|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.06.090 on November 8 2004 © 2005 American Society of Clinical Oncology. Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B StudyFrom The Ohio State University, Columbus, OH; The Cancer and Leukemia Group B Statistical Center; Duke University, Durham; Wake Forest University, Winston-Salem, NC; Dana-Farber Cancer Institute, Boston, MA; University of Alabama at Birmingham, Birmingham, AL; North Shore University Hospital, Manhasset; Roswell Park Cancer Institute, Buffalo, NY; University of Maryland Cancer Center, Baltimore, MD; University of Chicago, Chicago, IL; and Wayne State University School of Medicine, Detroit, MI Address reprint requests to Sherif S. Farag, MB, PhD, Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, A433A Starling-Loving Hall, 320 W Tenth Avenue, Columbus, OH 43210; e-mail: farag-1{at}medctr.osu.edu
PURPOSE: Evaluate the outcome of induction and postremission therapy in adults younger than 60 years with normal cytogenetics acute myeloid leukemia (AML). PATIENTS AND METHODS: In 490 patients, induction included cytarabine and daunorubicin (AD) or cytarabine and escalated doses of daunorubicin and etoposide ± PSC-833 (ADE/ADEP). Intensification included one cycle of high-dose cytarabine (HDAC) followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I), three HDAC cycles (group II), four intermediate-dose cytarabine (IDAC) or HDAC cycles (group III), or one HDAC/etoposide cycle and autologous stem-cell transplantation (ASCT; group IV). RESULTS: Of 350 patients receiving AD, 73% achieved complete remission (CR), compared with 82% of 140 receiving ADE/ADEP (P = .04). Splenomegaly was associated with a lower CR rate (P < .001), and ADE/ADEP, with a higher CR rate in younger patients (P = .005). The 5-year disease-free survival (DFS) rate was 28% each for intensification groups I and II, compared with 41% and 45% for groups III and IV, respectively (P = .02). The 5-year cumulative incidence of relapse (CIR) was 62% and 67% for groups I and II, respectively, compared with 54% and 44% for groups III and IV, respectively (P = .049). The type of postremission intensification remained significant for DFS and CIR in multivariable analysis. CONCLUSION: In younger adults with normal cytogenetics AML, splenomegaly predicts a lower CR rate, and the postremission strategies of either four cycles of I/HDAC or one cycle of HDAC/etoposide followed by ASCT are associated with improved DFS and reduced relapse compared with therapies that include fewer cycles of cytarabine or no transplantation.
Pretreatment cytogenetic abnormalities are among the most important prognostic factors predicting outcome of patients with acute myeloid leukemia (AML). In addition to stratifying patients into broad prognostic groups with different outcomes,1-6 cytogenetic studies are commonly used to guide postremission treatment, identifying AML subtypes more suited to specific therapies.7-9 Approximately 40% of adult patients with AML, however, have normal cytogenetics at diagnosis and compose the largest single group of cytogenetically defined patients.4-6 Although recent studies have indicated that AML cases with normal cytogenetics are molecularly heterogeneous and that certain molecular abnormalities are associated with inferior outcomes in cytogenetically normal AML patients,10-15 molecular testing is not yet widely available or used routinely to guide treatment. Karyotype analysis remains the most commonly used investigation for clinical decisions. Several studies have shown that AML patients with normal karyotype have an intermediate outcome relative to AML patients with defined good-risk or poor-risk karyotypic abnormalities.4-6 Furthermore, although we have previously shown that AML patients with normal cytogenetics have an improved outcome with the use of high-dose cytarabine (HDAC) after remission,9 the optimal postremission therapy for this group remains poorly defined. In this report, we describe the outcome of patients with normal cytogenetics AML and compare the results of different induction and postremission regimens in sequential Cancer and Leukemia Group B (CALGB) treatment protocols in this most common cytogenetically defined AML subgroup.
Patients Studied All patients included were enrolled onto CALGB 8461, a prospective cytogenetics companion study to adult AML treatment protocols. Consecutive patients with newly diagnosed AML, defined by the French-American-British (FAB) Cooperative Group criteria,16 with normal karyotypes confirmed after central karyotype review17 and enrolled onto sequential CALGB treatment studies for adults with untreated AML were examined (Table 1). Only patients younger than 60 years of age were included. All patients had de novo AML, except two patients, who had received treatment for a prior malignancy. Protocols were approved by the institutional review board of each participating institution, and informed consent was obtained from all patients before enrollment. Pathologic diagnoses were centrally reviewed.
Cytogenetic Studies As previously described, all cases had pretreatment cytogenetic analyses performed in CALGB-approved institutional cytogenetic laboratories and were judged to have a normal karyotype of adequate quality after CALGB central karyotype review.6,17 Chromosomal analysis was performed on pretreatment bone marrow (BM) from all patients at diagnosis. Specimens were processed using short-term (24-, 48-, or 72-hour) unstimulated cultures. Although G-banding was usually performed, Q-banding was also acceptable. To be considered as cytogenetically normal, at least 20 marrow metaphases had to have been analyzed and the karyotype found to be normal in each case. Karyotypes were interpreted according to the International System for Human Cytogenetic Nomenclature.18
Treatment
Definition of Response and Survival Outcomes
Statistical Analysis To compare the outcome of different postremission therapies, patients who achieved CR were divided into four groups according to the treatment they were assigned. Treatment included one cycle of HDAC followed by one cycle of etoposide and cyclophosphamide and one cycle of mitoxantrone and diaziquone (group I), three cycles of HDAC (group II), four cycles of intermediate-dose cytarabine (IDAC) or HDAC (group III), or HDAC with etoposide followed by high-dose busulfan and etoposide with autologous peripheral-blood stem-cell transplantation (ASCT; group IV). Patients who received identical induction followed by four cycles of IDAC or HDAC had similar DFS, CIR, and OS (see Effect of Cytarabine Dose on Outcome in Patients Receiving Repeated Cycles of Cytarabine After Remission) and were, therefore, combined in further analysis as group III. Estimates of DFS and OS were calculated using the Kaplan-Meier method,26 and differences in survival were compared using the log-rank test. Estimates of CIR, accounting for deaths as a competing risk, were calculated, and the difference among treatment groups was determined by Gray's k-sample test.27
Cox proportional hazards models were constructed for DFS and OS, and a multivariable model using Gray's method was constructed for CIR, using forward selection procedures. The proportional hazards assumption was checked individually for each variable in the DFS and OS models by testing whether the variable multiplied by the logarithm of the time variable (a time-dependent covariate) was significant. If the proportional hazards assumption was not met for a particular variable, then this time-dependent covariate was included in all models containing that variable. All analyses were performed on an intent-to-treat basis, and all tests of statistical significance were two-sided and performed at an
Patient Characteristics Of a total of 1,212 AML patients younger than 60 years with assessable cytogenetics registered on CALGB 8461 and enrolled on five successive treatment studies, 490 patients (40%) had a normal karyotype and are included in this analysis. The median age was 44 years (range, 16 to 59 years), almost half were male (49%), and the majority had FAB-M1 (19%), M2 (34%), or M4 (24%) subtypes, with a median BM blast count of 70% (range, 30% to 97%). Other baseline clinical features are listed in Table 2.
Induction Therapy Of 490 patients, 350 were enrolled on protocols 8221, 8525, 9022, and 9222 and received identical induction with cytarabine and daunorubicin (AD). On protocol 9621, 74 patients received ADE and 66 received ADEP. Although the doses of daunorubicin and etoposide were escalated in successive cohorts within the ADE- and ADEP-treated patients, there was no significant difference in CR rates among different dose levels within each treatment arm (P > .4).23 The pretreatment clinical characteristics of patients assigned to AD and ADE/ADEP are listed in Table 2. Eighty-one percent of those assigned to ADE achieved CR, compared with 83% of those assigned to ADEP (P = .83). Because there was no significant difference in CR rates between the two arms of protocol 9621, the two arms were combined for subsequent comparison of CR with patients who received AD. Of patients who received ADE/ADEP, 82% achieved CR, compared with 73% of those who received AD (P = .04). Furthermore, of patients who achieved CR after ADE/ADEP, 91% required only a single cycle of induction, compared with 77% of those who achieved CR after AD (P = .002).
In multivariable analysis examining age, sex, percentage of BM and blood blasts, hemoglobin, WBC count, platelets, FAB subtype, splenomegaly, hepatomegaly, lymphadenopathy, skin involvement, and induction treatment (ADE/ADEP v AD), only palpable splenomegaly (P < .001), log-transformed WBC (P = .03), and the interaction between age and induction treatment (P = .005) emerged as significant variables affecting CR. On fixing values for age (from 30 to 60 years by increments of 5 years), patients aged
Overall Outcome of All Patients
Effect of Cytarabine Dose on Outcome in Patients Receiving Repeated Cycles of Cytarabine After Remission To investigate the importance of postremission cytarabine dose on outcome, the DFS, CIR, and OS were compared for patients in CR assigned to receive four successive cycles of cytarabine at 100 mg/m2 for 7 days (n = 30), 400 mg/m2 for 5 days (IDAC; n = 35), and at least six doses of 3 g/m2 (HDAC; n = 35) on protocols 8221 and 8525 (Table 1). After a median follow-up of 12.5 years (range, 6.2 to 16.5 years), patients assigned to four cycles of cytarabine at 100 mg/m2 had significantly worse DFS as compared with those assigned to four cycles of cytarabine at 400 mg/m2 or 3 g/m2 (P = .008 and P = .01, respectively; Fig 2A). At 10 years, 13% (95% CI, 1% to 25%) of patients in the 100 mg/m2 group were free of disease, compared with 37% (95% CI, 21% to 53%) and 40% (95% CI, 23% to 56%) of patients in the 400 mg/m2 or 3 g/m2 groups, respectively. The 10-year CIR was 83% for patients assigned to 100 mg/m2, compared with 51% and 57% for patients assigned to 400 mg/m2 or 3 g/m2, respectively (P = .002) (Fig 2B). At 10 years, the survival rate was 17% (95% CI, 3% to 30%) for patients assigned to 100 mg/m2, compared with 40% (95% CI, 24% to 56%) and 42% (95% CI, 26% to 59%) for patients assigned to 400 mg/m2 or 3 g/m2, respectively (P = .07; Fig 2C). Of note, there was no significant difference in DFS (P = .99), CIR (P = .58), or survival (P = .81) between patients who were assigned to receive 400 mg/m2 and those assigned to 3 g/m2. Patients assigned to IDAC and HDAC were, therefore, combined in subsequent analyses.
Effect of Different Postremission Intensification Therapies on Outcome Of 370 patients in CR, 280 patients were assessable for analysis of the outcome of different postremission intensification therapies. Patients assigned to receive chemotherapy containing cytarabine at the dose of 100 mg/m2 (n = 30), alternative treatment using HDAC + etoposide followed by two cycles of HDAC (arm A of Protocol 9621; Table 1; n = 16), and ASCT in first CR (n = 12) or other therapies off protocol (n = 32) were excluded from further analysis. Assessable patients were divided into four groups according to the treatment assigned. Group I patients were assigned one cycle of HDAC followed by one cycle of etoposide plus cyclophosphamide and one cycle of mitoxantrone plus diaziquone (n = 85) on protocols 9022 and 9222. Patients in group II were assigned three cycles of HDAC (n = 43) on protocol 9222; patients in group III were assigned four cycles of IDAC or HDAC (n = 70) on protocols 8221 and 8525; and patients in group IV were assigned to one cycle of HDAC with etoposide followed by high-dose busulfan and etoposide with ASCT (n = 82) on protocol 9621. Although patients in group IV, all treated on protocol 9621, received different induction therapies (either ADE or ADEP), there were no significant differences in DFS (P = .29), CIR (P = .79), and survival (P = .39) between patients who received ADE and ADEP (data not shown), and patients were therefore combined as group IV. There were no significant differences in the pretreatment clinical variables across the different postremission treatment groups, except that patients in group IV had a lower median BM blast percentage and lower incidence of hepatomegaly as compared with patients in other groups (Table 3).
The outcome of postremission intensification after a median follow-up of 7.4 years (range, 3.0 to 16.6 years) is summarized in Table 4. As also shown in Figure 3A, groups I and II were associated with the lowest DFS. Although there was no significant difference in the proportion of deaths in remission between the four groups (P = .69), relapses were more frequent in patients in groups I and II. The 5-year CIR was highest for groups I (62%; SE = 5%) and II (67%; SE = 7%), compared with 54% (SE = 6%) and 44% (SE = 6%) for patients in groups III and IV, respectively (Fig 3B). The survival of patients in the four postremission groups is shown in Figure 3C. As shown in Table 4, there was a tendency for more patients in groups I and II to receive high-dose chemotherapy and stem-cell transplantation for relapsed disease.
Multivariable analyses for DFS, CIR, and survival were performed to test for differences among treatment groups while controlling for the number of induction cycles required to reach CR, age, WBC, percent BM and blood blasts, and other pretreatment variables (Table 5). The need for a second cycle of induction to achieve CR (P = .02), higher WBC (P = .009), older age becoming increasingly important over time beyond CR (P = .03), and type of postremission intensification (P = .004) were independently associated with inferior DFS. In particular, four cycles of IDAC or HDAC (group III) significantly improved DFS over treatment with three cycles of HDAC (group II; P = .02) and treatment with one cycle of HDAC followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I; P < .001), but resulted in similar DFS to that of patients assigned to HDAC/etoposide and ASCT (group IV; P = .21). The multivariable model for CIR was similar to that of DFS, except that age was not a significant predictor of relapse.
For survival, older age becoming an increasingly important factor over time after treatment (P = .001), presence of skin infiltrates (P = .02), and the need for two induction cycles to achieve CR (P = .004) independently predicted poorer outcome. Although postremission intensification therapy was not a significant predictor for survival (P = .14), individual P values from the Wald statistic suggested improved survival with four cycles of I/HDAC (group III) in comparison with patients assigned to receive one cycle of HDAC followed by other treatment (group I; P = .02) and similar survival to patients assigned to three cycles of HDAC (group II; P = .27) and HDAC/etoposide and ASCT (group IV; P = .20).
Previous studies investigating the outcome of therapy have generally included AML patients with normal karyotype together with patients with a variety of karyotypic aberrations in an intermediate-risk cytogenetic category. This study is the first to investigate the effects of different types of treatment, especially postremission therapy, on the outcome of younger adult patients with AML with normal cytogenetics treated on large sequential studies with prolonged follow-up. Our results suggest that differences in induction and intensity of postremission therapy can significantly affect outcome in AML patients with normal karyotype.
The results of several large studies indicate that approximately 60% to 70% of AML patients with intermediate-risk cytogenetics, most of whom have a normal karyotype, can achieve CR with standard induction chemotherapy that includes a 7-day infusion of cytarabine (100 to 200 mg/m2/d) and daunorubicin given as three daily bolus injections of 45 mg/m2 each.1 Our results showing that 73% of karyotypically normal patients who received AD achieved CR are consistent with these findings. However, our results suggest that the addition of etoposide may increase the CR rate in younger patients ( We have previously shown, in a combined analysis of younger and older patients, that AML patients with normal cytogenetics have improved outcome after intensification with repeated cycles of IDAC or HDAC compared with those receiving standard-dose cytarabine.9 Although our current analysis does not necessarily define the optimum treatment for this subgroup of patients, several conclusions can be reached. First, the results suggest that intermediate (400 mg/m2) and high-dose (3 g/m2) cytarabine given in repeated cycles achieve similar DFS and OS in patients with normal karyotype. However, it should be noted that only 35 patients in each arm, after combining patients from two separate studies (CALGB 8221 and 8525), were analyzed. Therefore, definitive recommendations for using the lower cytarabine dose can only be made after confirmation in large prospective studies. Second, intensification with four cycles of I/HDAC is associated with improved DFS compared with patients receiving less-intensive therapy that includes either three cycles of HDAC or only one cycle of HDAC followed by other chemotherapy. Although this result suggests that the number of cycles of I/HDAC is important for outcome, it does not exclude the possibility that a similar outcome could also be achieved with repeated cycles of lower doses of cytarabine (eg, standard-dose cytarabine), provided that one of the four postremission cycles of cytarabine is administered in intermediate or high doses. Furthermore, it is important to note that we compared different treatment strategies rather than simply the number of cytarabine cycles. The contribution of short-term intensive maintenance therapy to outcome in the group assigned to four cycles of I/HDAC, for example, remains unclear. However, our data suggest that the substitution of other chemotherapy for cycles of I/HDAC, including high-dose etoposide and cyclophosphamide, may compromise DFS. Finally, postremission treatment with one cycle of HDAC followed by ASCT results in similar DFS compared with four cycles of I/HDAC (plus four cycles of maintenance) but is associated with improved DFS compared with therapies including less I/HDAC. Although two randomized trials have shown that ASCT is associated with improved DFS compared with chemotherapy alone,30,31 this has not been uniformly observed,32,33 and no study has examined the effect of ASCT specifically in patients with normal karyotype. Once again, it should be noted that patients who were assigned to receive one cycle of HDAC followed by ASCT also received etoposide during induction and in combination with HDAC for mobilization of peripheral-blood stem cells. Although the effect of etoposide on long-term outcome remains unclear, at least one study has shown that its use during induction may prolong DFS.28 An additional potentially confounding factor is the use of interleukin-2 after transplantation. The effect of interleukin-2 maintenance after ASCT in younger patients with AML is currently being evaluated in a randomized trial, CALGB 19808. The improvement in DFS observed in patients assigned to four cycles of I/HDAC or one cycle of HDAC plus etoposide followed by ASCT, however, did not significantly impact survival when compared with patients receiving other postremission therapies. This is likely due to the positive effect of salvage treatment on patients receiving the less-intensive postremission intensification (ie, groups I and II). It is possible that patients who experience relapse after the most intensive postremission therapy may be less able to tolerate further treatments with curative potential or have more resistant disease. It is important to note that our analysis spanned clinical trials performed over a period of almost 20 years. Although we have adjusted for known important covariates among patients, the potential for confounding by latent variables, such as physician, supportive care, and institutional practices that might have changed over this period, exists. To address this issue, we have compared outcomes of the same patient treatment groups treated on different protocols and could not detect any significant differences in DFS, CIR, or survival for the same treatment administered on different protocols. For example, for group I patients, there was no significant difference in DFS (P = .88), CIR (P = .29), or survival (P = .45) between patients on protocols 9022 and 9222, after adjusting for other covariates. Similarly, no significant differences in these end points were observed for group III patients treated on protocols 8221 and 8525 (data not shown). Therefore, it is unlikely that any such trial effects contributed significantly to our results. A limitation of our analysis is the lack of molecular subtyping. It is apparent that AML patients with normal cytogenetics are molecularly heterogeneous, with different outcomes predicted by specific molecular abnormalities.10-15 Unfortunately, molecular data were not available for most patients included in this study, many of whom were enrolled before the significance of specific genetic abnormalities was known. It is likely that patients with certain molecular abnormalities may benefit from specific induction or postremission treatments, although this is currently unknown.
In summary, we conclude that for younger AML patients with normal cytogenetics, splenomegaly identifies a subset with poor response to induction treatment and that the inclusion of etoposide during induction with cytarabine and daunorubicin may result in an improved CR rate in patients
The following Cancer and Leukemia Group B institutions, principal investigators, and cytogeneticists participated in this study: Wake Forest University School of Medicine, Winston-Salem, NC: David D. Hurd, P. Nagesh Rao, and Mark J. Pettenati (grant No. CA03927); North Shore University Hospital, Manhasset, NY: Daniel R. Budman and Prasad R.K. Koduru (grant No. CA35279); Duke University Medical Center, Durham, NC: Jeffrey Crawford, Sandra H. Bigner, and Mazin B. Qumsiyeh (grant No. CA47577); University of Maryland Cancer Center, Baltimore, MD: Martin J. Edelman, Joseph R. Testa, Stuart Schwartz, Maimon M. Cohen, and Judith Stamberg (grant No. CA31983); Weill Medical College of Cornell University, New York, NY: Scott Wadler, Ram S. Verma, and Prasad R.K. Koduru (grant No. CA07968); Roswell Park Cancer Institute, Buffalo, NY: Ellis G. Levine and Anne Marie W. Block (grant No. CA02599); University of Iowa Hospitals, Iowa City, IA: Gerald H. Clamon and Shivanand R. Patil (grant No. CA47642); Dartmouth Medical School, Lebanon, NH: Marc S. Ernstoff, Doris H. Wurster-Hill, and Thuluvancheri K. Mohandas (grant No. CA04326); University of Alabama at Birmingham: Robert Diasio and Andrew J. Carroll (grant No. CA47545); Dana-Farber Cancer Institute, Boston, MA: George P. Canellos, Ramana Tantravahi, Cynthia C. Morton, and Leonard L. Atkins (grant No. CA32291); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry, Judith H. Miles, Jeffrey R. Sawyer, and Tim Huang (grant No. CA12046); The Ohio State University, Columbus, OH: Clara D. Bloomfield, and Karl S. Theil (grant No. CA77658); University of North Carolina, Chapel Hill, NC: Thomas Shea and Kathleen W. Rao (grant No. CA47559); Walter Reed Army Medical Center, Washington, DC: Joseph J. Drabick and Rawatmal B. Surana (grant No. CA26806); Finsen Institute, Copenhagen, Denmark: Nis I. Nissen and Preben Philip; State University of New York Upstate Medical University, Syracuse, NY: Stephen L. Graziano, Navnit S. Mitter, Lawrence P. Gordon, and Constance K. Stein (grant No. CA21060); University of California, San Diego, CA: Stephen L. Seagren, Renée Bernstein, and Marie L. Dell'Aquila (grant No. CA11789); Rhode Island Hospital, Providence, RI: William Sikov, Teresita Padre-Mendoza, Jennifer A. Ahearn, and Hon Fong L. Mark (grant No. CA08025); University of Massachusetts Medical Center, Worcester, MA: Pankaj Bhargava, Philip L. Townes, and Vikram Jaswaney (grant No. CA37135); Christiana Care Health System, Inc, Newark, DE: Stephen S. Grubbs, Digamber S. Borgaonkar, and Jeanne M. Meck (grant No. CA45418); Washington University School of Medicine, St. Louis, MO: Nancy L. Bartlett and Michael S. Watson (grant No. CA77440); University of Chicago Medical Center, Chicago, IL: Gini Fleming, Diane Roulston, and Michelle M. Le Beau (grant No. CA41287); Long Island Jewish Medical Center, Lake Success, NY: Kanti R. Rai, Alan L. Shanske, and Prasad R. K. Koduru (grant No. CA11028); Mount Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld (grant No. CA04457); University of Tennessee Cancer Center, Memphis, TN: Harvey B. Niell and Sugandhi A. Tharapel (grant No. CA47555); Eastern Maine Medical Center, Bangor, ME: Philip L. Brooks and Laurent J. Beauregard (grant No. CA35406); University of Minnesota, Minneapolis, MN: Bruce A. Peterson and Diane C. Arthur (grant No. CA16450); University of Vermont, Burlington, VT: Hyman B. Muss and Elizabeth F. Allen (grant No. CA77406); University of Illinois, Chicago, IL: Lawrence E. Feldman and Maureen M. McCorquodale (grant No.CA74811); Massachusetts General Hospital, Boston, MA: Michael L. Grossbard and Leonard L. Atkins (grant No. CA 12,449); Virginia Commonwealth University Minority Based Community Clinical Oncology Program, Richmond, VA: John D. Roberts and Colleen Jackson-Cook (grant No. CA52784); Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV: John Ellerton (grant No. CA35421); Ft. Wayne Medical Oncology/Hematology Inc, Ft. Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; University of Puerto Rico, San Juan, Puerto Rico: Enrique Velez-Garcia; McGill Department of Oncology, Montreal, Quebec, Canada: J.L. Hutchison and Jacqueline Emond (grant No. CA31809); State University of New York Maimonides Medical Center, Brooklyn, NY: Sameer Rafla and Ram S. Verma (grant No. CA25119); Georgetown University Medical Center, Washington, DC: Edward P. Gelmann and Jeanne M. Meck (grant No. CA77597); University of Cincinnati Medical Center, Cincinnati, OH: Orlando J. Martelo and Ashok K. Srivastava; Columbia-Presbyterian Medical Center, New York, NY: Rose R. Ellison and Dorothy Warburton (grant No. CA12011); Medical University of South Carolina, Charleston, SC: Mark R. Green and G. Shashidhar Pai (grant No. CA03927); and University of Nebraska Medical Center, Omaha, NE: Margaret A. Kessinger Wegner and Warren G. Sanger (grant No. CA77298).
The authors indicated no potential conflicts of interest.
Supported in part by grants from the National Cancer Institute to the Cancer and Leukemia Group B (grant Nos. CA101140, CA31946, CA77658, CA33601, CA41287, CA47545, CA03927, CA47577, CA35279, and CA32291), grant No. CA16058, and the Coleman Leukemia Research Fund. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Mrózek K, Heinonen K, Bloomfield CD: Clinical importance of cytogenetics in acute myeloid leukaemia. Best Pract Res Clin Haematol 14:19-47, 2001[Medline] 2. Bloomfield CD, Shuma C, Regal L, et al: Long-term survival of patients with acute myeloid leukemia: A third follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer 80:2191-2198, 1997 (suppl)[CrossRef][Medline] 3. Dastugue N, Payen C, Lafage-Pochitaloff M, et al: Prognostic significance of karyotype in de novo adult acute myeloid leukemia. Leukemia 9:1491-1498, 1995[Medline]
4. Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 92:2322-2333, 1998
5. 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
6. Byrd JC, Mrózek K, Dodge RK, et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325-4336, 2002
7. Fenaux P, Castaigne S, Dombret H, et al: All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: A pilot study on 26 cases. Blood 80:2176-2181, 1992
8. Licht JD, Chomienne C, Goy A, et al: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85:1083-1094, 1995
9. Bloomfield CD, Lawrence D, Byrd JC, et al: Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58:4173-4179, 1998
10. Caligiuri MA, Strout MP, Lawrence D, et al: Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 58:55-59, 1998
11. Döhner K, Tobis K, Ulrich R, et al: Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: A study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 20:3254-3261, 2002
12. Fröhling S, Schlenk RF, Breitruck J, et al: Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML Study Group Ulm. Blood 100:4372-4380, 2002
13. Whitman SP, Archer KJ, Feng L, et al: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: A Cancer and Leukemia Group B study. Cancer Res 61:7233-7239, 2001
14. Baldus CD, Tanner SM, Ruppert AS, et al: BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: A Cancer and Leukemia Group B Study. Blood 102:1613-1618, 2003
15. Fröhling S, Schlenk RF, Stolze I, et al: CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: Prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624-633, 2004 16. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 103:620-625, 1985 17. Bloomfield CD, Wurster-Hill D, Peng G, et al: Prognostic significance of the Philadelphia chromosome in adult acute lymphoblastic leukemia, in Gale RP, Hoelzer D (eds): Acute Lymphoblastic Leukemia: UCLA Symposia on Molecular and Cellular Biology—New Series (vol 108). New York, NY, Wiley-Liss, 1990, pp 101-109 18. Mitelman F (ed): An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995 19. Mayer RJ, Schiffer CA, Peterson BA, et al: Intensive postremission therapy in adults with acute nonlymphocytic leukemia using various dose schedules of ara-C: A progress report from the CALGB. Semin Oncol 14:25-31, 1987 (suppl 1)[Medline]
20. Mayer RJ, Davis RB, Schiffer CA, et al: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896-903, 1994
21. Moore JO, Dodge RK, Amrein PC, et al: Granulocyte-colony stimulating factor (filgrastim) accelerates granulocyte recovery after intensive postremission chemotherapy for acute myeloid leukemia with aziridinyl benzoquinone and mitoxantrone: Cancer and Leukemia Group B study 9022. Blood 89:780-788, 1997 22. Moore JO, Powell B, Velez-Garcia E, et al: A comparison of sequential non-cross-resistant therapy or Ara-C consolidation following complete remission in adult patients <60 years with acute myeloid leukemia: CALGB 9222. Proc Am Soc Clin Oncol 16:14a, 1997 (abstr 50)
23. Kolitz JE, George SL, Dodge RK, et al: Dose escalation studies of cytarabine, daunorubicin and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: Final Induction results of Cancer and Leukemia Group B study 9621. J Clin Oncol 22:4290-4301, 2004 24. Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813-819, 1990[Abstract] 25. Hosmer DW, Lemeshow S: Applied Logistic Regression (ed 2). New York, NY, Wiley, 2000 26. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 27. Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988
28. Bishop JF, Lowenthal RM, Joshua D, et al: Etoposide in acute nonlymphocytic leukemia. Blood 75:27-32, 1990
29. Hann IM, Stevens RF, Goldstone AH, et al: Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Blood 89:2311-2318, 1997
30. Zittoun RA, Mandelli F, Willemze R, et al: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 332:217-223, 1995 31. Burnett AK, Goldstone AH, Stevens RMF, et al: Randomized comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML 10 trial. Lancet 351:700-708, 1998[CrossRef][Medline]
32. 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
33. Harousseau J-L, Cahn J-Y, Pignon B, et al: Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 90:2978-2986, 1997 Submitted June 15, 2004; accepted September 23, 2004.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
5% blasts, 
1.5 x 109/L, and a platelet count of 
2 or Fisher's exact test for categoric data and the Wilcoxon rank sum or Kruskal-Wallis test, as appropriate, for continuous variables. To assess the independent effect of induction treatment on the probability of achieving CR, a multivariable logistic regression analysis was performed using a forward selection procedure. The Hosmer-Lemeshow goodness-of-fit test was performed to assess the adequacy of the model.
level of .05. All analyses were performed by the CALGB Statistical Center. 
