|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2007.11.1641 on December 17 2007 © 2008 American Society of Clinical Oncology. Sustained Remissions of High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome After Reduced-Intensity Conditioning Allogeneic Hematopoietic Transplantation: Chronic Graft-Versus-Host Disease Is the Strongest Factor Improving Survival
From the Hospital de la Santa Creu i Sant Pau (Universitat Autonoma Barcelona), Barcelona; Hospital Clínico Universitario Salamanca, Salamanca; Hospital Germans Trias i Pujol, Badalona; Hospital Morales Meseguer, Murcia; Hospital Son Dureta, Palma de Mallorca, Mallorca; Hospital Central de Asturias, Ovieda, Spain Corresponding author: David Valcárcel, MD, H. Santa Creu i Sant Pau, Sant Antoni Maia Claret 167, Barcelona, Spain 08025; e-mail: dvalcarcel{at}santpau.es
Purpose Reduced-intensity conditioning (RIC) for allogeneic stem-cell transplantation (allo-SCT) reduces nonrelapse mortality (NRM). This reduction makes it possible for patients who are ineligible for high-dose myeloablative conditioning allo-SCT to benefit from graft-versus-leukemia reaction. In this multicenter, prospective study of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of RIC allo-SCT from a human leukocyte antigen–identical sibling by using a regimen that uses fludarabine and busulfan. Patients and Methods Ninety-three patients with AML (n = 59) and MDS (n = 34) were included, and the median age was of 53 years. Follow-up for survivors was 43 months (range, 3 to 89 months). The conditioning regimen consisted of fludarabine (150 mg/m2) and oral busulfan (8 to 10 mg/kg). All except one patient received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine and methotrexate or mycophenolate mofetil. Results The 100-day, 1-year, and 4-year incidences of NRM were 8, 16%, and 21%, respectively. The 1- and 4-year relapse cumulative incidences were 23% and 37%, respectively, and leukemia recurrence was the main cause of death. The 4-year disease-free survival (DFS) and overall survival (OS) rates were 43% and 45%, respectively. The 4-year cumulative incidence of chronic GVHD was 53% (45% extensive), and its development was the major factor associated with lower relapse incidence and improved DFS and OS. Conclusion Our results confirm the capacity of this RIC regimen to obtain long-term remissions in patients ineligible for a conventional allo-SCT. The results suggest an important role of the development of chronic GVHD in reducing relapse and improving DFS and OS.
Initial uncertainties about reduced-intensity conditioning (RIC) regimens for allogeneic transplantation (allo-SCT) have been convincingly answered, by the demonstration of their efficacy in allowing engraftment and in decreasing nonrelapse mortality (NRM) in patients ineligible for conventional (high-dose conditioning) allo-SCT.1-3 Currently, a key aspect to be investigated is whether RIC regimens have a graft-versus-leukemia (GvL) effect that is strong enough to cure high-risk patients, even those who have relapsed after autologous SCT. Up-to-date, conventional allo-SCT is considered the best approach for patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), because it combines high-dose chemotherapy with an immune-mediated GvL reaction.4-7 However, this approach is not recommended in many patients because of an unacceptable high risk of NRM (eg, from second transplants, poor performance status, other comorbidities, or advanced age). An option for this group is autologous SCT, but the advantage compared with chemotherapy in high-risk AML is unclear.8,9 In contrast, it would be of interest to know if these patients could benefit from a GvL effect, especially when the tumor burden is low.10 To estimate the potential of this approach, Lazarus et al11 have reviewed the experiences from several groups that used RIC regimens in AML.12-18 These studies present several problems that hamper firm conclusions: most studies are retrospective; include diverse diagnoses and usually only a low number of AML/MDS; use different conditioning regimens and are often heterogeneous; pool sibling and unrelated transplants in the same study; and include bone marrow transplantation (BMT) and peripheral blood stem-cell transplantation (PBSCT) as sources (with or without in vivo or ex vivo T-cell depletion) in the same study. These studies report an NRM that ranges from 5% to 51%, a relapse incidence between 11% and 45%, an overall survival (OS) between 17% and 68%, and a disease-free survival (DFS) that ranges from 31% to 80%. The present study reports the outcome of patients with AML/MDS who underwent RIC allo-SCT with busulfan (8 to 10 mg/m2) and fludarabine (150 mg/m2) in six Spanish centers. The prospective design of the study and the long follow-up (median, 43 months) allow the analysis of patients who experienced late treatment failures with this RIC allo-SCT. All the patients were candidates for allo-SCT, but—for different reasons, mainly advanced age—the anticipated early high NRM precluded the use of conventional conditioning. Our results of 45% OS despite the presence of several high-risk factors in most patients (with 20% of them undergoing SCT with refractory disease) are encouraging. Of note, our study confirms that chronic GVHD is the most important factor for reducing relapses and for improving DFS and OS after RIC allo-SCT for myeloid malignancies.
Patients Ninety-three patients with AML/MDS received fludarabine and busulfan for RIC allo-SCT from human leukocyte antigen (HLA)–identical siblings on a phase II prospective trial conducted in six Spanish centers between 1998 and 2005. The inclusion criteria were an AML considered for allo-SCT but at high risk for NRM with conventional conditioning; and provision of written informed consent. Exclusion criteria were creatinine more than than twice the upper limit of normal (ULN); AST and/or ALT more than three times the ULN; bilirubin more than twice the ULN; other nonhematologic malignancies; or HIV positive status. Patient characteristics are listed in Table 1.19 The median age was 53 years (range, 21 to 70 years), and 38 patients (41%) were aged  60 years. The diagnoses were AML in 59 patients (63%) and MDS in 34 patients (37%). Patients who had MDS with increased blasts underwent the transplantation as first-line therapy if they had less than 10% bone marrow blasts. If they had more than 10% blasts, they received AML-type chemotherapy first and then proceeded to allo-SCT.
Patients were enrolled after protocol approval by the Spanish Drug Regulator Agency and by local research ethical committees, and written informed consent was obtained from patients and donors before conditioning.
Conditioning Regimen and Graft-Versus-Host- Disease Prophylaxis Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine (CsA) in all patients and a short course of methotrexate (MTX) (on days 1, 3, and 6) followed by folinic acid rescue for 82 patients. Mycophenolate mofetil (MMF) 1 g every 8 hours was used instead of MTX in 11 patients. The CsA dose was maintained until 3 months after transplantation and then was tapered if no acute GVHD appeared. In 2004, there was a modification in the conditioning regimen and the GVHD prophylaxis to further reduce drug-related toxicity. Patients previously reported as having the highest risk of 1-year NRM received busulfan 8 mg/kg instead of 10 mg/kg and received MMF instead of MTX.20 Because all outcomes were identical in these 11 patients, they are described together with the other 82 patient cases. Anti-infective measures were determined by local protocols and included (in all instances) the following: trimethoprim/sulfamethoxazole or nebulized pentamidine as prophylaxis for Pneumocystis jirovecii infections; and twice-weekly monitoring for cytomegalovirus (CMV) reactivation, with administration of pre-emptive ganciclovir or foscarnet therapy when monitoring resulted in positive results. Donor lymphocyte infusions (DLIs) were given because of relapse or because of persistent mixed chimerism after CsA tapering.
Statistical Considerations and Definitions
Chemotherapy sensitivity was defined as the achievement of complete remission (CR) after the last course of chemotherapy (CT), whereas chemotherapy refractoriness included responses different than CR. Those patients who did not receive CT before allo-SCT were described as untreated. An early disease status was defined according to accepted criteria.25,26 Specifically, this category included patients with poor-prognosis AML or refractory anemia with excess blasts–type 2 in first CR after induction chemotherapy and with untreated refractory anemia with excess blasts–type 1 (bone marrow blasts < 10%). Neutrophil and platelet engraftment were defined as the first of three consecutive days with an absolute neutrophil count greater than 0.5 x 109/L and an untransfused platelet count greater than 20 x 109/L. Acute and chronic GVHD were graded according to standard criteria27; the diagnoses of acute and chronic GVHD were not made on the basis of the classical 100-day cutoff only, but diagnoses were made by the clinical presentation and the histopathologic findings of biopsies, as recommended recently by an NIH working group.28 Response and relapse were defined according to standard hematologic criteria. All patients who survived at least 15 days were evaluated for hematologic recovery. Chimerism analyses was performed by using a polymerase chain reaction (PCR) of informative minisatellite loci, as previously specified.29 Complete donor chimerism (CDC) was defined as the presence of 100% donor DNA in the sample analyzed. CDC was defined on the basis of T-cell chimerism, if available (n = 46), or on unfractionated nucleated cells (n = 86).
Engraftment and Chimerism All but two patients, who died early (day 2 and 6), were assessable for hematologic reconstitution. Neutrophil recovery occurred in all patients at a median of 17 days (range, 7 to 27 days), and platelet recovery occurred at a median of 11 days (range, 0 to 59 days). There were neither primary nor secondary graft failures. Eighty-six patients (92%) were assessable for chimerism studies. The median time to reach complete donor chimerism (CDC) was shorter in total nucleated cells than in T lymphocytes (median, 30 days [range, 17 to 240 days] v median, 100 days [range, 17 to 731 days], respectively; P < .01).
GVHD Fifty-one patients developed chronic GVHD, which resulted in a 4-year cumulative incidence of 53% (95% CI, 44% to 65%). Thirty-nine patients (50%) developed extensive chronic GVHD, which resulted in a 4-year cumulative incidence of 45% (95% CI, 35% to 58%). The characteristics of chronic GVHD are listed in Table 3.
At the last follow-up, 29 patients (35%) had been completely withdrawn from immunosuppressive (IS) medication at a median of 6 months (range, 2 to 49 months) post-SCT. Nineteen (43%) of the 43 surviving patients were free of IS medication at the last follow-up, which was a median of 9 months (range, 3 to 41 months) post-transplantation.
Outcomes
Relapse and DFS. Thirty-three patients (35%) relapsed at a median of 4 months (range, 0.6 to 49 months) after SCT. The 3-month, 1-year, and 4-year cumulative incidences of relapse were 15% (95% CI, 9% to 25%), 29% (95% CI, 21% to 40%), and 37% (95% CI, 28% to 49%), respectively, for the entire group (Fig 3). The 4-year cumulative incidences for AML and MDS were 44% (95% CI, 32% to 59%) and 25% (95% CI, 14% to 46%), respectively.
In univariate analysis, variables associated with greater relapse risk were chemotherapy-refractory disease, high-risk cytogenetics, the presence of greater than than 5% blasts in BM at SCT, and the absence of chronic GVHD. In the multivariate analysis, risk factors were the absence of chronic GVHD (HR, 6.5; 95% CI, 3.1 to 13.8; P < .001) and an advanced disease status (HR, 2.2; 95% CI, 1.1 to 4.4; P = .03; Table 2; Fig 2). The 4-year probability of DFS for the entire group was 43% (range, 32% to 54%). The DFS rates for AML and MDS were 39% (95% CI, 26% to 52%) and 49% (95% CI, 31% to 67%), respectively (P = .3; Fig 1B). In univariate analysis, the variables associated with poorer DFS were advanced-phase disease, chemotherapy-refractory disease, high-risk cytogenetics, the presence of greater than 5% of blast in BM at SCT, and the absence of chronic GVHD. In the multivariate analysis, the only variables that influenced DFS were the absence of chronic GVHD (HR, 5.3; 95% CI, 2.4 to 13.8; P < .001) and an advanced disease status (HR, 2.6; 95% CI, 1.2 to 5.4; P = .01; Table 2; Fig 2). Eleven patients (12%) received at least one DLI, and all of them were for disease relapse. The median time from transplantation to DLI was 4.6 months (range, 3 to 43.5 months). Four (36%) of these patients received some type of chemotherapy before DLI. Complete response after DLI was obtained in five patients (42%), and four of these patients were alive and without AML/MDS at the last follow-up (1, 9, 10, and 35 months after DLI, respectively). Two patients received DLI in early relapse (ie, cytogenetic or molecular relapse without hematologic relapse), and both patients achieved CR and maintained CR at last follow-up. All patients who did not respond to DLI died as a result of AML/MDS. Nonrelapse mortality. Eighteen patients died as a result of nonrelapse causes at a median of 4.3 months (range, 0 to 21 months). The 3-month, 12-month, and 4-year cumulative incidences of acute NRM were 8% (95% CI, 4% to 15%), 16% (95% CI, 10% to 26%), and 20% (95% CI, 14% to 32%), respectively. The most frequent causes of NRM were GVHD (n = 13), infections without active GVHD (n = 5), and other toxicities (two episodes of CNS bleeding, one pancreatic adenocarcinoma, and one thromboembolism). In univariate analyses, variables associated with higher NRM rates were acute GVHD, age older than 60 years, greater than 5% blasts in BM, and the absence of prior chemotherapy. In multivariate analyses, acute GVHD (grades 2 to 4) was the most important variable associated with NRM (HR, 3.7; 95% CI, 1.4 to 13; P = .005), whereas age older than 60 years showed a trend (HR, 2.6; 95% CI, 1 to 6.9; P = .059; Table 2). Twenty seven (31%) of 86 assessable patients developed at least one CMV infection, and 7 patients (8%) developed CMV disease, which occurred in the setting of GVHD in all patients and was the cause of death in three patients (4%).
In the last 10 years, RIC allo-SCT has been increasingly used for providing the GvL effect to patients ineligible for conventional transplantation. Unfortunately, the GvL effect is closely linked to GVHD, and—so far—it is not possible to separate the two phenomena. The key finding of our study was that the development of chronic GVHD was the strongest variable that protected from relapse. Because chronic GVHD did not significantly increase NRM, this variable was also the strongest predictor for 4-year OS and DFS. Acute GVHD is also associated with the GvL effect, but in our study it led to an increased NRM and did not provide any benefit in OS or DFS. In our study, as in most other series about RIC allo-SCT, relapse was the main cause of treatment failure.30,31 As in other studies that involved AML and high-risk MDS, most relapses occurred a few months post-transplantation. In our series, a median time to relapse of only 4 months was too short to allow a powerful and sustained GvL effect29,32 The platform for this effect is complete T-cell chimerism, which was observed after 100 days or more in most patients who underwent transplantations. Additionally, most patients who relapsed were still under the influence of IS drugs. Two alternatives may contribute to a decrease in early relapse after SCT. First, earlier tapering of IS medications to allow faster T-cell complete donor chimerism and an earlier GvL effect, despite severe acute GVHD, may increase NRM; this approach in the Seattle experience was unsuccessful.33 Second, the use of agents with antineoplastic activity to control leukemia progression until the GvL effect takes place may contribute. RIC was designed for patients with a high-risk of NRM after conventional procedures. The observed NRM in this series was low (8% at 100 days and 16% at 1 year); thus we succeeded in achieving this initial goal. Because most occurrences of NRM resulted from acute GVHD, a simplistic approach could be to eliminate this complication with the in vivo use of alemtuzumab.34 However, this approach would also decrease occurrences of chronic GVHD, but GVHD was the strongest factor associated with improved outcome in our series. The dose-intensity of chemotherapy used as a conditioning regimen also may have a relevant impact on relapse.30,31,35-37 In a group of 18 patients with AML who were in first CR and who received total-body irradiation 2Gy and fludarabine 90 mg/m2, Feinstein et al.33 recently reported seven of 10 deaths associated with relapse at a median of 198 days and a 1-year NRM of 16%. Conversely, the low 29% relapse rate observed in the current study could be explained partially by the more potent conditioning regimen used. The use of DLI in relapses of AML and MDS after conventional allo-SCT has limited efficacy.38,39 In our limited experience (11 patients), DLI appeared effective in a minority of patient cases. Of note, in the two patients who received DLI because of nonovert hematologic relapse (one molecular and one cytogenetic), a sustained CR was achieved. In contrast, only three of nine patients with overt leukemia achieved a CR. These data argue in favor of using DLI when a low tumor burden is detected (ie, by immunophenotyping, cytogenetics, or molecular studies). The feasibility of intervening in such early relapses is still uncertain. Marks et al40 reported their results with DLI after RIC allo-SCT, mostly with T-cell depletion (ie, alemtuzumab or CD 34+ selection) in various hematologic malignancies. They showed that the achievement of a response was closely associated with the development of acute and/or chronic GVHD. This finding is in agreement with our results, which showed that chronic GVHD was the most important factor associated with DFS and relapse. The high relapse rate observed in patients who did not develop chronic GVHD may justify the use of DLI before relapse in these patients. However, because a significant proportion of patients developed severe GVHD after DLI, it is important to adequately select those patients who really need this intervention. In conclusion, our study lends further support to the use of RIC allo-SCT in patients with AML/MDS who are not appropriate candidates for a standard conditioning regimen. The current study shows that the development of chronic GVHD not only reduces relapse but also improves 4-year survival, which—to the best of our knowledge—has not been reported to date in a large and homogeneous series of patients with AML/MDS who were treated with RIC allo-SCT. Nevertheless, patients with advanced AML and high-risk MDS require novel approaches to reduce early post-transplantation relapses.
The author(s) indicated no potential conflicts of interest.
Conception and design: David Valcárcel, Rodrigo Martino Provision of study materials or patients: David Valcárcel, Rodrigo Martino, Dolores Caballero, Jesus Martin, Christelle Ferra, Jose B. Nieto, Antonia Sampol, M. Teresa Bernal, Jose L. Piñana, Lourdes Vazquez, Jose M. Ribera, Joan Besalduch, Jose M. Moraleda, Dolores Carrera, M. Salut Brunet, Jose A. Perez-Simón, Jorge Sierra Collection and assembly of data: David Valcárcel, Rodrigo Martino, Dolores Caballero, Jesus Martin, Christelle Ferra, Jose B. Nieto, Antonia Sampol, M. Teresa Bernal, Jose L. Piñana, Jose M. Ribera, Joan Besalduch, Jose M. Moraleda, Dolores Carrera, Jose A. Perez-Simón, Jorge Sierra Data analysis and interpretation: David Valcárcel, Rodrigo Martino Manuscript writing: David Valcárcel, Rodrigo Martino Final approval of manuscript: David Valcárcel, Rodrigo Martino, Dolores Caballero, Jesus Martin, Christelle Ferra, Jose B. Nieto, Antonia Sampol, M. Teresa Bernal, Jose L. Piñana, Lourdes Vazquez, Jose M. Ribera, Joan Besalduch, Jose M. Moraleda, Dolores Carrera, M. Salut Brunet, Jose A. Perez-Simón, Jorge Sierra
published online ahead of print at www.jco.org on December 17, 2007. Supported in part by the Instituto de Salud Carlos III (expedient Grant No. CM06/00,139, Ministerio de Sanidad to J.L.P., and Grants No. PI052312 and RD06/0020/0707 to J.S.); the Instituto de Recerca Hospital de la Santa Creu I Sant Pau (J.L.P.); and DURSI (Grant No. 2005SGR01075 to J.S.), Catalonia, Spain. Both D.V. and R.M. contributed equally to this work and should be considered co–first authors. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531-4536, 1997 2. Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91:756-763, 1998 3. Valcarcel D, Martino R, Sureda A, et al: Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies. Eur J Haematol 74:144-151, 2005[CrossRef][Medline] 4. Cassileth PA, Harrington DP, Appelbaum FR, et al: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339:1649-1656, 1998 5. Gale RP, Park RE, Dubois RW, et al: Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute myelogenous leukemia in 1st remission. Leuk Res 23:709-718, 1999[CrossRef][Medline] 6. Slovak ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075-4083, 2000 7. Zittoun RA, Mandelli F, Willemze R, et al: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia: European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 332:217-223, 1995 8. Cahn JY, Labopin M, Mandelli F, et al: Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: A retrospective analysis of the European Bone Marrow Transplant Group. Blood 85:575-579, 1995 9. De Witte T, Van BA, Hermans J, et al: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS: Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Blood 90:3853-3857, 1997 10. Martino R, Caballero MD, Simon JA, et al: Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 100:2243-2245, 2002 11. Lazarus HM, Rowe JM: Reduced-intensity conditioning for acute myeloid leukemia: Is this strategy correct. Leukemia 20:1673-1682, 2006[CrossRef][Medline] 12. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ: Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 23:5675-5687, 2005 13. Sayer HG, Kroger M, Beyer J, et al: Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: Disease status by marrow blasts is the strongest prognostic factor. Bone Marrow Transplant 31:1089-1095, 2003[CrossRef][Medline] 14. Hallemeier C, Girgis M, Blum W, et al: Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants. Biol Blood Marrow Transplant 10:310-319, 2004[CrossRef][Medline] 15. Hegenbart U, Niederwieser D, Sandmaier BM, et al: Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 24:444-453, 2006 16. Claxton DF, Ehmann C, Rybka W: Control of advanced and refractory acute myelogenous leukaemia with sirolimus-based non-myeloablative allogeneic stem cell transplantation. Br J Haematol 130:256-264, 2005[CrossRef][Medline] 17. Miller KB, Roberts TF, Chan G, et al: A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease. Bone Marrow Transplant 33:881-889, 2004[CrossRef][Medline] 18. Platzbecker U, Thiede C, Fussel M, et al: Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia. Leukemia 20:707-714, 2006[CrossRef][Medline] 19. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997 20. Gomez-Nunez M, Martino R, Caballero MD, et al: Elderly age and prior autologous transplantation have a deleterious effect on survival following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: Results from the Spanish multicenter prospective trial. Bone Marrow Transplant 33:477-482, 2004[CrossRef][Medline] 21. Kaplan EL MP: Non parametric estimation from incomplete observations. J Am StatAssoc 53:457-481, 1958 22. Klein JP, Rizzo JD, Zhang MJ, Keiding N: Statistical methods for the analysis and presentation of the results of bone marrow transplants: Part 2—Regression modeling. Bone Marrow Transplant 28:1001-1011, 2001[CrossRef][Medline] 23. Klein JP, Rizzo JD, Zhang MJ, Keiding N: Statistical methods for the analysis and presentation of the results of bone marrow transplants: Part I—Unadjusted analysis. Bone Marrow Transplant 28:909-915, 2001[CrossRef][Medline] 24. Baron F, Maris MB, Sandmaier BM, et al: Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 23:1993-2003, 2005 25. Appelbaum FR, Pearce SF: Hematopoietic cell transplantation in first complete remission versus early relapse. Best Pract Res Clin Haematol 19:333-339, 2006[Medline] 26. de Lima M, Giralt S: Allogeneic transplantation for the elderly patient with acute myelogenous leukemia or myelodysplastic syndrome. Semin Hematol 43:107-117, 2006[CrossRef][Medline] 27. Przepiorka D, Weisdorf D, Martin P, et al: 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15:825-828, 1995[Medline] 28. Filipovich AH, Weisdorf D, Pavletic S, et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I—Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945-956, 2005[CrossRef][Medline] 29. Valcarcel D, Martino R, Caballero D, et al: Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 31:387-392, 2003[CrossRef][Medline] 30. Martino R, Parody R, Fukuda T, et al: Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Blood 108:2928-2936, 2006 31. Shimoni A, Hardan I, Shem-Tov N, et al: Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: The role of dose intensity. Leukemia 20:322-328, 2006[CrossRef][Medline] 32. Childs R, Clave E, Contentin N, et al: Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: Full donor T-cell chimerism precedes alloimmune responses. Blood 94:3234-3241, 1999 33. Feinstein LC, Sandmaier BM, Hegenbart U, et al: Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission. Br J Haematol 120:281-288, 2003[CrossRef][Medline] 34. Ho AY, Pagliuca A, Kenyon M, et al: Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 104:1616-1623, 2004 35. Andersson BS, Thall PF, 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 8:477-485, 2002[CrossRef][Medline] 36. Clift RA, Buckner CD, Appelbaum FR, et al: Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 76:1867-1871, 1990 37. de Lima M, Anagnostopoulos A, Munsell M, et al: Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: Dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 104:865-872, 2004 38. Porter D, Levine JE: Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion. Semin Hematol 43:53-61, 2006[CrossRef][Medline] 39. Levine JE, Braun T, Penza SL, et al: Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 20:405-412, 2002 40. Marks DI, Lush R, Cavenagh J, et al: The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 100:3108-3114, 2002 Submitted March 9, 2007; accepted October 24, 2007.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
