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Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia
Accepted Manuscript
Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia Daniel A. Keesler , Andrew St. Martin , Carmem Bonfim , Adriana Seber , Mei-Jie Zhang , Mary Eapen PII: DOI: Reference:
S1083-8791(18)30475-0 https://doi.org/10.1016/j.bbmt.2018.08.010 YBBMT 55232
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
5 July 2018 6 August 2018
Please cite this article as: Daniel A. Keesler , Andrew St. Martin , Carmem Bonfim , Adriana Seber , Mei-Jie Zhang , Mary Eapen , Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia, Biology of Blood and Marrow Transplantation (2018), doi: https://doi.org/10.1016/j.bbmt.2018.08.010
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Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia
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Short title: Bone marrow versus peripheral blood transplants
Daniel A. Keesler1, Andrew St. Martin1, Carmem Bonfim2, Adriana Seber3, Mei-Jie Zhang1,4 and Mary Eapen1 1
Center for International Blood and Marrow Transplant Research, Department of Medicine,
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Medical College of Wisconsin, Milwaukee, USA; 2Bone Marrow Transplantation Unit, Federal University of Paraná, Curitiba, Brazil; 3Hospital Samaritano, Sao Paulo, Brazil; 4Division of
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Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, USA
Address Correspondence: Mary Eapen MBBS, MS, Center for International Blood and Marrow
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Transplant Research, Department of Medicine, 8701 Watertown Plank Road, Medical College of Wisconsin, WI 53226, USA
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Email: [email protected]
Highlights
Higher overall mortality after peripheral blood compared to bone marrow transplant. Lower relapse after peripheral blood compared to bone marrow transplant. No survival advantage despite lower relapse after peripheral blood transplant.
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Abstract: 224 Text: 2770 Tables: 2 Figures: 4
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Reference: 18
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FINANCIAL DISCLOSURE STATEMENT Conflict of interest: The authors declare none Funding Source: The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518
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from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-15-1-0848 and N00014-16-1-2020 from the
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Office of Naval Research. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S.
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Government.
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ABSTRACT As graft versus host disease (GVHD) rates are higher after unrelated donor transplantation, we examined whether there would be differences in transplant outcomes by graft type in children and adolescents with acute leukemia. The primary endpoint was overall survival. We studied
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872 patients aged less than 18 years transplanted with bone marrow (n = 650) or peripheral blood (n = 222) from unrelated donors. The characteristics of the two groups were comparable except recipients of bone marrow were younger compared to recipients of peripheral blood (median age 10 versus 12 years). Grade 2-4 (HR 1.48, p<0.001) and 3-4 acute (HR 1.69, p<0.001) and
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chronic GVHD (HR 1.92, p<0.001) were higher with transplantation of peripheral blood compared to bone marrow. Although relapse risks were lower after peripheral blood transplants (HR 0.76, p=0.05), transplant-related mortality (HR 1.91, p=0.003) and overall mortality (HR
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1.34, p=0.032) were higher compared to bone marrow transplants. The 8-year probability of overall survival after transplantation of bone marrow was 47% compared to 42% after peripheral
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blood. The 8-year probability of leukemia-free survival was 40% after transplantation of bone marrow and peripheral blood. Lower relapse after transplantation of peripheral blood negated
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the survival advantage after transplantation of bone marrow. The observed higher acute and
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chronic GVHD seen with peripheral blood suggest cautious use of this graft in children and
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adolescents with acute leukemia.
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INTRODUCTION Bone marrow is preferred over peripheral-blood for children and adolescents with acute leukemia undergoing human leukocyte antigen (HLA) matched sibling transplantation. 1 Compared to transplantation of bone marrow, higher chronic GVHD and transplant-related
survival.
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mortality after transplantation of peripheral blood resulted in lower leukemia-free and overall A multi-center trial (BMT CTN 0201 NCT#0075816) that randomized patients,
including children, to bone marrow or peripheral blood did not show survival differences between the treatment groups although chronic graft-versus-host disease (GVHD) rates were
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higher after transplantation of peripheral blood.2 A later report on trial participants that focused on the quality of life of a subset of adult survivors concluded that recipients of bone marrow reported better quality of life including mental health, occupational functionality, and chronic
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GVHD symptoms.3 Data reported to the Center for International Blood and Marrow Transplant Research suggest peripheral blood accounts for 20% of unrelated donor transplantations in
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children and adolescents with acute leukemia in the United States. Acute and chronic GVHD rates are generally higher after unrelated donor transplantation. The higher rates of chronic
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GVHD and lower survival after HLA-matched sibling donor transplantation for acute leukemia
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in children and adolescents1 may not be relevant in the setting of unrelated donor transplantation. In this study we examined whether transplant-outcomes would differ after transplantation of
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peripheral blood and bone marrow from unrelated donors in children and adolescents, as was the case after HLA-matched sibling transplantation. METHODS Patients
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The Center for International Blood and Marrow Transplant Registry is a voluntary group of over 400 transplant centers that report data prospectively on consecutive transplants. Of these, 122 transplant centers perform allogeneic hematopoietic cell transplants for acute leukemia in children and adolescents. Patients are followed longitudinally until death or until they are lost to
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follow-up. Included in the current analyses are patients, aged less than 18 years with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) who were transplanted in the U.S. between 2000 and 2012 and received a myeloablative transplant conditioning regimen (total body irradiation dose ≥1000 cGy, busulfan dose >8 mg/kg oral or >6.5 mg/kg IV or melphalan
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dose >140 mg/m2).4 Of the 872 eligible patients, 650 received bone marrow and 222, peripheral blood. Twenty-five centers transplanted only bone marrow grafts, 7 centers only peripheral blood, and 58 both bone marrow and peripheral blood. Donor-recipient pairs were HLA-matched
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at the allele-level for HLA-A, -B, -C, and –DRB1 (8/8) or mismatched at 1 HLA-locus (7/8). All patients received cyclosporine or tacrolimus-containing graft-versus-host disease (GVHD) Recipients of ex-vivo T-cell depleted bone marrow (n=96), CD34 selected
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prophylaxis.
peripheral blood grafts (n=11), or reduced intensity transplant conditioning regimens4 (n=50)
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were excluded. Parents provided written informed consent for research. The Institutional Review
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Board of the National Marrow Donor Program approved this study. Endpoints
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The primary endpoint was overall survival defined as death from any cause. Surviving patients were censored at last follow-up.
Neutrophil recovery was defined as achieving absolute
neutrophil count ≥0.5 x 109/L for 3 consecutive days and platelets ≥20 x 109/L, for 7 days unsupported by transfusion. Primary and secondary graft failure were considered as a single outcome. Primary graft failure was defined as failure to achieve an absolute neutrophil count of ≥
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0.5 × 109/L for 3 consecutive days or <5% donor chimerism. Secondary graft failure was defined as initial donor engraftment followed by graft loss, evidenced by a persistent decline in the absolute neutrophil count (<0.5 x 109/L), loss of donor chimerism (<5%), or second transplantation in patients with documented clinical remission.5 Grade II-IV acute GVHD and
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chronic GVHD were based on reports from each transplant center using standard criteria.6,7 Relapse was defined as morphologic, cytogenetic, or molecular recurrence of leukemia. Transplant-related mortality was defined as death in remission. Leukemia-free survival was defined as being alive in continuous remission; death or relaspe were considered events and
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surviving patients were censored at last follow up. GVHD-free, relapse free survival (GRFS) events included grade 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse or progression or death from any cause within the first year after transplantation.8
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Statistical Methods
Differences between treatment groups were compared using the Chi-squared test for
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categorical variables. The probabilities of overall and leukemia-free survival were calculated using the Kaplan-Meier estimator.9 The cumulative incidences of graft failure, acute and chronic
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GVHD, transplant-related mortality and relapse were calculated using the cumulative incidence
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estimator to accommodate competing risks.10 Multivariate models were built to examine the effect of graft type on overall mortality and leukemia-free survival, acute and chronic GVHD,
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transplant-related mortality and relapse using Cox regression models to accommodate competing risks.11 The variable for graft type (bone marrow vs. peripheral blood) was held in all steps of model building regardless of level of significance. Other variables tested included age, cytomegalovirus serostatus, performance score, disease type, disease status at transplantation, conditioning regimen, in vivo T cell depletion, GVHD prophylaxis, cell dose, donor-recipient
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HLA match and, transplant period (Table 1). The assumptions for proportionality were violated for models on transplant-related and overall mortality and adjusted for by introducing the variable for graft type as time-dependent co-variate. There were no first order interactions between graft type and other variables held in the final multivariate model. Only variables that
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attained p-value ≤0.05 were held in the final multivariate model. The potential effect of transplant center was tested using the frailty model.12 All p-values are two-sided and analyses were done using SAS version 9.4 (Cary, NC). RESULTS
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Patient, Disease and Transplant Characteristics
Patient, disease, and transplant characteristics by graft type are shown in Table 1. Patient, disease, and transplant characteristics were similar by graft type except recipients of bone
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marrow were younger and were more likely to receive cyclosporine-containing GVHD prophylaxis. The median age of bone marrow recipients was 10 years compared to 12 years for
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peripheral blood recipients (p<0.001). The median weight (inter quartile range [IQR]) of bone marrow recipients was 34 (20 – 55) kilograms compared to 43 (25 – 59) kilograms for peripheral
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blood recipients (p=0.001). Thirty of 389 (3%) patients with AML had secondary AML and the Disease status at
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distribution of secondary AML did not differ by graft type (p=0.60).
transplantation also did not differ by graft type. Total body irradiation (TBI) containing regimen
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(TBI dose ≥1000 cGy) with cyclophosphamide was the predominant regimen and accounted for 74% of bone marrow and 70% of peripheral blood transplants. Busulfan with cyclophosphamide was the predominant non-TBI regimen although this accounted for only 17% of bone marrow and 12% of peripheral blood transplants. Cyclosporine with methotrexate was the predominant GVHD prophylaxis regimen for bone marrow recipients and tacrolimus with methotrexate was
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the predominant regimen for peripheral blood recipients. In vivo T cell depletion did not differ by graft type (40% of bone marrow and 38% of peripheral blood transplants). The median total nucleated cell dose for bone marrow recipients was 3.9 (IQR 2.6 – 5.7) x 108/kilogram body weight. The median CD34 dose for peripheral blood recipients was 7.0 (IQR 5.1 – 9.8) x
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106/kilogram body weight. There were no differences in the proportion of bone marrow and peripheral blood transplants over the time-period studied. The median follow-up of surviving patients was 8 years (range 3-197 months) and 8 years (6-170 months) after bone marrow and peripheral blood transplants, respectively.
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Hematopoietic recovery
Most patients achieved neutrophil and platelet recovery. The day-28 probability of neutrophil recovery was lower after bone marrow 90% (95% CI 88-93) compared to peripheral blood
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transplants 96% (95% CI 93-98), p=0.002. Similarly, platelet recovery was lower after bone marrow transplants (p<0.001). The day-100 probabilities of platelet recovery were 81% (95% CI
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77-84) and 84% (95% CI 79-89) after bone marrow and peripheral blood transplants, respectively. The 1-year cumulative incidence of graft failure did not differ by graft type. The 1-
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year cumulative incidence of graft failure after transplantation of bone marrow and peripheral
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blood were 11% (95% CI 9 - 13) and 6% (95% CI 3 - 10), respectively, p=0.07. Acute and Chronic GVHD
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Compared to transplantation of bone marrow, grade 2-4 acute GVHD was higher after transplantation of peripheral blood compared to bone marrow after adjusting for conditioning regimen, GVHD prophylaxis, in vivo T-cell depletion and donor-recipient HLA-mismatch (Table 2). The day-100 incidence of grade 2-4 acute GVHD after transplantation of bone marrow and peripheral blood were 28% (95% CI 25 - 31) and 43% (95% CI 37 - 50),
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respectively (p<0.001) (Figure 1A). Similarly, grade 3-4 acute GVHD was higher after transplantation of peripheral blood compared to bone marrow (HR 1.69 [95% CI 1.25 – 2.28], p<0.001). The day-100 incidence of grade 3-4 acute GVHD after transplantation of bone marrow and peripheral blood were 13% (95% CI 11 - 16) and 25% (95% CI 20 - 31), respectively (p<
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0.001).
Chronic GVHD risks were also higher after transplantation of peripheral blood after adjusting for age, in vivo T-cell depletion and donor-recipient HLA-mismatch (Table 2). The 5-year incidence of chronic GVHD was 38% (95% CI 34 - 42) and 61% (95% CI 54 - 67) after
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transplantation of bone marrow and peripheral blood, respectively (p<0.001) (Figure 1B). Despite differences in chronic GVHD risk by graft type, there were no differences in its severity by graft type (p=0.61). Among bone marrow recipients (n=245) with chronic GVHD, severity
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was graded as mild for 49%, moderate for 29% and severe for 22%. Corresponding severity rates for peripheral blood recipients (n=129) were 46%, 28% and 26%.
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Overall Survival and Leukemia-free Survival
Three hundred and forty-five of 650 patients died after transplantation of bone marrow and 127
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of 222 patients after transplantation of peripheral blood. Mortality risks were lower after
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transplantation of bone marrow compared to peripheral blood beyond 6 months after transplantation, but not the earlier period (Table 2; Figure 2). The 8-year probabilities of overall
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survival after transplantation of bone marrow and peripheral blood were 47% (95% CI 43 - 51) and 42% (95% CI 35 - 49) respectively, p=0.03. Independent of graft type, mortality risks were higher in patients aged 10-17 years, poor performance score, transplantation in relapse or primary induction failure and donor-recipient HLA-mismatch. Transplant outcomes did not differ by transplant center (p=0.87).
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Treatment failure (relapse or death, inverse of leukemia-free survival) did not differ by graft type (Table 2). Treatment failure was higher in patients aged 10-17 years, poor performance score and transplantation in relapse or primary induction failure. The 8-year probability of leukemia-free survival was 40% (95% CI 36 - 44) and 40% (95% CI 33 - 47) after
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transplantation of bone marrow and peripheral blood respectively, p=0.97.
Causes of death were similar after transplantation of bone marrow and peripheral blood. Recurrent disease was the predominant cause of death, accounting for 49% of deaths in bone marrow recipients and 43% of deaths in peripheral blood recipients. Other causes of death after
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transplants from bone marrow or peripheral blood include organ failure (14% vs. 15%), infection (8% vs. 16%), and GVHD (10% vs. 10%), respectively. Relapse and Transplant-related Mortality
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Relapse risks were higher after transplantation of bone marrow compared to peripheral blood (Table 2; Figure 3). The 8-year incidences of relapse were 38% (35 - 42) and 30% (24 - 37) after
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transplantation of bone marrow and peripheral blood (p=0.05). Relapse risks were higher for patients with AML and transplantation in relapse or primary induction failure. The 1-year
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probability of GRFS was higher after transplantation of bone marrow compared to peripheral
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blood; 28% (95% CI 25 – 32) and 19% (95% CI 14 – 24), p=0.003. Transplant-related mortality was lower after transplantation of bone marrow compared to peripheral blood beyond 6 months
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after transplantation but not the earlier period (Table 2; Figure 4). The 8-year incidences of transplant-related mortality were 22% (19 - 25) and 30% (24 - 36) after transplantation of bone marrow and peripheral blood, p=0.003. Risks were higher in patients aged 10-17 years, poor performance score, diagnosis of ALL and 1 HLA-locus mismatched transplants.
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Table 1. Patient, disease and transplant characteristics Peripheral blood 222 12 (1 – 17) 85 (38%) 137 (62%)
506 (78%) 72 (11%) 72 (11%)
168 (76%) 35 (16%) 19 ( 9%)
323 (50%) 324 (50%0 3 (<1)
99 (45%) 121 (55%) 2 (<1)
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Bone marrow 650 10 (1 – 17) 323 (50%) 327 (50%)
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Number Age, median (range), years < 10 years 10 – 17 years Performance score 90 – 100 < 90 Not reported Recipient cytomegalovirus serostatus Negative Positive Not reported Disease Acute myeloid leukemia Acute lymphoblastic leukemia Disease status First complete remission Second complete remission Relapse / primary induction failure Conditioning regimen TBI + cyclophosphamide TBI + other agents Busulfan + cyclophosphamide Busulfan + fludarabine Busulfan + other agents Graft-versus-host-disease prophylaxis Tacrolimus/cyclosporine + mycophenolate Tacrolimus/cyclosporine + methotrexate Tacrolimus/cyclosporine ± other Donor-recipient HLA match HLA-matched (allele-level) A, B, C, DRB1 1 HLA-locus mismatch Donor-recipient sex match Female donor / male recipient Other Transplant period 2000 – 2007 2008 – 2012 Median follow-up (range) surviving patients, months Abbreviation TBI = total body irradiation HLA = human leukocyte antigen
283 (44%) 367 (56%)
106 (48%) 116 (52%)
201 (31%) 346 (53%) 103 (16%)
86 (39%) 101 (45%) 35 (16%)
483 (74%) 31 ( 5%) 113 (17%) 18 ( 3%) 5 (<1%)
155 (70%) 21 ( 9%) 27 (12%) 12 ( 5%) 7 ( 3%)
59 ( 9%) 528 (81%) 63 (10%)
34 (15%) 164 (74%) 24 (11%)
434 (67%) 216 (33%)
149 (67%) 73 (33%)
144 (22%) 506 (78%)
43 (19%) 179 (81%)
490 (75%) 160 (25%) 98 (10 – 196)
171 (77%) 51 (23%) 96 (6 – 170)
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Table 2. Transplant outcomes by graft type Hazard Ratio (95% confidence interval)
P-value
Grade 2-4 acute graft-versus-host disease* Bone marrow Peripheral blood
1.00 1.48 (1.19 – 1.81)
Chronic graft-versus-host disease§ Bone marrow Peripheral blood
1.00 1.92 (1.55 – 2.39)
<0.001
1.00 0.73 (0.47 – 1.12)
0.15
Relapse** Bone marrow Peripheral blood
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Overall mortality♯♯ (≤ 6 months) Bone marrow Peripheral blood Overall mortality♯♯ (> 6 months) Bone marrow Peripheral blood
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Treatment failure§§ Bone marrow Peripheral blood
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Transplant-related mortality# (≤ 6 months) Bone marrow Peripheral blood Transplant-related mortality# (> 6 months) Bone marrow Peripheral blood
<0.001
1.00 1.91 (1.25 – 2.91)
0.003
1.00 0.76 (0.58 – 0.99)
0.05
1.00 0.94 (0.77 – 1.15)
0.56
1.00 0.77 (0.55 – 1.06)
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1.00 1.34 (1.02 – 1.74)
0.032
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Other factors associated with transplant outcomes: *Grade 2-4 acute graft-versus-host disease: higher risks with TBI containing regimens (HR 1.43, 95% CI 1.09 – 1.88), p=0.010), calcineurin inhibitor with mycophenolate compared to calcineurin inhibitor with methotrexate (HR 1.54, 95% CI 1.14 – 2.08, p=0.006) and CNI alone (HR 3.70, 95% CI 2.22 – 6.25, p<0.001) GVHD prophylaxis, non-ATG regimens (HR 1.98, 95% CI 1.59 – 2.48, p<0.001) and 1 HLA-locus mismatched transplants (HR 1.42, 95% CI 1.16 – 1.74, p=0.001). §Chronic graft-versus-host disease: higher risks for patients aged 10-17 years (HR 1.25, 95% CI 1.02 – 1.54), p=0.036), with non-ATG regimens (HR 2.30, 95% CI 1.82 – 2.91, p<0.001) and transplantation of grafts from donors mismatched at 1 HLA-locus (HR 1.25, 95% CI 1.01 – 1.55, p=0.049).
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#Transplant-related mortality: risks were higher in patients aged 10-17 years (HR 2.09, 95% CI 1.55 – 2.83, p<0.001), performance score <90 (HR 1.79, 95% CI 1.25 – 2.56, p<0.001), diagnosis of ALL (HR 1.47, 95% CI 1.10 – 1.95, p=0.009) and 1 HLA-locus mismatched transplants (HR 1.71, 95% CI 1.30 – 2.24, p<0.001). **Relapse: risks were higher for patients with AML (HR 1.48, 95% CI 1.18 – 1860, p=0.007) and transplantation in relapse or primary induction failure compared to first (HR 2.67, 95% CI 1.99 – 3.58, p<0.001) and second (HR 3.04, 95% CI 2.03 – 4.03, p<0.001) complete remission. §§Treatment failure: higher in patients aged 10-17 years (HR 1.21, 95% CI 1.02 – 1.42, p=0.03), performance score <90 (HR 1.61, 95% CI 1.28 – 2.02, p<0.001) and transplantation in relapse or primary induction failure compared to transplantation in first (HR 2.26, 95% CI 1.78 – 2.86, p<0.001) or second (HR 2.12, 95% CI 1.71 – 2.63, p<0.001) complete remission. ♯♯Overall mortality: higher risks in patients aged 10-17 years (HR 1.27, 95% CI 1.06 – 1.53, p=0.01), performance score <90 (HR 1.59, 95% CI 1.24 – 2.05, p<0.001), transplantation in relapse or primary induction failure compared to first (HR 2.20, 95% CI 1.70 – 2.84, p<0.001) and second (HR 1.94, 95% CI 1.53 – 2.45, p<0.001) complete remission and 1 HLA-locus mismatched transplants (HR 1.31, 95% CI 1.08 – 1.58, p=0.005) DISCUSSION
We studied outcomes after transplantation of bone marrow or peripheral blood from unrelated
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donors in a relatively large cohort of children and adolescents with acute leukemia transplanted in the United States between 2000 and 2012. Acute and chronic GVHD, transplant-related
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mortality and overall mortality were higher after transplantation of peripheral blood compared to bone marrow. The adverse effects of peripheral blood on transplant-related and overall mortality
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were seen beyond the early post-transplant period (i.e., beyond 6 months) suggesting higher
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mortality may be attributed to higher GVHD after peripheral blood transplants. To our knowledge this is the first report to show differences in mortality risks after unrelated donor bone
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marrow and peripheral blood transplants for acute leukemia. Survival rates in children and adolescents with acute leukemia are relatively higher than in adults and as such, significant differences were observed after bone marrow and peripheral blood transplantation. A similar trend has been reported after unrelated donor transplantation for chronic myeloid leukemia in first chronic phase in adults and in severe aplastic anemia. This leaves us to conclude that for diseases were survival is generally high after allogeneic transplantation than typically seen after 14
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transplantation for acute leukemia in adults, peripheral blood recipients experience higher mortality compared to bone marrow recipients.13-15 The causes of mortality are multifactorial and a detailed study of the causes of death is beyond the scope of data reported to a transplant registry. In contrast to other reports, we observed lower relapse after unrelated donor peripheral
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blood transplantation that negated the effect of higher mortality resulting in a lack of difference in leukemia-free survival between the two treatment groups. Yet when the composite endpoint GRFS was considered we observed higher GRFS after transplantation of bone marrow compared to peripheral blood, leaving us to conclude bone marrow may be the preferred graft for children
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and adolescents with acute leukemia undergoing unrelated donor transplantation. Infused cell dose was not associated with transplant outcomes.
Consistent with all other reports our analyses confirm faster hematopoietic recovery after
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transplantation of peripheral blood, but failed to demonstrate a difference in graft failure between the two treatment groups.1,2 The lack of a difference in graft failure is in contrast to that reported
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after adult unrelated donor transplantation.2 We also observed more events (graft failure) after transplantation of bone marrow but this did not reach the level of significance set for the study
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although graft failure rates were higher in the current report after both bone marrow and
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peripheral blood transplants compared to that reported in adults.2 While we don’t have a clear understanding of this we hypothesize that the higher graft failure observed in children and
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adolescents may in part be explained by differences in disease characteristics, transplant strategies or the data source (data reported to a Registry versus a prospective randomized trial). Although in vivo T cell depletion was associated with lower acute and chronic GVHD this was
not associated with other transplant outcomes. The lack of a difference in severity of chronic GVHD after peripheral blood compared to bone marrow transplantation is consistent with that
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reported after adult unrelated donor transplantation.2,13,14 A long-term study on health-related quality of life in survivors of the randomized trial confirmed better psychological wellbeing, less burdensome chronic GVHD after bone marrow transplantation, and that these persons are more likely to return to work compared to those who received peripheral blood transplantation. 3
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Others have also reported on the burden of morbidity and mortality associated with chronic GVHD in survivors of hematopoietic cell transplantation including children and adolescents.15,16 Although both acute and chronic GVHD have a significant impact on quality of life, the strongest negative impact on a person’s general health and mental health was seen with chronic
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GVHD.17 In that report individuals who were successfully treated for chronic GVHD reported their quality of life and overall health status not different from those without chronic GVHD. Our study is limited in that we do not have quality of life data. So we studied the duration of immune
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suppression as a surrogate marker for wellbeing after transplantation. Treatment duration for chronic GVHD after peripheral blood transplants was longer compared to bone marrow
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transplants. Forty-six percent of patients with chronic GVHD after peripheral blood transplants were on immune suppression at their last follow-up compared to 33% of bone marrow recipients
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(p=0.02). Others have shown the adverse effect of chronic GVHD on survival in children and
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adolescents with AML and ALL with sustained remission for at least 1 year after related or unrelated donor transplantation.18
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In summary, these data support bone marrow as the optimal graft when considering unrelated donor transplantation for acute leukemia is children and adolescents. Although we report an advantage in regards to relapse after transplantation of peripheral blood, higher transplant-related and overall mortality seen after transplantation of peripheral blood negated a survival advantage.
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AUTHOR CONTRIBUTION DAK, ASM, MJZ, and ME designed the study. ASM and DAK prepared the study file for analyses. ASM and MJZ analyzed the data. DAK, ASM, MJZ, and ME summarized and interpreted the findings. DAK drafted the manuscript. ASM, CB, AS, MJZ, and ME critically
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reviewed and edited the manuscript. All authors approved the final manuscript.
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11.
1972;34(2):187-220. 12.
Andersen PK, Klein JP, Zhang MJ. Testing for centre effects in multi-centre survival studies: a Monte Carlo comparison of fixed and random effects tests. Stat Med
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1999;18(12):1489-1500.
Eapen M, Logan BR, Confer DL, et al. Peripheral blood grafts from unrelated donors are associated with increased acute and chronic graft-versus-host disease without improved
14.
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survival. Biol Blood Marrow Transplant. 2007;13(12):1461-1468. Eapen M, Logan BR, Appelbaum FR, et al. Long-term survival after transplantation of
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unrelated donor peripheral blood or bone marrow hematopoietic cells for hematologic malignancy. Biol Blood Marrow Transplant. 2015;21(1):55-59. Eapen M, Le Rademacher J, Antin JH, et al. Effect of stem cell source on outcomes after
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unrelated donor transplantation in severe aplastic anemia. Blood. 2011;118(9):26182621.
Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graft-versus-host disease on the
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health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006;108(8):2867-2873.
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17.
Sun CL, Kersey JH, Francisco L, et al. Burden of morbidity in 10+ year survivors of hematopoietic cell transplantation: report from the bone marrow transplantation survivor study. Biol Blood Marrow Transplant. 2013;19(7):1073-1080.
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Bitan M, Ahn KW, Millard HR et al. Personlaized risk score for long-term survival for
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children with acute leukemia after allogeneic transplantation. Biol Blood Marrow
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Transplant. 2017;23(9): 1523-1530.
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FIGURE LEGEND Figure 1A. Acute graft-versus-host disease (GVHD): The 100-day incidence of grades 2-4 acute GVHD were 43% (39 - 47) and 56% (50 - 63) after bone marrow (BM) and peripheral blood (PBSC) transplants.
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Figure 1B. Chronic graft-versus-host disease (GVHD): The 8-year incidences of chronic GVHD were 38% (34 - 42) and 61% (54 - 67) after bone marrow (BM) and peripheral blood (PBSC) transplants
Figure 2. Overall Survival: The 8-year probabilities of overall survival were 47% (43 - 51) and
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42% (35 - 49) after bone marrow (BM) and peripheral blood (PBSC) transplants
Figure 3. Relapse: The 8-year incidences of relapse were 38% (35 - 42) and 30% (24 - 37) after bone marrow (BM) and peripheral blood (PBSC) transplants
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Figure 4. Transplant-related mortality: The 8-year incidences of transplant-related mortality were 22% (19 - 25) and 30% (24 - 36) after bone marrow (BM) and peripheral blood (PBSC)
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transplants
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Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia Daniel A. Keesler , Andrew St. Martin , Carmem Bonfim , Adriana Seber , Mei-Jie Zhang , Mary Eapen PII: DOI: Reference:
S1083-8791(18)30475-0 https://doi.org/10.1016/j.bbmt.2018.08.010 YBBMT 55232
To appear in:
Biology of Blood and Marrow Transplantation
Received date: Accepted date:
5 July 2018 6 August 2018
Please cite this article as: Daniel A. Keesler , Andrew St. Martin , Carmem Bonfim , Adriana Seber , Mei-Jie Zhang , Mary Eapen , Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia, Biology of Blood and Marrow Transplantation (2018), doi: https://doi.org/10.1016/j.bbmt.2018.08.010
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Bone Marrow versus Peripheral Blood from Unrelated Donors for Children and Adolescents with Acute Leukemia
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Short title: Bone marrow versus peripheral blood transplants
Daniel A. Keesler1, Andrew St. Martin1, Carmem Bonfim2, Adriana Seber3, Mei-Jie Zhang1,4 and Mary Eapen1 1
Center for International Blood and Marrow Transplant Research, Department of Medicine,
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Medical College of Wisconsin, Milwaukee, USA; 2Bone Marrow Transplantation Unit, Federal University of Paraná, Curitiba, Brazil; 3Hospital Samaritano, Sao Paulo, Brazil; 4Division of
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Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, USA
Address Correspondence: Mary Eapen MBBS, MS, Center for International Blood and Marrow
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Transplant Research, Department of Medicine, 8701 Watertown Plank Road, Medical College of Wisconsin, WI 53226, USA
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Email: [email protected]
Highlights
Higher overall mortality after peripheral blood compared to bone marrow transplant. Lower relapse after peripheral blood compared to bone marrow transplant. No survival advantage despite lower relapse after peripheral blood transplant.
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Abstract: 224 Text: 2770 Tables: 2 Figures: 4
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Reference: 18
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FINANCIAL DISCLOSURE STATEMENT Conflict of interest: The authors declare none Funding Source: The Center for International Blood and Marrow Transplant Research is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518
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from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-15-1-0848 and N00014-16-1-2020 from the
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Office of Naval Research. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S.
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Government.
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ABSTRACT As graft versus host disease (GVHD) rates are higher after unrelated donor transplantation, we examined whether there would be differences in transplant outcomes by graft type in children and adolescents with acute leukemia. The primary endpoint was overall survival. We studied
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872 patients aged less than 18 years transplanted with bone marrow (n = 650) or peripheral blood (n = 222) from unrelated donors. The characteristics of the two groups were comparable except recipients of bone marrow were younger compared to recipients of peripheral blood (median age 10 versus 12 years). Grade 2-4 (HR 1.48, p<0.001) and 3-4 acute (HR 1.69, p<0.001) and
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chronic GVHD (HR 1.92, p<0.001) were higher with transplantation of peripheral blood compared to bone marrow. Although relapse risks were lower after peripheral blood transplants (HR 0.76, p=0.05), transplant-related mortality (HR 1.91, p=0.003) and overall mortality (HR
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1.34, p=0.032) were higher compared to bone marrow transplants. The 8-year probability of overall survival after transplantation of bone marrow was 47% compared to 42% after peripheral
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blood. The 8-year probability of leukemia-free survival was 40% after transplantation of bone marrow and peripheral blood. Lower relapse after transplantation of peripheral blood negated
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the survival advantage after transplantation of bone marrow. The observed higher acute and
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chronic GVHD seen with peripheral blood suggest cautious use of this graft in children and
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adolescents with acute leukemia.
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INTRODUCTION Bone marrow is preferred over peripheral-blood for children and adolescents with acute leukemia undergoing human leukocyte antigen (HLA) matched sibling transplantation. 1 Compared to transplantation of bone marrow, higher chronic GVHD and transplant-related
survival.
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mortality after transplantation of peripheral blood resulted in lower leukemia-free and overall A multi-center trial (BMT CTN 0201 NCT#0075816) that randomized patients,
including children, to bone marrow or peripheral blood did not show survival differences between the treatment groups although chronic graft-versus-host disease (GVHD) rates were
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higher after transplantation of peripheral blood.2 A later report on trial participants that focused on the quality of life of a subset of adult survivors concluded that recipients of bone marrow reported better quality of life including mental health, occupational functionality, and chronic
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GVHD symptoms.3 Data reported to the Center for International Blood and Marrow Transplant Research suggest peripheral blood accounts for 20% of unrelated donor transplantations in
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children and adolescents with acute leukemia in the United States. Acute and chronic GVHD rates are generally higher after unrelated donor transplantation. The higher rates of chronic
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GVHD and lower survival after HLA-matched sibling donor transplantation for acute leukemia
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in children and adolescents1 may not be relevant in the setting of unrelated donor transplantation. In this study we examined whether transplant-outcomes would differ after transplantation of
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peripheral blood and bone marrow from unrelated donors in children and adolescents, as was the case after HLA-matched sibling transplantation. METHODS Patients
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The Center for International Blood and Marrow Transplant Registry is a voluntary group of over 400 transplant centers that report data prospectively on consecutive transplants. Of these, 122 transplant centers perform allogeneic hematopoietic cell transplants for acute leukemia in children and adolescents. Patients are followed longitudinally until death or until they are lost to
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follow-up. Included in the current analyses are patients, aged less than 18 years with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) who were transplanted in the U.S. between 2000 and 2012 and received a myeloablative transplant conditioning regimen (total body irradiation dose ≥1000 cGy, busulfan dose >8 mg/kg oral or >6.5 mg/kg IV or melphalan
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dose >140 mg/m2).4 Of the 872 eligible patients, 650 received bone marrow and 222, peripheral blood. Twenty-five centers transplanted only bone marrow grafts, 7 centers only peripheral blood, and 58 both bone marrow and peripheral blood. Donor-recipient pairs were HLA-matched
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at the allele-level for HLA-A, -B, -C, and –DRB1 (8/8) or mismatched at 1 HLA-locus (7/8). All patients received cyclosporine or tacrolimus-containing graft-versus-host disease (GVHD) Recipients of ex-vivo T-cell depleted bone marrow (n=96), CD34 selected
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prophylaxis.
peripheral blood grafts (n=11), or reduced intensity transplant conditioning regimens4 (n=50)
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were excluded. Parents provided written informed consent for research. The Institutional Review
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Board of the National Marrow Donor Program approved this study. Endpoints
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The primary endpoint was overall survival defined as death from any cause. Surviving patients were censored at last follow-up.
Neutrophil recovery was defined as achieving absolute
neutrophil count ≥0.5 x 109/L for 3 consecutive days and platelets ≥20 x 109/L, for 7 days unsupported by transfusion. Primary and secondary graft failure were considered as a single outcome. Primary graft failure was defined as failure to achieve an absolute neutrophil count of ≥
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0.5 × 109/L for 3 consecutive days or <5% donor chimerism. Secondary graft failure was defined as initial donor engraftment followed by graft loss, evidenced by a persistent decline in the absolute neutrophil count (<0.5 x 109/L), loss of donor chimerism (<5%), or second transplantation in patients with documented clinical remission.5 Grade II-IV acute GVHD and
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chronic GVHD were based on reports from each transplant center using standard criteria.6,7 Relapse was defined as morphologic, cytogenetic, or molecular recurrence of leukemia. Transplant-related mortality was defined as death in remission. Leukemia-free survival was defined as being alive in continuous remission; death or relaspe were considered events and
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surviving patients were censored at last follow up. GVHD-free, relapse free survival (GRFS) events included grade 3-4 acute GVHD, chronic GVHD requiring systemic therapy, relapse or progression or death from any cause within the first year after transplantation.8
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Statistical Methods
Differences between treatment groups were compared using the Chi-squared test for
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categorical variables. The probabilities of overall and leukemia-free survival were calculated using the Kaplan-Meier estimator.9 The cumulative incidences of graft failure, acute and chronic
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GVHD, transplant-related mortality and relapse were calculated using the cumulative incidence
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estimator to accommodate competing risks.10 Multivariate models were built to examine the effect of graft type on overall mortality and leukemia-free survival, acute and chronic GVHD,
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transplant-related mortality and relapse using Cox regression models to accommodate competing risks.11 The variable for graft type (bone marrow vs. peripheral blood) was held in all steps of model building regardless of level of significance. Other variables tested included age, cytomegalovirus serostatus, performance score, disease type, disease status at transplantation, conditioning regimen, in vivo T cell depletion, GVHD prophylaxis, cell dose, donor-recipient
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HLA match and, transplant period (Table 1). The assumptions for proportionality were violated for models on transplant-related and overall mortality and adjusted for by introducing the variable for graft type as time-dependent co-variate. There were no first order interactions between graft type and other variables held in the final multivariate model. Only variables that
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attained p-value ≤0.05 were held in the final multivariate model. The potential effect of transplant center was tested using the frailty model.12 All p-values are two-sided and analyses were done using SAS version 9.4 (Cary, NC). RESULTS
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Patient, Disease and Transplant Characteristics
Patient, disease, and transplant characteristics by graft type are shown in Table 1. Patient, disease, and transplant characteristics were similar by graft type except recipients of bone
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marrow were younger and were more likely to receive cyclosporine-containing GVHD prophylaxis. The median age of bone marrow recipients was 10 years compared to 12 years for
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peripheral blood recipients (p<0.001). The median weight (inter quartile range [IQR]) of bone marrow recipients was 34 (20 – 55) kilograms compared to 43 (25 – 59) kilograms for peripheral
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blood recipients (p=0.001). Thirty of 389 (3%) patients with AML had secondary AML and the Disease status at
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distribution of secondary AML did not differ by graft type (p=0.60).
transplantation also did not differ by graft type. Total body irradiation (TBI) containing regimen
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(TBI dose ≥1000 cGy) with cyclophosphamide was the predominant regimen and accounted for 74% of bone marrow and 70% of peripheral blood transplants. Busulfan with cyclophosphamide was the predominant non-TBI regimen although this accounted for only 17% of bone marrow and 12% of peripheral blood transplants. Cyclosporine with methotrexate was the predominant GVHD prophylaxis regimen for bone marrow recipients and tacrolimus with methotrexate was
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the predominant regimen for peripheral blood recipients. In vivo T cell depletion did not differ by graft type (40% of bone marrow and 38% of peripheral blood transplants). The median total nucleated cell dose for bone marrow recipients was 3.9 (IQR 2.6 – 5.7) x 108/kilogram body weight. The median CD34 dose for peripheral blood recipients was 7.0 (IQR 5.1 – 9.8) x
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106/kilogram body weight. There were no differences in the proportion of bone marrow and peripheral blood transplants over the time-period studied. The median follow-up of surviving patients was 8 years (range 3-197 months) and 8 years (6-170 months) after bone marrow and peripheral blood transplants, respectively.
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Hematopoietic recovery
Most patients achieved neutrophil and platelet recovery. The day-28 probability of neutrophil recovery was lower after bone marrow 90% (95% CI 88-93) compared to peripheral blood
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transplants 96% (95% CI 93-98), p=0.002. Similarly, platelet recovery was lower after bone marrow transplants (p<0.001). The day-100 probabilities of platelet recovery were 81% (95% CI
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77-84) and 84% (95% CI 79-89) after bone marrow and peripheral blood transplants, respectively. The 1-year cumulative incidence of graft failure did not differ by graft type. The 1-
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year cumulative incidence of graft failure after transplantation of bone marrow and peripheral
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blood were 11% (95% CI 9 - 13) and 6% (95% CI 3 - 10), respectively, p=0.07. Acute and Chronic GVHD
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Compared to transplantation of bone marrow, grade 2-4 acute GVHD was higher after transplantation of peripheral blood compared to bone marrow after adjusting for conditioning regimen, GVHD prophylaxis, in vivo T-cell depletion and donor-recipient HLA-mismatch (Table 2). The day-100 incidence of grade 2-4 acute GVHD after transplantation of bone marrow and peripheral blood were 28% (95% CI 25 - 31) and 43% (95% CI 37 - 50),
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respectively (p<0.001) (Figure 1A). Similarly, grade 3-4 acute GVHD was higher after transplantation of peripheral blood compared to bone marrow (HR 1.69 [95% CI 1.25 – 2.28], p<0.001). The day-100 incidence of grade 3-4 acute GVHD after transplantation of bone marrow and peripheral blood were 13% (95% CI 11 - 16) and 25% (95% CI 20 - 31), respectively (p<
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0.001).
Chronic GVHD risks were also higher after transplantation of peripheral blood after adjusting for age, in vivo T-cell depletion and donor-recipient HLA-mismatch (Table 2). The 5-year incidence of chronic GVHD was 38% (95% CI 34 - 42) and 61% (95% CI 54 - 67) after
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transplantation of bone marrow and peripheral blood, respectively (p<0.001) (Figure 1B). Despite differences in chronic GVHD risk by graft type, there were no differences in its severity by graft type (p=0.61). Among bone marrow recipients (n=245) with chronic GVHD, severity
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was graded as mild for 49%, moderate for 29% and severe for 22%. Corresponding severity rates for peripheral blood recipients (n=129) were 46%, 28% and 26%.
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Overall Survival and Leukemia-free Survival
Three hundred and forty-five of 650 patients died after transplantation of bone marrow and 127
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of 222 patients after transplantation of peripheral blood. Mortality risks were lower after
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transplantation of bone marrow compared to peripheral blood beyond 6 months after transplantation, but not the earlier period (Table 2; Figure 2). The 8-year probabilities of overall
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survival after transplantation of bone marrow and peripheral blood were 47% (95% CI 43 - 51) and 42% (95% CI 35 - 49) respectively, p=0.03. Independent of graft type, mortality risks were higher in patients aged 10-17 years, poor performance score, transplantation in relapse or primary induction failure and donor-recipient HLA-mismatch. Transplant outcomes did not differ by transplant center (p=0.87).
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Treatment failure (relapse or death, inverse of leukemia-free survival) did not differ by graft type (Table 2). Treatment failure was higher in patients aged 10-17 years, poor performance score and transplantation in relapse or primary induction failure. The 8-year probability of leukemia-free survival was 40% (95% CI 36 - 44) and 40% (95% CI 33 - 47) after
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transplantation of bone marrow and peripheral blood respectively, p=0.97.
Causes of death were similar after transplantation of bone marrow and peripheral blood. Recurrent disease was the predominant cause of death, accounting for 49% of deaths in bone marrow recipients and 43% of deaths in peripheral blood recipients. Other causes of death after
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transplants from bone marrow or peripheral blood include organ failure (14% vs. 15%), infection (8% vs. 16%), and GVHD (10% vs. 10%), respectively. Relapse and Transplant-related Mortality
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Relapse risks were higher after transplantation of bone marrow compared to peripheral blood (Table 2; Figure 3). The 8-year incidences of relapse were 38% (35 - 42) and 30% (24 - 37) after
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transplantation of bone marrow and peripheral blood (p=0.05). Relapse risks were higher for patients with AML and transplantation in relapse or primary induction failure. The 1-year
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probability of GRFS was higher after transplantation of bone marrow compared to peripheral
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blood; 28% (95% CI 25 – 32) and 19% (95% CI 14 – 24), p=0.003. Transplant-related mortality was lower after transplantation of bone marrow compared to peripheral blood beyond 6 months
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after transplantation but not the earlier period (Table 2; Figure 4). The 8-year incidences of transplant-related mortality were 22% (19 - 25) and 30% (24 - 36) after transplantation of bone marrow and peripheral blood, p=0.003. Risks were higher in patients aged 10-17 years, poor performance score, diagnosis of ALL and 1 HLA-locus mismatched transplants.
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Table 1. Patient, disease and transplant characteristics Peripheral blood 222 12 (1 – 17) 85 (38%) 137 (62%)
506 (78%) 72 (11%) 72 (11%)
168 (76%) 35 (16%) 19 ( 9%)
323 (50%) 324 (50%0 3 (<1)
99 (45%) 121 (55%) 2 (<1)
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Bone marrow 650 10 (1 – 17) 323 (50%) 327 (50%)
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Number Age, median (range), years < 10 years 10 – 17 years Performance score 90 – 100 < 90 Not reported Recipient cytomegalovirus serostatus Negative Positive Not reported Disease Acute myeloid leukemia Acute lymphoblastic leukemia Disease status First complete remission Second complete remission Relapse / primary induction failure Conditioning regimen TBI + cyclophosphamide TBI + other agents Busulfan + cyclophosphamide Busulfan + fludarabine Busulfan + other agents Graft-versus-host-disease prophylaxis Tacrolimus/cyclosporine + mycophenolate Tacrolimus/cyclosporine + methotrexate Tacrolimus/cyclosporine ± other Donor-recipient HLA match HLA-matched (allele-level) A, B, C, DRB1 1 HLA-locus mismatch Donor-recipient sex match Female donor / male recipient Other Transplant period 2000 – 2007 2008 – 2012 Median follow-up (range) surviving patients, months Abbreviation TBI = total body irradiation HLA = human leukocyte antigen
283 (44%) 367 (56%)
106 (48%) 116 (52%)
201 (31%) 346 (53%) 103 (16%)
86 (39%) 101 (45%) 35 (16%)
483 (74%) 31 ( 5%) 113 (17%) 18 ( 3%) 5 (<1%)
155 (70%) 21 ( 9%) 27 (12%) 12 ( 5%) 7 ( 3%)
59 ( 9%) 528 (81%) 63 (10%)
34 (15%) 164 (74%) 24 (11%)
434 (67%) 216 (33%)
149 (67%) 73 (33%)
144 (22%) 506 (78%)
43 (19%) 179 (81%)
490 (75%) 160 (25%) 98 (10 – 196)
171 (77%) 51 (23%) 96 (6 – 170)
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Table 2. Transplant outcomes by graft type Hazard Ratio (95% confidence interval)
P-value
Grade 2-4 acute graft-versus-host disease* Bone marrow Peripheral blood
1.00 1.48 (1.19 – 1.81)
Chronic graft-versus-host disease§ Bone marrow Peripheral blood
1.00 1.92 (1.55 – 2.39)
<0.001
1.00 0.73 (0.47 – 1.12)
0.15
Relapse** Bone marrow Peripheral blood
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Overall mortality♯♯ (≤ 6 months) Bone marrow Peripheral blood Overall mortality♯♯ (> 6 months) Bone marrow Peripheral blood
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Treatment failure§§ Bone marrow Peripheral blood
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Transplant-related mortality# (≤ 6 months) Bone marrow Peripheral blood Transplant-related mortality# (> 6 months) Bone marrow Peripheral blood
<0.001
1.00 1.91 (1.25 – 2.91)
0.003
1.00 0.76 (0.58 – 0.99)
0.05
1.00 0.94 (0.77 – 1.15)
0.56
1.00 0.77 (0.55 – 1.06)
0.11
1.00 1.34 (1.02 – 1.74)
0.032
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Other factors associated with transplant outcomes: *Grade 2-4 acute graft-versus-host disease: higher risks with TBI containing regimens (HR 1.43, 95% CI 1.09 – 1.88), p=0.010), calcineurin inhibitor with mycophenolate compared to calcineurin inhibitor with methotrexate (HR 1.54, 95% CI 1.14 – 2.08, p=0.006) and CNI alone (HR 3.70, 95% CI 2.22 – 6.25, p<0.001) GVHD prophylaxis, non-ATG regimens (HR 1.98, 95% CI 1.59 – 2.48, p<0.001) and 1 HLA-locus mismatched transplants (HR 1.42, 95% CI 1.16 – 1.74, p=0.001). §Chronic graft-versus-host disease: higher risks for patients aged 10-17 years (HR 1.25, 95% CI 1.02 – 1.54), p=0.036), with non-ATG regimens (HR 2.30, 95% CI 1.82 – 2.91, p<0.001) and transplantation of grafts from donors mismatched at 1 HLA-locus (HR 1.25, 95% CI 1.01 – 1.55, p=0.049).
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#Transplant-related mortality: risks were higher in patients aged 10-17 years (HR 2.09, 95% CI 1.55 – 2.83, p<0.001), performance score <90 (HR 1.79, 95% CI 1.25 – 2.56, p<0.001), diagnosis of ALL (HR 1.47, 95% CI 1.10 – 1.95, p=0.009) and 1 HLA-locus mismatched transplants (HR 1.71, 95% CI 1.30 – 2.24, p<0.001). **Relapse: risks were higher for patients with AML (HR 1.48, 95% CI 1.18 – 1860, p=0.007) and transplantation in relapse or primary induction failure compared to first (HR 2.67, 95% CI 1.99 – 3.58, p<0.001) and second (HR 3.04, 95% CI 2.03 – 4.03, p<0.001) complete remission. §§Treatment failure: higher in patients aged 10-17 years (HR 1.21, 95% CI 1.02 – 1.42, p=0.03), performance score <90 (HR 1.61, 95% CI 1.28 – 2.02, p<0.001) and transplantation in relapse or primary induction failure compared to transplantation in first (HR 2.26, 95% CI 1.78 – 2.86, p<0.001) or second (HR 2.12, 95% CI 1.71 – 2.63, p<0.001) complete remission. ♯♯Overall mortality: higher risks in patients aged 10-17 years (HR 1.27, 95% CI 1.06 – 1.53, p=0.01), performance score <90 (HR 1.59, 95% CI 1.24 – 2.05, p<0.001), transplantation in relapse or primary induction failure compared to first (HR 2.20, 95% CI 1.70 – 2.84, p<0.001) and second (HR 1.94, 95% CI 1.53 – 2.45, p<0.001) complete remission and 1 HLA-locus mismatched transplants (HR 1.31, 95% CI 1.08 – 1.58, p=0.005) DISCUSSION
We studied outcomes after transplantation of bone marrow or peripheral blood from unrelated
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donors in a relatively large cohort of children and adolescents with acute leukemia transplanted in the United States between 2000 and 2012. Acute and chronic GVHD, transplant-related
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mortality and overall mortality were higher after transplantation of peripheral blood compared to bone marrow. The adverse effects of peripheral blood on transplant-related and overall mortality
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were seen beyond the early post-transplant period (i.e., beyond 6 months) suggesting higher
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mortality may be attributed to higher GVHD after peripheral blood transplants. To our knowledge this is the first report to show differences in mortality risks after unrelated donor bone
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marrow and peripheral blood transplants for acute leukemia. Survival rates in children and adolescents with acute leukemia are relatively higher than in adults and as such, significant differences were observed after bone marrow and peripheral blood transplantation. A similar trend has been reported after unrelated donor transplantation for chronic myeloid leukemia in first chronic phase in adults and in severe aplastic anemia. This leaves us to conclude that for diseases were survival is generally high after allogeneic transplantation than typically seen after 14
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transplantation for acute leukemia in adults, peripheral blood recipients experience higher mortality compared to bone marrow recipients.13-15 The causes of mortality are multifactorial and a detailed study of the causes of death is beyond the scope of data reported to a transplant registry. In contrast to other reports, we observed lower relapse after unrelated donor peripheral
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blood transplantation that negated the effect of higher mortality resulting in a lack of difference in leukemia-free survival between the two treatment groups. Yet when the composite endpoint GRFS was considered we observed higher GRFS after transplantation of bone marrow compared to peripheral blood, leaving us to conclude bone marrow may be the preferred graft for children
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and adolescents with acute leukemia undergoing unrelated donor transplantation. Infused cell dose was not associated with transplant outcomes.
Consistent with all other reports our analyses confirm faster hematopoietic recovery after
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transplantation of peripheral blood, but failed to demonstrate a difference in graft failure between the two treatment groups.1,2 The lack of a difference in graft failure is in contrast to that reported
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after adult unrelated donor transplantation.2 We also observed more events (graft failure) after transplantation of bone marrow but this did not reach the level of significance set for the study
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although graft failure rates were higher in the current report after both bone marrow and
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peripheral blood transplants compared to that reported in adults.2 While we don’t have a clear understanding of this we hypothesize that the higher graft failure observed in children and
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adolescents may in part be explained by differences in disease characteristics, transplant strategies or the data source (data reported to a Registry versus a prospective randomized trial). Although in vivo T cell depletion was associated with lower acute and chronic GVHD this was
not associated with other transplant outcomes. The lack of a difference in severity of chronic GVHD after peripheral blood compared to bone marrow transplantation is consistent with that
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reported after adult unrelated donor transplantation.2,13,14 A long-term study on health-related quality of life in survivors of the randomized trial confirmed better psychological wellbeing, less burdensome chronic GVHD after bone marrow transplantation, and that these persons are more likely to return to work compared to those who received peripheral blood transplantation. 3
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Others have also reported on the burden of morbidity and mortality associated with chronic GVHD in survivors of hematopoietic cell transplantation including children and adolescents.15,16 Although both acute and chronic GVHD have a significant impact on quality of life, the strongest negative impact on a person’s general health and mental health was seen with chronic
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GVHD.17 In that report individuals who were successfully treated for chronic GVHD reported their quality of life and overall health status not different from those without chronic GVHD. Our study is limited in that we do not have quality of life data. So we studied the duration of immune
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suppression as a surrogate marker for wellbeing after transplantation. Treatment duration for chronic GVHD after peripheral blood transplants was longer compared to bone marrow
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transplants. Forty-six percent of patients with chronic GVHD after peripheral blood transplants were on immune suppression at their last follow-up compared to 33% of bone marrow recipients
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(p=0.02). Others have shown the adverse effect of chronic GVHD on survival in children and
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adolescents with AML and ALL with sustained remission for at least 1 year after related or unrelated donor transplantation.18
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In summary, these data support bone marrow as the optimal graft when considering unrelated donor transplantation for acute leukemia is children and adolescents. Although we report an advantage in regards to relapse after transplantation of peripheral blood, higher transplant-related and overall mortality seen after transplantation of peripheral blood negated a survival advantage.
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AUTHOR CONTRIBUTION DAK, ASM, MJZ, and ME designed the study. ASM and DAK prepared the study file for analyses. ASM and MJZ analyzed the data. DAK, ASM, MJZ, and ME summarized and interpreted the findings. DAK drafted the manuscript. ASM, CB, AS, MJZ, and ME critically
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reviewed and edited the manuscript. All authors approved the final manuscript.
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FIGURE LEGEND Figure 1A. Acute graft-versus-host disease (GVHD): The 100-day incidence of grades 2-4 acute GVHD were 43% (39 - 47) and 56% (50 - 63) after bone marrow (BM) and peripheral blood (PBSC) transplants.
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Figure 1B. Chronic graft-versus-host disease (GVHD): The 8-year incidences of chronic GVHD were 38% (34 - 42) and 61% (54 - 67) after bone marrow (BM) and peripheral blood (PBSC) transplants
Figure 2. Overall Survival: The 8-year probabilities of overall survival were 47% (43 - 51) and
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42% (35 - 49) after bone marrow (BM) and peripheral blood (PBSC) transplants
Figure 3. Relapse: The 8-year incidences of relapse were 38% (35 - 42) and 30% (24 - 37) after bone marrow (BM) and peripheral blood (PBSC) transplants
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Figure 4. Transplant-related mortality: The 8-year incidences of transplant-related mortality were 22% (19 - 25) and 30% (24 - 36) after bone marrow (BM) and peripheral blood (PBSC)
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transplants
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