FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2087163735> ?p ?o ?g. }

• W2087163735 endingPage "1926" @default.
• W2087163735 startingPage "1921" @default.
• W2087163735 abstract "Hematopoietic stem cell transplantation (SCT) is routinely offered to suitable candidates with high-risk or advanced acute lymphoblastic leukemia (ALL). In this report, we update our experience with SCT in patients with ALL with a novel conditioning regimen. A total of 44 patients with high-risk or advanced (greater than first complete remission) ALL in remission underwent SCT after myeloablative conditioning with fludarabine + busulfan + total body irradiation. The median follow-up of surviving patients was 4.3 years (range, 1.0-9.0 years). The cohort consists of 32 patients with high-risk disease (median age, 40 years; range, 19-64 years) and 12 patients with advanced disease (median age, 25 years; range, 19-65 years) who underwent SCT: 25 with a related donor (21 fully matched) and 19 with an unrelated donor (16 fully matched). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 53.2%, and that of grade III-IV acute GVHD was 20.6%. The incidence of chronic GVHD was 55%. The 100-day nonrelapse mortality was 13.6%. Five-year progression-free survival was 56.7%, and 5-year overall survival was 66.0%. Nine patients (20%) died in remission, 6 (14%) died after relapse, and 2 survived after a second SCT for relapsed disease. Outcomes were inferior in older patients with comorbidities compared with other patients. Hematopoietic stem cell transplantation (SCT) is routinely offered to suitable candidates with high-risk or advanced acute lymphoblastic leukemia (ALL). In this report, we update our experience with SCT in patients with ALL with a novel conditioning regimen. A total of 44 patients with high-risk or advanced (greater than first complete remission) ALL in remission underwent SCT after myeloablative conditioning with fludarabine + busulfan + total body irradiation. The median follow-up of surviving patients was 4.3 years (range, 1.0-9.0 years). The cohort consists of 32 patients with high-risk disease (median age, 40 years; range, 19-64 years) and 12 patients with advanced disease (median age, 25 years; range, 19-65 years) who underwent SCT: 25 with a related donor (21 fully matched) and 19 with an unrelated donor (16 fully matched). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 53.2%, and that of grade III-IV acute GVHD was 20.6%. The incidence of chronic GVHD was 55%. The 100-day nonrelapse mortality was 13.6%. Five-year progression-free survival was 56.7%, and 5-year overall survival was 66.0%. Nine patients (20%) died in remission, 6 (14%) died after relapse, and 2 survived after a second SCT for relapsed disease. Outcomes were inferior in older patients with comorbidities compared with other patients. Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy that affects both children and adults. Although improvements in therapy have led to dramatic increases in survival rates in children, the majority of adults with ALL are not cured. Several factors present at diagnosis of ALL have been correlated with the outcome of chemotherapy without stem cell transplantation (SCT) and are used clinically to distinguish high-risk disease from standard-risk disease at the time of diagnosis. These factors include older age [1Pullarkat V. Slovak M.L. Kopecky K.J. et al.Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study.Blood. 2008; 111: 2563-2572Crossref PubMed Scopus (170) Google Scholar, 2Chessells J.M. Hall E. Prentice H.G. et al.The impact of age on outcome in lymphoblastic leukaemia: MRC UKALL X and XA compared. A report from the MRC Paediatric and Adult Working Parties.Leukemia. 1998; 12: 463-473Crossref PubMed Scopus (136) Google Scholar] and the presence and type of clonal cytogenetic abnormalities [3Moorman A.V. Harrison C.J. Buck G.A.N. et al.Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.Blood. 2007; 109: 3189-3197Crossref PubMed Scopus (564) Google Scholar]. A high WBC count at diagnosis also has been identified as an independent poor prognostic marker in ALL [4Rowe J.M. Buck G. Burnett A.K. et al.Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993.Blood. 2005; 106: 3760-3767Crossref PubMed Scopus (511) Google Scholar]. Patients with relapsed ALL may be offered allogeneic SCT provided that a suitable HLA-matched donor is available and they meet basic eligibility requirements for transplantation. Although SCT may be routinely offered to patients with high-risk or relapsed ALL, the optimal pretransplantation conditioning regimen has not yet been defined. Favorable results and equivalent survival rates have been reported with myeloablative [5Cornelissen J.J. van der Holt B. Verhoef G.E.G. et al.Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison.Blood. 2009; 113: 1375-1382Crossref PubMed Scopus (129) Google Scholar] and reduced-intensity [6Cho B.S. Lee S. Kim Y.J. et al.Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study.Leukemia. 2009; 23: 1763-1770Crossref PubMed Scopus (49) Google Scholar, 7Bachanova V. Verneris M.R. DeFor T. et al.Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation.Blood. 2009; 113: 2902-2905Crossref PubMed Scopus (85) Google Scholar] conditioning regimens. A recent large, international study reported a 5-year overall survival (OS) of 41% after induction and allogeneic SCT in patients with Philadelphia chromosome–negative high-risk ALL [8Goldstone A.H. Richards S.M. Lazarus H.M. et al.In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).Blood. 2008; 111: 1827-1833Crossref PubMed Scopus (580) Google Scholar]. Five-year OS for those with Philadelphia chromosome–positive ALL undergoing SCT in complete remission (CR) are 44% for recipients of matched sibling donor grafts and 35% for recipients of matched unrelated donor grafts [9Fielding A.K. Rowe J.M. Richards S.M. et al.Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993.Blood. 2009; 113: 4489-4496Crossref PubMed Scopus (224) Google Scholar]. In this report, we describe our experience with the use of a myeloablative regimen consisting of fludarabine, busulfan, and low-dose total body irradiation (TBI) previously shown to have low treatment-related mortality (TRM) in adults with acute leukemia (primarily acute myelogenous leukemia [AML]) [10Russell J.A. Savoie M.L. Balogh A. et al.Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 cGy total-body irradiation, and thymoglobulin.Biol Blood Marrow Transplant. 2007; 13: 814-821Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar] in a series of patients with high-risk or relapsed ALL. Between May 2000 and June 2008, a total of 44 patients age >18 years underwent SCT for ALL (Foothills Medical Center, Calgary, Alberta, Canada) while in first CR (CR1) with high-risk features (n = 32) or in second CR (CR2) (n = 12). Patients were eligible for SCT if a suitable related (n = 25) or unrelated (n = 19) donor was identified (matched in 8 of 10 HLA alleles), or if a suitable cord blood (CB) unit (n = 1) was available. Patients considered for SCT broadly had adequate performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) and organ function (left ventricular ejection fraction >40%, creatinine clearance >40% of normal, forced expiratory volume in 1 second >50% of predicted, no uncontrolled infections, no evidence of cirrhosis or advanced hepatic fibrosis) to undergo the procedure. Patients age >65 years were not considered for SCT. Pretransplantation conditioning consisted of fludarabine + busulfan + TBI in all cases. Intravenous busulfan dosing was guided by pharmacokinetics in 29 patients. In these patients, the dose was determined based on the results of a test dose (0.8 mg/kg) given on day −7 before SCT, with subsequent doses adjusted to target a busulfan exposure of 5000 μM·min if the predicted exposure was >6000 μM·min. Given the high rate of TRM observed at busulfan exposures >6000 μM·min, the busulfan doses were never increased [10Russell J.A. Savoie M.L. Balogh A. et al.Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 cGy total-body irradiation, and thymoglobulin.Biol Blood Marrow Transplant. 2007; 13: 814-821Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. Busulfan levels were measured by HPLC as described previously [12Heggie J.R. Wu M. Burns R.B. et al.Validation of a high-performance liquid chromatographic assay method for pharmacokinetic evaluation of busulfan.J Chromatogr B Biomed Sci Appl. 1997; 692: 437-444Crossref PubMed Scopus (32) Google Scholar]. Fludarabine 50 mg/m2/day i.v. was administered on days −6 to −2, and busulfan 3.2 mg/kg/day i.v. was administered on days −5 to −2. TBI comprised 400 cGy administered in 2 fractions on day −1 or 0 (before stem cell infusion), depending on Department of Radiation Oncology scheduling. All patients received prophylaxis for graft-versus-host disease (GVHD) in the form of antithymocyte globulin (ATG; Thymoglobulin; Genzyme, Cambridge, MA) 4.5 mg/kg administered in 3 divided doses on days −2, −1, and 0. Pharmacologic prophylaxis consisted of cyclosporine and short-course methotrexate, followed by leukovorin rescue [13Russell J.A. Woodman R. Poon M. et al.Addition of low-dose folinic acid to a methotrexate/cyclosporin A regimen for prevention of acute graft-versus-host disease.Bone Marrow Transplant. 1994; 14: 397-401PubMed Google Scholar]. Cyclosporine was tapered and discontinued by 3-6 months in patients with no clinical evidence of GVHD. Methotrexate was not given to the CB transplant recipient. Antiviral prophylaxis with acyclovir was given for at least 6 months posttransplantation. First-line prophylaxis for Pneumocystis jiroveci was trimethoprim-sulfamethoxazole for at least 6 months, with the option of dapsone or pentamidine in patients with allergy or intolerance to first-line prophylaxis. Patients with rising levels of cytomegalovirus (CMV) pp65 antigen or CMV DNA measurement (based on immunofluorescence antigenemia assay or quantitative CMV PCR) were offered preemptive treatment with ganciclovir or valganciclovir, as described previously [14Ugarte-Torres A. Hoegh-Petersen M. Liu Y. et al.Donor serostatus has an impact on cytomegalovirus-specific immunity, cytomegaloviral disease incidence, and survival in seropositive hematopoietic cell transplant recipients.Biol Blood Marrow Transplant. 2011; 17: 574-585Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. Antifungal prophylaxis and colony-stimulating factors were not routinely provided. The day of neutrophil engraftment was defined as the first day of an absolute neutrophil count ≥0.5 × 109/L (500/mm3) in 3 consecutive laboratory measurements obtained on different days. Platelet recovery was defined as the first of 3 consecutive laboratory values ≥20 × 109/L obtained on different days, with no platelet transfusions within the previous 7 days. For patients whose platelet counts never dropped below 20 × 109/L, the day of SCT was considered the day of engraftment. Comorbidities were scored using the Hematopoietic Stem Cell Transplantation Comorbidity Index (HCT-CI) described by Sorror et al. [15Sorror M.L. Giralt S. Sandmaier B.M. et al.Hematopoietic cell transplantation–specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences.Blood. 2007; 110: 4606-4613Crossref PubMed Scopus (275) Google Scholar]. We compared summary statistics (with median and range) used to describe the cohort with the Mann-Whitney U test. Kaplan-Meier estimates of OS and progression-free survival (PFS) and cumulative incidence statistics (nonrelapse mortality [NRM], engraftment, GVHD) were calculated as described previously [16Peto R. Pike M.C. Armitage P. et al.Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples.Br J Cancer. 1977; 35: 1-39Crossref PubMed Scopus (7006) Google Scholar]. These estimates were compared using the log-rank (Mantel-Cox) statistic. Statistical calculations were made using Prism Version 5.0 (GraphPad Software, San Diego, CA). Table 1 summarizes the clinical and biological features of the cohort at the time of SCT. Median follow-up of surviving patients was 4.3 years (range, 1.0-9.0 years).Table 1Patient Characteristics at Time of SCTCR1, High-Risk (n = 32)CR2 (n = 12)Age, years, median (range)40 (19-64)25 (19-65)∗P < .05.Donor, n Matched related173 Mismatched related31 Matched unrelated106 Mismatched unrelated21 Umbilical cord01Graft type, n Bone marrow41 Peripheral blood stem cells2810 Umbilical CB01Time from diagnosis to SCT, months, median (range)4.2 (2.1-6.9)48.7 (5.2-88.5)∗P < .05.Cytogenetics, n Normal45 Hyperdiploid-1 Near triploid1- t(9;22)16- t(4;11)21 Complex12 Other structural41 Not available42Age >35 years, n†Includes only those patients whose only high-risk feature at diagnosis was age >35 years or an elevated WBC count.101High WBC count, n†Includes only those patients whose only high-risk feature at diagnosis was age >35 years or an elevated WBC count.2-HCT-CI ≥1, n94∗ P < .05.† Includes only those patients whose only high-risk feature at diagnosis was age >35 years or an elevated WBC count. Open table in a new tab All patients engrafted neutrophils and platelets. The median time to neutrophil engraftment was 14 days (range, 11-28 days), and the median time to platelet engraftment was 18 days (range, 0-105 days). The recipient of a CB stem cell transplant engrafted neutrophils on day 16 and platelets on day 45. Four patients did not require platelet transfusions; these 4 patients achieved a median platelet count nadir of 24 × 109/L (range, 22-34 × 109/L), at a median of 11 days (range, 10-12 days) after transplantation. Figure 1 shows the onset of acute GVHD (aGVHD) and chronic GVHD (cGVHD). The incidence of grade II-IV aGVHD was 53.2%, and that of grade III-IV aGVHD was 20.6%. Only 2 patients (4.5%) developed aGVHD after day 60 post-SCT, one on day 99 and the other on day 110. Chronic GVHD complicated 57% of SCTs, occurring in 40.4% of recipients of a related donor transplant and in 66.1% of recipients of an unrelated donor transplant (P = .10). The mode of onset of cGVHD was progressive in 6 cases, quiescent in 3 cases, and de novo in 11 cases. cGVHD was of limited stage in 5 patients and extensive in 13 patients. Two patients were lost to follow-up, and their cGVHD staging is unknown. Twenty patients (45%) were treated with systemic immunosuppressive therapy for GVHD for a median of 360 days (range, 35-1702 days). All cases of cGVHD developed within 1 year of SCT. The pharmacokinetics of busulfan was assessed in 8 patients undergoing SCT in CR2 and in 21 patients undergoing SCT in CR1 with high-risk disease. The median busulfan area under the receiver-operating characteristic curve (AUC) value was 4247 μM·min (range, 3284-7794 μM·min) for patients in CR2 and 4662 μM·min (range, 3051-5844 μM·min) for patients in CR1 with high-risk disease (P = .42). Busulfan exposure was not affected by age or weight at the time of SCT. A tendency toward improved OS and PFS was noted for patients with a busulfan AUC value below the median value (4660 μM·min) (hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.093-1.06; P = .06 for both OS and PFS). PFS and OS are shown in Figure 2. Five-year PFS was 56.7%, with no difference between patients undergoing SCT for high-risk disease in CR1 and those undergoing SCT while in CR2 (P = .80). Two patients remained alive after undergoing a second SCT for relapsed disease. Five-year OS was 66%, once again with no difference between patients undergoing SCT in CR1 and those undergoing SCT in CR2. Seven patients died of recurrent ALL at a median of 365 days (range, 62-2989 days) after SCT. Eight patients died without relapse, at a median of 71 days (range, 14-152 days) after SCT. Causes of NRM include multiorgan failure (n = 5) and infection (n = 3). Infectious causes of death include 1 case of CMV, 1 case of Epstein-Barr virus–positive post-SCT lymphoproliferative disorder (before the availability of rituximab for this indication), and 1 case of bacterial sepsis in the setting of steroid-refractory aGVHD. Grade II-IV aGVHD was not associated with increased mortality, occurring in 10 of 15 patients who died and in 20 of 29 patients who survived (P = not significant). TRM was significantly influenced by age and comorbidity at the time of SCT. Patients with TRM and those with multiorgan failure/ARDS were significantly older than survivors (median, 49 years [range, 23-65 years] versus 35 years [19-64 years]; P = .01, and 53 years [47-65 years] versus 36 years [19-64 years]; P = .0058). Age >45 years was significantly associated with 5-year NRM (3.4% versus 64.4%; HR, 0.034; 95% CI, 0.0076-0.15; P < .0001). This difference was especially striking in older patients with comorbid medical conditions. Patients age >45 years with an HCT-CI of 0 experienced significantly less TRM than those with an HCT-CI ≥1 (HR, 0.15; 95% CI, 0.037-0.64; P = .01). Comorbidity did not influence TRM (HR, 3.2; 95% CI, 0.011-940; P = .69) or OS (HR, 0.53; 95% CI, 0.039-7.2; P = .23) in patients age <45 years. OS was significantly worse in patients age >45 years with an HCT-CI ≥1 compared with the rest of the cohort (HR, 0.15; 95% CI, 0.037-0.64; P = .01) (Figure 3). In absolute terms, patients age <45 years with an HCT-CI of 0 had a 5-year OS of 70.6%, and those with an HCT-OS ≥1 had a 5-year OS of 80%. For patients age >45 years, these respective values were 62.5% and 12.5%. Although allogeneic SCT remains the treatment of choice for patients with high-risk or relapsed ALL, the optimal conditioning regimen for this procedure remains unclear. Reduced-intensity regimens may result in low rates of TRM [17Diaconescu R. Flowers C.R. Storer B. et al.Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors.Blood. 2004; 104: 1550-1558Crossref PubMed Scopus (271) Google Scholar], but are associated with similar rates of PFS as obtained with more traditional myeloablative regimens [18Alyea E.P. Kim H.T. Ho V. et al.Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age.Blood. 2005; 105: 1810-1814Crossref PubMed Scopus (259) Google Scholar]. We have previously shown that NRM and OS are correlated with busulfan exposure for the fludarabine + busulfan regimen with or without TBI in patients with various hematologic malignancies [11Geddes M. Kangarloo S.B. Naveed F. et al.High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen.Biol Blood Marrow Transplant. 2008; 14: 220-228Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar]. The 36-month OS was 68% for patients with a busulfan AUC value <6000 μM·min and 23% for those with a busulfan AUC value >6000 μM·min (P = .001). This suggests that for this regimen, reducing exposure to severely myelotoxic agents may result in improved outcomes. Similar results were reported by Santarone et al. [19Santarone S. Pidala J. Di Nicola M. et al.Fludarabine and pharmacokinetic-targeted busulfan before allografting for adults with acute lymphoid leukemia.Biol Blood Marrow Transplant. 2011; 17: 1505-1511Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar] using a similar regimen without TBI, ATG only for SCT recipients of unrelated donor grafts, and busulfan exposure targeted to 5300 μM·min. In the present study, we demonstrate NRM of 18.2%, which is similar to rates reported with reduced-intensity conditioning regimens [6Cho B.S. Lee S. Kim Y.J. et al.Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study.Leukemia. 2009; 23: 1763-1770Crossref PubMed Scopus (49) Google Scholar, 7Bachanova V. Verneris M.R. DeFor T. et al.Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation.Blood. 2009; 113: 2902-2905Crossref PubMed Scopus (85) Google Scholar, 20Mohty M. Labopin M. Tabrizzi R. et al.Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation.Haematologica. 2008; 93: 303-306Crossref PubMed Scopus (80) Google Scholar]. Busulfan exposure did not influence the outcome of transplantation in this small group of patients, but we note a trend consistent with our previous findings and those of others [21Andersson B.S. Thall P.F. Madden T. et al.Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia.Biol Blood Marrow Transplant. 2002; 8: 477-485Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar]. The success of fludarabine + busulfan regimens with low-dose TBI or even no TBI raises the possibility of developing conditioning regimens for patients with ALL without the long-term consequences of irradiation. In contrast, however, we have shown that the addition of TBI to fludarabine and busulfan reduced the relapse rate without increasing TRM in patients with AML receiving ATG [10Russell J.A. Savoie M.L. Balogh A. et al.Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 cGy total-body irradiation, and thymoglobulin.Biol Blood Marrow Transplant. 2007; 13: 814-821Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. In this case, TBI may be compensating for an adverse effect of ATG on relapse, while the beneficial effects on TRM and quality of life are maintained. GVHD remains the major cause of NRM after allogeneic SCT [22Ferrara J.L.M. Reddy P. Pathophysiology of graft-versus-host disease.Semin Hematol. 2006; 43: 3-10Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar]. GVHD rates are affected by genetic (particularly HLA) disparity between donor and recipient, by stem cell source, and by conditioning regimen. The addition of ATG to standard pretransplantation conditioning has previously been shown to reduce rates of severe aGVHD and extensive cGVHD without changing TRM [23Bacigalupo A. Lamparelli T. Bruzzi P. et al.Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO).Blood. 2001; 98: 2942-2947Crossref PubMed Scopus (421) Google Scholar, 24Kim H.-J. Min W.-S. Cho B.-S. et al.Successful prevention of acute graft-versus-host disease using low-dose antithymocyte globulin after mismatched, unrelated, hematopoietic stem cell transplantation for acute myelogenous leukemia.Biol Blood Marrow Transplant. 2009; 15: 704-717Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 25Finke J. Bethge W.A. Schmoor C. et al.Standard graft-versus-host disease prophylaxis with or without anti–T cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial.Lancet Oncol. 2009; 10: 855-864Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar]. These results were recently confirmed when it was demonstrated that the addition of low-dose ATG to standard conditioning reduced the rate of grade II-IV aGVHD from 29% to 8% (P = .038) in a cohort of Korean AML patients receiving predominantly bone marrow stem cells [26Stewart B.L. Storer B. Storek J. et al.Duration of immunosuppressive treatment for chronic graft-versus-host disease.Blood. 2004; 104: 3501-3506Crossref PubMed Scopus (225) Google Scholar]. Also, the addition of rabbit anti-Jurkat T lymphoblast antibodies (Fresenius-ATG) to standard GVHD prophylaxis was recently shown to reduce the rate of cGVHD from 42.6% to 12.2% (P < .0001) in a randomized, open-label, multicenter study in the setting of SCT from matched unrelated donors [25Finke J. Bethge W.A. Schmoor C. et al.Standard graft-versus-host disease prophylaxis with or without anti–T cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial.Lancet Oncol. 2009; 10: 855-864Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar]. In the present cohort, the rate of grade II-IV aGVHD was 53.2% and that of cGVHD was 57%. These rates appear to be higher than those reported in the aforementioned studies, possibly reflecting effects of recipient age, use of TBI, use of cytokine-mobilized peripheral blood as the stem cell source, and differing doses or types of ATG. The low rates of GVHD-related mortality in our cohort and the relatively short duration of therapy for cGVHD compared with other published reports [26Stewart B.L. Storer B. Storek J. et al.Duration of immunosuppressive treatment for chronic graft-versus-host disease.Blood. 2004; 104: 3501-3506Crossref PubMed Scopus (225) Google Scholar] may reflect other beneficial effects of pretransplantation ATG as well. Regimen-related toxicity has traditionally restricted eligibility for myeloablative SCT to younger recipients. In many cases, older patients are treated with reduced-intensity or nonmyeloablative conditioning regimens, which are associated with lower regimen-related morbidity and mortality [17Diaconescu R. Flowers C.R. Storer B. et al.Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors.Blood. 2004; 104: 1550-1558Crossref PubMed Scopus (271) Google Scholar] compared with myeloablative conditioning. The exact benefits of this approach have been difficult to demonstrate, however, because in many cases OS and PFS are similar to those of patients receiving myeloablative conditioning [18Alyea E.P. Kim H.T. Ho V. et al.Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age.Blood. 2005; 105: 1810-1814Crossref PubMed Scopus (259) Google Scholar, 20Mohty M. Labopin M. Tabrizzi R. et al.Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation.Haematologica. 2008; 93: 303-306Crossref PubMed Scopus (80) Google Scholar]. In our cohort, OS was significantly worse for patients age >45 years with comorbid medical conditions. This effect is related primarily to increased TRM in these patients, and it is possible that reducing the intensity of conditioning for this population may translate into improved OS. It is important to emphasize the limitations of this single-center report. We describe a relatively small number of patients, treated over a period of several years. Although we noted a substantial difference in outcome for older patients with comorbid health conditions, we believe that these results should be interpreted cautiously, and ultimately the question should be examined in a larger number of patients. In conclusion, we report excellent long-term outcomes for young patients with high-risk or relapsed ALL who undergo SCT after fludarabine + busulfan + TBI conditioning. The OS and disease-free survival rates that we report compare favorably with those reported in larger series of 50% at 2 years and 39% at 5 years [27Marks D.I. Perez W.S. He W. et al.Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission.Blood. 2008; 112: 426-434Crossref PubMed Scopus (59) Google Scholar, 28Esperou H. Boiron J.M. Cayuela J.M. et al.A potential graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia: results from the French Bone Marrow Transplantation Society.Bone Marrow Transplant. 2003; 31: 909-918Crossref PubMed Scopus (52) Google Scholar]. Older patients without comorbidities had similar survival to that of younger patients, whereas those with comorbidities experienced high rates of TRM. In conclusion, this regimen has been shown to be a safe and effective treatment for ALL and should be studied further in larger patient cohorts. The effects of age and comorbidity should be examined carefully to determine whether this regimen is suitable for this subset of potential SCT recipients. We thank the nurses, allied health providers, and staff of the Alberta Blood and Marrow Transplant Program for their dedicated efforts on behalf of the patients who we treat. We also thank our patients for the trust they have shown us in allowing us to care for them. Financial disclosure: James Russell and Douglas Stewart both receive research funding from Otsuka Pharmaceuticals. The other authors have no conflicts of interest to disclose." @default.
• W2087163735 created "2016-06-24" @default.
• W2087163735 creator A5016527172 @default.
• W2087163735 creator A5017906484 @default.
• W2087163735 creator A5035331881 @default.
• W2087163735 creator A5047478186 @default.
• W2087163735 creator A5048122779 @default.
• W2087163735 creator A5065238694 @default.
• W2087163735 creator A5068947490 @default.
• W2087163735 creator A5070022492 @default.
• W2087163735 creator A5071194831 @default.
• W2087163735 creator A5076242219 @default.
• W2087163735 creator A5084879148 @default.
• W2087163735 creator A5091623372 @default.
• W2087163735 date "2012-12-01" @default.
• W2087163735 modified "2023-10-12" @default.
• W2087163735 title "Fludarabine, Busulfan, Antithymocyte Globulin, and Total Body Irradiation for Pretransplantation Conditioning in Acute Lymphoblastic Leukemia: Excellent Outcomes in All but Older Patients with Comorbidities" @default.
• W2087163735 cites W1971439170 @default.
• W2087163735 cites W1992011065 @default.
• W2087163735 cites W2003581043 @default.
• W2087163735 cites W2010222433 @default.
• W2087163735 cites W2015844812 @default.
• W2087163735 cites W2024184339 @default.
• W2087163735 cites W2027025310 @default.
• W2087163735 cites W2035343180 @default.
• W2087163735 cites W2037148599 @default.
• W2087163735 cites W2038252730 @default.
• W2087163735 cites W2039817295 @default.
• W2087163735 cites W2042138663 @default.
• W2087163735 cites W2063898537 @default.
• W2087163735 cites W2066863410 @default.
• W2087163735 cites W2067114649 @default.
• W2087163735 cites W2079167213 @default.
• W2087163735 cites W2085110573 @default.
• W2087163735 cites W2087380692 @default.
• W2087163735 cites W2088897722 @default.
• W2087163735 cites W2092401345 @default.
• W2087163735 cites W2105746514 @default.
• W2087163735 cites W2118322536 @default.
• W2087163735 cites W2127419842 @default.
• W2087163735 cites W2128491464 @default.
• W2087163735 cites W2129128251 @default.
• W2087163735 cites W2151210395 @default.
• W2087163735 cites W2164885965 @default.
• W2087163735 doi "https://doi.org/10.1016/j.bbmt.2012.07.017" @default.
• W2087163735 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22842330" @default.
• W2087163735 hasPublicationYear "2012" @default.
• W2087163735 type Work @default.
• W2087163735 sameAs 2087163735 @default.
• W2087163735 citedByCount "21" @default.
• W2087163735 countsByYear W20871637352013 @default.
• W2087163735 countsByYear W20871637352014 @default.
• W2087163735 countsByYear W20871637352016 @default.
• W2087163735 countsByYear W20871637352017 @default.
• W2087163735 countsByYear W20871637352018 @default.
• W2087163735 countsByYear W20871637352019 @default.
• W2087163735 countsByYear W20871637352020 @default.
• W2087163735 countsByYear W20871637352021 @default.
• W2087163735 countsByYear W20871637352023 @default.
• W2087163735 crossrefType "journal-article" @default.
• W2087163735 hasAuthorship W2087163735A5016527172 @default.
• W2087163735 hasAuthorship W2087163735A5017906484 @default.
• W2087163735 hasAuthorship W2087163735A5035331881 @default.
• W2087163735 hasAuthorship W2087163735A5047478186 @default.
• W2087163735 hasAuthorship W2087163735A5048122779 @default.
• W2087163735 hasAuthorship W2087163735A5065238694 @default.
• W2087163735 hasAuthorship W2087163735A5068947490 @default.
• W2087163735 hasAuthorship W2087163735A5070022492 @default.
• W2087163735 hasAuthorship W2087163735A5071194831 @default.
• W2087163735 hasAuthorship W2087163735A5076242219 @default.
• W2087163735 hasAuthorship W2087163735A5084879148 @default.
• W2087163735 hasAuthorship W2087163735A5091623372 @default.
• W2087163735 hasBestOaLocation W20871637351 @default.
• W2087163735 hasConcept C126322002 @default.
• W2087163735 hasConcept C143998085 @default.
• W2087163735 hasConcept C2776694085 @default.
• W2087163735 hasConcept C2776755627 @default.
• W2087163735 hasConcept C2778461978 @default.
• W2087163735 hasConcept C2778880498 @default.
• W2087163735 hasConcept C2779263901 @default.
• W2087163735 hasConcept C2780611847 @default.
• W2087163735 hasConcept C2909962599 @default.
• W2087163735 hasConcept C71924100 @default.
• W2087163735 hasConceptScore W2087163735C126322002 @default.
• W2087163735 hasConceptScore W2087163735C143998085 @default.
• W2087163735 hasConceptScore W2087163735C2776694085 @default.
• W2087163735 hasConceptScore W2087163735C2776755627 @default.
• W2087163735 hasConceptScore W2087163735C2778461978 @default.
• W2087163735 hasConceptScore W2087163735C2778880498 @default.
• W2087163735 hasConceptScore W2087163735C2779263901 @default.
• W2087163735 hasConceptScore W2087163735C2780611847 @default.
• W2087163735 hasConceptScore W2087163735C2909962599 @default.
• W2087163735 hasConceptScore W2087163735C71924100 @default.
• W2087163735 hasIssue "12" @default.
• W2087163735 hasLocation W20871637351 @default.
• W2087163735 hasLocation W20871637352 @default.
• W2087163735 hasOpenAccess W2087163735 @default.
• W2087163735 hasPrimaryLocation W20871637351 @default.

• next