8. Unrelated cord blood transplantation (UCBT) for transfusion-dependent thalassemia – A CIBMTR audited retrospective analysis of 51 consecutive patients. Jaing T-H, Tan P, Rosenthal J, Chan LL, Lin H-P, et al.
The authors used non-red cell reduced but plasma depleted (PD) CB, no post-thaw wash (NW), and double cord transplantation (DCT) where indicated. Between 7/2001 and 1/2006, 63 CB products were infused after Bu/Cy/ATG myeloablation in 51 pediatric thalassemia major patients (11 DCT and one re-transplant) at 14 transplant centers (TC) using 82% PD CD with 92% NW. Patient status: 20 Pesaro class 1, 11 class 2, 1 class 3 and 19 status unknown. Median age was 4.3 years (0.3-20) with a median weight of 17 kg (4-45). The data were audited by TC, NMDP and on-site by CIBMTR with 97.3% accuracy.
No significant adverse events were observed despite major ABO incompatibility in some cases and NW. Cumulative incidence estimates of neutrophil (ANC500), platelet 20K and platelet 50K engraftment were 86±8%, 64±9%, and 74±9%, and median times to ANC500, platelet 20K and 50K engraftment were 17 days (11-32), 40 days (16-135) and 60 days (30-144), respectively.
Seven patients died including 2 deaths prior to day 20 and one due to traumatic head injury. 42 patients engrafted, 9 with autologous recovery, and 38 patients are alive with a mean and median follow-up of 537and 296 days, respectively.
Results appear to show improvement with TC experience (> 5 cases of UCBT for thalassemia) and NW. Patients receiving PD versus red cell depletion (RCD) CB were compared by matched-pair analyses where patients were matched by TC experience, wash status, age, weight, TNC dose, and #HLA matches (Paired Prentice-Wilcoxon Test).
The results showed fewer autologous recovery (p=0.04) and better thalassemia-free survival (p=0.01) for PD compared to RCD patients. Overall survival (OS) and transplant-related mortality (TRM) also trended in favor of PD patients (both p=0.08). Selecting for experienced transplant centers, use of PD CBU, no-post-thaw and double CBT when necessary indicated 93% ANC engraftment and 88% one year DFS.
9. Feasibility of unrelated umbilical cord blood transplantation in congenital childhood diseases. Martinez C, Tolar J, Wagner JE, Tan P-L, et al.
The authors report the use of an unrelated UCB myeloablative transplantation in 55 consecutive children with a median age of 2.6 years (0.2-40.6) with Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, hemophagocytic lymphohistiocytosis, langerhans cell histiocytosis, osteopetrosis, Diamond-Blackfan anemia, Hurler syndrome, Maroteaux-Lamy, α-mannosidosis, cerebral X-linked adrenoleukodystrophy, metachromatic leukodystrophy and globoid-cell leukodystrophy transplanted over an 11.5 year period (1994-2006). Patients received grafts matched at 6 (14%), at 5 (56%) or at 4 HLA alleles (30%).
In the group of immune or hematological disorders, 6 of 10 patients achieved complete donor chimerism by day 21. In the metabolic disorders group, 8 of 13 patients achieved a complete donor chimerism at a median of 21 days and 3 additional patients at a median of 95 days. In the leukodystrophy group, 6 of 12 patients achieved complete donor chimerism at a median of 120.5 days. The incidences of grade II-IV and grade III-IV acute GVHD were 34% and 12%, respectively. The overall survival was 62% at 2-years.
The authors state that these results demonstrate the usefulness of unrelated UCB as an alternative stem cell source for patients lacking an HLA matched related or unrelated donor. The use of unrelated UCB transplantation creates new opportunities in the treatment of non-malignant diseases requiring expedient HCT in order to prevent irreversible disease progression.
10. Outcomes of unrelated umbilical cord blood transplantation in 159 young patients with peroxisomal and lysosomal storage disorders at a single center. Prasad VK, Mendizabal A, Parikh SH, Szabolcs P, et al.
Using myeloablative conditioning with busulfan+cyclophosphamide+ATG and GVHD prophylaxis with cyclosporine+methylprednisolone (n=125) or cyclosporine+cellcept (n=34), 159 consecutive LSD patients with Hurler, Krabbe, Sanfilippo, metachromatic leukodystrophy, adrenoleukodystrophy, Hunter and other diagnoses received UCBT in 1995-2007. CBU from 8 US public banks were screened and those with high-normal enzyme levels were utilized. Age was 1.5 years (0.5-26.3). Majority of grafts were 5/6 (47%) or 4/6 (46%) by intermediate-res HLA-A and –B and high-res HLA-DRB1. The median (range) cell dose/kg of TNC (pre-cryo), TNC (infused), CD34 (infused) and CFU (post-thaw) was 9.7 x 107 (2.2-50.4), 7.6 x 107 (1.5-32.4), 2.1 x 105 (0.4-104.8) and 5.7 x 104 (0.0-105.3), respectively.
Overall survival (OS) at 1, 3 and 5 years was 71.8% (95% CI 65-79%), 62.7% (95% CI 55-71%) and 58.2% (95% CI 50-67%), respectively. In multivariate analysis, Lansky 8-100 (p<0.0001), CFU infused >5.7 x 104/kg (p=0.02) and matched ethnicity (p=0.05) increased OS. Once engrafted, all but 3 maintained chimerism >90% and all but 4 normalized enzymes. In high performance status (Lansky 80-100) patients, the OS at 1, 3 and 5 years was 88.4%, 83.5% and 79%, respectively.
The authors concluded that unrelated cord blood is an excellent graft source for treatment of LSD patients, particularly when transplantation is performed in early stages. Pre-transplant performance status and post-thaw CFU dosing were highly predictive of overall survival.
11. Improved outcome for transplantation of pediatric patients with non-malignant disorders with unwashed plasma depleted cord blood (PD CB). Rosenthal J, Jaing T-H, Chan LL, Eames G, Graham M, et al.
The authors consistently employed 3 strategies to maximize cell dose – plasma depletion processing without red blood cell reduction, no post-thaw wash (NW), and the use of double cords (2X) when necessary. A retrospective CIBMTR-audited analysis was performed on all 87 pediatric (<50 kg) patients with non-malignant disorders transplanted with 98 PD CB products (15 double cords) at 21 US and 16 international institutions. Patients’ diseases were: 40 thalassemias, 12 congenital immunodeficiency syndromes, 9 aplastic anemia, 5 Hurler syndrome, 4 osteopetrosis, 2 chronic granulomatous disease, 2 familial hemophagocytosis, 2 Fanconi anemia, 2 inherited metabolic disorders and 9 other disorders. 34% of the units were washed post-thaw (W) and 66% were infused without post-thaw wash (NW) of those with known post-thaw status. The median pre-freeze TNC dose was 0.8 x 107/kg, median post-thaw dose as reported by TC was 6.7 x 107/kg; median pre-freeze CD34+ dose was 3.5 x 105/kg; transplants outside of the U.S. = 54 (62%); non-myeloablative = 13 (15%).
Foregoing post-thaw wash improved engraftment, TRM and survival, and significantly reduced extensive cGVHD. This series is unusual in its cell dose, high even for pediatric patients and shows that unrelated PD CB transplantation can be performed safely and effectively with outstanding neutrophil (92±9%) and platelet engraftment (85±9%), extensive cGVHD (3±3%), overall (90±4%), and disease free survival (78±6%) rates achieved when post-thaw wash is not employed, even in a diverse population of pediatric patients with non-malignant disorders.
12. Unrelated cord blood transplantation after myeloablative conditioning in 98 adult patients with acute leukemia: A single-institute experience in Japan. Ooi J, Takahashi S, Tomonari A, Tsukada N, et al.
The authors analyzed outcomes and risk factors after unrelated CBT for 98 adult patients with acute leukemia. Diagnoses included de novo AML (n=55), ALL (n=25), and MDS-related secondary AML (n=18). 59 (60%) were transplanted in an advanced status of the disease. All patients received four fractionated 12 Gy TBI and chemotherapy as myeloablative conditioning. 95 patients received standard cyclosporine (CyA) and methotrexate, and 3 patients received CyA only as GVHD prophylaxis. Median age was 40 years (18-55), median weight was 56 kg (36-76), the median number of cryopreserved nucleated cells was 2.46 x 107/kg (1.16-5.29) and the median number of cryopreserved CD34+ cells was 0.93 x 105/kg (0.15-8.97).
92 patients had myeloid reconstitution and the median time to ANC >500 was 21 days. A higher CD34+cell count was independently associated with faster neutrophil recovery (p=0.0001). A self-sustained platelet count >50 x 109/L was achieved in 86 patients at a median time of 42 days. Acute GVHD ≥grade III occurred in 6 of 92 evaluable patients and cGVHD occurred in 67 of 84 evaluable patients (19 extensive).
69 patients are alive and free of disease at between 116 and 3322 days after CBT. With a median follow-up of 1677 days, the probability of DFS at 5 years was 68.5 ± 5%. The cumulative incidence of TRM and relapse was 9.9±4% and 24.8 ±5%, respectively. In multivariate analyses, advanced disease status was an adverse factor for DFS (p=0.001) and relapse (p=0.007).
The authors suggest that their results indicate that adult acute leukemia patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.
13. A novel method to reduce rates of extensive chronic GVHD (cGVHD) without increased relapse for cord blood transplant. Chow R, Wang B, Rosenthal J, Nadamanee A, et al.
Post-thaw washing of frozen CB prior to transplantation is widely practiced to remove DMSO, red cell debris and free hemoglobin. However, washing a red cell containing product may result in cell loss. The authors analyzed outcomes of engraftment, survival, relapse and GVHD in 299 patients transplanted with plasma depleted but not red cell reduced (PD) CB where 154 were washed (W) and 145 were directly infused – (non-washed or NW). 207 (69%) of the patients had a malignant diagnosis.
Nucleated cell recovery after thawing, as reported by transplant centers, was higher for NW (median 85% vs 79%, p=0.003). The NW group had higher cumulative incidences of and faster neutrophil (ANC500) and platelet engraftment (Plt 20K and 50K) than the W group. No difference was seen for acute GVHD; however, the NW group had significantly lower rates of extensive cGVHD and higher rates of limited cGVHD (p= 0.0005 and <0.0001). Relapse rates were similar between W and NW. Multivariate analysis and matched pair analysis between W versus NW confirmed these observations. In univariate analysis, overall survival (OS) at 1 and 3 years were significantly higher for the NW group.
Prospective trials which may include infusion of wash supernatants into patients are necessary to confirm and better understand these observations.
14. Risk factors associated with graft failure after umbilical cord blood transplantation (UCBT): A single center analysis in 539 patients. Doshi K, Brunstein CG, Cao Q, Wagner JE.
The authors attempted to identify potential risk factors associated with graft failure (GF) in 539 patients (adult, n=297; pediatric, n=242) transplanted with UCB at the University of Minnesota. Patients received one (n=261) or two (n-278) UCB units after a myeloablative (MA, n=338) or reduced intensity (RI, n=201) conditioning regimen for malignant (n=418) or non-malignant (n=121) disease. GF was defined as evidence of <5% chimerism or failure to achieve neutrophil recovery by day 42. Median patient age and weight was 22 years (0-69) and 61 (4-149), respectively, with 66 having had a prior autologous transplant.
Median graft cell doses were 3.8 x 107 nucleated cells (NC/kg) (0.7-48.9) and 4.6 x 105 CD34/kg (0.4-275.3). Fifty-seven received 6/6 HLA-matched units, 196 received at least one 5/6 matched unit and 286 received at least one 4/6 matched unit. GF was observed in 43/338 (12.7%) after MA and 36/201 (17.9%) after RI UCBT.
Risk factors associated with GF in logistics regression were transplantation of HLA mismatched units (5/6 match, OR 9.13, 95% confidence interval, 1.19-70.38; 4/6 match, OR 11.66, (95% CI 1.53-89.00), treatment of non-malignant disease (OR 2.55, 95%CI, 1.35-4.81, p<0.01), low CD34 cell dose; and use of RIC (OR 2.40, 95% CI 1.35-4.26; p=<0.01). Patients who received a prior autologous transplant had lower odds of GF (OR 0.12, 95% CI, 0.03-0.52, p<0.01). Factors not impacting risk of GF were recipient age, sex-match, ABO-match, CMV serostatus, performance status, diagnosis, disease risk, interval from diagnosis to transplant, NC dose and CD3 cell dose.
In addition to CD34 cell dose and HLA match, patients with non-malignant disease and recipients of a RIC are at higher risk of GF. These results support the need for greater investment in banking UCB with larger cell doses and HLA diversity and development of improved strategies for overcoming GF in high risk patient populations.
15. Risk factor analysis of outcomes after unrelated cord blood transplantation for children with Hurlers syndrome. An Eurocord-Duke University collaborative study. Boelens JJ, Rocha V, Aldenhoven M, Wynn R, et al.
Hurlers syndrome (HS), the most severe form of mucopolysaccharidosis type-I, causes progressive deterioration of the central nervous system and death in childhood. Allogeneic stem cell transplantation before the age of two years halts disease progression and prolongs life.
The authors analyzed 93 HS children who received an UCBT from 1995 to 2007. Median age at UCBT was 1.3 years (0.2-4), and median follow-up was 24 months (3-140).The donor was HLA identical in 15 cases (16%) and incompatible in 78 cases (84%: most with 1 (62%) and 2 (34%) HLA disparities). The median nucleated cell dose/kg and CD34+/kg at infusion were, respectively, 7.2 (2-22) x 107 and 2.3 (0.5-17) x 105. With the exception of 5 patients, all received a Busulfan/ Cyclophosphamide (+Fludarabine: 6) regimen. All patients received ATG or Campath (4).
Median days to neutrophil and platelet recovery were 22 (10-46) and 35 (13-82) days, respectively. Mixed chimerism was found in only 4%. All patients had normal enzyme levels after engraftment. Acute GVHD (grade II-IV) was observed in 27%, while chronic GVHD was seen in 10% at 2 years. Two years OS and DFS were 78% and 70%, respectively. For 2 years OS, time from diagnosis to UCBT more than 6 months was associated with increased risk of death (6% for those children transplanted earlier and 30% for those transplanted later: p=0.04). Transplantation improved somatic features of HS.
The authors concluded that outcomes following UCBT for Hurlers syndrome are encouraging. UCB appears to be a good alternative allogeneic stem cell source to transplant children with HS, and is associated with a very low incidence of mixed-chimerism. Earlier transplantation and higher cell dose are associated with better outcomes after UCBT for HS.
16. Incidence and risk factors for chronic graft-versus-host disease (cGVHD) after cord blood transplantation (CBT). Saliba RM, Couriel D, Komanduri K, Patah P, et al.
A retrospective study was performed of all CBTs performed at the authors’ institution between 1996 and 2007, excluding primary graft failure cases. 114 patients were analyzed. All had high-risk hematologic malignancies; 59% were in complete remission or chronic phase at transplantation. Median age was 37 years (18-67) in the adult group (n= 61) and 7 years (0.5-17) in the pediatric group (n=53). Conditioning regimen was myeloablative for 92% of patients including TBI in 39%, and ATG in 55%. GVHD prophylaxis was tacrolimus-based (except for 2 patients) with methotrexate (75%) or MMF (19%). 44 patients (39%) received double CB units and 70 (61%) single units. Risk factors were evaluated by Cox’s regression analysis including age, gender, disease status at transplantation, a prior autologous transplant, conditioning regimen, use of ATG in conditioning, GVHD prophylaxis, number of CB units received, number of infused TNC, HLA-A, B, or DRB1 mismatch, and early withdrawal of immunosuppression.
With a median follow-up of 9 months, 21/114 patients developed cGVHD at a median of 126 days post CBT (100-276). 62% of these cases (n=13) were de novo. Recipient age was the strongest risk factor with a significantly higher 1-year cumulative incidence in adult patients (31%) compared with pediatric patients (n=4, 8%), p= 0.002, despite a comparable incidence of grade II-IV and III-IV aGVHD; and a superior disease free survival in the pediatric group. In adult patients, a prior autologous transplant (n=16) was the only significant risk factor, and was associated with a higher incidence (50% versus 23%, p=0.02). cGVHD was extensive in the majority of adult cases (12/17), yet it was associated with a lower rate of relapse (HR = 0.1, p= 0.07) and mortality (HR = 0.04. p=0.06) when evaluated as time dependent variable in a landmark analysis starting on post SCT day +100.
The authors concluded that recipient age is a significant predictor of cGVHD following CBT. In adult patients the impact of prior autologous transplant deserves further evaluation.
III. The 6th Annual International Umbilical Cord Blood Transplantation Symposium was held in Los Angeles, California on June 6-7, 2008. The faculty consisted of 31 scientists and clinicians who presented up to date data on Cord Blood Transplantation. The 8 sections of the program included discussions of (1) Transplantation of adults; Double cord blood transplants; Reduced-Intensity cord blood transplants, (2) Honoring the basic scientists and clinicians who were pioneers in the development of umbilical cord blood transplantation on the 20th anniversary of the first cord blood transplant [introduced by UCB transplant recipients] (3) Cord blood selection, processing and infusion, (4) Overcoming barriers to transplantation - Facilitating the search for a cord blood unit, (5) Biology of Hematopoietic cells, (6) Basic science and clinical studies addressing obstacles to successful UCBT; Immune reconstitution, opportunistic infections and GVHD, (7) Transplantation Immunology, and (8) Current Issues in cord blood banking.
A Summary and Abstracts of the Sixth Annual International Umbilical Cord Blood Transplantation Symposium will be published in a fall issue of Biology of Blood and Marrow Transplantation. To receive a reprint, send your postal mailing address now to: symposiumreprint@cordbloodforum.org.
[Note: the Seventh Annual International Umbilical Cord Blood Transplantation Symposium will be held at the Los Angeles Marriott Hotel June 5-6, 2009. For details, go to cordbloodforum.org – “Upcoming Conferences.”]
IV. The 5th Annual International Umbilical Cord Blood Transplantation Symposium was held in Los Angeles, California on May 11-12, 2007. The faculty consisted of 38 scientists and clinicians from North America, Europe, Japan and Australia. The 8 sections of the program included discussions of (1) Risk factors affecting survival in recipients of cord blood, (2) Strategies to improve engraftment after UCBT, (3) Cord blood banking, manipulation and unit selection, (4) Conditioning regimens, (5) Non-hematopoietic stem cells, (6) The graft versus tumor effect and (8) Governmental affairs.
The Summary and Abstracts of the Fifth Annual International Umbilical Cord Blood Transplantation Symposium have now been published: Biology of Blood and Marrow Transplantation 2007;13(11):1380-92. Reprints are still available. To receive a reprint, send your postal mailing address to: symposiumreprint@cordbloodforum.org.
V. Conference on Biology and Clinical Applications of Cord Blood Cells, Paris, France, October 19-21, 2007. This inaugural European conference on umbilical cord blood transplantation had a faculty consisting of 45 scientists and clinicians from Europe, North America, Israel and Japan. Topics included (1) Stem cells from cord blood, (2) Mesenchymal cells, (3) Non-hematopoietic stem cells, (4) Immunological properties, (5) Clinical results, (6) Ex-vivo expansion, (7) Graft facilitation/homing, and (8) Cord blood banking, organization, and regulatory issues.
VI. The First Latin American Symposium on Hematology, Stem Cell Transplantation, Regenerative Medicine and Cellular Therapy was held in Buenos Aires, Argentina on November 26-27, 2007. Although the meeting was not exclusively related to umbilical cord blood transplantation, there were a number of presentations relating to this topic by scientists from Peru, Argentina, Brazil, Israel, France and the United States.
VII. The 49th Annual meeting of American Society of Hematology was held in Atlanta, Georgia, December 8-11, 2007. Although this is a very large meeting and there are a generous number of presentations on Cord Blood Transplantation, these tend to be diffused among the more than 3,700 abstracts, multiple simultaneous sessions, special lectures, educational programs, scientific committee reports, and other activities. Nevertheless, cord blood was front and center on a number of occasions:
(A.) The E. Donnall Thomas Lecture was presented by Dr. Hal Broxmeyer, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN. The title of his presentation was, “The Road to and Future of Cord Blood Transplantation.” Dr. Broxmeyer reviewed the history of CB transplantation with discussion of the basic biology that formed the scientific basis for the first CB transplant in 1988, the current status of CB transplantation and his expectations regarding its future.
(B.) An Educational Program on Hematopoietic Stem cell Transplantation included a lecture, “Umbilical Cord Blood (UCB) Transplantation: An alternative to the Use of Unrelated Volunteer Donors?” by Dr. Juliet Barker of Memorial Sloan-Kettering Cancer Center. This is a succinct and authoritative review of the field. The complete text is available in the Educational Program of the ASH Meeting (pages 55-61).
(C.) The abstracts submitted for the program included at least 75 that were related to CBT. A number of these were devoted to the topic of double cord blood transplants, reduced-intensity conditioning in CBT, transplantation for specific disorders (e.g., marrow failure, hematologic malignancies, juvenile myelomonocytic leukemia, MDS), experimental transplantation, basic biology, and immune reconstitution. For a rather complete listing of pertinent abstracts, see the Annotated Bibliography, XXIII American Society of Hematology Abstracts 2007.
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