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Originally published as JCO Early Release 10.1200/JCO.2006.09.7865 on August 27 2007 © 2007 American Society of Clinical Oncology. Comorbidity and Disease Status–Based Risk Stratification of Outcomes Among Patients With Acute Myeloid Leukemia or Myelodysplasia Receiving Allogeneic Hematopoietic Cell Transplantation
From the Clinical Research Division, Fred Hutchinson Cancer Research Center; and the Departments of Medicine and Biostatistics, University of Washington School of Medicine, Seattle, WA Address reprint requests to Mohamed Sorror, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024; e-mail: msorror{at}fhcrc.org
Purpose Retrospective studies have shown similar survival among patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) after nonmyeloablative compared with myeloablative conditioning. Refined risk stratification is required to design prospective trials.
Patients and Methods We stratified outcomes among patients with AML (n = 391) or MDS (n = 186) who received either nonmyeloablative (n = 125) or myeloablative (n = 452) allogeneic hematopoietic cell transplantation (HCT) based on comorbidities, as assessed by a HCT-specific comorbidity index (HCT-CI), as well as disease status. Patients receiving nonmyeloablative conditioning were older, more frequently pretreated, more often received unrelated grafts, and more often had HCT-CI scores of
Results Patients with HCT-CI scores of 0 to 2 and either low or high disease risks had probabilities of overall survival at 2 years of 70% and 57% after nonmyeloablative conditioning compared with 78% and 50% after myeloablative conditioning, respectively. Patients with HCT-CI scores of Conclusion Patients with low comorbidity scores could be candidates for prospective randomized trials comparing nonmyeloablative and myeloablative conditioning regardless of disease status. Additional data are required for patients with low-risk diseases and high comorbidity scores. Novel antitumor agents combined with nonmyeloablative HCT should be explored among patients with high comorbidity scores and advanced disease.
Allogeneic hematopoietic cell transplantation (HCT) is potentially curative treatment for many patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Historically, high-intensity conditioning regimens have been used with the dual aims of disease eradication and host immunosuppression for acceptance of the allografts.1-5 Recently, reduced-intensity and truly nonmyeloablative conditioning regimens have been introduced to reduce toxicities and mortality that can be associated with high-intensity conditioning.6-12 The new regimens rely in part or entirely on graft-versus-leukemia effects for tumor eradication. Older patient age, failed high-dose HCT, and comorbidities have been the main reasons for the preference of nonmyeloablative versus myeloablative conditioning regimens. Retrospective comparisons have failed to demonstrate survival benefits of dose intensity among patients with AML or MDS, given that the lower relapse rates after myeloablative compared with reduced-intensity conditioning were offset by higher nonrelapse mortality (NRM).13-17 Comparable survivals were still seen when comparisons were limited to patients older than 50 years.18 Prospective studies randomly assigning patients between the two HCT strategies are needed to define optimal treatment selection. However, little is known about the most appropriate stratification method for such studies. Age, disease status, and cytogenetics have been proposed as the main determinants of outcomes of AML and MDS patients after allogeneic HCT.7,17,19-25 However, methods incorporating the impact of comorbidities in the decision-making process for patients with AML/MDS were under-reported in the literature (reviewed by Deeg et al26 and Deschler et al27). Comorbidities, as summarized by weighted scoring systems, were recently shown to be strong independent patient-specific predictors of HCT outcomes among patients with a variety of malignant and nonmalignant hematologic diseases.28,29 A highly sensitive HCT-specific comorbidity index (HCT-CI) was modeled to fit patients receiving conditioning regimens with variable intensities.30 Previously, we have reported comparable survival in a group of 150 patients with MDS or AML transformed from MDS and conditioned with nonmyeloablative versus myeloablative regimens.13 Here, we expanded the study to include additional MDS and all AML patients to investigate the role of comorbidities, among other risk factors, in stratifying and comparing patients conditioned with nonmyeloablative or myeloablative regimens.
Patients Comorbidity and outcome analyses included consecutive patients with AML or MDS administered either nonmyeloablative (n = 125) or myeloablative conditioning regimens (n = 452) before HCT from related or unrelated donors between December 1997 and June 2006. Patients younger than 18 years were excluded from this analysis. Age, pretransplantation comorbidities, and failed high-dose HCT were reasons to receive nonmyeloablative conditioning regimens, which consisted of 2 Gy total-body irradiation with (94%) or without (6%) fludarabine 90 mg/m2, followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine.31-33 Myeloablative regimens included either busulfan (levels targeted to plasma mean steady-state concentrations of 800 to 900 ng/mL)/cyclophosphamide (71%) or cyclophosphamide/  12 Gy total-body irradiation34 (29%), followed in most patients by a combination of methotrexate/cyclosporine for graft-versus-host disease prophylaxis.35 Patients and donors were matched for HLA-A, -B, and -C antigens by either intermediate resolution DNA typing or high-resolution techniques. Matching for HLA-DRB1 and -DQB1 was at the allele level.36 Patients received infection prophylaxis according to standard guidelines.37-41 Disease morphology was determined according to the French-American-British classification. Patients had either low-risk diseases, defined as de novo AML in first complete remission (CR) or MDS–refractory anemia or refractory anemia with ringed sideroblasts; intermediate-risk diseases, defined as de novo AML in at least second CR; or high-risk diseases, defined as all more advanced stages of AML and MDS. Cytogenetic risks were assessed and broken down into three risk groups: good, intermediate, and poor, as defined previously for patients diagnosed with AML42 or MDS.43 The analysis was approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center (Seattle, WA).
Comorbidities
Statistical Methods
Pretransplantation Characteristics Patient and disease characteristics are listed in Table 1. Differences between patients receiving nonmyeloablative and myeloablative conditioning at the time of HCT were the result of protocol inclusion criteria. Patients receiving nonmyeloablative conditioning had a median age of 60 years compared with 46 years for patients receiving myeloablative conditioning; 54% were age 60 years compared with 6% for patients receiving myeloablative conditioning. Patients receiving nonmyeloablative conditioning were more heavily pretreated; 54% of them had received three prior regimens compared with 27% of patients receiving myeloablative conditioning, and only 6% compared with 34% had not received chemotherapy, respectively. Most patients in both cohorts had received cytarabine for 7 days plus an anthracycline for 3 days as induction therapy. Consolidation chemotherapy consisted of standard doses of cytarabine for 5 days plus an anthracycline for 2 days or a regimen of high-dose cytarabine. Patients receiving nonmyeloablative conditioning were more likely to have experienced treatment failure after autologous HCT (18% v 2%), to have received unrelated grafts (54% v 45%), and to have received peripheral-blood mononuclear cell grafts (97% v 81%) than patients receiving myeloablative conditioning. The diagnoses were AML and MDS, respectively, in 80% and 20% of patients receiving nonmyeloablative conditioning and 66% and 34% of patients receiving myeloablative conditioning. Patients receiving nonmyeloablative conditioning with AML were more frequently in at least the first CR of de novo AML (53% v 39%), had more often transformed or secondary AML (21% v 5%), and were less often experiencing refractory or untested relapse (6% v 22%) compared with the cohort receiving myeloablative conditioning. Thirty-four percent and 29% of patients receiving nonmyeloablative conditioning had intermediate and high disease risks compared with 15% and 43% of patients receiving myeloablative conditioning. Poor-risk cytogenetics were found among 17% of patients receiving nonmyeloablative conditioning and 23% of patients receiving myeloablative conditioning. The percentages of recipient cytomegalovirus-positive serostatus and recipient/donor sex mismatch were similar between both patient cohorts.
Pretransplantation Comorbidities HCT-CI scores of 0, 1, 2, 3, 4, and 5 were assigned to 20%, 10%, 19%, 20%, 11%, and 20% of patients receiving nonmyeloablative conditioning compared with 37%, 17%, 16%, 15%, 9%, and 6% of patients receiving myeloablative conditioning, respectively. Overall, 51% of patients receiving nonmyeloablative conditioning and 30% of patients receiving myeloablative conditioning had scores of 3 (P < .001). Most comorbidities involved lungs, liver, and heart (Appendix Fig A1, online only); all of these organ-specific comorbidities were more frequent among patients receiving nonmyeloablative conditioning.
Risk Stratification of Outcomes Among All Patients
On the basis of these findings, we stratified all patients into four risk groups incorporating the impacts of both comorbidities and disease risks. The characteristics of the four groups included HCT-CI scores of 0 to 2 plus low disease risk (group I), HCT-CI scores of 0 to 2 plus intermediate and high disease risks (group II), HCT-CI scores of 3 plus low disease risk (group III), and HCT-CI scores of 3 plus intermediate and high disease risks (group IV). Incremental increases of NRM were observed with increasing comorbidity scores and disease risks among patients of groups I, II, III, and IV (Fig 1A). Patients in groups I and III, which included low disease risks, had lower rates of relapse compared with patients of groups II and IV, which included intermediate and high disease risks (Fig 1B). The most favorable OS and RFS rates were observed among patients of group I, whereas patients of group IV had the poorest survival rates. Those in groups II and III had intermediate OS and RFS rates (Figs 1C and 1D).
Outcomes After Nonmyeloablative Compared With Myeloablative Conditioning Table 3 shows 2-year outcomes according to conditioning intensity in the four patient groups as stratified by HCT-CI scores and disease risks. Overall, patients receiving nonmyeloablative conditioning tended to have lower incidences of NRM and higher incidences of relapse compared with patients receiving myeloablative conditioning, resulting in comparable rates of OS and RFS. However, none of these differences reached statistical significance with the exception of higher hazards for relapse (HR, 2.42; P = .02) and RFS (HR, 1.90; P = .05) in group I and a trend for a lower NRM hazard (HR, 0.60; P = .10) in group IV among patients receiving nonmyeloablative conditioning. Both patients receiving nonmyeloablative and myeloablative conditioning experienced incremental increases of NRM and decreases of RFS with increasing HCT-CI scores and disease risks (Figs 2 and 3). Cumulative incidences of 2-year NRM were 4%, 3%, 27%, and 29% compared with 11%, 24%, 32%, and 46% among patients receiving nonmyeloablative compared with myeloablative conditioning of risk groups I, II, III, and IV, respectively; RFS incidences were 63%, 56%, 36%, and 23% compared with 75%, 43%, 41%, and 20%, respectively.
After adjustment for pretransplantation differences, none of the outcomes of nonmyeloablative compared with myeloablative cohorts were statistically significant, with the exception of a borderline significance for a lower NRM hazard among patients of group IV (HR, 0.50; P = .05) favoring nonmyeloablative conditioning (Appendix Table A1, online only).
Conventional allogeneic HCT has been reserved for AML/MDS patients who are young and medically fit. Alternatively, reduced-intensity or nonmyeloablative HCT has been offered to older patients and those with comorbidities. In addition, reduced AML/MDS disease burden at the time of HCT has been preferred for many reduced-intensity or nonmyeloablative protocols. These inherent selection biases have limited the interpretability of retrospective comparisons between these two HCT strategies.13-18 Accurate risk determination would be useful for patient selection and stratification for prospective studies randomizing between nonmyeloablative and myeloablative conditioning. An ideal risk-stratification model should be balanced for the most influential prognostic factors. To our knowledge, this report is the first to show comorbidities as the most important patient-specific prognostic factor among a relatively large cohort of AML and MDS patients who have received allogeneic HCT, and to propose a simple risk-stratification model based on combined comorbidity scores and disease risks. Comorbidities strongly predicted NRM among AML and MDS patients, consistent with previous findings among all hematologic diseases.28,29 Furthermore, high HCT-CI scores were associated with increased relapse. This might be explained by the reported linkage between comorbidities such as prior malignancy,45 diabetes,46,47 obesity,48,49 autoimmune diseases,50-52 or smoking-associated lung disease53,54 and aggressive leukemia (reviewed by Extermann55). Advanced disease status and poor-risk cytogenetics predicted both increased relapse and NRM, consistent with previous observations among AML/MDS patients who received HCT.4,7,14,56 Overall, comorbidity, disease-status, and cytogenetics were the strongest factors influencing OS and RFS among all patients. High comorbidity scores (35%) and advanced disease status (58%) were more frequent than poor-risk cytogenetics (22%), and thus for simplicity, we elected to design our risk-stratification model on the basis of the two former factors. Most investigators have used disease status alone to stratify patients when assessing HCT outcomes or comparing conditioning regimens. Recently, Martino et al14 reported OS rates of 57% and 56% among patients in first CR, and 33% and 33% for those beyond first CR after reduced-intensity and myeloablative conditioning, respectively. Aoudjhane et al18 have shown inferior survivals for patients with advanced diseases (27% and 23%) compared with those in CR1 (53% and 56%) or CR2 (60% and 50%) after reduced-intensity and myeloablative conditioning, respectively. De Lima et al7 have shown lower incidences of 1-year NRM among patients in remission (4%) compared with those with more advanced AML or MDS (34%) after two different types of reduced-intensity conditioning regimens. Alyea et al57 have shown OS rates of 28% and 16% among patients older than 50 years and diagnosed with advanced AML and MDS given reduced-intensity compared with myeloablative conditioning regimens, respectively. Shimoni et al15 have demonstrated similar results of inferior survival among patients with active disease compared with those in remission. In that report, myeloablative conditioning was associated with a survival benefit compared with reduced-intensity regimens when administered to patients with active disease, but no benefit was observed among those in remission. In the current report, patients with HCT-CI scores of 0 to 2 and either low (group I) or high disease risks (group II) had probabilities of overall survival at 2 years of 70% and 57% after nonmyeloablative conditioning, respectively, compared with 78% and 50% after myeloablative conditioning, respectively. These results compared favorably with the previously reported survival rates based on disease status only, suggesting that the incorporation of a patient-specific risk factor such as comorbidities resulted in refinement of risk stratification. The comparable survival rates among patients receiving nonmyeloablative and myeloablative conditioning in risk groups I and II in this retrospective cohort analysis render them potential candidates for randomized prospective studies. Accordingly, we are conducting a prospective randomized trial comparing conditioning intensity among patients with HCT-CI scores of 0 to 2.
Patients with low disease risks but HCT-CI scores of Patients with high comorbidity and disease burdens (group IV) tended to have a lower risk of NRM after nonmyeloablative as compared with myeloablative conditioning. This was particularly striking when one considered the older age and more frequent prior chemotherapy regimens among patients receiving nonmyeloablative conditioning. Indeed, the lower NRM after nonmyeloablative conditioning in this risk group became statistically significant after adjustment for other risk factors. However, this benefit in NRM was offset by a slightly but not significantly increased relapse rate. The older age of patients receiving nonmyeloablative conditioning compared with myeloablative conditioning might have contributed to the increased relapse.58,59 New approaches are needed to improve outcomes in patients with both high comorbidity scores and disease risk. The unacceptably high NRM (46%) after myeloablative conditioning would favor using a reduced-intensity regimen even among young patients within the high risk category. An approach we are studying is to combine radiolabeled monoclonal antibody to CD45 for improved disease control with the nonmyeloablative conditioning regimen.60 Newer DNA hypomethylating agents, such as azacytidine and decitabine,61,62 or immunomodulatory agents, such as lenalidomide,63 could also be considered for maintenance treatment after nonmyeloablative HCT in high-risk patients. The current report demonstrates the importance of incorporating comorbidities in the assessment of HCT outcomes for patients with AML/MDS. The results set the stage for a risk-stratification system that could discriminate which patients could be enrolled onto prospective randomized studies comparing nonmyeloablative and myeloablative regimens and which patients might not benefit from either kind of conditioning and would require novel approaches. It remains to be seen how the model would work among patients who undergo transplantation at other institutions and are treated with different conditioning regimens.
The author(s) indicated no potential conflicts of interest.
Conception and design: Mohamed L. Sorror, Brenda M. Sandmaier, Barry E. Storer, Rainer Storb Provision of study materials or patients: Mohamed L. Sorror, Brenda M. Sandmaier, Michael Maris, David G. Maloney, Bart L. Scott, H. Joachim Deeg, Rainer Storb Collection and assembly of data: Mohamed L. Sorror, Frédéric Baron, Bart L. Scott Data analysis and interpretation: Mohamed L. Sorror, Brenda M. Sandmaier, Barry E. Storer, David G. Maloney, Bart L. Scott, H. Joachim Deeg, Rainer Storb Manuscript writing: Mohamed L. Sorror, Brenda M. Sandmaier, Barry E. Storer, Bart L. Scott, Frederick R. Appelbaum, Rainer Storb Final approval of manuscript: Mohamed L. Sorror, Brenda M. Sandmaier, Barry E. Storer, Michael Maris, Frédéric Baron, David G. Maloney, Bart L. Scott, H. Joachim Deeg, Frederick R. Appelbaum, Rainer Storb
We thank the data coordinators, Chris Davis, Gary Schoch, Heather Hildebrant, and Jennifer Freese; the study nurses, Mary Hinds, John Sedgwick, Michelle Bouvier, and Joanne Greene; and Bonnie Larson, Helen Crawford, Karen Carbonneau, and Sue Carbonneau for assistance with manuscript preparation.
published online ahead of print at www.jco.org on August 27, 2007. Supported by Grants No. CA78902, CA18029, HL36444, CA15704, and HL088021 from the National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Additional support was provided by awards from the Jose Carreras International Leukemia Foundation, the Josef Steiner Stiftung, the Paros Family, and the Oncology Research Faculty Development Program of the Office of International Affairs of the National Cancer Institute. F.B. is a research associate of the National Fund for Scientific Research Belgium and was supported in part by postdoctoral grants from the Fulbright Commission and from the Centre Anticancéreux près l'Université de Liège. Presented in part at the American Society of Hematology Meeting, December 3-6, 2005, Atlanta, GA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
