Outcomes of Patients Treated with Matched and Mismatched Unrelated Donors Using High-Resolution HLA Typing at 12 Loci

Abstract Abstract 3537 Donor-recipient HLA mismatches are associated with increased morbidity and mortality after UD hematopoietic stem cell transplants (HSCT). We hypothesized that HLA-DP mismatches would worsen outcomes of HSCT using donors mismatched at HLA-A,-B,-C,-DRB1 or -DQB1 and evaluated 391 consecutive patients (pts) with myeloid malignancies treated at our institution with 0,1,2,3 mismatches out of 12 alleles typed by high resolution at HLA-A,-B,-C,-DR,-DQ,-DP loci. Eighty-one pts were 12/12, 180 pts were 11/12, 113 pts were 10/12, and 15 pts were 9/12 HLA match with the recipients. Characteristics of the 4 groups (12/12, 11/12, 10/12, 9/12) were similar except source of stem cells; 87% of pts with 9/12 donors received bone marrow versus 60–62% for the other 3 groups. Results: Two-year overall survival (OS) and progression-free survival (PFS) were 40%, 44%, 45%, 53% and 33%, 40%, 44%, 49%, respectively (p=NS). However, OS was significantly worse with increasing number of mismatches for patients with AML/MDS with poor-risk cytogenetics (p=0.005, HR 1.6, 95% CI 2.1–4.2). Except for the 9/12 group, pts had a significantly higher non-relapse mortality (NRM) (11%, 24%, 36%) and lower risk of progression (32%, 25%, 20%). In the 9/12 group, NRM was 27% and progression rate was 40%. Grade II-IV, III-IV aGVHD as well as cGVHD were also progressively worse with increasing number of mismatches. Gr II-IV and III-IV aGVHD rates were 35%, 37%, 41%, 69%, and 8%, 8%, 15%, 16%, respectively. Cumulative incidence of cGVHD was 35%, 39%, 44% and 61%, respectively. Compared with 11–12/12 donors, pts who received a 9–10/12 donor had significantly higher rates of gr III-IV aGVHD and cGVHD (p=0.03, HR 2.1, CI 1.1–3.7 and p=0.02, HR 1.5, CI 1.1–2.1, respectively). Univariate analysis revealed that there is less NRM with a 12/12 donor (vs. other) (p=0.008, HR 1.9, 95% CI 1.2–2.9), while in multivariate analysis, compared with a 12/12 donor, the use of a donor with mismatch was significantly associated with higher NRM [HR and 95%CI were 2.1 and 1.04–4.4 for 11/12 donor (p=0.04); 3.1 and 1.5–3.3 for 10/12 donor (p=0.003); 2.8 and 0.9–9.3 for a 9/12 donor (p=0.08), respectively] (Figure). In multivariate analysis, factors significantly associated with OS were disease status at transplant (active disease vs. not) (p<0.001), cytogenetics for AML/MDS pts (poor-risk vs. other) (p=0.006, HR) and the use of fludarabine and busulfan conditioning (Bu 130mg/m2 × 4 days and Flu vs. other) (p=0.04, HR 0.7, CI 0.5–0.98), while factors significantly associated with NRM were, in addition to degree of mismatch, disease status at transplant (p=0.008, HR 1.9, CI 1.2–3.1) and use of BuFlu conditioning (p=0.004, HR 0.5, CI 0.4–0.8). In conclusion, these results suggest that, using 12/12 high-resolution HLA typing, a progressively higher NRM is encountered for unrelated donor pts with higher number of mismatches, at least in part related to higher rates of GVHD. Matching at DP loci appears to be protective of NRM and is associated with improved survival for patients with AML/MDS with poor-risk cytogenetics. Disclosures: No relevant conflicts of interest to declare.

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Allo-HSCT From Unrelated Donors Improves The Outcome Of Elderly AML Patients In CR1

Blood ◽

10.1182/blood.v122.21.2166.2166 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2166-2166

Author(s):

Yosuke Nagahata ◽

Yuichiro Ono ◽

Yotaro Ochi ◽

Yusuke Koba ◽

Yasuhiro Kazuma ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

Complete Remission ◽

Conflicts Of Interest ◽

Intensive Therapy ◽

Univariate Analysis ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Elderly Aml ◽

Unrelated Donors

Abstract Background Recent reports have suggested that allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donors improves the outcome of elderly acute myeloid leukemia (AML) patients in first complete remission (CR1) (Kurosawa et al BBMT 2011). However, the efficacy of allo-HSCT from alternative donors for the management of elderly AML patients in CR1 remains to be clarified. In this study, we examined the efficacy of allo-HCST for the management of elderly AML patients. Methods We retrospectively collected the data of consecutive AML patients who were aged 50-70 years and diagnosed in our hospital between January 1, 2000 and May 31, 2013. Patients with acute promyelocytic leukemia (APL) and patients who could not receive intensive therapy or died within 60 days after diagnosis were excluded. The primary endpoint of this study was overall survival (OS), which was defined as the interval between diagnosis and the last follow up. The unadjusted probabilities of OS were estimated using the Kaplan-Meier method. To compare OS between the treatment groups, the log-rank test was used. Multivariate analysis were performed with Cox proportional hazard regression models and 95% confidence intervals (CIs) were calculated. Results A total of 131 elderly AML (non-APL) patients were identified. Except for 14 patents, all received chemotherapy. 12 patients who died within 60 days were excluded from the study. Among the remaining 105 patients, 41 could not be induced into complete remission (CR) and showed a dismal outcome; the probabilities of 2 years (2y)-OS were 0% and 4.4% for 5 patients who received allo-HSCT and 36 patients who did not, respectively. In contrast, the probability of 2y-OS of 64 patients who achieved CR1 was 48.5%. Of these 64 patients, 20 proceeded to allo-HSCT. 13 patients were transplanted in CR1, 3 in second CR (CR2), and 4 in relapse. The probabilities of 2y-OS were 56.1% and 45.0% for patients who received and who did not receive allo-HSCT, respectively (p=0.27). When the disease status at allo-HSCT was considered, the 2y-OS of patients who received allo-HSCT in CR1 reached 83.3%, whereas that of patients transplanted in CR2 or relapse reached only 14.3%. Next, we performed univariate and multivariate analysis of OS of patients who achieved CR1. In addition to whether allo-HSCT was performed in CR1 or not, the following factors were also considered as covariates: age and leukocyte counts at diagnosis, cytogenetic classification according to National Comprehensive Cancer Network guidelines, presence or absence of preceding hematological diseases, and the number of induction regimens required for achieving CR1. Univariate analysis showed that allo-HSCT in CR1 was associated with improved OS (2y-OS: 83.3% vs 40.6%, p=0.013) (figure1). Multivariate analysis also showed that allo-HSCT in CR1 was the only favorable prognostic factor for OS (Hazard ratio=0.25, 95%CI: 0.077-0.82, p=0.022). Stem cell sources of allo-HSCT done in CR1 were 1 HLA-matched related donor and 12 unrelated donors including umbilical cord blood from 1 donor. Conclusion Allo-HSCT, even from an unrelated donor, improves the outcome of elderly AML patients in CR1. However, allo-HSCT for those with relapsed or refractory disease could hardly extend their survival. Disclosures: No relevant conflicts of interest to declare.

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The Effect of High-Resolution Donor-Recipient HLA Matching and Mismatching Frequencies On Choosing Donor in Chinese Population for Unrelated Allo-HSCT.

Blood ◽

10.1182/blood.v114.22.4503.4503 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4503-4503

Author(s):

Jun He ◽

Zi-Xing Chen ◽

Xiaojing Bao ◽

Qiaocheng Qiu ◽

Xiaoni Yuan ◽

...

Keyword(s):

High Resolution ◽

Conflicts Of Interest ◽

Human Leukocyte ◽

Hla Typing ◽

Unrelated Donor ◽

Hla Matching ◽

Hematopoietic Stem ◽

Leukocyte Antigen ◽

Resolution Level ◽

Selection Of

Abstract Abstract 4503 The relative importance of various human leukocyte antigen (HLA) loci and the resolution level at which they are matched has not been fully defined for unrelated donor (URDs) transplantation. Hematopoietic stem cell transplantation (HCT) from volunteer URDs may give a chance of cure for patients with malignant hematological diseases. Although donor-recipient HLA matching is associated with better outcomes, many are not able to identify an HLA-A, -B, -C, -DRB1, DQB1 matched URD and are faced with choosing the closest matching among the available donors. The Chinese Marrow Donor Program (CMDP) has completed a retrospective high-resolution HLA typing on sufficient patient-donor pairs to analyze high resolution matching and mismatches probability at specific loci. These data are critical for selecting the best available partially HLA-matched donor for patients undergoing HLA-mismatched URD HCT. We have performed high-resolution typing for HLA-A,-B,-C,-DRB1,-DQB1 by using SBT, SSOP and SSP techniques on 1092 donors and 931 patients from the data base of CMDP. Among 1092 donors, the allele with highest frequency were HLA-A*1101, A*0201, A*2402, A*0207, A*3303, A*0206 and A*3001; HLA-B*4001, B*4601, B*5801, B*1302, B*1501, B*5101and B*1301; HLA-Cw*0102, Cw*0702, Cw*0304, Cw*0801, Cw*0602, Cw*0303, Cw*0302 and Cw*0401; HLA-DRB1*0901, DRB1*1501, DRB1*1202, DRB1*0701, DRB1*0803, DRB1*0405, DRB1*0301 and DRB1*1101; HLA-DQB1*0301, DQB1*0303, DQB1*0601, DQB1*0202, DQB1*0602, DQB1*0302, DQB1*0401, DQB1*0201 and DQB1*0502. The probability of HLA high-resolution DNA matching between 1092 donors and 931 patients(10/10 match) was 16.7%. Mismatching at a single HLA-A, -B, -C, -DRB1 or DQB1 locus (9/10) was 17.7%. A single mismatch at each locus of HLA-A, -Cw,- DRB1,- DQB1,- B was 6.8%, 6.3%, 2.0%, 1.7%, and 0.8%, respectively. Double mismatch (8/10) was 18.4%, such as loci A+ Cw(5.0%), DRB1+DQB1(4.6%) and B+ Cw(3.8%). The donor/patient pairs mismatched between allele of A*0201 and A*0206, A*0201 and A*0207, A*1101 and A*1102, B*4006 and B*4002, B*1501 and B*1527, Cw*0304 and Cw*0302, Cw*0304 and Cw*0303, DRB1*1501 and DRB1*1502, DRB1*1202 and DRB1*1201, DRB1*0406 and DRB1*0403, DRB1*1401 and DRB1*1454, DQB1*0303 and DQB1*0302, respectively, were statistically associated with lower-risk Allo-HSCT. These results suggested that high-resolution DNA matching or mismatching for HLA-A, -B, -C, -DRB1 and DQB1 alleles could be associated with better clinical outcome and higher survival. Furthermore, the identification of high risk mismatch and permissive mismatch would be beneficial for the selection of a suitable donor. Disclosures: No relevant conflicts of interest to declare.

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Poor-Risk Acute Leukemia Patients with An EBMT Low-Risk Score and An 8/8 Matched Unrelated Donor Show Excellent Survival After Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.1196.1196 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1196-1196

Author(s):

Tom Lodewyck ◽

Machteld Oudshoorn ◽

Bronno van der Holt ◽

Eefke Petersen ◽

Eric Spierings ◽

...

Keyword(s):

High Resolution ◽

Acute Leukemia ◽

Risk Score ◽

Low Risk ◽

Risk Scores ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Poor Risk ◽

Risk Patients ◽

The Impact

Abstract Abstract 1196 Poster Board I-218 Introduction: Allogeneic hematopoietic stem cell transplantation (alloSCT) from volunteer unrelated donors (URD) may be associated with a higher non-relapse mortality (NRM) and worse outcome as compared to alloSCT using HLA-identical sibling donors. However, many parameters next to donor type define NRM. The impact on outcome of allele-matching for HLA-A, -B, -C and -DRB1 between donor and recipient has clearly been demonstrated. The prognostic impact of the EBMT risk score, that takes into account age, stage of disease, time from diagnosis to transplantation, donor type and donor-recipient gender combination, has recently been validated in a variety of hematological malignancies including acute leukemia and myelodysplastic syndrome (MDS). We evaluated the relative prognostic value of high-resolution HLA matching and the EBMT risk score for patients with poor-risk acute leukemia and MDS who received an URD transplant. Patients and methods: Between 1987 and 2006, 327 patients (≥16y) with poor-risk acute leukemia and MDS underwent URD alloSCT in the Netherlands. Patients were in 1st complete remission (CR1, n=129), 2nd CR (CR2, n=91), beyond CR2 or not in remission (n=107). The leukemia-risk was considered to be poor if patients had adverse cytogenetics or were not in CR1. The majority of the grafts was T-cell depleted (94%). High-resolution typing of HLA-A, -B, -C, and -DRB1 alleles was available for analysis in 270 donor-recipient pairs and had in part been performed retrospectively. Results: We evaluated the impact of high-resolution matching for HLA-A, -B, -C and -DRB1 on progression free survival (PFS) and overall survival (OS). Patients who were fully matched (8/8) with their donors (n=170) hadsignificantly superior PFS (40+/-4% vs 26+/-5%, hazard ratio (HR)=0.68; 95%CI 0.50–0.92, p=0.01) and OS (39+/-4% vs 29+/-5%, HR=0.70; 95%CI 0.51-0.96, p=0.03), compared to patients with mismatched (≤7/8) donors (n=100). Superior OS in the 8/8 group appeared to be due to a lower NRM (24+/-4% vs 39+/-5%, HR=0.54; 95%CI 0.35-0.85, p=0.008), while the relapse mortality rate was identical in both groups (37+/-4% vs 32+/-5%). Patients with EBMT risk scores of 1-2 (n=71), 3 (n=77), 4 (n=76) and 5-7 (n=103) had a predicted 5 year OS of 52%, 41% (HR=1.57; 95%CI 0.98-2.52), 29% (HR=2.07; 95%CI 1.32-3.26) and 19% (HR=2.69; 95%CI 1.76-4.11), respectively (p<0.001). Relapse mortality rate and NRM increased with increasing EBMT risk score. As shown in the table, the impact of allele-matching on OS was most evident in the EBMT low-risk group. EBMT low-risk (1-2) patients with 8/8 donors showed excellent 5 year OS compared to EBMT low-risk patients with ≤7/8 donors (73+/-8% vs 35+/-12%). The favorable impact of a fully matched donor was absent in patients with higher EBMT risk scores. Conclusions: Both the EBMT risk score and the degree of allele-matching independently predicted outcome after URD alloSCT. The predictive value of allele-matching was especially evident in EBMT low-risk patients, while patients with the highest EBMT risk scores (>4) had a dismal outcome, despite allele-matching. These results emphasize the importance of incorporating age, disease stage, donor-recipient gender combination and time interval from diagnosis to transplantation (EBMT risk score parameters) as well as high-resolution HLA-typing in the risk assessment prior to URD alloSCT. As excellent OS was noted in well matched EBMT low-risk patients, our data underscore the importance of an immediate search for an unrelated donor in poor-risk leukemia patients in CR1 below the age of 40, who should then receive their alloSCT as early consolidation therapy following induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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Defining Parameters That Can Guide Public Cord Blood Units (CBUs) in Korea

Blood ◽

10.1182/blood.v126.23.3102.3102 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3102-3102

Author(s):

Junglim Lee ◽

Byung-Su Kim ◽

Soon- Hi Jang ◽

Tai-Gyu KIM

Keyword(s):

Multivariate Analysis ◽

Cord Blood ◽

Umbilical Cord ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Female Gender ◽

Limiting Factor ◽

Study Cohort ◽

Normal Delivery ◽

Hematopoietic Stem

Abstract Background: It is well known that Total Nucleated Cell (TNC) and CD34 are the greatest limiting factor in the use of umbilical cord blood (UCB) for transplantation. To enhance high UCB quality, it is important that how the factors will affect the UCB. This study is to identify maternal, neonatal, obstetric factors that influence the suitability for banking and transplantation of UCB units collection. Study design and methods: This study examined 6534 UCB (3712 at the Catholic Hematopoietic Stem Cell Bank and 2822 at the Daegu Fatima Hospital Public Umbilical Cord Bank) collected at two banks from October 2003 to June 2015. The variables were collected from retrospective records at the time of donation. The associations between TNC, CD34+ and variables including maternal age (MA), gestational age (GA), fetal body weight (FBW), time from collection to processing (T), collecting volume (CV), preTNC, and delivery type were analyzed by logistic regression. Results: In our study cohort (n=6534, male 2988, female 2991, unkown 555, all Koreans), the median values of TNC, numbers of CD34+, MA, GA, FBW, T, preTNC, and CV were 9.24úI108/unit (range, 3.02-35.64), 2.0úI106/unit(range, 0.04-29.2), 31.0 years(range, 15-46), 277 days (range, 202-382), 3330g (range, 1740-4970), 19 hours (range, 1-54), 11.69úI108/unit (range, 3.41-50.32), and 83.5ml (range, 26.0-218.2) respectively. In univariate analysis, variables that were associated with high TNC (defined as a TNC of > 9.24úI108/unit) included GA (defined as GA > 277 days) [OR 1.29 (95% CI 1.16-1.42 p < 0.001)], FBW (defined as FBW > 3330g) [OR 1.52 (95% CI 1.37-1.68 p < 0.001)])], CV (defined as > 83.5mL) [OR 2.61 (95% CI 2.36-2.88 p < 0.001)], preTNC [OR 25.45 (95% CI 22.34-29.00 p < 0.001)], and T (defined as T> 19 hours) [OR 0.87 (95% CI 0.79-0.96 p < 0.005)]. Variables that were associated with high CD34+ (defined as a number of CD34+ > 2.0úI106/unit) included MA (defined as MA > 31.0 years) [OR 0.90 (95% CI 0.82-0.99 P=0.036)], GA [OR 0.74 (95% CI 0.67-0.82 p < 0.001)], FBW [OR 1.41 (95% CI 1.27-1.56 p<0.001)], preTNC [OR 3.38 95% CI 3.06-3.74 p < 0.001]], and CV [OR 1.41 (95% CI 1.28-1.60 p<0.001)] In multivariate analysis of TNC, preTNC [OR 20.71 (95% CI 17.87-24.00) p < 0.001]] was the best predictor of followed by normal delivery [OR 1.77 (95% CI 1.48-2.11 P<0.001)], FBW [OR 1.35 (95% CI 1.17-1.56 p<0.001)], CV [OR 1.31 (95% CI 1.13-1.53 p<0.001)], and female gender [OR 1.21 (95% CI 1.05-1.39 p=0.01)]. In multivariate analysis of CD34, was preTNC [OR 3.39 (95% CI 3.00-3.83 p < 0.001)] was the best predictor of followed by FBW [OR 1.41 (95% CI 1.25-1.58 P<0.001)], GA [OR 0.59 (95% CI 0.52-0.66 p<0.001)], MA [OR 0.84 (95% CI 0.75-0.94 p=0.003)], and female gender [OR 0.89 (95% CI 0.78-0.98 p=0.02)]. Conclusions: We established referential values of cord blood using large scaled CB units in Korea. In multivariate analysis, maternal/donor characteristics were associated with preTNC, FBW, and gender for both high TNC and CD34+. Our results confirm that is similar values to those reported in previous data. These associations could be used to prioritize donations, collections, optimizing resource utilization and financial modeling in Korean cord blood banks. We are focusing on collection education using the standard operation procedure to facilitate of high cells as well as on more recruits of healthy mothers. Disclosures No relevant conflicts of interest to declare.

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Influence of Allele Level HLA Typing on Unrelated Donor (UD) Transplantation for High Risk Myeloid Leukemias.

Blood ◽

10.1182/blood.v106.11.2916.2916 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2916-2916

Author(s):

S. Parmar ◽

M. Fernandez-Vina ◽

P. Liu ◽

P. Cano ◽

B. S. Andersson ◽

...

Keyword(s):

High Risk ◽

High Resolution ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Hla Typing ◽

Unrelated Donor ◽

Free Survival ◽

Gvhd Prophylaxis ◽

Myeloid Leukemias ◽

Reduced Intensity

Abstract Donor-recipient histocompatibility is a major determinant of outcome after UD HSCT, and matching pairs by high-resolution (Hi-res) HLA typing is likely to improve results. Methods: We studied 66 pts with myeloid leukemias in complete remission (CR) transplanted with UD bone marrow (n=58) or peripheral blood (n=8) from 01/02 to 12/04. Preparative regimens were ablative [Busulfan (Bu)/Cyclophosphamide (Cy)(n=13), Cy/TBI (n=2), Fludarabine (Flu)/Bu 130 mg/m2x4 doses (n=33)] and reduced intensity [Flu/Bu 130 mg/m2x2 doses+Gleevec (n=7), Flu/Melphalan 140mg/m2 (n=11)]. ATG was given in 61 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate, with additional pentostatin in 24 pts. Hi-res typing of HLA-A, B, DRB1 and DQB1 loci was done prospectively; HLA-DPB1 and C loci were typed prospectively in 50% of cases and retrospectively in 50%. Hi-res typing was sequencing-based for HLA-A, B, DRB1, SSP-based for DRB3/4/5, DQB1 and DPB1; and SBT/SSOP-based for HLA-C. A Cox’s proportional hazards regression model was used to study overall (S), event-free (EFS) and aGVHD-free survival. Variables with a p-value <0.25 by univariate analysis were included in the multivariate model (MV). Variables were age, conditioning regimen, use of pentostatin, diagnosis, cytogenetics, SC source, ABO typing, infused total nucleated cell (TNC) dose, HLA matching and GVHD. Results: Median age was 45yrs (21–72). Diagnoses were MDS (n=5), AML (n=39), and CML (n=22). 21 pts were in 1st CR, 23 pts in 2nd or 3rd CR, 22 pts in 2nd or greater chronic phase (CP) CML. 45 pts were 10/10 HLA match (HLA-A, B, C, DRB1, DQB1), and 21 had one or more mismatches. All pts engrafted neutrophils at a median of 13 days; 32 pts (48%) had gd. II–IV aGVHD and 33 pts (57%) had cGVHD. With a median follow-up of 9 mo, 44 pts are alive; 11 pts have relapsed. There were no regimen-related deaths; 100-day mortality was 13% due to aGVHD (n=7), relapse (n=1) and infection (n=1). Median S and aGVHD-free survival in 10/10 pts have not been reached. Median EFS for 10/10 pts vs others is 34 vs.9.66 mos. MV for S: age ≥60yrs (P=0.02; HR 4.17 (95%CI 1.24–14), Flu-based regimen (P=0.0004; HR 0.14 (95%CI 0.05–0.41), use of pentostatin (P=0.02; HR 0.27 (95%CI 0.09–0.78) and grade II–IV aGVHD (P=0.02; HR 3.25 (95%CI 1.19–8.88). MV for EFS: age ≥60yrs (P=0.046; HR 3.06 (95%CI 1.02–9.18), Flu-based regimen (P=0.001; HR 0.21 (95%CI 0.08–0.54) and use of pentostatin (P=0.02; HR 0.34 (95%CI 0.13–0.85). MV for aGVHD-free survival: age ≥60yrs (P=0.039; HR 3.43 (95%CI 1.06–11.1), Flu-based regimen (P=0.0027; HR 0.09 (95%CI 0.02–0.43), use of pentostatin (P=0.003; HR 0.22 (95%CI 0.08–0.6) and CP CML (P=0.004; HR 0.06 (95%CI 0.01–0.41). S and EFS for 10/10 matched pts were improved with Flu-based regimen (p=0.01), and higher infused TNC dose (p=0.02). aGVHD-free survival was improved by using reduced intensity regimens (p=0.004) and worsened by presence of 2 DPB1 mismatches (1.18 mo vs not reached; HR=3.43; p=0.08). Conclusion: A combination of donor selection by high-resolution typing, less toxic preparative regimens and improved GVHD prophylaxis can optimize outcomes in this high-risk disease context. Figure Figure

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Variations In Efficiency of Donor Searches Between International Unrelated Blood and Marrow Donor Registries.

Blood ◽

10.1182/blood.v116.21.1524.1524 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1524-1524

Author(s):

Roisin Dunwoody ◽

Richard Szydlo ◽

Linda Casey ◽

John Davis ◽

Susan LLoyd ◽

...

Keyword(s):

Stem Cell ◽

High Resolution ◽

Conflicts Of Interest ◽

Mixed Race ◽

Median Number ◽

Hla Typing ◽

Search Process ◽

Unrelated Donor ◽

Cell Counts ◽

African Caribbean

Abstract Abstract 1524 The websites of the WMDA and BMDW list almost 100 registries providing volunteer unrelated donor (VUD) stem cells to the transplant community. A minority of these registries have completed a formal accreditation process although the majority of donors (>80%) in BMDW are contained within WMDA accredited registries. As a user of these registry services we were interested to assess variations in the efficiency of services in order to optimise our own search process and maximise our ability to transplant patients who might benefit in a timely manner. Within a national health service we are careful to contain costs and are aware that not only does the level of HLA typing of individual donors differ between registries but the costs of, and time to, obtaining confirmatory samples and the costs of eventual stem cell procurement also vary considerably. Since January 2004 we have maintained a comprehensive database to follow the progress of VUD searches in our institution. During this time searches were commenced for 193 patients (139 Caucasian, 15 African-Caribbean, 24 Asian and 15 mixed-race), and donors identified for 149 (77%). After high resolution typing of the potential recipient our initial request goes to our national hub which then provides a list of possible donors worldwide, including known degree of match and registry source. The simple parameter of time to donor identification is heavily influenced by the transplant centre which often categorises recipients in degrees of urgency and was not thought to be a useful measure of efficiency. Instead we looked at the availability of, time to obtain, and value of (as defined by degree of matching), confirmatory tissue typing samples once the request had been initiated, in addition to normal measures of the quality of the received stem cell product. For the 193 patients we requested further samples from 1226 donors with a median number of requests per patient of 7 (range 1–20). We utilised 30 registries (median number of requests per registry (R/R) of 3, range 1–387), although some 50% of the requests went to only 5 registries with a median of 220 R/R, range 43–387. 806 confirmatory samples were received from 1226 requests (66%). Donor availability and the time to sample arrival were compared in the 5 most frequently utilised registries, hereafter known as registries A-E. The percentage of the requests that resulted in samples and the percentages of samples found to be HLA-matched were 76%, 72%, 70%, 67% and 53% and 31%, 41%, 40%, 46% and 28% from registries A,B,C,D and E respectively. The chance of obtaining a suitable HLA-matched donor was highest from registry D at 31% and lowest from registry E at 15%. Failure to supply a confirmatory sample is due to inability to contact the donor, temporary unavailability or donor refusal and was unacceptably high in registry E at 47%. The median times from request to sample arrival ranged from 15–22 days. We confirmed the difficulties in finding donors for non-Caucasian patients with fewer potential donors provided initially by our hub and a reduced chance of finding fully HLA matched donors (defined generously as 8/8 antigens matched). Such donors were found for 62%, 26%, 46% and 40% of Caucasian, African-Caribbean, Asian and mixed-race patients. 61 patients have been transplanted to date. No differences were found between the 5 registries in the hours to infusion, viability at infusion, volume collected, total nucleated cell counts, CD34+cell numbers or time to engraftment. Of the 88 patients for whom donors were found but no transplant has been performed, 72 remain alive on treatment. Many of these have chronic myeloid leukemia (CML) and are responding to second generation tyrosine kinase inhibitors. The costs of obtaining samples varies from approximately $500-2000 per sample resulting in a range of 500 to several thousand dollars per patient. Cost cannot be recouped in our country if the transplant is not performed. As a result of this audit we have refined our search process using the initial search as a surrogate for the ease of finding a donor subsequently, so that full searches are only initiated in patients failing imatinib if they have few donors and/or donors with low resolution typing and focussing on those registries most likely to provide HLA-matched blood samples. Registries also have a responsibility to improve their service and minimise costs by focussing on donor retention and high resolution typing. Disclosures: No relevant conflicts of interest to declare.

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The Addition of ONE-Day Rest Between LAST ATG Infusion and STEM CELL Infusion DID NOT Affect Gvhd Occurrence After Allogeneic TRANSPLANTATION with Fludarabine-Busulfan-ATG Conditioning.

Blood ◽

10.1182/blood.v120.21.3029.3029 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3029-3029

Author(s):

Roberto Crocchiolo ◽

Sabine Fuerst ◽

Jean El-Cheikh ◽

Angela Granata ◽

Claire Oudin ◽

...

Keyword(s):

Stem Cell ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Disease Status ◽

Allogeneic Transplantation ◽

Unrelated Donor ◽

Progression Rate ◽

Gvhd Prophylaxis

Abstract Abstract 3029 Introduction: Antithymocyte globulin (ATG) is part of many conditioning regimens for allogeneic stem cell transplantation (AlloSCT) with the aim of reducing graft-versus-host disease (GvHD), due to in vivo T-cell depletion. ATG administration may be accompanied by fever, chills, headache or other side effects that affect patient's management and can cause a delay in stem cell infusion. In order to improve ATG tolerance, since November 2010 we modified our fludarabine-busulfan-ATG (FBA) conditioning for RIC transplants with the addition of 1-day rest between the last ATG administration and stem cell infusion. No modification of drugs or GvHD prophylaxis occurred: five days of fludarabine, two days of i.v. busulfan and two days of ATG Thymoglobuline (10 mg/kg total dose) were administered during conditioning, and ciclosporine for GvHD prophylaxis together with MMF only in the presence of a mismatched unrelated donor (MMUD). Aim: To analyse whether the addition of 1-day rest between ATG administration and stem cell infusion impacted on outcome of adult patients receiving AlloSCT after FBA conditioning with respect to previous no-rest modality, in particular acute grade 2–4 or grade 3–4 GvHD. Methods: The 1-day rest cohort (ATG-rest) was compared with a previous consecutive cohort of patients (no rest) transplanted at our center. Analysis of acute GvHD among the two groups was performed as well as of chronic GvHD, OS, PFS, NRM, relapse/progression. Results: A total of 64 and 63 patients were included in ATG-rest and no-rest cohorts respectively. First patient in the no-rest cohort received AlloSCT on November 2008. Follow-up was thus longer in this cohort: median 27 months (21–37) vs. 15 (11–20), p<0.0001. No significant differences of patients' age, diagnosis and disease status at AlloSCT between the two groups were observed; matched unrelated donors (MUDs) were higher in the ATG-rest group whereas the number of MMUDs was similar in both groups (see Table 1). Rate of acute and chronic GvHD and NRM, probabilities of OS and PFS did not differ between the two groups (Table 1). Unexpectedly, relapse/progression rate was lower in the ATG-rest groups (p=0.002), although disease status at AlloSCT was not significantly different between the two cohorts. Median day of relapse or progression from AlloSCT in the no-rest group was +165 (35–476) vs. +57 (8–215) in ATG-rest one, p=0.004. No difference in relapse/progression was observed according to donor (HLA-identical sibling vs. MUD vs. MMUD) and a lower relapse risk in 1-day rest group is confirmed after adjustment for type of donor: HR = 0.29 (0.12–0.72), p=0.01. Conclusion: The addition of 1-day rest between last ATG administration and stem cell infusion did not impacted on GvHD occurrence after AlloSCT after FBA conditioning. The finding of a reduced rate of relapse/progression in the ATG-rest group deserves to be investigated and requires longer follow-up. Disclosures: No relevant conflicts of interest to declare.

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Risk Factor of Hepatic Veno-Occlusive Disease: Analysis of Clinical Data of 5024 Patients Extracted from the Database of the Japan Marrow Donor Program.

Blood ◽

10.1182/blood.v108.11.2970.2970 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2970-2970

Author(s):

Miwa Sakai ◽

Kazuteru Ohashi ◽

Takuya Yamashita ◽

Hideki Akiyama ◽

Hisashi Sakamaki

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Stem Cell ◽

Clinical Data ◽

Univariate Analysis ◽

Disease Status ◽

Occlusive Disease ◽

Blood Type ◽

Hematopoietic Stem ◽

Increased Risk

Abstract Hepatic veno-occlusive disease (VOD) is one of the most serious complication of hematopoietic stem cell transplantation (HSCT). Various factors have been identified as increasing the risk of hepatic VOD, but few of them have been associated with a significantly increased risk. We retrospectively analyzed the clinical data of 5024 transplant recipients (median age28, range 0–68) which extracted from the Japan Marrow Donar Program. The diagnosis of VOD was made according to the McDonald’s criteria, and 324 out of 4833 patients (6.7%) were eventually diagnosed with VOD. The possible risk factors based on the previous studies were counted on an initial univariate analysis, and cumulated significant factors were further analyzed for their potential value for VOD development in multivariate analysis. Variables correlated with an increased risk of VOD were: time of transplant >2 times (relative risk (RR) 2.7; p=0.006), pretransplant disease status (RR 2.3; p=0.000), prior liver disease (RR 2.1; p=0.017), ABO blood type mismatch (RR1.7; p=0.000). In patients receiving either busulfan or melphalan for conditioning increased VOD risk (RR 1.5 and 1.8; p=0.007 and 0.002, respectively). In our multivariate analysis, stem cell source, and prophylactic use of heparin and Ursodiol had no significant effect on VOD development. This analysis might contribute to revise the previously reported risk factors for VOD and the data could be used to know which patients might be suitable subjects for new trials for VOD prevention.

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Reduced Relapse and Similar Progression-Free Survival After Double Umbilical Cord Blood Transplantation (DUCBT): Comparison of Outcomes Between Sibling, Unrelated Adult and Unrelated DUCB Hematopoietic Stem Cell (HSC) Donors.

Blood ◽

10.1182/blood.v114.22.662.662 ◽

2009 ◽

Vol 114 (22) ◽

pp. 662-662 ◽

Cited By ~ 3

Author(s):

Claudio G. Brunstein ◽

Jonathan A Gutman ◽

Todd E. DeFor ◽

Ted Gooley ◽

Michael R Verneris ◽

...

Keyword(s):

Multivariate Analysis ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Hematologic Malignancies ◽

P Value ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Hematopoietic Recovery

Abstract Abstract 662 For patients with hematologic malignancies who lack a matched or mismatched unrelated donor, UCBT is an alternative. However, only a minority of larger adolescents and adults are able to find a single UCB with an adequate cell dose. Double UCB unit grafts (DUCB) have previously been shown to extend this HSC option. In order to understand the relative merits of each HSC source, we combined the datasets at the University of Minnesota and Fred Hutchinson Cancer Research Center. Between 2001- and 2008, 536 patients with leukemia (AML, n=211; ALL, n=236; CML, n=70 and MDS, n=19) were transplanted with HSC from a matched sibling (SIB, n=204), 8/8- (MUD, n=152) or 7/8-HLA (MMUD, n=52) matched unrelated donor or DUCB (n=128). All patients received myeloablative conditioning with cyclophosphamide 120 mg/kg and total body irradiation 1200-1320cGy with fludarabine 75mg/m2administered prior to DUCB. All patients received GVHD immunosuppression with a calcineurin inhibitor and either methotrexate (SIB, MUD and MMUD) or mycophenolate mofetil (DUCB). While patient weight and sex distribution and proportion with standard risk disease (STD, AML and ALL in CR1-2, and CML in CP1) were similar, DUCB pts were younger (median age 25 yrs, SIB 40 yrs, MUD 31 yrs, MMUD 31 yrs; p<.01). The proportion of AML and ALL was similar among groups, although more CML patients received a MUD or MMUD. Recipient CMV seropositivity was lower among MUD (44%; SIB 58%; MMUD 60; DUCB 62%, p<.01). The median follow-up of survivors was 3.1 yrs (0.3-8.1). The univariate point estimates at the stated timepoints and multivariate outcomes are summarized in the Table.Outcomes after SIB vs. MUD vs. MMUD vs. DUCBSIB* Ref.MUD* RR (95%CI)MVA p-value†MMUD* RR (95%CI)MVA p-value†DUCB* RR (95%CI)MVA p-value†Neutrophil Recovery at day 4598% 1.097% 0.62 (0.50-0.78). . <0.0198% 0.63 (0.46-0.86). . <0.0187%; 0.29 (0.23-0.37). . <0.01Platelet Recovery at day 10086% 1.081% 0.83 (0.64-1.09). . 0.1875% 0.71 (0.48-1.04). . 0.0845% 0.22 (0.17-0.29). . <0.01Grade II-IV aGVHD at day 10065% 1.080% 1.68 (0.32-2.14). . <0.0185% 2.17 (1.46-3.23). . <0.0160% 1.01 (0.76-1.35). . 0.94cGVHD at 2 year47% 1.043% 1.04 (0.75-1.46). . 0.8048% 1.24 (0.77-2.0). . 0.3726% 0.73 (0.47-1.13). . 0.16TRM at 3 years24% 1.014% 0.92 (0.53-1.60). . 0.7627% 1.83 (0.97-3.42). .0.0634% 2.86 (1.81-4.51). . <0.01Relapse at 5 years43% 1.037% 0.83 (0.58-1.19). . 0.3235% 0.68 (0.39-1.20). . 0.1915% 0.27 (0.16-0.47). . <0.01PFS at 5 years33% 1.048% 0.83 (0.62-1.11). . 0.2038% 1.04 (0.70-1.53). . 0.8551% 1.00 (0.73-1.37). . 0.99*Results are shown as pointwise estimates, relative risk (RR) and the 95% confidence interval. SIB group was the reference (Ref) group for the multivariate analysis (MVA).†P-value shown relates to multivariate analysis. In summary, after a Cy/TBI based myeloablation, DUCB is associated with slower hematopoietic recovery compared to other HSC sources. While incidence of acute GVHD was similar to that observed after SIB, DUCB was associated with less acute and trend toward less chronic GVHD relative to unrelated donors. Despite reduced risk of GVHD after DUCBT, risk of relapse was remarkably low while TRM was elevated, resulting in similar PFS. In the absence of a SIB donor, using either MUD or DUCB yield encouraging PFS and are promising donor options. These results support a) the front line use of HLA 0-2 antigen mismatched DUCB in patients with hematological malignancy, b) development of new strategies to enhance hematopoietic recovery after DUCBT, potentially reducing the risk of TRM, c) studies to understand why relapse rates are reduced with DUCBT and d) quality of life assessments long term between HSC groups, as there appears to be less risk of acute and chronic GVHD after DUCBT. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Outcomes for Non-Myeloablative (NMA) and Myeloablative (MA) Conditioning for Adults with Acute Lymphoblastic Leukaemia (ALL) in First and Second Complete Remission (CR): a Center for International Blood and Marrow Transplant Research (CIBMTR) Analyisis.

Blood ◽

10.1182/blood.v114.22.872.872 ◽

2009 ◽

Vol 114 (22) ◽

pp. 872-872 ◽

Cited By ~ 3

Author(s):

David I. Marks ◽

Tao Wang ◽

Waleska S. Peréz ◽

Donald W. Bunjes ◽

John F. DiPersio ◽

...

Keyword(s):

Multivariate Analysis ◽

T Cell ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Cell Depletion ◽

Unrelated Donor ◽

Conditioning Group ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

Donor Transplant

Abstract Abstract 872 The efficacy of reduced intensity or NMA conditioning for allogeneic hematopoietic stem cell transplantation (HCT) for adults with ALL is uncertain. Using CIBMTR data we compared the outcomes of 92 patients ≥16 years who had NMA conditioning with 1421 patients who had myeloablative conditioning (MC) for allografts using sibling and unrelated donors for ALL in CR1 or CR2. Conditioning in the NMA group included regimens containing busulfan ≤ 9 mg/kg (27), melphalan ≤ 150 mg/m2 (23) or low-dose total body irradiation (36) and others (7). The NMA conditioning group were older (median 45 vs. 28 years, p<0.001) and more received peripheral blood grafts (73% vs. 43%, p<0.001). Other major potential prognostic factors were similar in the two groups. After a median follow-up of 54 vs. 38 months respectively, the NMA vs. MA conditioning groups had slightly less acute grade 2-4 graft-vs-host-disease (GVHD), less chronic GVHD but similar transplant-related mortality (TRM). However the NMA conditioning group experienced slightly more relapse (35% vs. 26%, p=0.08) yet similar overall survival (OS) (Figure): Outcome:MANMAP-value Acute GVHD @ 100 days, grades (2-4)46 (43-49)39 (29-49)0.16 Chronic GVHD @ 3 years42 (39-44)34 (24-44)0.16 TRM @ 3 years, %33 (31-36)32 (23-43)0.86 Relapse @ 3 years, %26 (23-38)35 (25-46)0.08 Leukemia-free survival (LFS) @ 3 years, %41 (38-44)32 (22-43)0.12 OS @ 3 years, %43 (40-46)38 (28-49)0.39 Multivariate analysis showed that a low Karnofsky score (KPS) and T cell depletion were associated with higher TRM but conditioning intensity had no impact on TRM (RR with NMA 0.97, P=0.89). Relapse risk with NMA conditioning was slightly, but not significantly higher ( (RR)=1.34, p=0.15) as was a CR2, particularly with a short (<12 months) initial CR (RR=2.74; longer remission (12 months) RR1.51, P<0.0001). Multivariate analysis demonstrated significantly improved OS with: KPS>80, CR1, lower WBC, no extramedullary disease, a well matched unrelated or a sibling donor, transplant since 2001, in younger patients (<30y), conditioning without TBI and GVHD prophylaxis without T-cell depletion. However ATG use did not affect survival.. The most common cause of death was relapse; which was similar in MA and NMA HCT (46% vs. 35%). Despite the older age in the NMA group, OS and LFS at 3 years was similar to those receiving MA HCT. In comparing the outcomes of NMA and MA conditioning in sibling vs. unrelated donor transplant recipients we found that there was slightly, but not significantly more relapse with NMA [34 (18-52)% vs. 26 (23-30)%, p=NS and 36 (24-49)% vs. 25 (22-28)%, p=NS respectively]. This was associated with similar OS of 40 (23-59)% vs. 50 (45-54)% and 37 (25-50) vs. 38 (34-41)% in the sibling and unrelated donor groups. Conclusions: These data suggest that NMA conditioning is worthy of investigation in prospective clinical trials of adult ALL. These trials should include both well matched unrelated and related donors, but importantly, NMA conditioning may not fully overcome the adverse impact of poor pre-HCT KPS on outcome. >Disclosures: No relevant conflicts of interest to declare.

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