Alternative Donor Transplantation for Aplastic Anemia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 43-46 ◽  
Author(s):  
Mary Eapen ◽  
Mary M. Horowitz
Keyword(s):  
Cord Blood ◽  
Aplastic Anemia ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Graft Failure ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Term Survival ◽  
Alternative Donor

AbstractPatients with severe aplastic anemia who do not have a human leukocyte antigen (HLA)-identical sibling generally receive immunosuppressive therapy as a first-line therapy, with allogeneic transplantation being reserved for those who do not have an adequate sustained response. Barriers to the use of unrelated-donor transplantation for aplastic anemia include identifying a suitable alternative donor, and risks of graft failure, regimen-related toxicity, and graft-versus-host disease (GVHD). Despite the more than 14 million adults registered with donor registries worldwide, only approximately 50% of patients of Caucasian descent will have an available and fully HLA-matched unrelated adult donor; the rate is substantially lower for non-Caucasians. While umbilical cord blood allows transplantation with greater donor-recipient HLA disparity (without excessive risk of GVHD), risks of graft failure and transplant-related mortality are higher than after transplantation of adult donor grafts. Among patients with a suitable donor, recent changes in pre-transplant conditioning regimens have lowered the risks of organ toxicity and graft failure. Although advances in donor HLA typing and selection practices and improved GVHD prophylaxis have lowered the risk, GVHD remains an important obstacle to long-term symptom-free survival. Despite these limitations, unrelated-donor transplantation offers the best chance of long-term survival for many patients in whom current immunosuppression strategies are not effective. Wider applicability of alternative-donor transplantation for aplastic anemia will require better approaches to prevent graft failure and GVHD and to expand the pool of unrelated-donor grafts. This includes exploring strategies to effectively use alternative grafts such as umbilical cord blood.

Allele Level HLA Matching On Outcomes After Double Umbilical Cord Blood (dUCB) Transplantation for Hematological Malignancies: Stronger Graft Vs. Leukemia with HLA Mismatch

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1976-1976
Author(s):  
Claudio G Brunstein ◽  
Todd E. Defor ◽  
Harriet Noreen ◽  
David Maurer ◽  
Margaret L. MacMillan ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Treatment Failure ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Hla Typing ◽  
P Value ◽  
Hla Matching ◽  
Transplant Outcomes

Abstract Abstract 1976 Multiple single center and registry reports have documented the critical impact of donor-recipient HLA match on engraftment, transplant-related mortality (TRM) and survival after umbilical cord blood (UCB) transplantation. However, nearly all reports have only considered HLA A and B at antigen level and HLA DRB1 at allele level typing without consideration of HLA C or DQ. Therefore, we retrospectively performed allele level HLA typing for HLA-A, B, C, DRB1, DQB1 for UCB donor-recipient pairs in order to assess the importance of high resolution HLA typing on transplant outcomes. After 2002, most patients received a dUCB transplant in order to achieve the desired cell doses of ≥3, ≥4 and ≥5 × 10e7 NC/kg for grafts that were HLA 6/6, 5/6 and 4/6 matched by original typing resolution, respectively. Therefore, the analysis was limited to 275 recipients of dUCBT for hematological malignancy and whom DNA from both units was available. The effect of HLA match was based on the HLA type of the predominant long term engrafting unit. The median recipient age and weight was 44 years (range, 0.6–69) and 76.9 kg (range, 7.1–148), respectively. Conditioning was myeloablative (40%) consisting of cyclophosphamide (CY) 120 mg/kg, fludarabine (FLU) 75 mg/m2 and total body irradiation (TBI) 1320 cGy, or non-myeloablative (60%) consisting of CY 50 mg/kg, FLU 200 mg/m2, TBI 200 cGy with 95% receiving cyclosporine A (CsA) and mycophenolate mofetil (MMF) immunosuppression. Patients had acute leukemia (62%), standard risk disease (62%), cytomegalovirus seropositive (59%), and received at least one UCB unit that was sex mismatched to the recipient (78%). Results reported are based on the long-term predominant UCB unit. Notably, survival was not adversely affected by HLA mismatch. The probability of survival at 5 years was 46% (95%CI, 33–58%), 47% (95%CI, 38–54%) and 29% (95%CI, 13–47%) in patients engrafting with a 3–5/10, 6–8/10 and 9–10/10 HLA-matched UCB grafts, respectively (p=.47). In multivariable analysis after adjusting for disease risk, CMV serostatus, and KPS, there was similar risk of overall mortality for all groups regardless of HLA matching level. All other transplant outcomes including the incidence of acute and chronic GVHD were similar for all HLA-matching groups (data not shown). In the subset with acute leukemia (n=174), however, greater HLA mismatch was associated with a significantly lower risk of relapse without a deleterious effect on risk of TRM, resulting in a benefit in LFS (inverse of treatment failure) as shown below. Transplant Outcome for Acute Leukemia HLA 3–5/10 match (n=84) RR (95%CI), p-value HLA 6–8/10 match (n=168) RR (95%CI), p-value HLA 9–10/10 match (n=34) RR (95%CI), p-value TRM at 2 years 1.0 1.1 (0.6–2.4)
 P=.73 1.1 (0.6–2.4)
 P=.73 Leukemia Relapse 1.0 1.9 (0.9–4.3)
 P=.11 3.5 (1.3–9.5)
 P=.01 Treatment failure 1.0 1.4 (0.8–2.4)
 P=.19 2.2 (1.1–4.2)
 P=.02 Together these data indicate that UCB units with greater HLA mismatch may confer greater GVL effect without greater TRM compared to HLA better-matched UCB grafts. These results suggest importance of evaluating allele level HLA typing in the setting of dUCB transplantation. If confirmed, these results could have major implications not only on graft selection (ie avoidance of HLA matched units), but also the target size of the international UCB banking inventory. Disclosures: No relevant conflicts of interest to declare.

Alternative Donor Transplantation For Adults With Lymphoma: Comparison Of Umbilical Cord Blood Versus 8/8 HLA-Matched Donor (URD) Versus 7/8 URD

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 161-161
Author(s):  
Veronika Bachanova ◽  
Claudio Brunstein ◽  
Linda J. Burns ◽  
Tao Wang ◽  
Jeanette Carreras ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Significant Difference ◽  
Alternative Donor ◽  
Matched Sibling

Abstract Allogeneic donor hematopoietic cell transplantation (HCT) is increasingly used to treat relapsed lymphoma with curative intent; however, many patients will not have a suitable matched sibling donor. Transplant centers are investigating the use of alternative stem cell sources although data comparing outcomes by stem cell source are limited. We compared outcomes of 1593 non-Hodgkin and Hodgkin lymphoma patients who underwent alternative donor HCT from 2000-2010 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Umbilical cord blood (UCB) (n=142), 8/8 (human leukocyte antigen [HLA] –A, B, C, and DRB1) matched adult unrelated donor (URD) (n=1176) and 7/8 HLA matched URD (n=275) HCT recipients were followed for a median of 25, 57 and 65 months, respectively. The median age in the 3 groups were UCB: 45 years (range 19-73 yrs), 8/8 URD: 50 (range 18-75 yrs) and 7/8 URD: 45 years (range 18-71yrs). Male gender and mantle cell lymphoma were more frequent in 8/8 URD recipients. 7/8 URD HCT recipients had lower Karnofsky performance scores, and UCB recipients were more likely to be non-Caucasian, have chemosensitive disease and to have undergone HCT in recent years. UCB recipients had inferior neutrophil and platelet engraftment rates at 100 days; however they were less likely to develop acute and chronic graft versus host disease (GVHD) compared to 7/8 URD and 8/8 URD (Table). The cumulative incidence of treatment related mortality (TRM) at 3 years was higher in 7/8 URD. There were no differences among the 3 groups in the 3-year relapse/progression, progression free survival (PFS) or overall survival (OS).Table.OutcomesUCBURD 8/8URD 7/8% (95%CI)% (95%CI)%( (95%CI)P-valueTime to ANC>0.5 x 109/L at 28 days66 (57-73)94 (92-95)94 (90-96)<0.001Platelet recovery ≥ 20 x 109/L at 100 days68 (59-76)86 (84-88)85 (80-89)<0.001Acute GVHD (II-IV) at 100 days26 (19-34)37 (35-40)49 (43-55)<0.0013 years Chronic GVHD at 3 years22 (15-30)51 (48-54)48 (42-54)<0.0013 years Treatment related mortality38 (29-46)35 (32-37)46 (41-52)0.0023 years Relapse/Progression29 (22-37)32 (29-34)25 (20-31)0.1073 years Progression free survival33 (25-42)33 (31-37)29 (23-34)0.1863 years Overall survival44 (35-53)43 (40-46)34 (29-40)0.017 In multivariate analysis stratified for performance status, lymphoma histology, GVHD prophylaxis, and disease status, no significant difference in OS was detected between UCB and 8/8 URD (HR 0.87 [95% CI 0.68-1.12]; p=0.29), UCB and 7/8 URD (HR 1.04 [95% CI 0.78-1.40]; p=0.77), and 8/8 and 7/8 URD (HR 1.19 [95%CI 0.97-1.45; p=0.08). Lower risk of treatment failure (death or relapse; inverse of PFS) was observed in transplants performed after 2007 (HR 0.79 [95% CI 0.66-0.96]; p=0.01) as compared to the time periods 2000-2003. Patients' age, time from diagnosis to HCT, race, history of prior HCT, and conditioning intensity did not influence OS or PFS. In conclusion, our results suggest that UCB and 7/8 URD grafts for patients with advanced lymphoma provide similar survival to 8/8 URD, extending allogeneic HCT to most patients with no suitable matched sibling donors. Graft source needs to be determined by availability, the clinical urgency of transplant, and transplant center experience. Disclosures: No relevant conflicts of interest to declare.

Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 1972-1980 ◽  
Author(s):  
Karen K. Ballen ◽  
John Koreth ◽  
Yi-Bin Chen ◽  
Bimalangshu R. Dey ◽  
Thomas R. Spitzer
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Hla Typing ◽  
Cellular Immunotherapy ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Donor Choice

Abstract Only 30% of patients who require an allogeneic hematopoietic cell transplant will have an HLA-matched sibling donor. A search for an unrelated donor will be undertaken for patients without a matched family donor. However, many patients, particularly patients of diverse racial and ethnic backgrounds, may not be able to rapidly identify a suitably matched unrelated donor. Three alternative graft sources, umbilical cord blood (UCB), haploidentical (haplo)–related donor, and mismatched unrelated donor (MMUD) are available. UCB is associated with decreased GVHD, but hematologic recovery and immune reconstitution are slow. Haplo-HCT is characterized by donor availability for transplantation and after transplantation adoptive cellular immunotherapy but may be complicated by a high risk of graft failure and relapse. A MMUD transplant may also be an option, but GVHD may be of greater concern. Phase 2 studies have documented advances in HLA typing, GVHD prophylaxis, and infection prevention, which have improved survival. The same patient evaluated in different transplant centers may be offered MMUD, UCB, or haplo-HCT depending on center preference. In this review, we discuss the rationale for donor choice and the need of phase 3 studies to help answer this important question.

Factors With an Impact on Chimerism Development and Long-Term Survival After Umbilical Cord Blood Transplantation

2012 ◽  
Vol 94 (10) ◽  
pp. 1066-1074 ◽  
Author(s):  
Sofia Berglund ◽  
Katarina Le Blanc ◽  
Mats Remberger ◽  
Jens Gertow ◽  
Mehmet Uzunel ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Umbilical Cord Blood Transplantation ◽  
Term Survival ◽  
Long Term Survival ◽  
Blood Transplantation

scholarly journals Utilization of Total Body Irradiation Is Not Necessary for Unrelated Donor Umbilical Cord Blood Transplants: a Single-Center Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5844-5844
Author(s):  
Jeffrey J. Pu ◽  
Elizabeth L Miller ◽  
Arthur Berg ◽  
Melanie Comito ◽  
Robert J. Greiner ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Systemic Infection ◽  
Unrelated Donor ◽  
Blood Transplantation ◽  
Conditioning Regimens

Abstract Background: Umbilical cord blood (UCB) is rich in primitive hematopoietic stem cells (HSC) and progenitor cells that can reconstitute the hematopoietic system in recipients under proper conditioning. Initially umbilical cord blood transplantation was limited to children because of the low cell dose requirement. Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders in the pediatric setting. To overcome the disadvantage of low cell dose in a single unit of UCB, the double-units umbilical cord blood transplantation (dCBT) strategy was introduced to adult patients with various hematological malignant diseases who had no suitable related or unrelated stem cell donor. Over the last decade, this dCBT strategy has been validated in several elegant adult HSC transplantation studies. Because of its loose HLA-matching requirement and abundant UCB resource available, UCB transplantation (UCBT) has emerged as an effective alternative therapy for both pediatric and adult HSC transplantations. However, the optimal conditioning regimens prior to UCBT remains unclear in regards to engraftment, treatment related mortality (TRM), graft-versus-host-disease (GVHD), and prevention of disease relapse. Further more, most published UCBT conditioning regimens have utilized total body irradiation (TBI), but there is no stringent study to evaluate the efficacy of this treatment in regards to UCBT outcome. Method: This is a retrospective study to analyze the outcomes of 47 patients with various hematological diseases receiving UCBT at Pennsylvania State University Hershey Cancer Institute in last 13 years. In this study, individual patient was characterized by his/her gender, age and weight at the time of receiving UCBT, disease status, the HLA compatibilities among UCB units and recipient, the conditioning regimens prior to UCBT, the ABO and gender compatibilities among UCB units and recipient, time to engraftment and chimerism status post UCBT, the incidence and severity of GVHD (acute and chronic), and the incidence of systemic infection. The rates for TRM, event free survival (EFS), and overall survival (OS) were calculated and compared among patients who received different conditioning regimens that contained TBI and those that did not. Result: This study analyzed 47 patients with an age range from 0.5 years old to 65.4 years old (mean: 14.3) at the time of UCBT. The lengths of individual patient follow up ranged from 0.9 years to 12.8 years (mean: 6.8 years). The long term OS rate was 55.3%, which was comparable to progress-free survival rate. Twenty-six patients were male (55%) and 21 patients were female (45%). Days to neutrophil engraftment (absolute neutrophil count ≥500/dl) post UCBT ranged from 10 days to 38 days (mean: 21.8 days). Nine patients (19%) developed severe acute GVHD (≥degree 3) and 8 patients (8%) had severe chronic GVHD. Twenty eight patients (58%) had a systemic infection, of which 5 patients (11%) had systemic CMV infection. Thirty eight patients underwent a busulfan and cyclophosphamide (Bu/Cy) combination as conditioning regimen, 9 patients used fludarabine and cyclophosphamide (Flu/Cy) combination as conditioning regimen. Thirty four patients didn’t utilize TBI as part of conditioning regimens and 13 patients utilized TBI. The long term OS rate of patients not receiving TBI was 55.9% (19/34) and the long term OS rate of patients receiving TBI was 53.8% (7/13). The TRM rate of patients not receiving TBI was 32.4% (11/34) and receiving TBI was 38.5% (5/13). Conclusion: UCBT has a comparable outcome to HSC transplantation from suitable related or unrelated blood or bone marrow donors in regards to TRM, EFS, and OS. The conditioning regimens not utilizing TBI are not inferior to the conditioning regimens utilizing TBI for unrelated donor UCBT. Disclosures No relevant conflicts of interest to declare.

Unrelated Donor Umbilical Cord Blood Transplantation in Children with Acquired Aplastic Anemia. Korean Experience of 12 Cases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5402-5402
Author(s):  
Hoon Kook ◽  
Hee-Jo Baek ◽  
Tai-Ju Hwang ◽  
Hong-Hoe Koo ◽  
Keon-Hee Yoo ◽  
...  
Keyword(s):  
Cord Blood ◽  
Aplastic Anemia ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Cell Dose ◽  
Blood Transplantation

Abstract Matched unrelated donor transplants have been reserved for patients with severe aplastic anemia (SAA) who fail a round of immunosuppressive therapy (IST). Despite the general acceptance of cord blood as an alternative stem cell source, unrelated donor cord blood transplantation (CBT) has not yet been recommended for SAA because of the high risk of graft failure and infectious complications. Only a few cases of successful CBT in SAA have been reported in the literature. From July, 2003 to Dec., 2005, twelve cases of unrelated donor CBTs in Korean children with acquired SAA were performed, and enrolled in this retrospective study. Two of them received double unit CBT. One patient who rejected a CBT received the second transplant with double unit CBT. All patients had no matched family donors. The median age and weight at the time of transplant were 7.0 years (2.8–18.8 years) and 23.3 kg (12.1–49.4 kg), respectively. Seven patients received previous IST including ATG/ALG plus cyclosporine (CyA). The median interval from the diagnosis to transplant was 20.5 months. The HLA discrepancy between the single unit umbilical cord blood and the patient was 0/6 in 1, 1/6 in 8, and 3/6 in 1. The conditioning regimen was heterogeneous, but included radiation in 3, and fludarabine in 3. The median infused nucleated cell dose was 3.3 × 107/kg (0.3–9.4 × 107/kg), and median CD34+ cell dose was 1.7 × 105/kg (0.4–6.6 × 105/kg) of recipient weight. Graft-versus-host disease (GvHD) prophylaxis was CyA plus methylprednisolone in 9 cases. Primary engraft failure was encountered in 3. The absolute neutrophil count ≥500/μL was achieved at 17.0 days (15–34 days), and platelet count ≥20,000/μL at 57.0 days (32–122 days), respectively. Complete donor chimerism was promptly observed in 8, with transient mixed chimerism in another patient. Acute GvHD ≥ II was observed in 5 cases, and extensive chronic GvHD was found in 2 among 8 evaluable cases. The 3-year overall survival was 74.1%, and 3-year estimated failure-free survival was 58.3%. The causes of death were sepsis, cytomegloviral pneumonitis, and chronic GvHD with intracranial hemorrhage in each patient. Cytomegaloviral disease was found in 3 cases. These results are comparable with those from unrelated donor BMT in refractory SAA. Considering the better tolerability of HLA mismatching, CBT should be considered as an alternative source of transplants. A randomized, prospective study comparing the 2nd-line IST, unrelated bone marrow transplants, or CBT is warranted to answer the best option for those who fail to 1st line IST without matched siblings.

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