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Bone Marrow Transplantation (2006) 38, 745–750& 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 Low mortality of children undergoing hematopoietic stemcell transplantation from 7 to 8/10 human leukocyte antigenallele-matched unrelated donors with the use of antithymocyte globulin P Sedla´cˇek1, R Forma´nkova´1, P Keslova´1, L Sˇra´mkova´1, P Huba´cˇek1, L Kro´l1, M Kulich2 and J Stary´1 1Department of Pediatric Hematology and Oncology, University Hospital Motol, Charles University Prague, Prague, Czech Republicand 2Department of Probability and Mathematical Statistics, Faculty of Mathematics and Physics, Charles University Prague,Prague, Czech Republic Human leukocyte antigen (HLA)-matched sibling donor HSCT have a human leukocyte antigen (HLA) matched hematopoietic stem cell transplantation (HSCT) is sibling donor (MSD) available. For the remaining 85%, available for only approximately 30% patients needing unrelated donors (UDs) are searched for. For patients with HSCT. Use of alternative donors is associated with a rare HLA haplotypes, it is difficult to identify fully matched high incidence and severity of graft-versus-host disease UD. Mismatched UD transplantation is associated with a (GVHD). Here we report our experience with GVHD high risk of graft-versus-host disease (GVHD) and prophylaxis using pre-transplant rabbit antithymocyte transplant-related mortality. Cord blood or a haploiden- globulin (rATG), in addition to post transplant cyclos- tical related donor graft can also be used, but this is porin A and methotrexate. Seventy-five children received associated with an increased risk of post transplant unmanipulated grafts from 7 to 10/10 HLA allele- morbidity/mortality due to increased risk of GVHD, graft matched unrelated donors. Median follow-up was 25 failure or infections.1,2 Here we report our experience with months (range, 6–65 months). Only 2/75 patients (2.5%) GVHD prophylaxis using pre-transplant rabbit antithymo- developed acute GVHD grades III–IV, and 17/75 (25%) cyte globulin (rATG) added to standard post transplant developed extensive chronic GVHD. Overall survival was cyclosporin A (CsA) and methotrexate (MTX) in children.3,4 79%. It was similar in patients receiving grafts from 7 or8/10 to 9 or 10/10 allele-matched donors, and similar inpatients receiving peripheral blood stem cells and marrow.
Six (11%) patients died owing to relapse, and 10 (13%)due to transplant-related complications. The addition of rATG appears to result in a low incidence of severe Between January2001 and December 2005, 88 children underwent allogeneic HSCT at our center using an UD.
Bone Marrow Transplantation (2006) 38, 745–750.
Rabbit ATG (Fresenius, dose and schedule below) for doi:10.1038/sj.bmt.1705524; published online 16 October 2006 GVHD prophylaxis was used in 75 children (48 boys and 27 girls). Thymoglobuline once and Campath twice were used in three other patients, T-cell depletion in twoincluding one with rATG and no serotherapyin fourpatients with advanced leukemia. Furthermore, patientsreceiving cord blood units were excluded from this cohorteven though same rATG was used in them. These 75 patients (median age at transplant 12.8 years, range0.3–20.5 years) received HSCT for malignant (n ¼ 54) or Allogeneic hematopoietic stem cell transplantation (HSCT) non-malignant disease (n ¼ 21) (Table 1). The grafts were is a potentiallycurative treatment for certain malignant obtained from HLA allele matched or partiallymismatched and non-malignant diseases. Unfortunately, in the Czech UDs (age 21–57 years, median 32 years). HLA typing was Republic, onlyapproximately15% of the children needing performed at the high-resolution level (four digits) in A, B,Cw, DRB1 and DQB1 alleles. Most (72%) pairs werematched in 9 or 10/10, 17% in 8/10 and 11% in 7/10 alleles.
Correspondence: Dr P Sedla´cˇek, Department of Pediatric Hematology Onlyone allele mismatch was accepted in A, B or DRB1 and Oncology, UniversityHospital Motol, Charles UniversityPrague, loci. Donors and patients were sex mismatched in 42 cases, V Uvalu 84, Prague 15006, Czech Republic.
with a female donor for a male recipient in 20 cases.
Cytomegalovirus (CMV) immunoglobulin (Ig) G was Received 30 May2006; revised 15 September 2006; accepted 18September 2006; published online 16 October 2006 detected pre-transplant in 28 (37%) donors and 44 (59%) Prophylaxis with ATG, HLA-mismatched donor, children Characteristics of primarygrafts and engraftment Abbreviations: ABiL ¼ acute biphenotypic leukemia; ALL ¼ acute lympho- FHL ¼ familial hemophagocytic lymphohistiocytosis; AA ¼ Fanconi anemia – aplastic anemia; IMF ¼ idiopathic myelofibrosis; mal.IM ¼ malignant infectious mononucleosis; MDS ¼ myelodysplastic syndrome; MPS ¼ mucopolysaccharidosis; NHL ¼ non-Hodgkin’s lym- binuria; s ¼ secondary; SAA ¼ severe aplastic anemia; SCID ¼ severe Abbreviations: aGVHD ¼ acute graft-versus-host disease; ANC ¼ absolute recipients. The interval between the start of the UD search neutrophil count; BM ¼ bone marrow; bw ¼ bodyweight; cGVHD ¼ and the dayof HSCT ranged from 49 to 944 days, median chronic graft-versus-host disease; EFS ¼ event-free survival; HLA ¼ human leukocyte antigen; PBSC ¼ peripheral blood stem cell.
The studywas approved bythe local Ethics Committee and all parents signed informed consents.
Characteristics of conditioning regimens used before first Filgrastim-mobilized peripheral blood stem cells (PBSCs)were used for 35 patients and bone marrow (BM) for 40 patients. The decision about the type of graft was made by the donor and/or local harvest center, and was based in part on transplant center preference. Characteristics ofgrafts are shown in Table 2. No graft manipulation other than plasma or erythrocyte depletion was carried out.
Primaryconditioning regimens varied according to primary disease (see Table 3). Rabbit ATG (Fresenius) was infused to all 75 patients over 1 h5 on days À4 to À1. The dailydosewas 10 or 15 mg/kg (total 40 mg/kg in 70 patients; range (1–3 mg/kg), antihistamines and antipyretics was used as pre-medication before each infusion. CsA (used in 74/75 patients) was given two to three times dailyin a 2-hinfusion, initially1.5 mg/kg/dose in malignant and 2.5 mg/ kg/dose in non-malignant disease. The prophylactic dose of CsA was adjusted to maintain targeted blood levels, lower (80–150 ng/ml) for malignant and higher (200–250 ng/ml)for non-malignant diseases. MTX was given to 68/74 Abbreviations: ATG ¼ antithymocyte globulin; BU ¼ busulfan; Flu ¼ evaluable patients on days þ 1, þ 3 and þ 6. The first dose fludarabine; HSCT ¼ hematopoietic stem cell transplantation; TBI ¼ totalbodyirradiation.
was 10 or 15 mg/m2, and other doses were 10 mg/m2.
Leucovorine (15 mg/m2) was given as a single dose 24 hafter each MTX dose. In one patient, CsA was substitutedbymycophenolate mofetil (MMF) for elevated creatinine one with MMF, and no substitution in one patient.
during conditioning regimen, and in six patients MTX was Acute and chronic GVHD were primarilytreated with not used; it was substituted in four patients with steroids, in prednisone, CsA, tacrolimus, sirolimus or MMF.6–8 Acute Bone Marrow Transplantation
Prophylaxis with ATG, HLA-mismatched donor, childrenP Sedla´cˇek et al and chronic GVHD were diagnosed and graded using patients developed graft failure; their donors were 8/10 (B, Cw), 8/10 (B, Cw) and 9/10 (A) allele-matched. Detailedcharacteristics of grafts and engraftment are shown in Chimerism analyses and minimal residual disease monitoringChimerism was assessed byusing poly reaction (PCR)-based analyses of polymorphic variable Grade II–IV acute GVHD developed in 48 (65%) of 74 number tandem repeats using peripheral blood leukocytes evaluable patients. The median dayof onset was day30 starting on day þ 14 and then once a week till day þ 100, (range, 8–85). As shown in Table 4, grade III–IV acute with decreased frequencythereafter, especiallyin patients GVHD was observed in two (3%) patients only. Overall with stable full donor chimerism.11 PCR assayof specific incidence of chronic GVHD in 69 evaluable patients was fusion genes and IgH/T-cell receptor (TCR) receptors 32%, 7% experienced limited and 25% extensive disease.
according to the type of leukemia was used for minimal There was no significant difference in the incidence or residual disease (MRD) monitoring pre- and post-HSCT.
severityof acute GVHD (grades II–IV) or extensive chronic This was performed according to the criteria of the GVHD between patients receiving PBSC compared to BM European studygroup on detection of MRD in acute recipients (Table 2). Even though there was no difference in lymphoblastic leukemia (ESG-MRD-ALL).12,13 A marrow the incidence of grade III–IV acute GVHD and limited sample was obtained routinelyfrom patients with hemato- chronic GVHD, both acute GVHD of grades II–IV and logical malignancybefore HSCT, and at 28, 60 and 100 extensive chronic GVHD were higher (76 vs 59% for acute, days and 6 and 12 months after transplantation. A 29 vs 20% for chronic) in patients undergoing grafting complete hematological remission was defined as less than from 7 to 8/10 compared to those grafting from 9 to 10/10 allele-matched donors. However, this did not adverselyaffect the overall outcome.
Monitoring of viral infectionsEpstein–Barr virus (EBV) and CMV reactivation was monitored weeklybyquantitative PCR using whole blood.
EBV reactivation (DNAemia above 1000 copies in Results were normalized to 100 000 human genomic 100 000 g.e.) was detected in 26 (29.4%) patients, and equivalents (g.e.) assessed byquantification of albumin EBV lymphoproliferation/lymphoma developed in four gene. When samples obtained less than 1000 g.e., frequent (5%) patients. CMV reactivation (DNAemia above 1000 monitoring was indicated, but pre-emptive therapywas not copies in 100 000 g.e.) was detected in 25 (28.4%) patients.
CMV disease developed in six (7%) patients. Other viraldiseases included BK virus (BKV) cystitis in eight patients (11%) and adenovirus pneumonitis in one patient (1%).
The two-sample Welch t-test for unequal variances was The viral diseases were not fatal, except for one case of used to compare the means of continuous variables for two groups. The Fisher’s exact test was used to examine thestatistical significance of a relationship within a 2-by-2 table of categorized factors. The log-rank test was used to Hematological relapse occurred in 12 of 54 (22%) patients compare distributions of censored failure times between following HSCT for malignant disease (see Table 5) at 153– groups. P-values less than 0.05 were considered to indicate 842 days after transplant (median 314 days). Six patients Incidence and severityof acute and chronic GVHD The median dayof neutrophil engraftment (X0.5 Â 109/lfor 3 consecutive days) was 16 for PBSC and 20 for BM recipients (Po0.0001). The median dayof platelet engraft- ment (X20 Â 109/l for 7 consecutive days without platelet transfusion) was 23 for PBSC and 27 for BM recipients(P ¼ 0.01) as shown in Table 2. Complete donor chimerism was observed in 67 (92%) out of 73 evaluable patients, and was documented after a median of 21 days (range 14–180 days) with no difference between PBSC and BM recipients.
There was no difference in the dayof neutrophil or platelet engraftment between patient undergoing grafting from 7 to 8/10 and 9 to 10/10 allele-matched donors (median neutrophil engraftment 18 days in both groups, medianplatelet engraftment 24 and 23 days, respectively). Three Abbreviation: GVHD ¼ graft-versus-host disease.
Bone Marrow Transplantation
Prophylaxis with ATG, HLA-mismatched donor, children Outcome of patients with ALL according to leukemia status before HSCT (22 patients, 23 HSCT) ALL ¼ acute lymphoblastic leukemia; CR ¼ complete remission; HSCT ¼hematopoietic stem cell transplantation; MRD ¼ minimal residual disease TRM ¼ transplant-related mortality.
Overall survival (OS) in patients following HSCT using PBSC subsequentlydied, retransplantation was performed inthree patients (all surviving without leukemia), two patientsare currentlyscheduled for retransplantation and one at the time of analysis lives in untreated extramedullary relapse.
There is clear trend that even in our group of patients withALL, the incidence of relapse was dependent on the level of pre-transplant MRD (see Table 5).12,14 Donor lymphocyteinfusion (DLI) directed according to the level of post transplant MRD (IgH/TCR 41 Â 10À4) or increasingmixed chimerism was given to 10 patients with malignancy.
Initial dose of CD3 þ cells was 1 Â 106/kg. In nine of them, there was no or onlytransient response. In none of those patients, DLI was used at the time of frank leukemia SurvivalOverall survival was not statisticallydifferent (P ¼ 0.49) between patients transplanted using PBSC (82.9%) and BM (75.0%) (Figure 1). Overall survival was also not Overall survival (OS) in patients following HSCT from HLA- statisticallydifferent (P ¼ 0.76) between patients receiving matched (9–10/10; n ¼ 54) or -mismatched UD (7–8/10; n ¼ 21).
grafts from donors HLA matched in 9–10/10 alleles(77.8%) and 7–8/10 alleles (80.9%) as shown in Figure 2.
There was no significant difference (P ¼ 0.66) in overall survival and event-free survival (P ¼ 0.65) between patients undergoing HSCT for malignant and non-malignant Sixteen patients died, 6/54 (11%) due to relapse and 10/75 (13%) due to transplant-related complications (7% before day100). Six patients received a second graft fromthe same donor (median 155 days post transplant, range 22–502 days), three for graft failure/rejection and three for relapse. Four of the six patients are alive and well with median follow-up of 26 months (range, 16–49 months)following the second HSCT and two died with GVHD.
Overall survival (OS) in patients with malignant disease (n ¼ 54) The first important finding of this studyis the similar and non-malignant disease (n ¼ 21).
outcome of transplantation using 7–8/10 and 9–10/10allele-matched donors. This is contraryto previous studies undisclosed HLA disparities account for the increased in which HLA typing was not performed at the high- rate of post transplant complications. With more than resolution level (four digits) in all typed loci. Serologically 1300 alleles (A, B, Cw, DRB1) currentlyidentified, Bone Marrow Transplantation
Prophylaxis with ATG, HLA-mismatched donor, childrenP Sedla´cˇek et al ATG (persisting beyond day 0) could kill anti-viral T cells contained in the graft. However, the incidence of viralcomplications in our cohort was not unusuallyhigh.
Incidence of CMV disease or EBV-LPD in our cohort was not higher compared to published data.19–22 Relapse is another significant problem of transplant recipients, which could be theoreticallyworsened bythe useof ATG (through the killing of T cells mediating graft-versus-leukemia effect). However, the incidence of relapse in our cohort was not high. Moreover, the level of MRD before HSCT has been shown to be crucial for outcome.
This fullycorrelates with published data where level of MRD proved to be the onlysignificant risk factor in multivariate analysis and independent on the use of If our results are confirmed in prospective randomized studies, the use of ATG will possiblywiden the choice of EFS in patients with malignant disease (n ¼ 54) and non- donors and grafts for children needing HSCT.
high-resolution molecular typing techniques have to beapplied to distinguish the extensive degree of allelic We thank our collaborators from CPH (Czech Pediatric polymorphism of the HLA system. Whereas an HLA- HematologyWorking Group) for referring patients, national ABDR serologicallyidentical donor can be identified in the registries of donors in Pilsen and Prague, HLA laboratories International Registryfor 490% of the patients, onlyup namelyin Institute of Hematologyand Blood Transfusion and to half of them can have a highlycompatible donor if CLIP (Childhood Leukemia Investigation Prague) in Prague.
donor selection is based on allele level matching for HLA- We thank Jan Storek for editorial help. This work was partly A/B/Cw/DRB1/B3/B5/DQB1 loci among the Caucasian population. Our results suggest that a higher percent ofpediatric patients could have an UD available, as even a7/10 allele-matched donor (with limitation of maximum one allele mismatch in A, B or DRB1 loci) appears acceptablewhen ATG is used.
1 Klingebiel T, Handgretinger R, Lang P, Bader P, Niethammer The second important finding of this studyis the similar D. Haploidentical transplantation for acute lymphoblasticleukemia in childhood. Blood Rev 2004; 18: 181–192.
outcome of PBSC vs BM transplantation. After years of 2 Lang P, Greil J, Bader P, Handgretinger R, Klingebiel T, using PBSC for allogeneic HSCT, there is still ongoing Schumm M et al. Long-term outcome after haploidentical stem discussion on whether PBSC or BM is the superior graft cell transplantation in children. Blood Cells Mol Dis 2004; 33: source. Perhaps, the reason for ongoing discussion is that studies comparing PBSC vs BM enrolled various patient 3 Duggan P, Booth K, ChaudhryA, Stewart D, Ruether JD, populations in terms of primarydisease, GVHD prophy- Gluck S et al. Unrelated donor BMT recipients given laxis, donor type and level of HLA matching, etc.15,16 These pretransplant low-dose antithymocyte globulin have outcomes studies mostlyconfirm faster engraftment and higher equivalent to matched sibling BMT: a matched pair analysis.
incidence of chronic GVHD in recipients of PBSC from Bone Marrow Transplant 2002; 30: 681–686.
MSD. There are no published randomized studies compar- 4 Finke J, Schmoor C, Lang H, Potthoff K, Bertz H. Matched and mismatched allogeneic stem-cell transplantation from ing PBSC and BM in the UD settings. Two retrospective unrelated donors using combined graft-versus-host disease studies found significantlyhigher risk of chronic GVHD prophylaxis including rabbit anti-T lymphocyte globulin.
after PBSC transplantation and no survival advantage of PBSC transplantation over BM transplantation.17,18 5 Seidel MG, Fritsch G, Matthes-Martin S, Lawitschka A, Lion Compared to our cohort, onlyone-third of patients in T, Potschger U et al. Antithymocyte globulin pharmaco- the published retrospective studies received ATG or OKT3 kinetics in pediatric patients after hematopoietic stem cell pre-transplant. In our cohort (uniformlytreated with ATG), transplantation. J Pediatr Hematol Oncol 2005; 27: 532–536.
we have observed similar incidence of extensive chronic 6 Carpenter PA, Sanders JE. Steroid-refractorygraft-vs host GVHD and similar survival in PBSC and BM recipients.
disease: past, present and future. Pediatr Transplant 2003; 7 Thus, the use of ATG appears to eliminate the difference in 7 Simpson D. New developments in the prophylaxis and the incidence of chronic GVHD. This maybe important, as treatment of graft versus host disease. Expert Opin Pharmaco- chronic GVHD is the major determinant of the qualityof 8 Vogelsang GB, Arai S. Mycophenolate mofetil for the Viral diseases remain a significant problem after prevention and treatment of graft-versus-host disease follow- unrelated HSCT.18 Theoreticallythe use of ATG might ing stem cell transplantation: preliminaryfindings. Bone be associated with an increased incidence of viral disease, as Marrow Transplant 2001; 27: 1255–1262.
Bone Marrow Transplantation
Prophylaxis with ATG, HLA-mismatched donor, children 9 Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty 16 Ringden O, Labopin M, Bacigalupo A, Arcese W, Schaefer P, Hows J et al. 1994 Consensus Conference on Acute GVHD UW, Willemze R et al. Transplantation of peripheral blood Grading. Bone Marrow Transplant 1995; 15: 825–828.
stem cells as compared with bone marrow from HLA-identical 10 Shulman HM, Sullivan KM, Weiden PL, McDonald GB, siblings in adult patients with acute myeloid leukemia Striker GE, Sale GE et al. Chronic graft-versus-host syndrome and acute lymphoblastic leukemia. J Clin Oncol 2002; 20: in man. A long-term clinicopathologic studyof 20 Seattle patients. Am J Med 1980; 69: 204–217.
17 Forinder U, Lof C, Winiarski J. Qualityof life and health in 11 Bader P, Beck J, FreyA, Schlegel PG, Hebarth H, children following allogeneic SCT. Bone Marrow Transplant Handgretinger R et al. Serial and quantitative analysis of mixed hematopoietic chimerism byPCR in patients with acute 18 Patel SR, Ridwan RU, Ortin M. Cytomegalovirus reactivation leukemias allows the prediction of relapse after allogeneic in pediatric hemopoietic progenitors transplant: a retrospective BMT. Bone Marrow Transplant 1998; 21: 487–495.
studyon the risk factors and the efficacyof treatment.
12 Krejci O, van der Velden VH, Bader P, Kreyenberg H, J Pediatr Hematol Oncol 2005; 27: 411–415.
Goulden N, Hancock J et al. Level of minimal residual disease 19 Morfin F, Boucher A, Najioullah F, Bertrand Y, Bleyzac N, prior to haematopoietic stem cell transplantation predicts Poitevin-Later F et al. Cytomegalovirus and adenovirus prognosis in paediatric patients with acute lymphoblastic infections and diseases among 75 paediatric unrelated allo- leukaemia: a report of the Pre-BMT MRD StudyGroup.
geneic bone marrow transplant recipients. J Med Virol 2004; Bone Marrow Transplant 2003; 32: 849–851.
13 Eckert C, Scrideli CA, Taube T, Songia S, Wellmann S, 20 Qamruddin AO, Oppenheim BA, Guiver M, Mutton KJ, Manenti M et al. Comparison between TaqMan and Light- Chopra R. Screening for cytomegalovirus (CMV) infection in Cycler technologies for quantification of minimal residual allogeneic bone marrow transplantation using a quantitative disease byusing immunoglobulin and T-cell receptor genes whole blood polymerase chain reaction (PCR) method: consensus probes. Leukemia 2003; 17: 2517–2524.
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Formankova R et al. Detectable minimal residual disease 21 Faye A, Quartier P, Reguerre Y, Lutz P, Carret AS, Dehee A before allogeneic hematopoietic stem cell transplantation et al. Chimaeric anti-CD20 monoclonal antibody(rituximab) predicts extremelypoor prognosis in children with acute in post-transplant B-lymphoproliferative disorder following lymphoblastic leukemia. Pediatr Blood Cancer 2006 (in press).
stem cell transplantation in children. Br J Haematol 2001; 115: 15 Champlin RE, Schmitz N, Horowitz MM, Chapuis B, Chopra R, Cornelissen JJ et al. Blood stem cells compared with bone 22 van Esser JW, van der Holt B, Meijer E, Niesters HG, marrow as a source of hematopoietic cells for allogeneic Trenschel R, Thijsen SF et al. Epstein–Barr virus (EBV) transplantation. IBMTR Histocompatibilityand Stem Cell reactivation is a frequent event after allogeneic stem cell Sources Working Committee and the European Group for transplantation (SCT) and quantitativelypredicts EBV-lympho- Blood and Marrow Transplantation (EBMT). Blood 2000; 95: proliferative disease following T-cell-depleted SCT. Blood Bone Marrow Transplantation

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Polo de medina, jacinto, academia de jardin

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