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Repetitive Cycles of High-Dose Cytarabine Benefit Patients With Acute Myeloid Leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461

From The Ohio State University, Columbus, OH; Cancer and Leukemia Group B Statistical Center; Duke University Medical Center, Durham; Wake Forest University Medical Center, Winston Salem, NC; University of Alabama at Birmingham, Birmingham, AL; National Cancer Institute, Bethesda; University of Maryland Cancer Center, Baltimore, MD; North Shore University Hospital, Manhasset; State University of New York Upstate Medical University, Syracuse, NY; Dana-Farber Cancer Institute, Boston, MA; and University of Chicago, Chicago, IL

Address reprint requests to John C. Byrd, MD, Division of Hematology and Oncology and the Comprehensive Cancer Center, The Ohio State University, B302A Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210-1240; e-mail: byrd-3{at}medctr.osu.edu

	ABSTRACT

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PURPOSE: To study the impact of repetitive (three to four courses) versus a single course of high-dose cytarabine (HDAC) consolidation therapy on outcome of patients with acute myeloid leukemia (AML) and inv(16)(p13q22) or t(16;16)(p13;q22).

PATIENTS AND METHODS: We examined the cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) for 48 adults younger than 60 years with inv(16)/t(16;16) who had attained a complete remission on one of four consecutive clinical trials and were assigned to receive HDAC consolidation therapy. Twenty-eight patients were assigned to either three or four courses of HDAC, and 20 patients were assigned to one course of HDAC followed by alternative intensive consolidation therapy.

RESULTS: Pretreatment features were similar for the two groups. The CIR was significantly decreased in patients assigned to receive three to four cycles of HDAC compared with patients assigned to one course (P = .03; 5-year CIR, 43% v 70%, respectively). The difference in RFS also approached statistical significance (P = .06). In a multivariable analysis that adjusted for potential confounding covariates, only treatment assignment (three to four cycles of HDAC) predicted for superior RFS (P = .02). The OS of both groups was similar (P = .93; 5-year OS, 75% for the three to four cycles of HDAC group v 70% for the one cycle of HDAC group), reflecting a high success rate with stem-cell transplantation salvage treatment administered among patients in both treatment groups.

CONCLUSION: We conclude that, in AML patients with inv(16)/t(16;16), repetitive HDAC therapy decreases the likelihood of relapse compared with consolidation regimens including less HDAC.

	INTRODUCTION

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Multiple studies have established pretreatment karyotype in adult acute myeloid leukemia (AML) as one of the most useful diagnostic tools to predict initial response to therapy, relapse risk, and overall survival (OS) [1-5]. In addition, we have demonstrated that pretreatment cytogenetics also influence the degree of benefit from remission consolidation with high-dose cytarabine (HDAC) in AML patients [6]. Specifically, AML patients with t(8;21)(q22;q22), inv(16)(p13q22)/t(16;16)(p13;q22), and normal cytogenetics benefited from HDAC therapy as measured by prolonged relapse-free survival (RFS), whereas those with other abnormalities did not [6]. In a follow-up study [7], we have shown that patients with t(8;21) who received three or four cycles of HDAC had a significantly improved RFS and OS compared with patients receiving only one course of HDAC followed by alternative intensive consolidation therapy. However, despite the fact that the t(8;21) and inv(16)/t(16;16) are related at the molecular level and patients with either of these abnormalities have a relatively favorable clinical outcome, it is unknown whether administration of repetitive cycles of HDAC in patients with inv(16)/t(16;16) has a beneficial effect similar to that in t(8;21)-positive patients. Therefore, we examined the importance of repetitive courses of HDAC in improving the RFS, cumulative incidence of relapse (CIR), and OS in patients with inv(16)/t(16;16) enrolled onto four consecutive Cancer and Leukemia Group B (CALGB) treatment trials.

	PATIENTS AND METHODS

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Patients
All patients included in this analysis were enrolled onto CALGB 8461, a prospective cytogenetics trial initiated in 1984. The study included consecutive patients under the age of 60 years who had a primary diagnosis of AML as defined by the French-American-British classification [8] and a centrally confirmed pretreatment cytogenetic abnormality of inv(16)/t(16;16), and who were enrolled onto one of four consecutive treatment studies performed by CALGB [9-12]. Only patients who achieved a complete remission (CR) and who were assigned to receive HDAC chemotherapy were included in this analysis of postremission therapy. Forty-nine patients fulfilled this criteria. One of these patients received an allogeneic bone marrow (BM) transplantation in first CR and was excluded from the analysis. Pathologic diagnoses were reviewed centrally. Patients with a prior history of myelodysplasia, other antecedent hematologic malignancies, prior nonsteroidal cytotoxic chemotherapy or radiation therapy, pre-existing liver disease, or uncontrolled infection were excluded. Written informed consent was obtained from all patients.

Cytogenetic Studies
Cytogenetic analyses of BM were performed in institutional CALGB cytogenetics laboratories, and karyotypes were reviewed centrally. Specimens were obtained at diagnosis from all patients and processed using unstimulated short-term (24-, 48-, and 72-hour) cultures, a direct method, or both. G-banding was usually performed, although Q-banding was also acceptable. The criteria used to describe a cytogenetic clone and description of karyotype followed the recommendations of the International System for Human Cytogenetic Nomenclature (1995) [13].

Treatment
The therapies administered to patients included in this study have been described previously and are listed in Table 1 [9-12]. Induction therapy was identical in each of the four trials for patients younger than 60 years. The postremission dose and schedule of HDAC were similar in each of the trials. Patients assigned to four cycles of HDAC (CALGB 8221, nonrandomized; and CALGB 8525, randomized v low- or intermediate-dose cytarabine) or three cycles of HDAC (9222, randomized v one cycle followed by alternative intensive therapy) had identical doses and schedules of treatment. The alternative intensive consolidation therapy that included one postremission course of HDAC was assigned to 20 patients and is described in Table 1. After HDAC consolidation therapy, the 12 patients enrolled onto CALGB 8221 or 8525 were also assigned to maintenance therapy. Long-term outcome among patients assigned to sequential HDAC plus maintenance compared with patients assigned to only sequential HDAC was similar (OS, P = .56; RFS, P = .32).

Criteria for Response and Definition of Relapse
A CR was defined as the presence of morphologically normal BM in patients with at least 1.5 x 10⁹/L granulocytes and 100 x 10⁹/L platelets in the blood. Relapse was defined as 5% leukemic blasts in a BM aspirate or new extramedullary leukemia [14].

Statistical Analyses
The primary prestudy hypothesis for this analysis was that patients with inv(16)/t(16;16) would have improved outcome if repetitive doses of HDAC were administered. To test this hypothesis, patients with the inv(16)/t(16;16) who were less than 60 years old and assigned to HDAC as postinduction therapy were analyzed. An intent-to-treat analysis was performed based on the assignment either to one cycle or to three or four cycles of HDAC. Baseline clinical features at presentation were compared for patients who were assigned to receive one cycle and patients who were assigned to receive three or four cycles of HDAC. Categoric variables were compared between the two groups using Fisher's exact test, and the medians of continuous variables, such as age, were compared using the Wilcoxon rank sum test. The two-sided level of significance was set at alpha = 0.05.

OS was measured from the protocol on-study date until the date of death regardless of cause, censoring for those alive at last follow-up. RFS was measured from the CR date to the date of relapse or death, whichever came first. Patients alive and relapse free at last follow-up were censored. Patients undergoing transplantation after relapse were not censored in the analysis for OS, and the one patient who received a transplantation before relapse was excluded from all analyses. Both OS and RFS were analyzed by the Kaplan-Meier method, and the log-rank test was used to compare differences between estimated survival curves.

To adjust for potential confounding covariates, a Cox proportional hazards model was constructed for RFS, using backward elimination. Univariate models integrating an artificial time-dependent covariate, expressed as the product of the fixed-time covariate and the log of time, were fit to check the proportional hazards assumption. Next, covariates that had univariate models reflecting a P < .20 from the likelihood ratio test were included in a full model. Variables with least significance from the Wald statistic were eliminated one at a time until the only variables in the model reported a P < .05. Any variables that were initially excluded from the model were added back into the model to confirm that they were neither statistically significant nor an important confounder, defined by a change in the estimated coefficients of at least 20%.

Last, to assess the difference in relapse rate, as opposed to relapse or death rate, CIR was measured from CR date until date of relapse, with random censoring at time of death and censoring for patients alive at last follow-up. A CIR plot gives the probability of relapsing by time t in a setting where death without relapse is treated as a competing risk. The difference in time to relapse between the two groups was measured using Gray's test [15]. Statistical analyses were performed by the CALGB Statistical Center.

	RESULTS

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Forty-eight patients were assigned to HDAC consolidation therapy as prescribed by the treatment protocols outlined in Table 1 and form the basis for this report. The median age of these patients was 36 years (range, 17 to 58 years), and 54% were male. The median leukocyte count at diagnosis was 36.9 x 10⁹/L (range, 2.2 to 203.7 x 10⁹/L). Twenty-eight patients were assigned by protocol to receive consolidation that included three to four cycles of HDAC, and 20 patients were assigned to receive one cycle of HDAC followed by alternative consolidation therapy. The pretreatment features of patients assigned to these two groups are listed in Table 2. There were no significant differences in pretreatment features between the two groups. Only the presence of skin infiltrates (P = .09) and splenomegaly (P = .06) approached statistical significance.

View larger version (15K): [in this window] [in a new window]   Fig 1. Relapse-free survival of inv(16)/t(16;16) patients based on assignment to treatment with 3 to 4 cycles compared with only 1 cycle of high-dose cytarabine (HDAC) consolidation therapy.

Of the 28 patients who experienced an event in the RFS model, two were deaths while in CR that occurred long after completion of therapy (one patient died at 6.5 years after induction during hernia surgery, and one died at 7.1 years as a result of pneumonia and hepatitis C). Both of the patients who died were in the three to four cycles of HDAC treatment group. Because our primary interest was in time to relapse as opposed to time to relapse or death, we also assessed the CIR. A CIR analysis gives the probability of relapsing in the setting where competing risks in the form of death without relapse is acknowledged to exist. Patients with inv(16)/t(16;16) assigned to three to four cycles of HDAC had a 5-year CIR rate of 43% compared with 70% for patients assigned to one cycle of HDAC. The CIR, as depicted in Figure 2, was significantly improved in patients assigned to three to four cycles of HDAC compared with patients assigned to one cycle (P = .03). Because patients treated on CALGB 8221 [12] and CALGB 8525 [10] were assigned to four cycles of HDAC and maintenance, whereas those treated on CALGB 9222 [11] were assigned to only three cycles of HDAC and no maintenance, we compared RFS and CIR between these groups. No differences in RFS (P = .32) or CIR (P = .68) were observed. The estimated 5-year RFS rate was 50% (95% CI, 22% to 78%) for the group assigned to four cycles of HDAC with maintenance compared with 63% (95% CI, 39% to 86%) for the group assigned to three cycles of HDAC and no maintenance; the 5-year CIR rates were 50% (SE = 0.15) and 38% (SE = 0.13), respectively.

View larger version (17K): [in this window] [in a new window]   Fig 2. Cumulative incidence of relapse of inv(16)/t(16;16) patients based on assignment to treatment with 3 to 4 cycles compared with only 1 cycle of high-dose cytarabine (HDAC) consolidation therapy.

View larger version (13K): [in this window] [in a new window]   Fig 3. Overall survival of inv(16)/t(16;16) patients based on assignment to treatment with 3 to 4 cycles compared with only 1 cycle of high-dose cytarabine (HDAC) consolidation therapy.

	DISCUSSION

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Biologic explanations for the increased sensitivity of inv(16)/t(16;16)-positive blast cells to cytarabine have been reported. Tosi et al [24] demonstrated that inv(16)/t(16;16) blasts had increased chemosensitivity to cytarabine, as measured by several viability assays, and also had higher uptake of [3H]-cytarabine into DNA of blast cells compared with other types of AML. Incorporation of cytarabine into DNA of primary leukemia cells correlates with sensitivity to this agent [25,26], thus forming the basis for alternative schedules of administration and augmentation with other agents such as the nucleoside analogs fludarabine [27] and cladribine [28]. Braess et al [29] demonstrated that leukemia blasts from inv(16)/t(16;16) AML patients have a higher proliferation rate that in vitro studies correlate with increased DNA uptake and sensitivity to cytarabine. Other chemotherapy drugs that are active in AML may not be able to substitute for cytarabine with regard to killing inv(16) leukemia cells.

There are several limitations of our analysis. We studied only a small number of patients because we focused our analysis on one specific cytogenetic subtype of AML from a large series of AML patients. However, with the recognition of specific genetic subsets within AML, such analyses are necessary to detect improved outcomes when new interventions that incorporate either targeted therapy or a conventional therapy, such as HDAC, are administered based on the biology of the disease [24,29]. In addition, this was not a randomized clinical trial comparing one versus several cycles of HDAC. Patients were assigned to one or to three to four cycles of HDAC according to protocol designs, raising the possibility of a disproportionate number of patients with adverse features in one group. However, examination of pretreatment prognostic features demonstrated small differences between the two patient groups, and a multivariable analysis demonstrated that only intensification treatment (three to four v one cycle of HDAC) was associated with improved RFS. This same analysis was performed based on the actual treatment received with similar results in the multivariable analysis, which demonstrated that only treatment received (three to four cycles v one cycle of HDAC) was predictive of improved RFS. Finally, postinduction therapy within the group who received three to four cycles of HDAC was slightly different depending on specific protocols, with the group assigned to receive four cycles of HDAC also receiving a short course of maintenance. Despite this, no differences in RFS, CIR, or OS were seen between the patients assigned to receive three cycles and the patients assigned to receive four cycles of HDAC and maintenance therapy. Thus, although our data are retrospectively derived, this study and our previous study evaluating patients with t(8;21) [7] suggest that repetitive doses of HDAC are important for both inv(16) and t(8;21) AML. It is also possible that alternative treatment approaches that use more intensive induction therapy will be equally effective for treating this genetic subtype of AML, as demonstrated by several different groups [30,31].

Given the similar improved outcome among patients with inv(16) and t(8;21) AML with repetitive doses of HDAC in our series, future prospective randomized clinical trials should be considered for this patient population, examining the importance of the number of courses and amount of HDAC that should be administered during consolidation. In addition, detailed assessment of disease eradication early in the course of the disease should occur based on the observations of others [32,33], with consideration of altering therapy if the presence of blasts during early induction predicts for eventual treatment failure. Such a randomized trial with associated correlative studies would likely require international collaboration to accrue the required number of patients. For now, the CALGB has continued to include three repetitive courses of HDAC consolidation for treatment of all t(8;21) and inv(16)/t(16;16) patients in first CR.

	Appendix

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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 and Mark J. Pettenati (grant no. CA03927); University of Alabama at Birmingham, Birmingham, AL: Robert Diasio and Andrew J. Carroll (grant no. CA47545); University of Maryland Cancer Center, Baltimore, MD: Martin 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 and Ram S. Verma (grant no. CA07968); Dartmouth Medical School, Lebanon, NH: Marc S. Ernstoff and Doris H. Wurster-Hill (grant no. CA04326); University of Iowa Hospitals, Iowa City, IA: Gerald H. Clamon and Shivanand R. Patil (grant no. CA47642); University of Massachusetts Medical Center, Worcester, MA: Mary Ellen Taplin and Philip L. Townes (grant no. CA37135); Roswell Park Cancer Institute, Buffalo, NY: Ellis G. Levine and AnneMarie W. Block (grant no. CA02599); Dana-Farber Partners Cancer Care, Boston, MA: George P. Canellos and Ramana Tantravahi (grant no. CA32291); North Shore-Long Island Jewish Health System, Manhasset, NY: Daniel R. Budman and Prasad R.K. Koduru (grant no. CA35279); University of Chicago Medical Center, Chicago, IL: Gini Fleming and Michelle M. LeBeau (grant no. CA41287); Mount Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld (grant no. CA04457); Massachusetts General Hospital, Boston, MA: Michael L. Grossbard and Leonard L. Atkins (grant no. CA 12,449); Columbia Medical Center, Columbia, NY: Rose Ruth Ellison and Dorothy Warburton; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry and Tim Huang (grant no. CA12046); Ft. Wayne Medical Oncology/Hematology, Ft. Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; Rhode Island Hospital, Providence, RI: William Sikov and Hon Fong L. Mark (grant no. CA08025); and Duke University Medical Center, Durham, NC: Jeffrey Crawford and Sandra H. Bigner (grant no. CA47577).

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by National Cancer Institute grants CA101140, CA31946, CA16058, and CA77658, the Kimmel Cancer Research Foundation, the Leukemia and Lymphoma Society of America, the D. Warren Brown Foundation, and the Coleman Leukemia Research Fund. Additional grant support for participating institutions is listed in the online Appendix. J.C.B. is a Clinical Scholar of the Leukemia and Lymphoma Society of America.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted July 2, 2003; accepted January 6, 2004.

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