Biology of Blood and Marrow Transplantation
Volume 14, Issue 5 , Pages 583-590, May 2008

Umbilical Cord Blood Transplantation after Reduced-Intensity Conditioning for Elderly Patients with Hematologic Diseases

Department of Hematology, Toranomon Hospital, Tokyo, Japan

Received 13 October 2007; accepted 11 March 2008.

Article Outline

Abstract 

Although allogeneic hematopoietic stem cell transplantation is a potentially curative approach for advanced hematologic diseases, its application to elderly people is limited because of their comorbid physical conditions and lower chance of finding suitable related donors. Umbilical cord blood transplantation with reduced-intensity pretransplant conditioning (RI-UCBT) is 1 way to avoid these obstacles. We analyzed elderly patients aged 55 years and older with hematologic diseases who underwent RI-UCBT at our institute to assess feasibility and effectiveness of this treatment approach. Among the 70 patients included, 50 died, 74% of them from nonrelapse causes. Infection was the primary cause of death. Estimated overall survival and progression-free survival at 2 years were both 23%. In multivariate analyses, standard-risk diseases, age younger than 61 years, grade 0-II acute graft-versus-host disease, and the absence of preengraftment immune reaction were significantly associated with better overall survival. RI-UCBT is a potentially curative and applicable approach for elderly patients. Higher mortality, especially from nonrelapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

Key Words: Cord blood transplantation, Reduced intensity, Elderly patients, Hematologic diseases

 

Back to Article Outline

Introduction 

Although morbidity associated with hematologic malignant diseases in elderly patients is higher than that in younger patients [1], elderly patients are less likely to be candidates for allogeneic stem cell transplantation, because of the fact that they are more likely to have comorbid organ conditions, either clinically or subclinically, which result in a higher rate of procedure-related mortality [2], and that they are less likely to have HLA-matched related donors available, as siblings also tend to be elderly.

The development of reduced-intensity conditioning (RIC) for transplants, which results in less toxicity and depends largely on graft-versus-tumor effects rather than high-dose therapy to eliminate malignant cells, has been shown to allow elderly patients to undergo allogeneic transplants 3, 4, 5. The use of umbilical cord blood transplantation (UCBT) has been increasing because of the potential advantage of rapid availability and the lower risk of graft-versus-host disease (GVHD), thus permitting less stringent HLA matching 6, 7. The outcome of UCBT has been reported to be similar to unrelated bone marrow in the myeloablative setting 8, 9, 10. UCBT with reduced-intensity pretransplant conditioning (RI-UCBT) for adults, mostly younger than 55 years old, has been increasingly reported, and has been shown to be applicable even in patients with a relatively low number of nucleated cells for their body weight 11, 12, 13, 14, 15, 16. However, little information has been available on whether elderly patients can tolerate slower engraftment, more infectious complications [17], and the unique preengraftment immune reaction (PIR) associated with UCBT 18, 19. PIR has been described by us and others 18, 19, characterized by the symptoms induced possibly by hypercytokinemia, which sometimes cause severe organ damage and fatal outcome. We therefore retrospectively evaluated the use of the RI-UCBT in patients aged 55 and older by analyzing engraftment, nonrelapse mortality (NRM), GVHD, progression-free (PFS), and overall survival (OS) to address the feasibility and effectiveness of this method in older patients.

Back to Article Outline

Patients, Materials, and Methods 

Patients 

This study included patients aged 55 and older who underwent RI-UCBT at our institute from July 18, 2002 through October 28, 2005. Patients were eligible for this study if they had any hematologic malignancies at high risk for relapse or severe aplastic anemia (AA) refractory to standard immunosuppressive therapy, as well as if they were unable to find suitable related or unrelated bone marrow (BM)/peripheral blood (PB) donors within reasonable time periods relative to their disease conditions. Patients with acute leukemia could be at first remission but at high risk for relapse because of adverse cytogenetic abnormalities, have a prior hematologic disorder, or be at any status beyond first remission. Patients with myelodysplastic syndrome (MDS) had to be refractory anemia with excess of blasts or chronic myelomonocytic leukemia, or have refractory anemia with transfusion dependency and/or severe neutropenia. Patients with chronic myeloid leukemia (CML) had to be beyond the first chronic phase. Lymphoma patients had to be beyond the first remission except those with acute or lymphoma type adult T cell leukemia. Patients who had end-stage organ dysfunction (DLco <30% predicted or LVEF <35%), or active serious infection at the time of transplantation were not eligible. All patients gave written informed consent, and the study was approved by the appropriate institutional review boards.

Donor Selection 

UCB units were obtained from Japanese Cord Blood Bank Network. HLA-A and HLA-B antigens were identified by serologic typing. HLA-DRB1 alleles were determined by high-resolution molecular typing using polymerase chain reaction (PCR) sequence-specific primers. UCB grafts had at least 4 of 6 HLA-A, B antigens, and DRB1 alleles that were matched to the recipient and had a cryopreserved cell dose of at least 1.8 × 107 nucleated cells per kg of recipient body weight. The median total nucleated cell number and median CD34+ cell number were 2.8 (range: 1.8–5.2) × 107/kg and 0.84 (0.11-3.28) × 105/kg, respectively.

Patient Characteristics 

Seventy consecutive patients were included in this study. Their characteristics are shown in Table 1. Of these 70 patients, 25 were women and 45 were men. Their median age was 61 years (range: 55-79 years). The patients' diagnoses included acute myeloid leukemia (AML; n = 28), acute lymphoblastic leukemia (ALL; n = 11), MDS (n = 3), CML (n = 4), non-Hodgkin lymphoma (NHL; n = 8), adult T cell leukemia (n = 12), plasma cell leukemia (n = 1), multiple myeloma (n = 1), and AA (n = 2). Three patients had previous autologous hematopoietic cell transplantation. For disease status, those with hematologic malignancies in first or second complete remission at the time of transplant, those in the chronic phase or accelerated phase of CML, those with refractory anemia of MDS, and those with nonmalignant diseases were defined as being at standard risk (n = 15), whereas those in other situations were defined as being at high risk (n = 55). Patients were assessed for their comorbidity by the previously reported scoring system [20].

Table 1. Patient and Donor Umbilical Cord Blood Characteristics
CharacteristicNo. (%) of Patients
Sex
Male45 (64)
Female25 (36)
Age (years)
Median (range)61 (55-79)
Age distribution (years)
55 to 5931 (44)
60 to 6416 (23)
65 to 6917 (24)
At least 706 (9)
Diagnosis
AML28 (40)
MDS3 (4)
CML4 (6)
ALL11 (16)
NHL8 (11)
ATL12 (17)
MM1 (1)
PCL1 (1)
AA2 (3)
HCT-CI
024 (34)
125 (36)
211 (16)
3 or greater10 (14)
History of prior chemotherapy
Yes59 (84)
No11 (16)
History of prior documented infections
Yes15 (21)
No55 (79)
Disease status
Standard risk15 (21)
High risk55 (79)
Conditioning regimen
Flu/Mel/TBI65 (93)
Flu/Bu/TBI4 (6)
Others1 (1)
GVHD prophylaxis
Cyclosporine A alone37 (53)
Tacrolimus alone33 (47)
HLA disparity to UCB
5/69 (13)
4/661 (87)
Sex mismatch to UCB
Yes51 (73)
No19 (27)

AML indicates acute myeloid leukemia; MDS, myelodysplastic syndrome; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma; ATL, adult T cell leukemia; MM, multiple myeloma; PCL, plasma cell leukemia; AA, aplastic anemia; Flu, fludarabine; Mel, melphalan; TBI, total body irradiation; Bu, busulfan; UCB, umbilical cord blood: HCT-CI, hematopoietic cell transplantation-specific comorbidity index.

Conditioning Regimens and Postgrafting Immunosuppression 

Pretransplant conditioning varied, and was determined by each attending physician according to the patient's disease, disease status, and history of prior therapy. Sixty-five patients underwent conditioning regimens with 125-180 mg/m2 of fludarabine (Flu; 25 mg/m2 for 5 days or 30 mg/m2 for 6 days), along with 80 mg/m2 of melphalan (Mel; 40 mg/m2 for 2 days) and total-body irradiation (TBI) at a total dose of 4 Gy for 63 and 2 Gy for 2. Four patients in relatively poor performance status were conditioned with busulfan to avoid severe gastrointestinal tract toxicity induced by the use of Mel. One patient underwent a conditioning regimen with thiotepa (5 mg/kg for 2 days) in addition to 125 mg/m2 of Flu and 80 mg/m2 of Mel, because of the urgent transplant schedule that did not allow access to TBI. Valproate sodium (300 mg/day) was administered to all patients who received Bu. Immunosuppressive therapy with cyclosporine A (CsA, 3 mg/kg continuous infusion, aiming for a serum concentration of 250-400 ng/mL) or tacrolimus (Tac, 0.03 mg/kg continuous infusion, aiming for 12-17 ng/mL) was started on day −1. CsA was used for patients in the early phase of this study, and, based on our early experience of high early mortality related to PIR in the patients with CsA prophylaxis, Tac was subsequently used to substitute for CsA.

Supportive Care 

Prophylactic antibiotics, including fluorquinolone, fluconazole, and acyclovir, were used routinely. Patients received ganciclovir or foscarnet for any sign of a cytomegalovirus reactivation, such as isolation of CMV or detection of viral proteins (pp65) or nucleic acid in any body fluid or tissue specimen. Pneumocystis jiroveci prophylaxis included trimethoprim-sulfamethoxazole as first-line therapy.

Definition of Engraftment, Preengraftment Immune Reaction, and End Points 

OS ands PFS were computed from the date of transplantation. Engraftment was defined as absolute neutrophil count >0.5 × 109/L for 3 consecutive days. Chimerism was assessed using fluorescent in situ hybridization in sex-mismatched donor-recipient pairs. In sex-mismatched pairs, PCR for variable number of tandem repeats was used with donor cells detected at a sensitivity of 10%. Whole blood or BM cells were assessed at the time of granulocyte engraftment. PIR was characterized by the presence of at least 2 of the following symptoms with no direct consequences of infection or adverse effects of medication 6 or more days before engraftment, as described previously 12, 18; a high fever (>38.5°C), skin eruptions, diarrhea, jaundice (serum levels of total bilirubin >2.0 mg/dL), or body weight gain >10% of baseline. NRM was defined as death in the absence of disease progression. Deaths occurring after disease progression were categorized as relapse regardless of the cause of death. Infection was considered the cause of death when bacterial, viral, or fungal infection was determined to be the proximate cause of death in patients who had not relapsed. Patients underwent BM aspiration at the time of engraftment or if clinically indicated. Relapse for AML, ALL, CML, or MDS was determined by flow cytometric, morphologic, or cytogenetic evidence of malignant or dysplastic cells with clonal markers similar to those observed before transplantation. Relapse for NHL was defined as progressive adenopathy or BM involvement. Acute and chronic GVHD (aGVHD, cGVHD) were defined and graded by standard criteria [21]. The following factors were considered potential predictors of outcomes: recipient's age, disease risk (standard versus high), ECOG performance status, HCT-specific comorbidity index score, history of prior chemotherapy (all cytoreductive chemotherapy excluding hydroxyurea and imatinib mesylate), history of prior documented infections (infectious episode with positive culture results for bacterial or yeast infections, and at least probable diagnosis of mold infection by EORTC/NIH-MSG criteria [22]), number of total nucleated cord blood cells, number of CD34+ cells, HLA disparity, conditioning regimen, GVHD prophylaxis, grade of aGVHD, and the presence or absence of PIR.

Statistical Methods 

OS was calculated from the day of transplantation until death from any cause or last follow-up. Disease-free survival (DFS) was calculated from the day of transplantation until relapse or death from any cause or last follow-up. The probabilities of survival and DFS were estimated and plotted using the Kaplan-Meier method [23]. Relapse and NRM rates were estimated using cumulative incidence analysis and were considered competing risks [24]. Similarly, in the analysis of GVHD rates, death because of other causes or relapse leading to early withdrawal of immune suppression were considered competing risks. The effect of various patient and disease categoric variables on survival probabilities was studied with the log-rank test. A Cox proportional hazard model with limited variables because of small sample was used to determine the significance of multiple variables in determining these outcomes. Cumulative incidence curves were drawn using Gray's method [25].

Back to Article Outline

Results 

Engraftment 

Ten of the 70 patients were not evaluable for donor engraftment because of early death (before 28 days posttransplant) from disease progression (n = 1), infection (n = 7), and complications of central nervous system (n = 2). Of the 60 evaluable patients, the cumulative incidence of primary donor engraftment was 92% at a median of 18 days after transplantation (range: 11-53 days). Platelet recovery >20 × 109/L was observed in 38 patients (63%), at a median of 35 days (range: 25-95 days). All patients required transfusions of platelets and red blood cells. Recovery of neutrophil counts >0.5 × 109/L did not occur in 5 patients who survived beyond 28 days posttransplant; these patients were classified as primary graft failures. Two of these patients received secondary RI-UCBT and died of infection. The remaining 3 patients died of infection. All engrafting patients without BM relapse were complete donor chimeras beyond 1 month after transplantation (data not shown). Remarkably, all 3 evaluated patients of 10 who died before day 28 showed complete donor chimerism (94%, 100%, and 94.6% on days 12, 15, and 20 posttransplant, respectively).

PIR and GVHD 

Forty-three patients experienced clinical symptoms defined as PIR, as described previously 12, 18. Patients who received Tac as GVHD prophylaxis tended to have a lower chance of experiencing PIR compared with those who received CsA, although differences were not statistically significant (53% versus 72%, respectively; P = .1).

Among 54 evaluable patients, 33 patients (61%) developed aGVHD of grade II or higher, including 23 patients (43%) who developed that of grade III or IV. Of the 30 patients who survived longer than 100 days posttransplant, 12 (40%) developed cGVHD, including 7 with limited and 5 with extensive form (Table 2).

Table 2. The Incidence and Severity of Graft-versus-Host Disease (GVHD)
Patients (n = 54)
No. (%)
Acute GVHD45 (83)
Grade II-IV33 (61)
Grade III-IV23 (43)
Patients (n = 30)
No. (%)
Chronic GVHD12 (40)
Limited7 (23)
Extensive5 (17)

Survival, Disease Progression, and NRM 

At the time of analysis, 20 of 70 patients survived a median of 512 days (range: 103-1213 days) after transplantation. The Kaplan-Meier estimates of OS and PFS at 2 years were both 23% (Figure 1). The median OS time was 114 days (range: 7–1213 days), and the median PFS time was 92 days (range: 7–1213 days).

Eighteen patients (26%) showed progression of the underlying disease at a median of 134 days (range: 13–785 days) after transplantation, and 15 of these patients died of their disease.

Thirty-seven patients died of nonrelapse causes (Table 3). Nineteen of them were from infections, which was the leading cause of NRM. Among 33 deaths observed before day 100 posttransplant, 30 were from nonrelapse causes and 3 from disease progression. The cumulative incidences curves of NRM and disease progression are shown in Figure 2.

Table 3. Causes of Death
Patients (n = 70)
No. (%)
NRM37 (53)
Infection19 (27)
GVHD9 (12)
IP4 (6)
TMA3 (4)
Others2 (3)
Relapse13 (19)
Total50 (71)

NRM indicates nonrelapse mortality; GVHD, graft-versus-host disease; IP, interstitial pneumonia; TMA, thrombotic microangiopathy.

Factors Contributing to OS and NRM 

In univariate analyses, survival was associated with recipient's age (P = .01), disease risk (P < .01), aGVHD (P < .01), and PIR (P < .01), with favorable outcomes in younger recipients (<61 years), those with standard risk, those with lower grade aGVHD (grade 0-II), and those without PIR (Figure 3A-D). Potential risk factors such as ECOG performance status, HCT-specific comorbidity index score, history of prior documented infection, history of prior chemotherapy, HLA disparity, sex mismatch, number of infused cells, number of infused CD34+ cells, and cGVHD did not reach statistical significance.

In the Cox regression analyses, recipient's age equal to or older than 61 (hazard ratio [HR] = 3.33; 95% confidence interval [CI] = 1.39-7.14; P = .006), high risk disease (HR = 3.33; 95% CI = 1.01; 8.33 P = .049), grade III-IV aGVHD (HR = 2.5; 95% CI = 1.28; 5.88 P = .0002), and the presence of PIR (HR = 2.5; 95% CI = 1.14; 6.25 P = .023) were associated with statistically worse OS (Table 4). No other factors were significantly or suggestively associated with OS.

Table 4. Cox Regression Analyses of Factors Potentially Associated with OS and NRM after RI-UCBT
VariablesHR95% CIP
OS
Age
Less than 61 years (n = 33)0.30.14-0.72.006
At least 61 years (n = 37)1.0
Disease risk
Standard (n = 15)0.30.12-0.995.049
High (n = 55)1.0
PIR
No (n = 25)0.40.16-0.88.023
Yes (n = 43)1.0
Acute GVHD
Grade 0-II (n = 31)0.40.17-0.78.0002
Grade III-IV (n = 23)1.0
NRM
GVHD prophylaxis
CsA (n = 37)3.91.3-11.6.01
Tac (n = 33)1.0
Acute GVHD
Grade 0-II (n = 31)1.0
Grade III-IV (n = 43)5.72.1-15.7.001

GVHD indicates graft-versus-host disease; CsA, cyclosporine A; Tac, tacrolimus; NRM, nonrelapse mortality; CI, confidence interval; HR, hazard ratio; OS, overall survival.

Regarding toxicity, multivariate analyses revealed that GVHD prophylaxis (HR = 3.9, 95% CI = 1.3-11.6 for CsA versus Tac; P = .01) and aGVHD (HR = 5.7, 95% CI = 2.1-15.7 for grade III–IV versus 0-II; P = .001) were associated with NRM.

Back to Article Outline

Discussion 

This study was undertaken to evaluate engraftment and toxicities in elderly patients with advanced hematologic diseases who received UCBT matched for at least 4 loci of HLA-A, -B, and –DRB1 using a nonmyeloablative regimen.

Several observations were made. First and foremost, RI-UCBT was a feasible treatment strategy for elderly patients with a successful engraftment rate of 92% without secondary graft failure except disease progression. The average interval between transplant and neurtophil recovery to 500/μL was 18 days, which is comparable to previously reported in RIC 11, 12. The chimerism study confirmed rapid engraftment of donor cells in all engrafted patients. Together with the fact that all 3 evaluated patients who died before day 28 already achieved complete donor chimerism, these data indicate that our pretransplant conditioning regimens, mainly consisting of Flu, Mel, and TBI, along with single calcineurin inhibitors for GVHD prophylaxis, can exert sufficient immunosuppressive effects that allow engraftment of CB cells. Compared to the conditioning regimen containing cyclophosphamide reported from Minnesota group [11], which allow mixed chimeric state especially for myeloid lineages during the early period of posttransplant, our conditioning is more powerful in eradicating host myeloid cells as well, which may have beneficial effect for rapid control of myeloid malignancies. The OS and PFS were estimated as both 23% at 2 years posttransplant, almost comparable to or slightly less than the data reported previously 15, 16, 26, which can be reasonably explained by higher age range and poor disease status before transplant in this study cohort, which can be further supported by the result of subgroup analysis indicating those with standard disease status showed much better outcome (Figure 3B).

UCBT has been associated with lower incidence of aGVHD, possibly because of the immunologic naïvety of transplanted lymphocytes; however, this naïvety raises a concern about whether transplanted cells will have sufficient antimalignant activity. Several reports indicate the in vivo antimalignancy effect of cord blood cells 27, 28, 29, 30. Cumulative incidence of disease progression at 2 years posttransplant in our series was 24%, which is comparable to those previously reported 15, 16, 26. It plateaued later than 795 days, indicating that our RI-UCBT treatment protocol offered fairly good disease control.

The incidence of GVHD was higher than previous reports in RIC 11, 12, and was almost comparable to those of BM transplants, PB cell transplants, or UCBT with conventional conditioning 8, 9, 10, 31, 32, 33, 34, 35, 36. Because of the poor disease status of the majority of patients included in this study, GVHD prophylaxis was initially planned to be less intensive with single calcineurin inhibitors. Older patients' age [37] or high incidence of infectious complications, which possibly induced excessive inflammatory cytokine secretions, could have been relevant to this result [38].

Although RI-UCBT has been a feasible approach in terms of engraftment, a significant number of patients died from treatment-related complications. NRM was close to 3 times higher than mortality from relapse or disease progression, and most NRM occurred within 100 days posttransplant. Of 37 deaths because of NRM, 19 were from infection. Delayed engraftment relative to other stem cell sources such as BM or PB cells has been suggested to account for the higher rate of infectious complications after UCBT 32, 39, 40, but the time to engraftment in our series of patients was not delayed. Higher grade of aGVHD and the presence of PIR were found to be significantly associated with poor OS in multivariate analysis, indicating that immune-mediated events have strong impact on patients' outcome (Table 4). PIR is the syndrome observed in our setting of RI-UCBT. Although the mechanism behind PIR has not been investigated extensively yet, it is assumed to be reflecting allo-immune event, given our experience that more intensive GVHD prophylaxis with Tac had tendency to decrease the incidence of PIR. Moreover, development of PIR may have been suppressed in reported cases from other institutes that utilized additional agents to calcineurin inhibitors, such as methotrexate 10, 19, antithymocyte globulin [31], or mycophenolate mofetil [16]. There has been a similar early immune reaction-like syndrome reported as “hyperacute GVHD” observed following BM or PBSC transplant, and responded poorly to corticosteroids compared to traditional aGVHD 41, 42. The incidence of PIR was higher than that of hyperacute GVHD, and further investigation on biologic mechanisms may help us define PIR more precisely relative to other immune-mediated diagnosis and develop optimal treatment approach. The presence of PIR was shown to cause more NRM than the absence in univariate analysis (P = .02), although it did not reach statistical significance in multivariate analysis. Thus, better management of immune-mediated complications will be the key to reduce NRM and improve OS. Based on our early experience of high early mortality related to PIR in the patients with CsA prophylaxis, Tac was subsequently used to substitute for CsA, because Tac was shown to be more potent than CsA in BM transplant 43, 44, 45. Patients who received Tac as GVHD prophylaxis had less chance of experiencing PIR compared with those who received CsA and had less NRM, indicating the potential benefit of using Tac as a standard agent for GVHD prophylaxis. Adding methotrexate, mycophenolate mofetile, or sirolimus to the calcineurin inhibitor may further improve the final outcome 10, 11, 46, 47. Older age was another factor that influenced OS with statistical significance, even within the age range studied (Figure 3A and Table 4). Patients aged 61 years and older experienced more NRM than patients younger than 61 years (65% versus 39%), whereas their death rate because of disease progression was comparable (19% versus 18%), suggesting the vulnerability of higher aged population to procedure toxicity. Although the possible impact of slight variation in conditioning regimen to the outcome cannot be excluded, it is unlikely, because the great majority (93%) were conditioned with Flu/Mel/TBI regimen fairly uniformly, and comparison between Flu/Mel/TBI and others did not reach statistical significance.

In conclusion, this is the first study specifically focusing on elderly patients aged 55 years and older with advanced hematologic diseases to show the feasibility of RI-UCBT. Older age per se cannot be considered to be contraindication to RI-UCBT, although a high NRM has been observed. Further optimization of the treatment protocol, such as immunosuppressive therapy for GVHD prophylaxis, is warranted to establish the safety of this promising treatment strategy for elderly patients with advanced hematologic diseases.

Back to Article Outline

Acknowledgments 

The authors wish to thank the data coordinators Kiku Morishita, Kaori Kobayashi, Sumiko Tanaka, and Naomi Yamada for their invaluable help in making this study possible. The authors also wish to thank all physicians, nurses, pharmacists, and support personnel for their care of patients in this study.

Back to Article Outline

References 

  1. Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006;107:2099–2107
  2. Ringden O, Horowitz MM, Gale RP, et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA. 1993;270:57–60
  3. Giralt S, Thall PF, Khouri I, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97:631–637
  4. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390–3400
  5. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756–763
  6. Brunstein CG, Wagner JE. Cord blood transplantation for adults. Vox Sang. 2006;91:195–205
  7. Schoemans H, Theunissen K, Maertens J, Boogaerts M, Verfaillie C, Wagner J. Adult umbilical cord blood transplantation: a comprehensive review. Bone Marrow Transplant. 2006;38:83–93
  8. Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351:2265–2275
  9. Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med. 2004;351:2276–2285
  10. Takahashi S, Iseki T, Ooi J, et al. Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation of adult patients with hematologic malignancies. Blood. 2004;104:3813–3820
  11. Barker JN, Weisdorf DJ, DeFor TE, et al. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003;102:1915–1919
  12. Miyakoshi S, Yuji K, Kami M, et al. Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clin Cancer Res. 2004;10:3586–3592
  13. Koh LP, Chao NJ. Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens. Biol Blood Marrow Transplant. 2004;10:1–22
  14. Komatsu T, Narimatsu H, Yoshimi A, et al. Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan. Ann Hematol. 2006;86:49–54
  15. Ballen KK, Spitzer TR, Yeap BY, et al. Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant. 2007;13:82–89
  16. Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplant outcomes in 110 adults with hematological disease. Blood. 2007;110:3064–3070
  17. Narimatsu H, Matsumura T, Kami M, et al. Bloodstream infection after umbilical cord blood transplantation using reduced-intensity stem cell transplantation for adult patients. Biol Blood Marrow Transplant. 2005;11:429–436
  18. Kishi Y, Kami M, Miyakoshi S, et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation. 2005;80:34–40
  19. Narimatsu H, Terakura S, Matsuo K, et al. Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transplant. 2007;39:31–39
  20. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity intex: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919
  21. Sullivan KM. Graft-versus-host-disease. In:  Thomas ED,  Blume KG,  Forman SJ editor. Hematopoietic Cell Transplantation. 4th ed.. Boston, MA: Blackwell Science; 1999;p. 515–536
  22. Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34:7–14
  23. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481
  24. Gooley TA, Leisenring W, Crowley J, et al. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706
  25. Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Statist. 1988;16:1141–1154
  26. Rocha V, Rio B, Brunstein C, et al. Unrelated cord blood transplantation after reduced intensity conditioning (RIC) in adults with hematological malignancy. An EBMT-Eurocord-Netcord, Société Française de Greffe de Moelle et de Therapie Cellulaire and University of Minnesota Collaborative study. Blood. 2007;110:603a
  27. Takami A, Takamatsu H, Yamazaki H, et al. Reduced-intensity unrelated cord blood transplantation for treatment of metastatic renal cell carcinoma: first evidence of cord-blood-versus-solid-tumor effect. Bone Marrow Transplant. 2006;38:729–732
  28. Howrey RP, Martin PL, Driscoll T, et al. Graft-versus-leukemia-induced complete remission following unrelated umbilical cord blood transplantation for acute leukemia. Bone Marrow Transplant. 2000;26:1251–1254
  29. Rocha V, Cornish J, Sievers EL, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood. 2001;97:2962–2971
  30. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611–1617
  31. Sanz GF, Saavedra S, Planelles D, et al. Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies. Blood. 2001;98:2332–2338
  32. Long GD, Laughlin M, Madan B, et al. Unrelated umbilical cord blood transplantation in adult patients. Biol Blood Marrow Transplant. 2003;9:772–780
  33. Cornetta K, Laughlin M, Carter S, et al. Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT). Biol Blood Marrow Transplantation. 2005;11:149–160
  34. Beatty PG, Clift RA, Mickelson EM, et al. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985;313:765–771
  35. Beatty PG, Hansen JA, Longton GM, et al. Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies. Transplantation. 1991;51:443–447
  36. Kanda Y, Chiba S, Hirai H, et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991-2000). Blood. 2003;102:1541–1547
  37. Anasetti C, Beatty PB, Storb R, et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990;29:79–91
  38. Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol. 2006;43:3–10
  39. Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344:1815–1822
  40. Ballen KK. New trends in umbilical cord blood transplantation. Blood. 2005;105:3786–3792
  41. Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood. 1986;67:1172–1175
  42. Saliba RM, de Lima M, Giralt S, et al. Hyperacute GVHD: risk factors, ontcomes, and clinical implications. Blood. 2007;109:2751–2758
  43. Hiraoka A, Ohashi Y, Okamoto S, et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28:181–185
  44. Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92:2303–2314
  45. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96:2062–2068
  46. Osunkwo I, Bessmertny O, Harrison L, et al. A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant. 2004;10:246–258
  47. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007;109:3108–3114

PII: S1083-8791(08)00112-2

doi:10.1016/j.bbmt.2008.03.003

Biology of Blood and Marrow Transplantation
Volume 14, Issue 5 , Pages 583-590, May 2008

Article Tools

* Image Usage & Resolution