuya Yamashita ◽  
Hideki Akiyama ◽  
Kazuteru Ohashi ◽  
Makoto Onizuka ◽  
Shin-ichiro Mori ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Body Weight ◽  
Bone Marrow Transplantation ◽  
Clinical Data ◽  
Marrow Transplantation ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Data Set ◽  
Cell Dose ◽  
Harvest Volume

Abstract In allogeneic bone marrow transplantation (BMT) from unrelated donor of Japan Marrow Donor Program (JMDP), the standard bone marrow nucleated cell dose for transplantation is regulated as 3.0×10E8 total nucleated cells (TNC)/recipient’s body weight (RBW) (kg). RBW are also used to estimate the target harvest volume of bone marrow from the donor. So RBW determine the dose of harvested TNC, and these factors will influence the outcomes of BMT. We retrospectively analyzed the clinical data of 3,114 adult transplant patients (median age 33, range 16–70) from extracted the database of JMDP. The diagnosis of these patients were AML (n=1257), ALL (n=927) and CML (n=930). Five years overall survival (OAS) of all cases was estimated as 47.6%. Possible factors that could influence on survival and hematological recovery were analyzed by using proportional hazards analysis. In univariate analysis, TNC&gt;=3.0×10E8/RBW was one of the significant factors to improve OAS (p=0.022). TNC/recipients’ ideal body weight (IBW) whose body mass index (BMI) was over 22 could be also a significant favorable factor for OAS (p=0.014). In multivariate analysis, variables correlated with improving OAS were TNC&gt;=2.0×10E8/IBW (p=0.011), using tacrolimus for GVHD prophylaxis (p=0.011), younger recipient’s age (p=0.013). TNC&gt;=2.0×10E8/IBW were also powerful variables correlated with the recovery of neutrophils, reticulocytes and platelets. These findings suggest that TNC/IBW can substitute for TNC/RBW to evaluate infused cell dose. And in our data set, use of IBW to estimate the harvest volume from the donor brought 10.7% reduction of target bone marrow volume compared with use of RBW. JMDP sets up the upper limit of harvested bone marrow volume based on the donor’s BW, but heavyweight recipients often require larger volume of bone marrow from the donors. Appropriate evaluation of TNC for transplantation and recipients’ BW by using BMI may be one of the useful methods to improve outcomes of unrelated BMT and avoid excess risk and stress of unrelated donors.

Effects of Recipients’ Body Weight on Engraftment after Unrelated Bone Marrow Transplantation: Analysis of Clinical Data of 4065 Patients from the Database of the Japan Marrow Donor Program.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5083-5083
Author(s):  
Takuya Yamashita ◽  
Kazuteru Ohashi ◽  
Hideki Akiyama ◽  
Hisashi Sakamaki
Keyword(s):  
Bone Marrow ◽  
Body Weight ◽  
Bone Marrow Transplantation ◽  
Clinical Data ◽  
Marrow Transplantation ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Neutrophil Recovery ◽  
Unrelated Bone Marrow Transplantation ◽  
Cell Dose

Abstract In allogeneic bone marrow transplantation from unrelated donor of Japan Marrow Donor Program (JMDP), the standard nucleated cell dose for transplantation is regulated as 3.0x10E8 bone marrow nucleated cells/recipient’s body weight. But if a recipient is heavyweight, it it often diffecult to get enough bone marrow from the donor for transplantation. Infused cell number and recipients’ body weight may infuence the engraftment and outcome of transplantation. We retrospectively analysed the clinical data of 4065 adult transplant recipients (median age 35, range 16–70) from extracted the database of JMDP. Based on the previous studies, the possible factors which could influence on engraftment were collected. The correlations of these factors with engraftment and neutrophil recovery after transplantation were analysed by using multiple logistic regression. Variables correlated with an increased possibility of engraftment were: incrased recipient’s body weight (p<0.001), increased transplanted cells/recipient’s body weight (p=0.0016), younger recipient’s age (p=0.0019) and using TBI for conditioning (p=0.0358). Variables correlated with early attaining of neutrophil>500 were: use of G-CSF after transplantation (p<0.0001), increased transplanted cells/recipient’s body weight (p<0.0001), and no use of MTX for GVHD prophylaxis (p<0.0001). But in the subset analysis of G-CSF use group, first 25 percentile group reached neutrophil>500 significantly earlier than other group (p<0.0001). These results suggested that recipients’ heavy body weight positively influenced on engraftment, but obesity of recipients might delay neutrophil recovery. This study may contribute to consider the adequate cell dose for unrelated bone marrow transplantation and assess the value of recipients’ body weight as a risk factor of hematopoietic cell transplantation.

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