Infectious Complications after Unrelated Umbilical Cord Blood Transplantation in Adult Patients with Hematologic Malignancies Academic research paper on "Clinical medicine"

ASBMI

American Society for Blood and Marrow Transplantation

Infectious Complications after Unrelated Umbilical Cord Blood Transplantation in Adult Patients with Hematologic Malignancies

Xavier Cahu,1 Fanny Rialland,1 Cyrille Touzeau,1 Patrice Chevallier,1 Thierry Guillaume,1 Jacques Delaunay,1 Sameh Ayari,1 Viviane Dubruille,1 Steven Le Gouill,1,2 Beatrice Mahe,1 Thomas Gastinne,1 Nicolas Blin,1 Beatrice Saulquin,1 Jean-Luc Harousseau,1,2

12 12 3

Philippe Moreau, 2 Mohamad Mohty1,23

Unrelated umbilical cord blood (UCB) is being increasingly used as an alternative stem cell source for allogeneic stem cell transplantation (allo-SCT). This retrospective study assessed infectious complications occurring in adult patients after UCB transplantation (UCBT). 31 patients received a single (n=4) or double UCBT (n=27) with a median dose of 4.7x 107 nucleated cells/kg (range: 2.4-7.7). Patients received either a reduced-intensity conditioning (RIC; n=23) or a standard myeloablative (MA) regimen (n=8). The cumulative incidence of neutrophil recovery was 90%. Neutrophil recovery was achieved at a median time of 24 (range: 8-60) days after UCBT. The cumulative incidences of bacterial, fungal, and parasitic infections were, respectively, 16%, 10%, and 6%. Bloodstream infections were neither lethal nor required any intensive care therapy. Similarly, invasive fungal infections and parasitic infections did not cause any death in those patients with sustained engraftment. Although the cumulative incidence of cytomegalovirus (CMV) recurrence was 21%, no CMV disease was observed. With a median follow-up of 10 (range: 3-30) months, 10 patients have died (relapse, n = 5; nonrelapse mortality, [NRM] n=5). Overall, the cumulative incidence of infectious-related mortality (IRM) was 8%. In conclusion, this data suggests that UCBT can be performed in adult patients with hematologic malignancies with an acceptable incidence of IRM provided a sufficient dose of nucleated cells is infused to the patient.

Biol Blood Marrow Transplant 15: 1531-1537 (2009) © 2009 American Society for Blood and Marrow Transplantation KEY WORDS: Cord blood transplantation, Infectious complications

INTRODUCTION

The majority of adult patients with hematologic malignancies requiring allogeneic stem cell transplantation (allo-SCT) lack a matched related donor [1]. The search for an HLA-matched unrelated donor (MUD) used to be the only possibility to proceed to allo-SCT. Unrelated umbilical cord blood (UCB) is now being increasingly used as an alternative stem cell source for allo-SCT. In various hematologic dis-

From the 1CHU de Nantes, Service d'Hematologie Clinique, Nantes, France; 2Université de Nantes and INSERM CRCNA U892, Nantes, France; and 3Centre d'Investigation Clinique en Cancéerologie (CI2C), CHU de Nantes, Nantes, France. Financial disclosure: See Acknowledgments on page 1536. Correspondence and reprint requests: Prof. Mohamad Mohty, Hematologie Clinique, CHU de Nantes, Place A. Ricordeau, F-44093 Nantes Cedex, France (e-mail: mohamad.mohty@ univ-nantes.fr). Received May 26, 2009; accepted July 24, 2009 © 2009 American Society for Blood and Marrow Transplantation 1083-8791/09/1512-0005$36.00/0 doi:10.1016/j.bbmt.2009.07.021

eases including acute leukemia or lymphoid malignancies, UCB cells exhibit an immunologic activity against neoplastic cells, a phenomenon known as the graft-versus-tumor (GVT) effect [2-5]. However, like with other stem cell sources, this GVT effect can be offset by a significant incidence of non-relapse mortality (NRM). Most of the time, NRM originates from graft failure, graft-versus-host disease (GVHD), or infections [6]. Initial studies depicted a high rate of severe or fatal infections among UCB transplant recipients [7,8], especially in adult patients [9]. However, more recent studies reported an infectious-related mortality (IRM) incidence similar to that of allo-SCT using HLA-MUD [10]. These conflicting results highlight the need for a thorough assessment of infectious complications after UCB transplantation (UCBT) toward improving patients' outcome. The aim of this retrospective analysis was to define the incidence and features of opportunistic infectious complications in a series of 31 adult patients who received UCBT, and to assess its impact on clinical outcome.

Table 1. Patients' Characteristics

Characteristics N (%)

Median age (range) 47 (20-63)

Recipient sex male 13 (42%)

Weight, kg (range) 63 (47-I03)

Diagnosis and status ALL: 7 CR: 5

at transplant PD: 2

AML: 8 CR: 7

Refractory: 1

CLL: 2 CR: 1

NHL: 8 CR: 2

Relapse: 1

MDS: 3 Upfront: 2

Secondary graft failure: 1

MPD: 2 Upfront: 2

Previous transplant Auto-SCT: 7

Allo-SCT: 3

Recipient CMV serology Positive: 12

Negative: 19

ALL indicates acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; NHL, non-Hodgkin lymphoma; MDS, myelodysplasia; MPD, myeloproliferative disorder; CR, complete response; PR, partial response; PD, progressive disease.

PATIENTS AND METHODS

Study Design

This was a retrospective analysis of 31 consecutive patients treated between February 2003 and October 2008, in a single institution (University-Hospital of Nantes, Nantes, France). Patients' characteristics are detailed in Table 1. During this study period, UCBT was performed in those patients lacking an HLA-matched related or unrelated donor. Written informed consent was obtained from each patient. The study was performed according to institutional guidelines. HLA A, B serologic typing and DRB1 high-resolution typing were performed for both patients and UCB units. Selected UCB units displayed a 4/6, 5/6, or 6/6 HLA donor-recipient matching. In 27 of 31 cases, and as per institutional guidelines, 2 UCB units were used to increase the total number of nucleated cells (TNC) infused to the patient (target TNC >2.5 x 107/kg).

Transplant Procedures and Graft Characteristics

Transplant procedures are summarized in Table 2. Patients received either a reduced-intensity conditioning (RIC) regimen (n=23) or a standard myeloablative (MA) regimen (n=8). The choice between a standard MA or an RIC regimen was based on patients' age and comorbidities as previously described [11]. To accelerate engraftment, all patients received granulocyte colony-stimulating factor (G-CSF) starting from day 5 after UCB infusion. GVHD prophylaxis included cy-closporine (CsA) and mycophenolate mofetil (MMF;

Table 2. UCBT Procedures

Number of CBT units Single: 4 Double: 27

HLA matching Single: 6/6: 0 5/6: 1 4/6: 3

Double: 6/6 and 6/6: 1 5/6 and 5/6: I3

6/6 and 5/6: 0 5/6 and 4/6: 6

6/6 and 4/6: 0 4/6 and 4/6: 7

Total nucleated 4.7 (2.4-7.7)

cells - l07/kg*

CD34+ • l05/kg* 1.4 (0.5-3.6)

Conditioning regimen Reduced-intensity conditionning: 23

Myeloablative: 8

GVHD prophylaxis CsA-Mycophenolate mofetil: 27CSA-CT: 4

Steroids ($2mg/kg) 7

GVHD indicates graft-versus-host disease; CsA, cyclosporine; CBT, cord blood transplantation; UCBT, umbilical cord blood transplantation. Conditioning regimens included: fludarabine (Flu) (200 mg/m2), Cyclophosphamide (Cy) (50 mg/kg), total body irradiation (TBI) (2 gy)±ATG (n= 18); F (150 mg/m2)-Cy (100 mg/kg)-ATG (5 mg/kg) (n=3) F (120 mg/m2)-Cy (1200 mg/m2)-TBI (2 gy)-ATG (7.5 mg/kg) (n= I); Clofara-bine (150 mg/m2)-AraC 5000 mg/m2-Cy (60 mg/kg)-Bu (6.4 mg/kg)-ATG (5 mg/kg) (n= 1); Cy (120 mg/kg)-TBI (12 gy) (n=7); Bu (orally) (16 mg/kg)-Cy (120 mg/kg) (n = 1).

*Before thawing. In case of double UCBT, addition of cell numbers of UCBI and UCB2.

1000 mg/12 hours; n=27) or CsA in combination with corticosteroids (2 mg/kg/day; n=4). Chimerism was determined from nucleated blood cells or CD3+-T cell fraction as previously described [12]. In the absence of GVHD, MMF and CsA were progressively decreased starting from day +60 and day +120 after UCBT, respectively.

Infection Prophylaxis, Monitoring, and Supportive Care

Allo-SCT was performed in rooms with laminar air flow devices. All blood products were leukocyte-depleted and irradiated before transfusion. No antibacterial prophylaxis was delivered prior to engraftment. Fluconazole (400 mg/day) and valacyclovir (500 mg x2/day) were given to all patients starting from day 0. Amoxicillin or penicillin was used after neutrophil recovery to prevent encapsulated bacterial infections. Similarly, cotrimoxazole prophylaxis against Pneumocystis jiroveci and toxoplasmosis was started after neutrophil recovery. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, and Human Herpes Virus 6 (HHV6) were routinely screened by quantitative polymerase chain reaction (PCR). CMV reactivation was defined as a positive PCR $1000 copies/106 cells. Adenovirus was documented in the stools and on gut biopsies. Galactomannan antigen was tested twice a week to detect Aspergillosis species (Aspergillus sp.). In the case of positive Galactomannan test or any respiratory symptom, a thoracic computed tomography (CT) scan and/or a respiratory endoscopy with bronchoal-veolar lavage (BAL) were performed. If temperature was $38.3°C, $38°C for 1 hour, or patient showed

any sign of infection, blood and fungal cultures were performed and broad-spectrum antibiotics were administered. For the purpose of this analysis, and except for coagulase negative staphylococci and cory-nebacteria, all positive blood cultures were recorded. In the case of persistent fever and prolonged neutropenia, an antifungal therapy was empirically added. Probable or proved aspergillosis was classified according to Ascioglu et al. [13]. Invasive aspergillosis was treated primarily with voriconazole. In the case of positive CMV detection, preemptive therapy with ganciclovir was started as soon as the viral load was $1000 copies/106 cells. In the case of rising or persistent CMV infection after 5 to 7 days of ganciclovir preemptive therapy, patients were switched to foscarnet therapy (180 mg/kg/day) for 14 days. Patients did not receive systematic maintenance therapy after preemptive therapy. CMV disease was defined as described previously [14]. After discharge, patients received routine prophylactic i.v. immunoglobulins.

Statistical Analysis

All time-related data were measured from the day of UCBT. Complete remission (CR) and overall survival (OS) were defined according to standard criteria, and OS was estimated with the Kaplan-Meier method. NRM and IRM were evaluated using the cumulative incidence method [15]. Neutrophil recovery was defined as the first of 3 consecutive days with neutrophils $0.5 x 109/L. Partial and complete neutrophil engraft-ments were defined as neutrophil recovery with donor chimerism $10% and $90%, respectively. Engraft-ment was calculated by cumulative incidence evaluation using death without engraftment as a competing event. All data were computed using the R package (R Development Core Team, 2006. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org).

RESULTS

Engraftment

The cumulative incidence of neutrophil recovery was 90% (n=28). Neutrophil recovery was achieved at a median time of 24 (range: 8-60) days after UCBT. Platelet recovery >20x 109/L was achieved in 26 patients (cumulative incidence, 84%) at a median time of 43 (range: 0-176) days after UCBT. Partial and complete engraftment occurred in 22 and 20 patients, respectively (CI: 71% and 64%, respectively). Among the 9 patients with primary graft failure, 5 patients experienced spontaneous autologous recovery, 1 patient was successfully rescued by autologous bone marrow (BM; auto-SCT), and 3 patients remained without

any neutrophil recovery. Two secondary graft failures were observed, 1 ofwhich had spontaneous autologous recovery.

Survival and Causes of Death

With a median follow-up of 10 (range: 3-30) months in surviving patients, the OS was 57% (95% CI, 38-84). At last follow-up, 10 patients have died. Relapse (n=5) and NRM (n=5) were the primary causes of death. In the 5 patients who died from NRM, the causes of death were secondary graft failure (n= 1), refractory GVHD (n=2) and infectious-related mortality (n=2; cumulative incidence, 8%; Figure 1A). The 2 patients who died from infectious causes had an EBV-related lymphoproliferative disorder and adeno-virus infection, respectively.

Features of Bacteremia

Overall, 7 documented bacteremia were observed in 5 patients, at a median time of 7 (range: 3-277) days after UCBT (Table 3). The isolated bacteria included Streprococcus mitis (n=3), Stapylococcus aureus (n=1), Escherichia coli (n = 1), Enterobacter cloacae (n=1), and Pseudomonas aeruginosa (n=1). Of note, none of these bacteria had been isolated from the same patient prior to UCBT. The cumulative incidence of first bacteremia was 16% (Figure 1B) in the whole study population and 21% (n=4/20) when excluding patients with graft failure. Except for 1 patient with relapsed acute myelogenous leukemia (AML), these bacteremia were neither fatal nor required a transfer into the intensive care unit (ICU).

Viral Infections

Recurrent CMV infection was detected in 6 patients at a median time of 36 (range: 26-89) days. No CMV disease developed after preemptive CMV therapy. The cumulative incidence of recurrent CMV infection was 21% (Figure 1C). Of note, 4 of these 6 cases of CMV recurrences were diagnosed in patients with primary graft failure. Therefore, the cumulative incidence was only 11% when focusing on patients without graft failure. EBV reactivation occurred in 6 patients with a median time of 101 (range: 28-438) days after UCBT. Except for 1 patient who developed a fatal EBV-related lymphoproliferative disorder refractory to Rituximab, all other 5 cases ofEBVinfec-tions were asymptomatic. Other isolated viruses included: BK-virus with hemorrhagic cystitis (n=6), adenovirus (detected in the blood, n=3), varicella-zoster virus (VZV; n=1), respiratory syncytial virus (RSV; rhinitis, n= 1), and parainfluenzae 3 virus (rhinitis, n= 1). Of note, HHV6 was systematically detected in recipient blood samples. Except for the 2 fatal cases with EBV-related lymphoproliferative disorder and

Figure 1. Cumulative incidence of infectious-related mortality (A), bacteremia (B), CMV recurrence (C), and invasive fungal infections (D).

gut adenoviral infection described above, the different viral infections did not require transfer into the ICU.

Fungal and Parasitic Infections

In all, 5 cases of fungal or parasitic infections were documented. Two cases of Toxoplasmosis gondii encephalitis were diagnosed in 1 patient with a primary graft failure and in another patient with a secondary graft failure (cumulative incidence of parasitic infections, 6%). Three probable pulmonary invasive aspergillosis were also diagnosed, 2 of which occurred in patients with refractory acute leukemias. The cumulative incidence of invasive fungal infections (IFI) was 10%. None of these fungal or parasitic infections was the primary cause of death.

DISCUSSION

In the current study, we report the incidence and features of infectious complications occurring in our

first series of 31 adult patients receiving UCBT. Overall, IRM was relatively low (8%), and was exclusively because of viral agents. Such low incidence of IRM is somewhat at odd with the initial series reporting UCBT in adult patients [6-9]. The high TNC doses used in our study (almost all patients received TNC >2.5 x 107/kg) might explain this discrepancy, at least in part. Indeed, and although not statistically significant, based on the median number of TNC, the cumulative incidence of bacteremia, parasitic, or invasive fungal infections was higher in patients transplanted with TNC #4.7x107/kg compared to patients receiving TNC >4.7 x 107/kg (44% versus 20%; P=.17; Figure 2). In previous studies assessing UCBT outcome in adult patients, patients used to be transplanted with lower numbers of TNC, a parameter that has been shown to a be major prognostic factor in UCBT [10,16,17]. To circumvent the inconvenience of a lower TNC, a majority of the patients (87%) included in this study, received double UCBT [18].

Table 3. Isolated Microorganisms after UCBT

Toxoplasmosis

TNC Serology Primary Cause Secondary Bacteraemia* Other Bacterias,

No. (x l07/kg) Recipient/Donor of Death Cause of Death (Day) Site (Day) Viruses (Day) Fungi/Parasites (Day)

1 2.40 +/- R/PD CMV recurrence (26)

2 2.80 +/+ R/PD PIPA BK (20) PIPA (10)

3 3.49 +/- BK (33) CMV recurrence (37) T. gondii, CNS (26)

4 3.58 NE/- R/PD E coli E cloacae (173) E. coli (277) E coli, CVC (173)

5 3.88 +/+

6 4.00 +/+

7 4.00 - /-

8 4.04 NE/- Graft failure T. gondii BK (5) T. gondii, CNS (54)

9 4.04 +/+

10 4.12 -+ E coli, cystitis (54)

11 4.23 +/+ IRM (EBV) BK (64) CMV recurrence (89) EBV-rel LPD (275) PIPA (1)

12 4.26 - /+

13 4.54 +/+ P. aeruginosa (3) C. difficile, gut (6)

14 4.62 - /+ EBV recurrence (29)

15 4.69 - /- GVHD P. aeruginosa S. mitis (4) S. aureus (238) P. aeruginosa, bronchi (507) Adenovirus (80)

16 4.70 +/- GVHD P. mirabilis, cystitis (52) E. coli, cystitis (73) BK (51)

17 18 4.71 4.81 +/+ - /+ VZV(435) EBV recurrence (438)

19 4.98 - /- S. mitis (7) Adenovirus (79)

20 4.98 +/+ CMV recurrence (34)

21 5.04 +/+ CMV recurrence (45)

22 5.16 -+

23 5.16 - /+ EBV recurrence (28)

24 5.20 - /+ IRM (adenovirus) Adenovirus (63)

25 5.35 - /-

26 5.42 +/-

27 5.46 +/+ SRV (34) BK (38) EBV recurrence (117) Parainfl. virus 3 (161)

28 5.49 +/+

29 5.82 +/- R/PD S. mitis (4)

30 7.06 NE/+ R/PD CMV recurrence (35) PIPA(6l)

31 7.68 - /- EBV recurrence (85)

E. coli indicates Escherichia coli;C. difficile, Clostridium difficile; E. cloacae, Enterobacter cloacae; P. mirabilis, Proteus mirabilis; P. aeruginosa, Pseudomonas aeruginosa; S. mitis, Streptococcus mitis; CMV, cytomegalovirus; EBV, Epstein-Barr virus; LPD, lymproliferative disorder; VZV, Varicella-Zona-virus; Parainfl. Virus, Parainfluenzae virus;PIPA, probable invasive pulmonary aspergillosis; T gondii, Toxoplasmosis gondii; SRV, human respiratory syncytial virus; NE, not evaluated; CVC, central venous catheter; CNS, central nervous system.

For toxoplasmosis serology, in case of double UCBT, the donor was considered as positive if at least one of the CB units was from a positive donor. *Two patients had catheter related-infections with documentation of Staphylococcus epidermidis at day + 18 and at day +6 and +70.

in u> In

<S 0.2 £

p = 0.17

—I— 12

—I— 18

—I—

months

Figure 2. Cumulative incidence of bacteremia, parasitic, or invasive fungal infections in patients grafted with TNC #4.7x 107/kg (dashed line) or TNC >4.7x 107/kg (solid line).

In conventional allo-SCT from HLA-matched related and unrelated donors, the transplant period is classically divided into 3 phases. The first phase is related to the aplastic period, with neutropenia and toxicity ofthe conditioning regimen favoring a majority of bacterial infections, but also favoring fungal infections [19]. The second phase is characterized by neu-trophil recovery, but with a major T cell dysfunction because of the immunosuppressive therapies used for acute GVHD (aGVHD) management and thus favoring viral infections, especially CMV [19]. Athird phase might develop in some long-term surviving patients with several complex immune dysfunctions because of chronic GVHD (cGVHD) and/or prolonged immunosuppression [19]. Findings from our study are in line with such pattern, because bacteremia occurred mainly in the early period after UCBT [20-22]. Despite the lack of antibiotic prophylaxis during the aplastic period, bacteremia was not the primary cause of death in any patient. This is all the more important as vancomycin or fluoroquinolones prophylaxis may trigger the emergence of bacterial resistance such as vancomycin-resistant Enterococcus or fluoroquinolone-resistant Escherichia coli [19]. Similarly, fungal infections did not cause any death in patients with sustained neutro-phil recovery. However, because of the low number of events, one cannot exclude that some prophylaxis with drugs such as voriconazole might be needed in patients with prolonged neutropenia to decrease the incidence of invasive aspergillosis as previously reported by Miyakoshi etal. [23].

In terms of viral infections, CMV reactivation was regularly detected in UCBT recipients but preemptive therapy efficiently prevented the onset of CMV dis-

ease. As it is the case for bacterias, the overuse of prophylactic (val)ganciclovir may potentially trigger the emergence of ganciclovir-resistant strains of CMV. Our results suggest that CMV prophylactic treatment is not mandatory in UCBT recipients. However, we could document a relatively higher incidence of other viral infections such as BK-virus, EBV, or adenovirus. Of note, 2 EBV and adenovirus cases were fatal despite regular and close patient monitoring. In addition, the HHV6 virus was almost systematically detected in blood samples from all patients, but without clinical manifestations, highlighting the need for prospective studies focusing on such emergent viruses in the field of allo-SCT. Indeed, delayed immune recovery has been already shown to be a major limitation after UCBT [24]. Such delayed immune recovery would favor the emergence ofopportunistic viral infections further enhancing the need for a stringent biologic monitoring for assessment of the potential differences between UCBT and allo-SCT using conventional donors. Such biologic monitoring would also pave the way for the use of newer cytokines such as IL-7 or IL-15 toward enhancing the kinetics of immune recovery after UCBT [25-26].

In addition to its obvious limitations in terms of cohort size and follow-up, bloodstream and fungal infections may have been underestimated because of the use of empirical broad-spectrum antibiotics and antifungal therapy before neutrophil recovery. In this respect, broad-spectrum b-lactamins, glycopeptides, and antifungal agents (caspofungin or liposomal amphotericin B) were empirically administered to 87%, 76%, and 50% of patients, respectively. Also, bacterial and fungal infections usually vary depending on the local microbial ecology.

Overall, and in contrast to the common belief, our study suggests that IRM is not excessively high after UCBT provided a sufficient dose of TNC is infused to the patient. Life-threatening infections do still occur, especially in patients with severe GVHD or those patients with primary or secondary graft failure, underlining the need for prospective efforts to develop optimal antimicrobial preventive strategies in such challenging situations. However, close monitoring, broad screening of the different opportunistic micro-bial agents, and adhering to the guidelines of the CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation [19] should reduce the severity of opportunistic infections among UCBT recipients, prevent the emergence of microbial resistance, and would allow for early diagnosis and efficient treatment.

ACKNOWLEDGMENTS

The authors thank the nursing staff for providing excellent care for our patients.

Financial disclosure: They also thank the "Region Pays de Loire,'' the "Association pour la Recherche sur le Cancer (ARC),'' the "Fondation de France,'' the "Fondation contre la Leucemie,'' the "Agence de Biomedecine,'' the "Association Cent pour Sang la Vie,'' and the "Association Laurette Fuguain,'' for their generous and continuous support for our clinical and basic research work.

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