Economic Evaluation of Treatment Strategies for Benign Prostatic Hyperplasia—Is Medical Therapy More Costly in the Long Run? Christopher S. Saigal,* Mehran Movassaghi, Jennifer Pace, Geoffrey Joyce and the Urologic Diseases in America Project From the Department of Urology, University of California-Los Angeles Medical Center, Los Angeles, California Purpose: Although medical therapy fo
Advantag of ingestion administration way is its easiness even when applied at home. But with their help necessary treatment concentration in blood cannot be always quickly achieve amoxil online transaction is carried out on anonymity and mutual profit principles, and in addition customers will be positively surprised with quality and speed of service.
1laug.oaOutcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Leukemia Mary J. Laughlin, M.D., Mary Eapen, M.B., B.S., Pablo Rubinstein, M.D., John E. Wagner, M.D., Mei-Jei Zhang, Ph.D., Richard E. Champlin, M.D., Cladd Stevens, M.D., Juliet N. Barker, M.D., Robert P. Gale, M.D., Ph.D., Hillard M. Lazarus, M.D., David I. Marks, M.D., Ph.D., Jon J. van Rood, M.D., Andromachi Scaradavou, M.D., and Mary M. Horowitz, M.D.
b a c k g r o u n d
Data regarding the outcome of cord-blood transplantation in adults are scant, despite From the Case Comprehensive Cancer Cen- the fact that these grafts are increasingly used in adults.
ter and University Hospitals of ClevelandIreland Cancer Center, Cleveland (M.J.L.,H.M.L.); the International Bone Marrow Transplant Registry, Health Policy Institute, We compared the outcomes of the transplantation of hematopoietic stem cells from Medical College of Wisconsin, Milwaukeeunrelated donors in adults with leukemia who had received cord blood that was mis- (M.E., M.-J.Z., M.M.H); the National Cord matched for one HLA antigen (34 patients) or two antigens (116 patients), bone mar- New York (P.R., C.S., A.S.); the University row that had one HLA mismatch (83 patients), and HLA-matched bone marrow (367 of Minnesota Medical School, Minneapolispatients). We used Cox proportional-hazards models to analyze the data.
(J.E.W., J.N.B.); the M.D. Anderson CancerResearch Center, Houston (R.E.C.); theCenter for Advanced Studies in Leukemia, Los Angeles (R.P.G.); the Adult Blood and Cord-blood recipients were younger and more likely to have advanced leukemia than Marrow Transplant Unit, United Bristol Health Care Trust, Bristol, United Kingdom were bone marrow recipients, and they received lower doses of nucleated cells. Hema- (D.I.M.); and Leiden University Medical topoietic recovery was slower with transplantation of mismatched bone marrow and Center, Leiden, the Netherlands (J.J.R.). Ad-cord blood than with matched marrow transplantations. Acute graft-versus-host dis- dress reprint requests to Dr. Horowitz at ease (GVHD) was more likely to occur after mismatched marrow transplantation, and Registry, Medical College of Wisconsin, chronic GVHD was more likely to occur after cord-blood transplantation. The rates of 8701 Watertown Plank Rd., P.O. Box 26509,treatment-related mortality, treatment failure, and overall mortality were lowest among Milwaukee, WI 53226, or at [email protected] patients who received matched marrow transplants. Patients who received mismatchedbone marrow transplants and those who received mismatched cord-blood transplants N Engl J Med 2004;351:2265-75.
had similar rates of treatment-related mortality (P=0.96), treatment failure (P=0.69), Copyright 2004 Massachusetts Medical Society.
and overall mortality (P=0.62). There were no differences in the rate of recurrence ofleukemia among the groups. There were no differences in outcome after cord-bloodtransplantation between patients with one HLA mismatch and those with two HLA mis-matches.
c o n c l u s i o n s
HLA-mismatched cord blood should be considered an acceptable source of hemato-poietic stem-cell grafts for adults in the absence of an HLA-matched adult donor.
Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ographic and clinical data are collected on a repre- plantation of allogeneic bone marrow or sentative sample of patients in the registry. Centers t stem cells from the peripheral blood is lim- that obtain cord-blood grafts from the NCBP are ited by the scarcity of HLA-matched related donors. required, under the Investigational New Drug rules
Only 30 percent of otherwise eligible patients with of the Food and Drug Administration, to report data
leukemia in the United States have a related his- on the outcome of transplantation procedures.
tocompatible donor and, of the remainder, only
about 20 percent receive a transplant from an unre- inclusion criteria
lated donor or an HLA-mismatched related donor.1 The study included patients 16 to 60 years of age
The higher risk of acute and chronic graft-versus- who had received either an HLA-matched marrow
host disease (GVHD) is an important drawback to transplant or a marrow transplant with a single
be considered when grafts from unrelated donors HLA mismatch from an unrelated donor or had re-
or related donors with partially matched HLA anti- ceived a cord-blood transplant with one or two HLA
gens are used.2-5
mismatches. HLA matching was performed with Cord-blood grafts from unrelated donors have the use of serologic or low-resolution molecular been used successfully, primarily in children.6-11 In typing methods for HLA-A and HLA-B and high-children, these grafts reconstitute hematopoiesis resolution molecular typing for HLA-DRB1. Themore slowly than do bone marrow grafts and there- matching process identified all specificities thatby contribute to relatively high rates of post-trans- were recognized by the World Health Organiza-plantation infection and early death.11-14 The in- tion at the time of transplantation. There were notcidence and severity of GVHD are not excessive, enough transplantations performed with HLA-however, even with cord-blood grafts mismatched matched cord blood (5 patients) or cord blood withfor more than one HLA antigen, and graft-versus- three mismatches (19 patients) to include these inleukemia effects are well maintained.11-13,15 Re- the comparison. Also excluded were recipients ofports of cord-blood transplantation in adults also T-cell–depleted marrow, peripheral blood, reduced-suggest slower hematopoietic recovery and varia- intensity preparative regimens, ex vivo expandedble rates of leukemia-free and overall survival, but grafts, or multiple cord-blood units and those inthese studies have been small and did not compare whom prior transplantation had failed. Trans-cord-blood with bone marrow transplantation.14-18 plantations were performed between January 1, We analyzed data on a large number of adult pa- 1996, and December 31, 2001, in various locations tients that were reported to the International Bone throughout the United States. Eligible for the study
Marrow Transplant Registry (IBMTR) and the Na- were 450 bone marrow recipients and 150 cord-
tional Cord Blood Program (NCBP) of the New York blood recipients. The patients had been given a
Blood Center. We compared the outcomes after diagnosis of acute lymphoblastic leukemia, acute
transplantation of hematopoietic stem cells from myeloid leukemia, chronic myeloid leukemia, or
cord blood from unrelated donors that was mis- myelodysplastic syndrome.
matched for one or two HLA antigens (150 patients),
from bone marrow that was mismatched for one end points
HLA antigen (83 patients), or from HLA-matched Neutrophil recovery was defined by an absolute
bone marrow (367 patients).
neutrophil count of at least 500 cells per cubic milli-meter for three consecutive days; platelet recoverywas defined by a count of at least 20,000 platelets per cubic millimeter, unsupported by transfusions, c o l l e c t i o n o f d a t a
for seven days. The incidence of grade 2, 3, or 4 acute Data on patients who underwent bone marrow and GVHD was determined in all patients,19 and thecord-blood transplantation were obtained from the incidence of chronic GVHD was determined inIBMTR and the NCBP of the New York Blood Cen- patients who survived for at least 90 days.20 Treat-ter. The IBMTR is a working group of more than ment-related death was defined as death during400 transplantation centers worldwide. Participat- a continuous remission. Relapse was defined asing centers register basic information on consecu- a recurrence of leukemia; patients in whom a remis-tive transplantations at a statistical center located sion failed to occur after transplantation were con-at the Medical College of Wisconsin. Detailed dem- sidered to have had a recurrence at day 1. Leuke- Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. t r a n s p l a n t a t i o n o f c o r d b l o o d o r b o n e m a r r o w i n a d u l t s w i t h l e u k e m i a mia-free survival was defined as survival in a state plants with two antigen mismatches, and theseof continuous complete remission.
groups were combined for further analyses. Thevariable for graft type was retained in all steps of s t a t i s t i c a l a n a l y s i s
model building. Other variables that were consid- Variables related to patients, disease, and trans- ered were the age of the transplant recipient, theplants were compared among the groups with the serologic status with respect to cytomegalovirus inuse of the chi-square statistic for categorical varia- both donor and recipient before transplantation,bles and the Kruskal–Wallis test for continuous the type of leukemia and the status of the diseasevariables. The probabilities of overall and leukemia- at transplantation, the sex of the recipient and thefree survival were calculated with the use of the donor, the conditioning regimen (i.e., with irradi-Kaplan–Meier estimator.21 For analyses of surviv- ation vs. without it), the regimen for GVHD prophy-al rates, death from any cause was considered an laxis (e.g., treatment with cyclosporine and meth-event, and data on patients who were alive at the otrexate vs. treatment with alternative regimens),last follow-up contact were censored. For leukemia- and the total dose of nucleated cells (for each graftfree survival, relapse or death (i.e., treatment fail- type separately). There were no first-order inter-ure) was considered an event, and data on patients actions between the graft type and the other varia-who were alive and in continuous complete remis- bles studied. No statistically significant effects ac-sion were censored at the last follow-up. The prob- cording to treatment center were noted.23 P valuesabilities of neutrophil and platelet recovery, acute are two-sided. Analyses were completed with theand chronic GVHD, treatment-related death, and use of PROC PHREG in SAS software, version 8.2relapse were calculated with the use of the cumula- (SAS Institute).
tive-incidence–function method.21 For neutrophiland platelet recovery and for GVHD, death without an event (hematopoietic recovery or GVHD) was
the competing event; for treatment-related mor- patients
tality, relapse was the competing event; and, for re- Table 1 shows features of the patients, the types of
lapse, treatment-related death was the competing leukemia they had, and the types of transplant they
event. Data on patients who were alive without an received. As compared with bone marrow recipi-
event were censored at the last follow-up.
ents, cord-blood recipients were younger, were less Confidence intervals were calculated with the likely to be white, were more likely to have acute leu- use of a log transformation.21 Adjusted probabil- kemia, were more likely to have advanced leukemia
ities of overall and leukemia-free survival were esti- at transplantation, and weighed less. The average
mated with the use of the Cox proportional-haz- total dose of nucleated cells for marrow recipients
ards regression model, with consideration of the was generally 10 times as high as that for cord-blood
variables in the final multivariate models.22 Multi- recipients. All cord-blood grafts were HLA-mis-
variate models were built with the use of stepwise matched — 23 percent for one antigen, and 77 per-
forward selection, with a P value of 0.05 or less con- cent for two antigens. The median period of fol-
sidered to indicate statistical significance; all varia- low-up for survivors after marrow and cord-blood
bles met the proportional-hazards assumption. The transplantation was 48 months and 40 months, re-
primary objective was to compare outcomes accord- spectively. Completeness of follow-up for the study
ing to graft type: HLA-matched bone marrow, sin- population was 91 percent.24
gle-antigen–mismatched bone marrow, and cord
blood with one or two antigen mismatches. Results neutrophil and platelet recovery
were expressed as hazard ratios — the relative rate Among patients who had neutrophil and platelet
of occurrence of the event with one graft type as recovery, the recovery times were longer after cord-
compared with another.
blood transplantation than after bone marrow trans- Before comparing bone marrow and cord-blood plantation. Median times to neutrophil recovery grafts, we analyzed the effect of HLA matching in were 18 days (95 percent confidence interval, 18 tocord-blood transplantation. There were no statis- 19) after HLA-matched bone marrow transplanta-tically significant differences in outcome between tion, 20 days (95 percent confidence interval, 18 topatients who had received transplants with one 22) after mismatched marrow transplantation, andantigen mismatch and those who received trans- 27 days (95 percent confidence interval, 25 to 29) Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 1. Characteristics of Patients Who Received Bone Marrow or Cord-Blood Transplants from Unrelated Donors, 1996 to 2001.
Cord Blood Mismatched
Matched Bone Marrow
Bone Marrow Mismatched
for 1 or 2 Antigens
for 1 Antigen (N=83)
Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. t r a n s p l a n t a t i o n o f c o r d b l o o d o r b o n e m a r r o w i n a d u l t s w i t h l e u k e m i a Table 1. (Continued.)
Cord Blood Mismatched
Matched Bone Marrow
Bone Marrow Mismatched
for 1 or 2 Antigens
for 1 Antigen (N=83)
* Race was reported by the transplantation center.
† CR indicates clinical remission (numbers represent first or second remission), CP chronic phase (numbers represent first or second chronic phase), RA refractory anemia, AP accelerated phase, PIF primary induction failure, BP blast phase, RAEBT refractory anemia with excess blast in transformation, and GVHD graft-versus-host disease.
‡ The P value is for a conditioning regimen that involves total-body irradiation as compared with a regimen without irradiation (variable as test- § Transplants were classified as matched or as having one or two antigen mismatches, according to the total number of antigen mismatches at HLA-A and HLA-B loci (defined by serologic or low-to-intermediate-resolution DNA typing) and the number of allele mismatches at HLA-DRB1 (defined by high-resolution DNA typing). HLA data for cord-blood and bone marrow transplantations as reported by the International Bone Marrow Transplant Registry were provided by the transplantation centers. Typing of cord-blood units from the National Cord Blood Program and the blood of recipients was done at the F.H. Allen Immunogenetics Laboratory of the New York Blood Center and, in most cases, also at the HLA laboratory of each transplantation center before transplantation. Among one-antigen–mismatched bone-marrow transplants, 38 were mismatched at the A locus, 27 at the B locus, and 18 at the DRB1 locus. Among one-antigen–mismatched cord-blood transplants, 17 were mismatched at the A locus, 18 at the B locus, and 7 at the DRB1 locus. Among two-antigen–mismatched cord-blood transplants, 21 were mismatched at the A and DRB1 loci, 33 at the B and DRB1 loci, 49 at the A and B loci, 2 at both DRB1 loci, and 1 at both B loci.
¶ Matched donors and recipients are of the same blood group (A, B, or O). A minor mismatch indicates that donor blood from group O has been used in patients with group A, B, or AB and that donor blood from group A or B has been used in patients with group AB. A major mis-match indicates that donor blood from group A, B, or AB has been used in patients with group O and that donor blood from group AB has been used in patients with group A or B. A bidirectional match indicates that donor blood from group A has been used in patients with group B and that donor blood from group B has been used in patients with group A.
Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine after cord-blood transplantation (P<0.001). Corre- year (P=0.16) were similar after transplantations
sponding times to platelet recovery were 29 days of mismatched bone marrow and of cord blood.
(95 percent confidence interval, 27 to 30), 29 days Corresponding cumulative incidence rates after
(95 percent confidence interval, 27 to 34), and 60 transplantation of HLA-matched bone marrow
days (95 percent confidence interval, 54 to 71), re- were significantly higher (P<0.01) (Fig. 1).
spectively (P<0.001). Despite early differences, the
cumulative incidence of neutrophil recovery at day acute and chronic gvhd
100 (P=0.29) and that of platelet recovery at one Acute GVHD of grade 2, 3, or 4 developed in 176
of 367 recipients of HLA-matched bone marrow,in 43 of 83 recipients of mismatched bone marrow,and in 61 of 150 recipients of mismatched cord blood. The rate of acute GVHD grade 2, 3, or 4 was similar between patients who received mismatched cord blood and those who received HLA-matchedbone marrow (hazard ratio, 0.81; 95 percent con- fidence interval, 0.59 to 1.10; P=0.17). However, acute GVHD was less likely after transplantationof mismatched cord blood than after that of mis- Cumulative Incidence
matched bone marrow (hazard ratio, 0.66; 95 per- of Neutrophil Recovery (%)
cent confidence interval, 0.44 to 0.99; P=0.04).
Among patients who survived for 90 days or longer, chronic GVHD developed in 86 of 243 re- No. at Risk (alive without neutrophil recovery)
cipients of HLA-matched bone marrow, in 17 of 43 recipients of mismatched bone marrow, and in 35 of 69 recipients of mismatched cord blood. The rate of chronic GVHD was higher among patients who received cord blood than among those who re-ceived HLA-matched marrow (hazard ratio, 1.62; 95 percent confidence interval, 1.08 to 2.42; P=0.02) but similar to the rate among recipients of mis- matched marrow (hazard ratio, 1.12; 95 percent confidence interval, 0.63 to 2.02; P=0.69). Among patients with chronic GVHD, the proportion with extensive disease was lower among cord-blood re- cipients than among HLA-matched or mismatched Cumulative Incidence
of Platelet Recovery (%)
marrow recipients, with rates of 33 percent, 52 per- cent, and 71 percent, respectively (P=0.03).
t r e a t m e n t - r e l a t e d m o r t a l i t y
No. at Risk (alive without platelet recovery)
Death from treatment-related complications oc- curred in 169 of 367 recipients of HLA-matched bone marrow, in 54 of 83 recipients of mismatched marrow, and in 95 of 150 recipients of cord blood.
Rates of treatment-related death were similar amongpatients who received mismatched bone marrow Figure 1. Cumulative Incidence of Neutrophil and Platelet Recovery
and those who received mismatched cord blood; the after Bone Marrow and Cord-Blood Transplantation.
rate was significantly lower among patients who Despite early differences, the cumulative incidence of neutrophil recovery at received HLA-matched bone marrow (Table 2).
day 100 (Panel A) and of platelet recovery at one year (Panel B) was similar af-ter the transplantation of mismatched bone marrow and of cord blood. The corresponding cumulative incidence after transplantation of HLA-matched bone marrow was significantly higher.
Leukemia recurred after transplantation in 83 of367 recipients of HLA-matched marrow, in 12 of Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. t r a n s p l a n t a t i o n o f c o r d b l o o d o r b o n e m a r r o w i n a d u l t s w i t h l e u k e m i a 83 recipients of mismatched marrow, and in 26 of Rates of treatment failure were similar among pa-150 recipients of mismatched cord blood. All of tients who had received mismatched marrow andthese rates were similar (Table 2).
those who had received cord blood, but the rateswere significantly lower among patients who had l e u k e m i a - f r e e s u r v i v a l
received HLA-matched marrow (Table 2). The prob- Treatment failure (i.e., relapse or death) occurred ability of surviving for three years without a recur-in 252 of 367 recipients of HLA-matched marrow, in rence of leukemia, after adjustments were made66 of 83 recipients of mismatched marrow, and in for other significant factors, was 19 percent (95 per-121 of 150 recipients of mismatched cord blood. cent confidence interval, 12 to 27 percent) for re- Table 2. Results of Multivariate Analysis of Outcomes in 367 Recipients of Matched Marrow, 83 Recipients
of Mismatched Marrow, and 150 Recipients of Mismatched Cord Blood.
Hazard Ratio (95% CI)*
Mismatched cord blood vs. matched marrow Mismatched cord blood vs. mismatched marrow Mismatched cord blood vs. matched marrow Mismatched cord blood vs. mismatched marrow Mismatched cord blood vs. matched marrow Mismatched cord blood vs. mismatched marrow Mismatched cord blood vs. matched marrow Mismatched cord blood vs. mismatched marrow * CI denotes confidence interval.
† Other significant variables were age, 16 to 40 years (baseline hazard ratio, 1.0) and more than 40 years (hazard ratio, 1.56; 95 percent confidence interval, 1.24 to 1.97; P<0.001); disease status, clinical remission (CR) 1, chronic phase (CP) 1, or refractory anemia (RA) (baseline hazard ratio, 1.0), CR2, CR3, or CR4, CP2, or accelerated phase (AP) (hazard ratio, 1.21; 95 percent confidence interval, 0.92 to 1.60; P=0.16), relapse, primary induction failure (PIF), blast phase (BP), re-fractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEBT) (hazard ra-tio, 1.47; 95 percent confidence interval, 1.11 to 1.96; P=0.01); and donor–recipient serologic cytomegalovirus status, negative for donor and recipient (baseline hazard ratio, 1.0) and positive for donor, recipient, or both (hazard ratio, 1.58; 95 percent confidence interval, 1.24 to 2.01; P<0.001).
‡ Other significant variables were disease status, CR1, CP1, or RA (baseline hazard ratio, 1.0), CR2, CR3, or CR4, CP2, or AP (hazard ratio, 2.95; 95 percent confidence interval, 1.66 to 5.26; P<0.001), relapse, PIF, BP, RAEB, or RAEBT (hazard ratio, 7.71; 95 percent confidence interval, 4.48 to 13.27; P<0.001).
§ Other significant variables were age, 16 to 40 years (baseline hazard ratio, 1.0) and more than 40 years (hazard ratio, 1.43; 95 percent confidence interval, 1.17 to 1.74; P=0.001); disease status, CR1, CP1, or RA (baseline hazard ratio, 1.0), CR2, CR3, or CR4, CP2, or AP (hazard ratio, 1.47; 95 percent confidence interval, 1.15 to 1.88; P=0.002), relapse, PIF, BC, RAEB, or RAEBT (hazard ratio, 2.26; 95 percent confidence interval, 1.77 to 2.88; P<0.001); and donor–recipient serolog-ic cytomegalovirus status, negative for donor and recipient (baseline hazard ratio, 1.0) and positive for donor, recipient, or both (hazard ratio, 1.58; 95 percent confidence interval, 1.28 to 1.94; P<0.001).
¶ Other significant variables were age, 16 to 40 years (baseline hazard ratio, 1.0) and more than 40 years (hazard ratio, 1.43; 95 percent confidence interval, 1.17 to 1.75; P=0.001); disease status, CR1, CP1, or RA (baseline hazard ratio, 1.0), CR2, CR3, or CR4, CP2, or AP (hazard ratio, 1.44; 95 percent confidence interval, 1.13 to 1.85; P=0.004), relapse, PIF, BC, RAEB, or RAEBT (hazard ratio, 2.25; 95 percent confidence interval, 1.76 to 2.87; P<0.001); and donor–recipient serolog-ic cytomegalovirus status, negative for donor and recipient (baseline hazard ratio, 1.0) and positive for donor, recipient, or both (hazard ratio, 1.58; 95 percent confidence interval, 1.28 to 1.94; P<0.001).
Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine cipients of mismatched marrow and 23 percent (95 megalovirus in the donor, recipient, or both. Afterpercent confidence interval, 17 to 30 percent) for we adjusted for these factors, treatment-relatedrecipients of cord blood (P = 0.69); the probabili- mortality, the rate of treatment failure, and overallty of such survival after transplantation with HLA- mortality were significantly lower after the trans-matched marrow was higher, at 33 percent (95 per- plantation of HLA-matched marrow than after thecent confidence interval, 28 to 37 percent; P=0.001) transplantation of HLA-mismatched marrow or(Fig. 2A).
cord blood. The rate of recurrence of leukemia wassimilar among the three groups. It is important to o v e r a l l m o r t a l i t y
note that there were no significant differences in Death due to any cause after transplantation oc- treatment-related mortality, the rate of treatmentcurred in 247 of 367 recipients of HLA-matched failure, or overall mortality between recipients ofmarrow, in 65 of 83 recipients of mismatched mar- HLA-mismatched marrow and those who receivedrow, and in 117 of 150 recipients of mismatched mismatched cord blood despite the fact that 77 per-cord blood (Table 3). Mortality rates were similar cent of cord-blood grafts were mismatched for twoafter transplantation of mismatched marrow and HLA antigens, whereas all mismatched-marrowof cord blood but significantly lower after trans- grafts were mismatched for only one antigen. Theplantation of HLA-matched marrow (Table 2). Ad- relative efficacy of HLA-matched and mismatchedjusted probabilities of three-year survival were 20 bone marrow and cord-blood grafts did not differpercent (95 percent confidence interval, 12 to 28 per- according to age, type of leukemia, or other prog-cent) for recipients of mismatched marrow, 26 nostic variables we studied.
percent (95 percent confidence interval, 19 to 32 An HLA mismatch is perhaps the strongest risk percent) for recipients of cord blood (P=0.62), and factor for GVHD and other outcomes after bone35 percent (95 percent confidence interval, 30 to marrow transplantation. The association of HLA39 percent) for recipients of HLA-matched marrow disparity with GVHD after cord-blood transplanta-(P<0.001) (Fig. 2B).
tion is less clear.8-10,18 We did not observe differ- The proportion of deaths that occurred dur- ences in outcome between transplantations that ing the first 100 days after transplantation of mis- involved cord blood mismatched for one and twomatched marrow or cord blood was significantly HLA antigens; this finding contrasts with our re-higher than that after transplantation of HLA- cent analysis in which an increasing HLA dispari-matched marrow (70 percent vs. 50 percent, P< ty in children was associated with worse outcomes0.001). The proportion of deaths that were related after transplantation of cord blood (unpublishedto infections within 100 days after transplantation data). However, in that study, overall outcomes werewas significantly higher among recipients of mis- better, the number of patients was larger, doses ofmatched cord blood than among recipients of ei- nucleated cells were higher, and the range of HLAther HLA-matched marrow or mismatched marrow disparity was wider (from 0 to 3 antigens). All of(45 percent, 21 percent, and 24 percent, respective- these factors may have produced an effect thatly; P=0.01). Beyond day 100, the proportions of was easier to detect. Most of the cord-blood graftsinfection-related deaths were similar in the three (77 percent) in the current study were mismatchedgroups. Of the infection-related deaths, the propor- at two HLA loci; the relatively small number mis-tions that resulted from bacteria, viruses, and fungi matched at one HLA locus gave the study low sta-did not differ among the groups.
tistical power to detect an effect of the number ofmismatches. Moreover, the definition of an HLAmatch in this study included only six HLA loci and low-resolution typing for class I antigens. This is Our objective was to compare the effectiveness of how cord-blood units were typed and selected dur-hematopoietic stem-cell transplantation with the ing the study period, but bone marrow donors wereuse of cord-blood grafts mismatched for one or two often selected with the use of criteria that includedHLA antigens, HLA-matched bone marrow, and high-resolution typing for 8 or 10 HLA antigens. Itbone marrow mismatched for one antigen, all from may be that undetected mismatches also decreasedunrelated donors, in adults with leukemia. Signif- our ability to find an effect of the HLA matching.
icant prognostic factors were older age (over 40 Further analysis of larger numbers of patients, withyears), advanced leukemia, and positivity for cyto- the use of more sensitive typing techniques, will be Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. t r a n s p l a n t a t i o n o f c o r d b l o o d o r b o n e m a r r o w i n a d u l t s w i t h l e u k e m i a necessary before we can conclude that increasing HLA disparity does not affect the outcome of cord- A major limitation to the use of cord-blood grafts in adults is the concern that these grafts have an insufficient number of precursor cells as comparedwith bone-marrow grafts. Reports of cord-blood transplantation in adults suggest that hematopoi- etic recovery is faster with higher cell doses.16-18 Adjusted Probability
The median dose of nucleated cells in our study was of Leukemia-free Survival (%)
2.2¬107 per kilogram of body weight, which is sim- ilar to that reported in other studies, and the ratesof neutrophil and platelet recovery were lower with No. at Risk
cord blood than with bone marrow. However, we did not find a significant effect of the cell dose on the rates of mortality and treatment failure among cord-blood recipients. The range of doses was rela- tively narrow (80 percent of patients received a dose of less than 3.0¬107 per kilogram), which may have precluded the detection of a cell-dose effect.
We observed, as others have, that the propor- tion of deaths related to infection was higher soon after cord-blood transplantation than after trans-plantation of HLA-matched and mismatched bone marrow — a difference that is possibly the result of Survival (%)
of slower myeloid recovery.14,15 Although infec- tions were more common with transplantation of cord blood, the distribution of types of infection did not differ significantly among recipients of No. at Risk
HLA-matched marrow, mismatched marrow, and cord blood. Others have also reported delayed neu- trophil and lymphocyte recovery and higher rates of bacterial infections in the early post-transplan- tation period (i.e., less than 50 days) in the case ofcord blood, with overall rates of infection at latertimes being similar to those for marrow transplan- Figure 2. Adjusted Probability of Leukemia-free and Overall Survival
after Bone Marrow and Cord-Blood Transplantation.
tation.15 Several ongoing studies are attempting to The adjusted probability of three-year survival without a recurrence of leuke- improve hematopoietic recovery and thereby de- mia (Panel A) was 19 percent for recipients of mismatched marrow, 23 percent crease infection in the early period after cord-blood for recipients of cord blood, and 33 percent for recipients of HLA-matched marrow. The probability of overall survival at three years (Panel B) was 20 per- All aspects of the transplantation regimen, in- cent for recipients of mismatched marrow, 26 percent for recipients of cord cluding the choice of graft type, were determined blood, and 35 percent for recipients of HLA-matched marrow. Probabilities were adjusted for age, disease status at transplantation, and positivity for by the transplantation centers. A higher proportion cytomegalovirus in the donor, recipient, or both.
of cord-blood recipients than marrow recipientshad advanced leukemia at the time of transplanta-tion, which probably reflects a practice of usingthese grafts in patients with limited treatment op- tors made a controlled (though not randomized)tions. Any observational study that compares dif- comparison possible. The results support a standardferent interventions is subject to bias owing to the of care in which transplantation of HLA-matchedcomplex criteria for selection that underlie the marrow is performed when a donor is available inchoice of intervention, and our study is no excep- a timely manner. In the absence of such a donor,tion. However, our ability to adjust for key risk fac- cord blood mismatched for one or two antigens or Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 3. Causes of Death, According to Type of Transplant.*
* Early death was defined as death that occurred during the first 100 days after transplantation, and late death as death more than 100 days after transplantation.
marrow grafts mismatched for one antigen are ac- Supported by a Public Health Service grant (U24-CA76518) from ceptable alternatives and have similar outcomes. the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute, The rapid availability of a unit of cord blood (i.e., the Abraham J. and Phyllis Katz Foundation, the Leukemia andafter a median of 13.5 days)29 may be a particular Lymphoma Society of America, the American Society of Clinicaladvantage for patients who require urgent trans- Oncology, and the Children’s Leukemia Research Association. Dr.
Laughlin is a Leukemia Scholar in Clinical Research, the Leukemia plantation. The slow rate of hematopoietic recovery and Lymphoma Society of America. Dr. Eapen is the recipient of aremains a major deterrent to the use and success of Clinical Research Career Development award from the Americancord-blood transplantation in adults, and novel Society of Clinical Oncology.
Dr. Champlin reports having received consulting fees from strategies to overcome this obstacle are needed.
r e f e r e n c e s
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et al. Placental blood as a source of hema- 13. Barker JN, Davies SM, DeFor T, Ramsay
topoietic stem cells for transplantation into NKC, Weisdorf DJ, Wagner JE. Survival after therapy for chronic myelogenous leukemia: unrelated recipients. N Engl J Med 1996;335: transplantation of unrelated donor umbili- initial experience of the National Marrow cal cord blood is comparable to that of hu- Donor Program. Blood 1993;81:543-50.
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ly infections in adult patients undergoing Kernan NA, Bartsch G, Ash RC, et al.
A, et al. Outcome of cord blood transplan- Analysis of 462 transplantations from unre- tation from related and unrelated donors.
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15. Hamza NS, Lisgaris M, Yadavalli G, et al.
Factors associated with outcome after cord Kinetics of myeloid and lymphocyte recov- Szydlo R, Goldman JM, Klein JP, et al. Re- blood transplantation in children with acute ery and infectious complications after unre- sults of allogeneic bone marrow transplants for leukemia using donors other than HLA- 11. Rocha V, Wagner JE Jr, Sobocinski KA,
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row transplant from an HLA-identical sib- comparison of unrelated cord blood trans- et al. Successful transplantation of HLA- ling. N Engl J Med 2000;342:1846-54.
plantation and unrelated bone marrow trans- Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved. t r a n s p l a n t a t i o n o f c o r d b l o o d o r b o n e m a r r o w i n a d u l t s w i t h l e u k e m i a plantation for adult patients with acute leu- analysis: techniques of censored and trun- cells: results of a phase 1 trial using the kaemia in complete remission. Br J Haematol cated data. New York: Springer-Verlag, 2003.
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al. Unrelated umbilical cord blood trans- transplantation in adults with hematologic ing for centre effects in multi-centre survival plants in adults: early recovery of neutrophils studies: a Monte Carlo comparison of fixed by supportive co-transplantation of a low 18. Laughlin MJ, Barker J, Bambach B, et al.
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21. Klein JP, Moeschberger ML. Survival
transplantation with ex vivo expanded UCB Copyright 2004 Massachusetts Medical Society. journal editorial fellow
The Journal’s editorial office invites applications for a one-year research fellowship beginning in July 2005 from individuals at any stage of training. The editorial fellow will work on Journal projects and will participate in the day-to-day editorial activities of the Journal but is expected in addition to have his or her own inde-pendent projects. Please send curriculum vitae and research in-terests to the Editor-in-Chief, 10 Shattuck St., Boston, MA 02115 (fax, 617-739-9864), by January 15, 2005.
Downloaded from www.nejm.org at UIO BIBLIOTEK MEDISIN OG on May 12, 2005 . Copyright 2004 Massachusetts Medical Society. All rights reserved.
Journal of Antimicrobial Chemotherapy (2002) 50 , Suppl. S2 , 21–26 DOI: 10.1093/jac/dkf503 Susceptibility patterns of bacteria causing community-acquired respiratory infections in Spain: the SAUCE project Juan García-de-Lomas1,2*, César García-Rey3 and Lorena López1, Concepción Gimeno1,2 and the Spanish Surveillance Group for Respiratory Pathogens† 1Instituto Valenci