Equality Of Access To Transplant For Ethnic Minority Patients Through Use Of Cord Blood and Haploidentical Transplants

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2138-2138 ◽  
Author(s):  
Robert N Lown ◽  
Steven GE Marsh ◽  
Helen Blake ◽  
Sergio Querol ◽  
Irina Evseeva ◽  
...  
Keyword(s):  
Cord Blood ◽  
Ethnic Groups ◽  
Unrelated Donor ◽  
Northern European ◽  
Equal Chance ◽  
Significant Difference ◽  
Unrelated Donors ◽  
The Impact ◽  
Unrelated Adult ◽  
Matched Donor

Abstract It is well accepted that patients of ethnic minorities who lack a sibling donor are poorly represented on the international unrelated donor panels. As recently as 2000, only 30% of such patients were able to find an unrelated donor suitable for transplantation. Historically these patients would have either not been transplanted, or would receive transplants from unrelated donors with two or more HLA mismatches. Continued expansion of the international donor inventory, and the advent of cord blood and haploidentical transplantation has improved the prospects for transplantation for such patients and, through the expertise of search staff within donor registries and histocompatibility laboratories, transplant centres are increasingly able to identify early on those patients who are unlikely to find a well-matched unrelated adult donor. Surprisingly, however, few contemporary data have been published to show the impact of these search strategies and alternative stem cell sources on provision of transplant to those of non-white Northern European origin. We consecutively enrolled and prospectively followed up (from search request to last contact or death) 332 patients referred by four UK transplant centres to the Anthony Nolan Graft Identification and Advisory Service (GIAS) for identification of an unrelated adult donor or cord blood unit. Of these, 248 (74.7%) were of white Northern European (WNE) descent, and 84 (25.3%) non-WNE. The underlying disease did not differ significantly between ethnicities. The median number of UK donors listed on the search report was 8 (range 0 to 3395) and 0 (0 to 42) respectively, and on BMDW 127 (0 to 38245) and 5.5 (0 to 380) respectively. 69.3% of WNE and 20.5% of non-WNE patients found a 10/10 HLA-matched donor at confirmatory typing (CT) (p<0.001); 96.3% of WNE and 61.4% of non-WNE found at least a 9/10 HLA-matched donor (p<0.001). Non-WNE patients had more cord blood transplants (21.3% vs 3.8%, p<0.001) and more haploidentical transplants (10.6% vs 1.3%, p<0.001). There was no significant difference in the number of patients reaching transplant (WNE 63.3%, non-WNE 56.0%, p=0.185) when considering all of the graft sources. Patients of non-WNE background had a significantly slower time from first CT request to identification of an unrelated donor for transplant (median 27 days vs 33.5 days, p= 0.02), and from search request to transplant with any graft source (median 110 days vs 132 days, p=0.03). However, when the cumulative incidence of transplantation with death as a competing risk was considered, there was no difference between ethnic groups (log rank p=0.185, see figure). The median time from search request to transplant by graft source was 120.5 days for adult unrelated donors (n=179), 143 days for cord blood (n=16) and 91 days for haploidentical donors (n=6) (p=0.626). These data show that the chance of receiving a transplant for patients of a non-WNE descent has improved considerably compared to historical literature. The majority of non-WNE patients were able to find a 9 or 10/10 matched donor, and many of those who could not were afforded the option of a cord blood or haploidentical donor transplant within a similar timescale. Whilst times to transplant do remain slightly longer for non-WNE patients, mainly due to a more protracted CT stage, they now stand an equal chance of reaching transplant. However, whether survival following transplant is similar between ethnic groups remains to be seen. Disclosures: No relevant conflicts of interest to declare.

Amelioration of Late Complications Following Unrelated Donor Bone Marrow Transplantation When Anti-Thymocyte Globulin Is Used as a Part of Conditioning.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5319-5319
Author(s):  
Matthew E. Adess ◽  
Patrick Stiff ◽  
Tulio Rodriguez ◽  
John Norton ◽  
Mala Parthasarthy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Graft Rejection ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Donor Bone Marrow ◽  
Number Of Patients ◽  
Significant Difference ◽  
Unrelated Donors ◽  
The Impact

Abstract Polyclonal anti-thymocyte globulin (ATG) reduces the risk for primary graft rejection as well as acute graft-versus-host disease (GVHD) by depleting T cells in both the host and the infused allograft. However, the impact of ATG on late outcomes is less certain. We report the results of a retrospective landmark analysis of consecutive patients who underwent an unrelated donor bone marrow transplant at our center between January 2001 and October 2005 (n=45) and survived at least 90 days following transplant. We compared late outcomes in patients who either recieved ATG (n=25) or did not (n=20) as a part of their conditioning regimen. Conditioning was with either busulfan and cyclophosphamide (n= 28; 17 without ATG) or BCNU, etoposide, cytarabine, and melphalan (n=18; 3 without ATG). Most patients (20) received rabbit ATG at a median dose of 3 mg/kg (range: 1.5–9 mg/kg) on day -4 and -3. Others were given equine ATG. GVHD prophylaxis consisted of tacrolimus + methotrexate in both groups. Median age was 42 years (range 18–65; 14 female). Bone marrow from unrelated donors matched at HLA-A, B, C, and DRB1 (7/8 and 8/8 matches) was used as the stem cell source. Diseases treated were CML (11), HD (9), AML (8), MDS (6), NHL (3), MM (3), and other (5). A median of 3 prior therapies had been given before transplant (range 1–5). There was no significant difference (Pearson χ2) in the number of patients beyond CR1/CP1 (n=25) and those having failed a prior autograft (n=17) between the two groups. The median overall survival in the recipients of ATG was 1382 days (95% CI: 373– 2391 days) as opposed to 364 days (95% CI: 0–851) in those not receiving ATG (P=0.125 by Log-Rank test); with a 1-year overall survival of 76% (59%–93%) vs. 50% (28–72) in the ATG vs. no ATG cohorts respectively, and 69% (49–89) vs. 44% (22–66) at 2-years. The 1-year progression free survival was 84% (69–98) vs.90% (77–100) in the ATG vs. no ATG cohorts, and 84% (69–98) vs. 67% (37–97) at 2 years. Chronic GVHD developed in 15/20 (75%) patients not receiving ATG (45% extensive), and in 12/25 (48%) in those recieving ATG (16% extensive) (P=0.06 Pearson χ2). Graft rejection was seen in 2/20 patients in the non-ATG arm and 1/25 patients in the ATG arm. Despite a lower incidence of chronic GVHD, the relapse rate was similar in the two groups (16% in the ATG group vs. 20% in the non-ATG group; P=0.73). Lymphoid recovery was similar in the two groups. The absolute lymphocyte counts at day-90 and day-180 post transplant were 680 vs 800/microL and 1100 vs. 1500/microL in the no ATG vs. ATG cohorts (P=0.275 repeated measures ANOVA). Serious late infections requiring parenteral antimicrobial treatment occured in 8 patients (32%) receiving ATG, and in 9 patients (45%) in the non-ATG arm ((P=0.248). CMV reactivation was seen in 8 patients (32%) receiving ATG, and 7 (35%) in the non-ATG arm. Eleven patients (55%) have died in the no ATG cohort from either relapse (2), GVHD (4) or infection (5); whereas in the ATG cohort 9 (36%) have died of either relapse (4), GVHD (3) or infection (2). In conclusion, ATG appears to reduce delayed transplant related complications, such as chronic GVHD and infections, in patients receiving bone marrow from unrelated donors. This may lead to a favorable trend towards improved survival in patients recieving ATG as a part of non-total body irradiation based conditioning.

scholarly journals Racial disparities in access to HLA-matched unrelated donor transplants: a prospective 1312-patient analysis

2019 ◽  
Vol 3 (7) ◽  
pp. 939-944 ◽  
Author(s):  
Juliet N. Barker ◽  
Kirsten Boughan ◽  
Parastoo B. Dahi ◽  
Sean M. Devlin ◽  
Molly A. Maloy ◽  
...  
Keyword(s):  
Cord Blood ◽  
Racial Disparities ◽  
Racial Disparity ◽  
Racial Minorities ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Modest Increase ◽  
Unrelated Donors ◽  
African Patients ◽  
To Receive

Abstract Availability of 8/8 HLA-allele matched unrelated donors (URDs) is a barrier for ethnic and racial minorities. We prospectively evaluated receipt of 8/8 HLA-allele matched URD or either 7/8 URD or cord blood (CB) transplants by patient ancestry from 2005 to 2017. Matched URDs were given priority if they were available. Of 1312 patients, 723 (55%) received 8/8 URD, 219 (17%) 7/8 URD, 319 (24%) CB, and 51 (4%) had no 7/8 or 8/8 URD or CB graft. Europeans were more likely to receive an 8/8 URD transplant than non-Europeans (67% vs 33%) and less likely to have no URD or CB graft (1% vs 9%). Southern Europeans received 8/8 URD transplants (41%) at rates similar to those of Asians (34%) and white Hispanics (35%); Africans were the least likely (18%) to undergo 8/8 URD transplantation. CB and 7/8 URDs extended transplant access to all groups. In 742 recent patients, marked racial disparity in 8/8 URD access between groups observed in earlier years persisted with only a modest increase in the percentage of 8/8 URD transplants. Of 78 recent African patients, 46% received a CB transplant and 14% had no 7/8 or 8/8 URD or CB graft. Increasing registry size has not resolved the racial disparity in URD access, which emphasizes the importance of alternative graft sources.

Culture of CD34+ Umbilical Cord Blood Progenitors with Notch Ligand Results in Enhanced and More Rapid Human Engraftment in a Preclinical NOD/SCID Mouse Model.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 190-190 ◽  
Author(s):  
Colleen Delaney ◽  
Irwin D. Bernstein
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Culture Period ◽  
Unrelated Donor ◽  
Culture Vessel ◽  
Notch Ligand ◽  
Significant Difference

Prior clinical studies have indicated that total nucleated and CD34+ cell dose is a critical determinant of hematopoietic reconstitution and survival after unrelated donor umbilical cord blood (UCB) transplantation. Efforts to overcome the problem of small cell numbers in UCB grafts by ex vivo expansion, primarily by culture with cytokines, have not met with success. We have previously shown that culture of CD34+CD38− UCB progenitors with the Notch ligand, Delta1, results in enhanced generation of NOD/SCID repopulating cells. Here we develop a clinically feasible cGMP method for Notch ligand-based expansion of cord blood precursors. Specifically, we investigated the use of CD34+ versus CD34+CD38− cells as a starting population, optimal cytokines and medium, selection of culture vessel and culture period for effects on generation of NOD/SCID repopulating cells. UCB progenitors were cultured in the presence of a Notch ligand form consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1 (Delta 1ext-IgG) or control human IgG. Initial studies demonstrated optimal cytokines consisted of SCF, FL, TPO, IL6 and IL3, together with fibronectin fragments in serum free medium. There was no significant difference seen in the CD34 fold expansion with CD34+ versus CD34+CD38− starting cells, however, upon transplantation into NOD/SCID mice, there was a significant increase in the level of human engraftment seen with the CD34+ starting cell population (6.93% vs 2%; p=0.01). Further results from 5 independent experiments in which cord blood CD34+ progenitor cells were cultured for 17 days with immobilized Delta1extIgG or control resulted in a mean fold expansion of CD34+ cells of 230 (± 53) for the Delta cultured cells versus 65 (±31) for the control cultured cells (p=0.03). Delta cultured cells demonstrated significantly enhanced levels of human engraftment as measured by percent CD45 in the marrow of the animals at both 3 weeks (Delta1 15.5%, control 2.6%, uncultured 0.2%; p<0.0001) and at 9 weeks (Delta1 29.4%, control 8.9%, uncultured 7.3%; p<0.0001). We also found significantly greater numbers of SCID repopulating cells (SRC) detected 3 and 9 weeks following transplantation in the Delta1ext-IgG cultured cells compared to control cultured or non-cultured cells (frequency of SRC per 106: 3 weeks, 125 versus 37 or 8, respectively; p=0.0001; 9 weeks, 99 versus 56 or 15, respectively; p=0.01 and p=0.0001). Additional experiments demonstrated that the 17 day culture period was superior to shorter (10 days) or longer (21 days) periods. Relevant to anticipated administration of cultured cord blood units together with a second non-cultured unit in clinical trials, we determined the relative contribution to engraftment of co-infused expanded versus non-manipulated cells in immunodeficient mice, using tissue culture bags as a closed system. We found increased human engraftment in mice that received co-infusions of cultured and uncultured cells compared to either unit alone. Moreover, studies demonstrated that both units contributed to the observed human engraftment suggesting absence of cross-immunologic rejection. This data demonstrate the ability to ex vivo expand UCB repopulating cells using a clinically relevant Notch ligand-based closed culture system and suggests clinical evaluation of this approach to provide more rapid engraftment to overcome the major disadvantage of UCB transplantation.

Comparison of Outcomes of Bone Marrow and Umbilical Cord Blood Transplants from Unrelated Donors in Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2010-2010
Author(s):  
Kazuhiro Masuoka ◽  
Shigesaburo Miyakoshi ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract &lt;Objectives&gt; Promising results of cord blood transplants from unrelated donors have been reported in adults. To compare of outcomes of bone marrow transplants (BMT, n = 51), and umbilical cord blood transplants (UCBT, n = 110) from unrelated donors in adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS), we analyzed retrospectively the results of 161 adult patients with AML and MDS in our hospital. &lt;Patients and Methods&gt; We reviewed medical records of 161 patients with AML/MDS who had received a hematopoietic stem cell transplant from an unrelated donor between August 2000 and April 2007 at Toranomon Hospital, Tokyo, Japan. &lt;Results&gt; Patient’s median age was 55 years (17–71). Diagnoses include de novo AML (n =85), MDS overt AML (n=48), refractory anemia (RA) (n=13), and refractory anemia with excess of blasts (RAEB) (n=15). Disease status consisted of standard (CR1 of AML and RA, n=30) and advanced (other status, n=131). Recipients of UCBT had more advanced disease than recipients of BMT at the time of transplantation (89 percent vs. 65 percent, P&lt;0.001). The median number of nucleated cells that were infused was 0.26×108 per kilogram of the recipient’s body weight for cord blood and 2.5×108 per kilogram for bone marrow (P&lt;0.001). The major difference were higher number in the UCBT group of HLA mismatches (defined by serology for class 1 and molecular typing for DRB1).The donor was HLA mismatched in 96% of UCBT recipients, and in 41% of BMT recipients (P&lt;0.001). Other significant differences were observed in preparative regimens, and graft-versus-host disease (GVHD) prophylaxis. Nonadjusted estimates of 2-year OS and DFS rates were 53% and 48% in the BMT group, and 33% and 25% in the UCBT group (P&lt;0.001). However, 2-year OS and DFS rates in the standard group were not significantly different in the two groups (63% and 63% in the BMT group, and 75% and 58% in the UCBT group; p=0.98 and 0.32). Compared with BMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR]= 0.52; 95% confidence interval [95CI]: 0.36–0.75; p&lt;0.001), increased 100 day TRM (HR=3.07; 95CI 1.45–6.51; p&lt;0.01) and decreased grade II–IV acute graft-versus-host disease (aGVHD) (HR=0.58; 95CI 0.35–0.96; p=0.03). Two-year relapse rate was not significantly different in the two groups. &lt;Conclusion&gt; We conclude that UCBT from an unrelated donor is a therapeutic option for adult AML/MDS patients who lack an HLA-identical donors. Higher mortality, especially from non-relapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

Comparative Study of French Unrelated Registered Stem Cell Donors and Cryopreserved Cord Blood Units.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5068-5068
Author(s):  
Marie-Lorraine M.L. Balere ◽  
Valerie V. Lapierre ◽  
Federico F. Garnier ◽  
Evelyne E. Marry
Keyword(s):  
Cord Blood ◽  
Equivalent Rate ◽  
The Em Algorithm ◽  
Significant Difference ◽  
Blood Banks ◽  
Haplotype Frequencies ◽  
National Patient ◽  
Unrelated Donors ◽  
Hla Haplotypes ◽  
Cord Blood Banks

Abstract The question of the HLA complementarity between unrelated Donors Registries and Cord Blood banks is often raised. On december 31th 2006, three methods were used to qualify and quantify the genetic diversity and complementarity between French marrow unrelated donors (FMUD) and French cryopreserved cord blood units (FCBU). The first one is based on HLA haplotype frequencies performed according to the EM algorithm method, the second on the contribution in new phenotypes (CinNP), the third on the presence of no, one or two frequent haplotypes within MUD/CBU phenotypes. Preliminary operations on HLA typings were necessary to homogenize data: split level, exclusion of only typed at class I level donors. HLA haplotype frequencies comparison does not lead to a global significant difference between FMUD and FCBU. The 5 most frequent haplotypes are identical in both populations: 01-08-17, 29-44-07, 03-07-15, 02-44-04, 02-07-15. Then some haplotypes, characteristic of either Nord or South of Europe, were more frequent among the FMUD than among the FCBU: 02-44-07, 02-51-13, 11-35-01, 02-60-13. On the contrary, some haplotypes of Middle East and Eastern Europe were more frequent among the FCBU than among the FMUD: 30-18-17, 24-35-11, 02-13-07, 33-65-01. In 2006 CinNP does not differ significantly between FMUD and FCBU. 49% of new MUD/CBU bring new HLA-ABDR low resolution split level phenotypes to the FMUD and FCBU populations present the year before, with differences between regions: Martinique and Reunion islands have the largest CinNP, Britanny the smallest. Effectiveness in term of CinNP have been studied for France during the past 6 years, by 2 year sections: 2001–2002, 2003–2004, 2005–2006. As expected, in order to reach an equivalent rate of CinNP, a growing number of donors must be registered every year. The 25 most frequent haplotypes among the FMUD and FCBU were calculated, and called “frequent haplotypes” (FH) among the French population. We could then categorize individuals according to the number of FH they had: none, one or two. 85% of harvested FMUD for a national patient between 2000 and 2006 had one or two FH versus 54% of infused FCBU. 50% of harvested FMUD/ infused FCBU for an international patient had no FH, versus 26% for a national patient. FMUD registry and FCBU banks are complementary: they answer to various HLA haplotypes needs for national and international patients. Incontestably, international patients benefit from French MUD/CBU, which present HLA characteristics not or under-represented in their Registry of origin.

Decreased Relapse Rates without Excessive Transplant Related Mortality Following Cord Blood Transplantation (CBT): A Matched Cohort Analysis Comparing Myeloablative Cord, Matched Unrelated, and Mismatched Unrelated Donor Transplants.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 968-968 ◽  
Author(s):  
Jonathan A Gutman ◽  
Wendy Leisenring ◽  
Frederick R. Appelbaum ◽  
Ann E Woolfrey ◽  
Colleen Delaney
Keyword(s):  
Cord Blood ◽  
Blast Crisis ◽  
Cohort Analysis ◽  
Disease Status ◽  
Unrelated Donor ◽  
Matched Cohort ◽  
Unrelated Donors ◽  
Relapse Rates ◽  
Related Mortality

Abstract We conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving transplants from cord blood, matched unrelated donors, and mismatched unrelated donors following myeloablative conditioning in our center’s recent experience. Between April 2006, when our current cord blood protocols opened, and February 2008, 26 consecutive patients underwent CBT following conditioning with 13.2 Gy TBI, 120 mg/kg cyclophosphamide (CY), and 75 mg/m2 fludarabine (FLU) for acute leukemias in morphologic CR (n=24) or chronic myeloid leukemia not in blast crisis (n=2). Twenty-three patients received two units (5 of whom had one of the two units ex vivo expanded) and three received single units. Matching between units and patient was 4/6:4/6 (n=10), 4/6:5/6 (n=5), 5/6:5/6 (n=7), 6/6:6/6 (n=1), and single 5/6 (n=3). For paired analysis with each cord patient, waiver of consent was obtained from the IRB and one matched 10/10 unrelated donor patient (MURD) and one mismatched (9/10 n=23, 8/10 n=3) unrelated donor patient (MMURD) was selected from our center’s database on the basis of identical disease status and similar age without knowledge of transplant outcome. All unrelated donor patients underwent myeloablative transplantation following conditioning with CY/TBI or busulfan (BU)/CY between November 2001 and February 2008 (median April 2005). Patients were matched for disease type, cytogenetic risk status, minimal residual disease status (MRD), and, for patients beyond CR1, time from diagnosis to relapse. Specific diseases and disease status were ALL n=10: CR1 n=8 (MRD n=3), CR2 n=1, CR3 n=1 (MRD n=1), Philadelphia chromosome positive n=3; AML n=14: CR1 n=8 (MRD n=1), CR2 n=6 (MRD n=2); CML n=2 (CP1 n=1, CP2 following blast crisis n=1). Median ages and range for patients were: CBT 23 (0.6–42), MURD 25 (1–41), and MMURD 25 (1–48), and median differences in age between the cord recipient and their unrelated donor matched pairs were 7.8 and 4.6 years for MMURD and MURD, respectively. Median follow-up for surviving cord patients is 16 months (range 7.5–26). There has been only 1 relapse among cord patients versus 8 relapses among MURDs and 5 relapses among MMURDs. Transplant related mortality (TRM) between each group is comparable. Cause specific hazard for relapse is significantly decreased when comparing cords to MURDs by logrank test (p=0.014) and trends toward decrease when comparing cords to MMURDs (p=0.068) (Figure 1). Two year cumulative incidence (CI) of relapse is 3.8% (95% CI 0.3–16.4) for cord patients, 31.4% (95% CI 14.9–49.6) for MURDs, and 21% (95% CI 7.6–38.9) for MMURDs. Two year CI of TRM is 21.6% (95% CI 7.5–40.4) for cord patients, 22.9% (95% CI 8.3–41.8) for MURDs, and 31.8% (95% CI 15–50.1) for MMURDs. Previous data suggest that double unit CBT, as compared to single unit CBT, may markedly reduce relapse rates. The majority of CBT patients included in this analysis underwent double unit CBT, and this strategy may contribute to our observations. Additionally, myeloablative MURD and MMURD TBI regimens at our center involve 12 Gy in contrast to the 13.2 Gy in our CBT regimens. This may also account to some degree for lower relapse rates. Larger numbers and longer follow-up will be needed to confirm these observations, but the possibility of decreased relapse rates without increased TRM is promising. Growing inventories of high quality cord blood units coupled with ongoing improvements in supportive care for CBT patients should lead to continued expansion of the role of CBT. Figure 1: Relapse and TRM following transplantation. Figure 1:. Relapse and TRM following transplantation.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

Allogeneic Bone Marrow Transplantation From HLA Mismatched Family Donors in Children with Aplastic Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 831-831 ◽  
Author(s):  
Hideki Muramatsu ◽  
Hiromasa Yabe ◽  
Ryoji Kobayashi ◽  
Akira Kikuchi ◽  
Kazuko Kudo ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Secondary Malignancy ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Unrelated Donors ◽  
Related Donor ◽  
Family Donor

Abstract Abstract 831 The first-line therapy for children with severe aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-matched family donor, and immunosuppressive therapy (IST) is indicated for patients without HLA-matched family donors. While the standard therapy for children who fail to respond to IST is allogeneic HSCT from an HLA-matched unrelated donor, HSCT from an HLA-mismatched family donor has also been indicated. Compared with unrelated donors, an HLA-mismatched family donor has some advantages especially for children who need urgent transplantation. We analyzed the clinical outcome of 578 children (325 boys and 253 girls) with AA (age, <20 years) who received allogeneic BMT between 1990 and 2009 in Japan, and registered to the Transplant Registry Unified Management Program (TRUMP). The median age at transplantation was 11 years (0–19), and the donors were serological 6/6 HLA-matched related donors (MRD) (n = 312), 1 locus-mismatched related donor (1MMRD) (n = 44), 2–3 loci-mismatched related (haploidentical) donors (n = 9), and HLA-matched unrelated donors (MUD) (n = 213). Causes of deaths were as follows: acute graft-versus-host disease (GVHD) (n = 4), chronic GVHD (n = 4), acute respiratory distress syndrome (n = 2), severe hemorrhage (n = 7), engraftment failure (n = 5), infection (n = 18), idiopathic pneumonia (n = 8), organ failure (n = 19), secondary malignancy (n = 4), and others (n = 4). The probability of severe acute GVHD (grade III–IV) in patients transplanted from 1MMRD (26.9% ± 7.4%) was significantly higher than that in patients transplanted from MRD (4.9% ± 1.3%) (p < 0.001). The probability of 5-year overall survival (5y OS) of patients transplanted from 1MMRD (93.1% ± 3.9%) was comparable to that of patients transplanted from MRD (93.1% ± 1.5%) (p = not significant, NS), but it was significantly better than that of patients transplanted from haploidentical donors (66.7% ± 15.7%, p =.016) and MUD (79.0% ± 2.9%, p =.014). In the subgroup analysis of 1MMRD, no significant difference was observed between HLA class I-mismatched (n = 32) and class II-mismatched patients (n = 12) (5y OS; 93.8% ± 4.3% vs. 91.7% ± 8.0%, p = NS). Comparison of the survival outcome based on the transplant period (1990–1999 vs. 2000–2009) revealed that the probability of 5y OS of patients transplanted from 1MMRD was not significantly different (92.3% ± 5.2% (n = 26) vs. 94.4% ± 5.4% (n = 18), p = NS), while that of patients transplanted from MUD significantly improved in the same period as we reported previously (67.1% ± 5.5% (n = 73) vs. 86.1% ± 3.1% (n = 140), p =.001)(Yagasaki et al., Blood 2011). In multivariate analysis, haploidentical donors (p <.001), MUD (p <.001), age ≥ 10 years (p <.001), and transplant period (1990–1999 vs. 2000–2009, p =.006) were identified as independent covariates associated with unfavorable OS. In summary, our analysis revealed that an HLA-mismatched related donor, especially 1MMRD, could be selected as a donor candidate for children with AA who need urgent transplantation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A perspective on the selection of unrelated donors and cord blood units for transplantation

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 259-265 ◽  
Author(s):  
Stephen R. Spellman ◽  
Mary Eapen ◽  
Brent R. Logan ◽  
Carlheinz Mueller ◽  
Pablo Rubinstein ◽  
...  
Keyword(s):  
Cord Blood ◽  
Marrow Transplant ◽  
Hematopoietic Stem ◽  
Blood And Marrow Transplant ◽  
Unrelated Donors ◽  
Matching Criteria ◽  
Graft Selection ◽  
Transplantation Outcomes ◽  
Unrelated Adult ◽  
Selection Of

Abstract Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient donor-recipient HLA matching to ensure engraftment and acceptable rates of GVHD. In this Perspective, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection.

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