Prognostic Factors and Outcome of Core Binding Factor Acute Myeloid Leukemia Patients With t(8;21) Differ From Those of Patients With inv(16
http://www.100md.com
▲還散笫雖悝◎
the Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH
The CALGB Statistical Center and Duke University Medical Center, Durham, NC
North Shore University Hospital, Manhasset, NY
Dana-Farber Cancer Institute, Boston, MA
Wake Forest University School of Medicine, Winston-Salem, NC
University of Chicago, Chicago, IL
Wayne State University School of Medicine, Detroit, MI
University of Alabama at Birmingham, Birmingham, AL
ABSTRACT
PURPOSE: Because both t(8;21) and inv(16) disrupt core binding factor (CBF) in acute myeloid leukemia (AML) and confer relatively favorable prognoses, these cytogenetic groups are often treated similarly. Recent studies, however, have shown different gene profiling for the two groups, underscoring potential biologic differences. Therefore, we sought to determine whether these two cytogenetic groups should also be considered separate entities from a clinical standpoint.
PATIENTS AND METHODS: We analyzed 144 consecutive adults with t(8;21) and 168 with inv(16) treated on Cancer and Leukemia Group B front-line studies. We compared pretreatment features, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) between the two groups.
RESULTS: With a median follow-up of 6.4 years, for CBF AML as a whole, the CR rate was 88%, 5-year OS was 50% and CIR was 53%. After adjusting for covariates, patients with t(8;21) had shorter OS (hazard ratio [HR] = 1.5; P = .045) and survival after first relapse (HR = 1.7; P = .009) than patients with inv(16). Unexpectedly, race was an important predictor for t(8;21) AML, in that nonwhites failed induction more often (odds ratio = 5.7; P = .006) and had shorter OS than whites when certain secondary cytogenetic abnormalities were present. In patients with t(8;21) younger than 60 years, type of induction also correlated with relapse risk. For inv(16) AML, secondary cytogenetic abnormalities (especially +22) and male sex predicted better outcome.
CONCLUSION: When the prognostic impact of race, secondary cytogenetic abnormalities, sex, and response to salvage treatment is considered, t(8;21) and inv(16) AMLs seem to be distinct clinical entities and should be stratified and reported separately.
INTRODUCTION
Nonrandom chromosome abnormalities are identified in approximately 55% of adults with de novo acute myeloid leukemia (AML) and have long been recognized as important independent predictors for clinical outcome.1每6 Translocation (8;21)(q22;q22) and its variants [abbreviated t(8;21)] and inv(16)(p13q22) or t(16;16)(p13;q22) [abbreviated inv(16)] are among the most common cytogenetic aberrations, occurring in approximately 7% and 8% of adults with de novo AML, respectively.6 At the molecular level, t(8;21) and inv(16) result in the creation of the fusion genes RUNX1/CBFA2T1 and CBFB/MYH11 that disrupt the and ? subunits, respectively, of core binding factor (CBF), a heterodimeric transcription factor involved in the regulation of hematopoiesis.7每10 Both cytogenetic groups (collectively referred to as CBF AML) have also been associated with a relatively favorable prognosis compared with patients with normal or adverse karyotypes, and clinical studies have often stratified these patients together, into one favorable-risk prognostic category, and treated them similarly.3,5,6,11每13
However, patients with t(8;21) or inv(16) AML seem to differ with respect to several biologic features. Recently, microarray gene expression profiling studies showed that patients with t(8;21) and inv(16) AML segregated into two14,15 or more16 different groups. This diversity might reflect the morphologic and cytogenetic differences between patients with t(8;21) and those with inv(16) that are evident at diagnosis. Patients with t(8;21) frequently present with the French-American-British (FAB) morphologic subtype M2 and display loss of a sex chromosome (每Y or 每X) and/or deletions of the long arm of chromosome 9 [del(9q)] as secondary cytogenetic changes.3每6,17,18 In contrast, patients with inv(16) are more often diagnosed with the FAB subtype M4Eo and present with this rearrangement as a sole chromosome aberration or with trisomies of chromosomes 22, 8, and 21, if secondary cytogenetic changes are present.3每6,18,19
Hence, the question arises of whether patients with t(8;21) and inv(16) AML should be considered distinct entities on the basis not only of biologic differences but also from a clinical standpoint. To answer this question, we directly compared the differential effect of prognostic features and treatment regimens on long-term outcome of 144 patients with t(8;21) AML with those of 168 patients with inv(16) AML.
PATIENTS AND METHODS
Patients and Cytogenetic Analysis
We identified 312 consecutive adult patients with AML enrolled onto the prospective cytogenetic study Cancer and Leukemia Group B (CALGB) 846120 who had a successful cytogenetic analysis of bone marrow (BM) and/or blood at diagnosis that detected t(8;21) or inv(16). All karyotypes, interpreted according to the International System for Human Cytogenetic Nomenclature,21 were analyzed in CALGB-designated institutional laboratories and confirmed by central review. BM samples underwent central pathology review to confirm diagnosis of AML and FAB morphologic classification.
Patients were enrolled onto one of the CALGB frontline treatment protocols, and signed an IRB-approved, protocol-specific informed consent. Details of the therapeutic schemas for the CALGB protocols have been reported previously.12,13,22每29 Of the 312 enrolled patients, only 303 [139 with t(8;21) and 164 with inv(16)] received treatment and were included in outcome analyses. Of the nine patients excluded, one refused treatment, four died before starting treatment, and four received therapy off-study. The majority of the patients received one of the following induction regimens: (1) cytarabine 200 mg/m2/d x 7 days in combination with daunorubicin 45 mg/m2/d x 3 days (AD) [83 patients with t(8;21) and 98 with inv(16) on CALGB 8221, 8525, 8821, 8923, 9022, 9222] or (2) cytarabine 100 mg/m2/d x 7 days in combination with daunorubicin and etoposide x 3 days ㊣ PSC-833, a multidrug resistance modulator (ADE ㊣ P) [53 patients with t(8;21) and 62 with inv(16) on CALGB 9420, 9621, 9720, 19808]. Only seven remaining patients were assigned to different induction regimens [three patients with t(8;21) and four with inv(16) on CALGB 8321, 8361, 8621, 9120].
As part of consolidation, most patients received cytarabine, according to one of the following doses and schedules: (a) 100 mg/m2/d for 5 days x four courses; (b) 400 mg/m2/d for 5 days x four courses; (c) 3 g/m2 every 12 hours on days 1, 3, and 5 x 3 or 4 courses; or (d) 3 g/m2 every 12 hours on days 1, 3, and 5 x one course followed by consolidation with etoposide/cyclophosphamide (x one course) and diaziquinone/mitoxantrone (x one course).
Definition of Clinical End Points
Complete remission (CR) was defined as recovery of morphologically normal BM and normal blood counts (ie, neutrophils 1500/米L and platelets 100,000/米L) and no circulating leukemic blasts or evidence of extramedullary leukemia. Relapse was defined by 5% BM blasts, circulating leukemic blasts, or development of extramedullary leukemia.30
Overall survival (OS) was measured from the date on study until date of death or date last known alive. Cumulative incidence of relapse (CIR) was measured only in patients who achieved a CR, from the date of CR to date of relapse, death, or date last known alive, in which death in CR was considered a competing risk.
Statistical Analysis
The purpose of the study was to identify and compare prognostic factors for AML patients with t(8;21) and inv(16). Fisher's exact and Wilcoxon rank sum tests compared categoric and continuous variables, respectively. To analyze factors related to the probability of achieving CR and to determine whether cytogenetic group was significant once adjusting for other covariates, logistic regression models were constructed using a limited backward selection procedure. Variables remaining in the model were significant at = .05, unless found to be important confounders, defined by a change in the estimated coefficients of at least 15%. Odds ratios and 95% confidence intervals (CI) were obtained to describe the odds of induction failure for significant prognostic factors.
Estimated probabilities for OS were calculated by the Kaplan-Meier method, and the log-rank test evaluated differences between survival distributions. Estimates of CIR were calculated, and Gray's k-sample test was used to evaluate differences in relapse rates.31
A proportional hazards model was constructed for OS, whereas a multivariable model using Gray's method was constructed for CIR, using a limited backward selection procedure.32 Adjusted survival curves from the proportional hazards and Gray models were generated using average covariate values. Estimates for hazard ratios and corresponding 95% CIs were obtained for each significant prognostic factor. The proportional hazards assumption was checked individually for each variable in the OS model. Appropriate transformations were made for continuous variables with highly skewed distributions.
To assess the prognostic impact of consolidation with high-dose cytarabine (HDAC), patients younger than 60 years who had achieved a CR and were assigned to receive at least one cycle of HDAC were classified according to the assigned consolidation treatment. Because no significant differences in OS (P = .48) or CIR (P = .66) were noted among patients receiving cytarabine 3 g/m2 every 12 hours on days 1, 3, and 5 x three or four courses and those receiving cytarabine 400 mg/m2/d for 5 days x four courses, these patients were pooled together as the "multicourse HDAC" group and compared with patients receiving only a single course of HDAC (ie, 3 g/m2).
All tests of statistical significance were two-sided at an level of .05. The CALGB Statistical Center performed all analyses.
RESULTS
Patients' Clinical Characteristics at Diagnosis
Of 312 patients, 144 had t(8;21) and 168 had inv(16). The two groups differed significantly in several pretreatment characteristics (Table 1). There was a significant association between cytogenetic group and race. Patients with t(8;21) were less frequently white (69% versus 82%; P = .01) and more frequently African American (19% versus 8%) than those with inv(16). Normal metaphases were present more frequently in patients with t(8;21) than in those with inv(16) (47% versus 31%; P = .004) as were secondary chromosome abnormalities (69% versus 35%; P < .001). A summary of the most common secondary chromosomal abnormalities in each cytogenetic group is provided in Table 2.
Complete Remission After Induction
Of the 303 patients who received treatment on CALGB protocols and were assessable for response, 89% with t(8;21) and 87% with inv(16) achieved a CR (Table 3). On multivariable analysis, higher BM blasts (P = .008), older age (P = .01), lower platelets (P = .006), and nonwhite race (P = .005) adversely affected the achievement of CR when the two cytogenetic groups were considered together (Table 4). Most interestingly, race was an adverse factor for t(8;21) in that nonwhite patients in this cytogenetic group had 5.7 times the odds of not achieving a CR compared with the corresponding white population. Of 42 nonwhite patients with t(8;21), four (10%) died with refractory disease and five (12%) with hypoplastic BM after induction compared with only four (4%) and two (2%), respectively, among whites (Table 5). In contrast, for patients with inv(16), race was not a predictor of CR attainment, and the only adverse prognostic factors were hepatomegaly (P = .04) and lower platelets (P = .009; Tables 4 and 5).
Clinical Outcome〞OS and CIR
Estimated 5- and 10-year rates for OS and CIR are summarized in Table 3. With a median follow-up of 6.4 years (range, 0.3 to 19.0 years), patients with t(8;21) showed a trend toward shorter OS compared with patients with inv(16) (median 4.4 versus 7.1 year; P = .19), whereas no significant difference in CIR was observed between the two groups (median not reached versus 2.2 years; P = .60). Importantly, in a multivariable analysis, after adjusting for WBC, age and platelet count, patients with t(8;21) had a significantly shorter OS (Fig 1A) and risk of death 1.5 times higher than risk of death of patients with inv(16) (P = .045, Table 4). In addition to having t(8;21), older age (P < .001) and lower platelets (P = .05) significantly increased the risk of death (Table 4), whereas no significant prognostic factors were identified for CIR.
When the analysis was restricted to patients with t(8;21), older age (P = .05) and lower platelets (P = .05) were associated with a lower survival rate, and a moderate interaction (P = .13) was observed between race and secondary cytogenetics. Thus corresponding results are presented by race (Table 4). The long-term survival for nonwhite patients with t(8;21) and del(9q), those with sole t(8;21), and those with t(8;21) and secondary abnormalities other than del(9q) were 76%, 50%, and 20%, respectively (P = .02; Fig 2A). In contrast, no difference (P = .97) in long-term survival (ie, 40% to 50%) was observed among white patients with t(8;21) and del(9q), sole t(8;21), or t(8;21) with secondary cytogenetic abnormalities other than del(9q) (Fig 2B). Again, there were no significant variables that predicted CIR.
Prognostic factors for OS in patients with inv(16) were older age (P < .001) and lower platelets (P = .01) (Table 4). Furthermore, patients with inv(16) and one or more secondary abnormalities had lower risk of relapse compared with those with sole inv(16) (P = .02), with estimated long-term CIR rates of 42% and 66%, respectively. The favorable impact of secondary abnormalities on decreasing the risk of relapse could largely be attributed to the presence of +22 (Fig 3). This was also confirmed in a multivariable model in which risk of relapse was lower for patients with inv(16) who also had +22 (as the only secondary aberration or with other aberrations) compared with patients who had a sole inv(16) (P = .02; Table 4).
Survival After First Relapse
Despite similar CIR, patients with t(8;21) had a shorter survival than those with inv(16), suggesting an inferior response to salvage treatment. Indeed, survival of patients with t(8;21) after first relapse was significantly shorter than that of patients with inv(16) (median, 0.7 versus 1.2 years; P = .02), with a 5-year postrelapse survival of 14% compared with 34%, respectively (Fig 4A). Cytogenetic type of CBF AML (P = .009) and age (P = .004) were the only pretreatment factors that predicted shorter survival after relapse in a multivariable analysis. The risk of death after relapse was 1.7 times higher (95% CI, 1.1 to 2.6) for patients with t(8;21) than for those with inv(16). Even though there was no significant interaction between the cytogenetic groups and age, when the two cytogenetic groups were analyzed separately, older age significantly correlated with worse survival after relapse only in patients with inv(16) (P = .01). Interestingly, of the 132 patients with CBF who relapsed, 22 were known to have subsequently received an autologous stem cell transplantation (SCT) and 26 an allogeneic SCT. Patients who had received an autologous SCT had a longer survival than those who had received an allogeneic SCT (P = .03), with estimated 5-year postrelapse survival rates of 72% and 35%, respectively (Fig 4B). Because of small numbers, however, it was difficult to assess the benefit of the type of SCT after relapse for the cytogenetic groups individually. Of the patients with t(8;21), only six were known to have received an autologous SCT and 10 an allogeneic SCT. Of the patients with inv(16), 16 were known to have received an autologous and 16 an allogeneic SCT after relapse. A trend for longer survival was observed for those who received an autologous SCT (P = .06).
Outcome of CBF Patients Younger Than 60 Years
We reported previously that patients with CBF AML younger than 60 years who received HDAC postinduction had significantly longer remission.1,33,34 In this work, we expanded our previous studies and sought to determine whether the benefit from HDAC is similar in patients with t(8;21) and those with inv(16). The subsequent analyses comparing multicourse HDAC and single-course HDAC (regimens are described in detail under Statistical Analysis) were first conducted for all CBF AML patients and then, separately, for the t(8;21) and inv(16) groups (Tables 6 and 7).
Patients in the two consolidation groups, multicourse HDAC (n = 149) and single-course HDAC (n = 48), had similar presenting features at diagnosis (data not shown). Three patients who received off protocol SCT in first CR were excluded. It is noteworthy that 15 patients, 10 with t(8;21) and five with inv(16), in the multicourse HDAC group died in CR, whereas none of the patients in the single-course HDAC group did (P = .02). Nevertheless, with a median follow-up of 5.7 years (range, 0.3 to 19.0 years), patients with CBF assigned to multicourse HDAC were less likely to relapse (P < .001) (Fig 5A). The favorable impact of multicourse HDAC on outcome was also observed for both patients with t(8;21) (Fig 5B) and those with inv(16) (Fig 5C), when they were evaluated separately. The estimated 5- and 10-year rates of survival and CIR are summarized in Table 6.
To evaluate whether there was a difference in outcome between cytogenetic groups and/or consolidation regimens after adjusting for other variables, multivariable models were constructed. The variables included in the final models for CIR are summarized in Table 7. In CBF patients, multicourse HDAC reduced the risk of relapse (P < .001) compared with single-course HDAC. Patients with t(8;21) had a shorter survival (P = .008) (Fig 1B) with an estimated risk of death 2.0 times (95% CI, 1.2 to 3.4) higher than patients with inv(16); patients receiving HDAC consolidation survived longer, but not significantly so (P = .22) (Table 6).
When patients with t(8;21) and those with inv(16) were considered separately (Table 7), consolidation with multicourse HDAC reduced the risk of relapse in both cytogenetic groups when adjusting for other variables (P < .001 for both). Other factors that reduced the risk of relapse in patients with t(8;21) were AD induction therapy and lower platelets. Among the patients with inv(16), sex and secondary chromosome abnormalities were factors affecting CIR. Men had approximately half the risk of relapse compared with women (P = .006; Fig 6), and patients with +22 (P = .001) or other secondary cytogenetic abnormalities (P = .03) had a significantly lower risk of relapse than those with sole inv(16). No predictors for survival were identified for either patients with t(8;21) or those with inv(16).
DISCUSSION
Previous studies have evaluated the prognostic and clinical characteristics of patients with t(8;21) and inv(16) AML,17每19 but rarely have these two cytogenetic groups been compared directly.18 In the present study, one of the largest analyses of CBF AML reported so far and, to our knowledge, that with the longest follow-up, we show for the first time that after controlling for confounding variables, patients with t(8;21) have a significantly worse outcome than those with inv(16), despite similar treatment. Although the basis for such a difference remains to be fully elucidated, a dissimilar response to salvage therapies after relapse seems to be an important factor. In our study, patients with t(8;21) had a significantly shorter survival after relapse than those with inv(16). Similar results were also shown in a previous report by Schlenk et al.18 Interestingly, in our study, for relapsed inv(16) AML, autologous SCT seemed to be equally if not more effective treatment than allogeneic SCT. However, this observation should be confirmed prospectively in a larger patient population. Likewise, more patients with t(8;21) should be assessed to determine the effectiveness of autologous versus allogeneic SCT in relapsed patients with this translocation.
A novel finding of the current analysis was the prognostic impact of race.17每19 We have already reported a higher number of nonwhites among patients with t(8;21) than among those with inv(16).35 In the current analysis, we show for the first time that the nonwhite patients with t(8;21) also had higher odds of failing induction therapy compared with the corresponding white patient population. The reasons for such a disparity are unknown. Treatment outcomes could vary among distinct race or ethnic groups because of social issues such as unequal access to health care and compliance. For patients treated on the same protocols, however, these differences in outcome might reflect a true biologic diversity resulting in a more resistant disease and/or higher susceptibility to drug toxicity. Thus, future trials should pursue microarray and pharmacogenomic studies to define distinct patterns of gene activation or repression that might elucidate the molecular bases for different outcomes among racial subpopulations of patients with CBF AML and perhaps allow adjustments of the treatment approaches accordingly.36,37 Similar considerations are applicable to sex. In our subanalysis of patients with inv(16) younger than 60 years, women were significantly more likely to relapse than the corresponding male population, after controlling for other variables, a finding thus far not reported by others.
Patients with CBF AML can also be subdivided with regard to secondary cytogenetic abnormalities accompanying t(8;21) or inv(16). Our study confirms earlier observations that the incidence of secondary cytogenetic aberrations is significantly higher in t(8;21) than in inv(16) AML and that the distribution of specific secondary aberrations differs between patients with t(8;21) and those with inv(16).2每4,6,38,39 Previous studies by others3,38每45 and us6 also reported that the presence of these secondary aberrations did not negatively affect the prognosis in either cytogenetic group. In the current study, however, we showed for the first time a possible interaction between race and secondary cytogenetic abnormalities in patients with t(8;21). In fact, nonwhites with t(8;21) and secondary cytogenetic abnormalities other than del(9q) had shorter survival compared with nonwhites presenting with sole t(8;21) or t(8;21) with del(9q). In contrast, among white patients with t(8;21), neither del(9q), suggested previously to confer poor prognosis,46 nor loss of the Y chromosome, reported to bestow favorable47 and poor18 prognosis in single studies, affected clinical outcome. Importantly, we also report that patients with inv(16) and secondary +22 were less likely to relapse than those with sole inv(16). Our data are consistent with recent results of the German AML Intergroup study, in which secondary +22 was the only prognostic variable for longer relapse-free survival in adults with inv(16) aged 60 years.18 Further investigation is required to confirm these results and define the molecular basis for the differences in outcome determined by the presence or absence of these specific secondary abnormalities.
Although we did not confirm high WBC17,18 or WBC index18 as adverse predictors for clinical outcome in patients with t(8;21), we showed that older age negatively affected survival in both cytogenetic groups, in agreement with some,17 but not all,19 previous reports. However, when the analysis was limited to patients younger than 60 years, age ceased to be a prognostic factor within t(8;21) and inv(16) groups. Although a direct comparison between younger patients and those 60 years or older was not possible because of differences in postinduction therapies and the limited number of older patients, it is possible that worse outcome of older patients is related to the less aggressive treatment they received compared with the younger patients. With improvements of comorbidity management and supportive care, it is likely that intensive chemotherapeutic regimens, including consolidation with multicourse HDAC, can be adequately tolerated by older patients with AML. Therefore, we propose that future treatment studies adopt similar criteria of eligibility and treatment approaches for all patients with t(8;21) or inv(16) AML regardless of age.
Administration of consolidation with multicourse HDAC in patients younger than 60 years decreased the relapse rate; surprisingly, however, this did not translate into a more favorable survival in both cytogenetic groups. Although the reasons for this observation require further investigation, it is possible that in inv(16) AML, a favorable impact of the multicourse HDAC consolidation on survival was somewhat attenuated by the poorer outcome of patients (n = 10) in this consolidation group who had relapsed and were treated with salvage allogenic SCT compared with that of the corresponding patients (n = 4) in the single-course HDAC group (data not shown). Another surprising finding of our study in this younger subset of patients was that the type of induction treatment seemed to affect the two cytogenetic groups differently. The risk of relapse of patients with t(8;21) treated with AD seemed lower than that of patients who received ADE ㊣ P, whereas no significant differences in outcome were observed in patients with inv(16). Whether these results are related to the addition of etoposide and/or PSC-833 to the AD combination or to the lower dose of cytarabine (100 mg/m2) included in ADE ㊣ P compared with that in AD (200 mg/m2) remains unknown. However, because relatively few patients were included in this subanalysis, the superiority of AD compared with ADE ㊣ P requires confirmation in a prospective randomized study.
As in other similar reports,17每19 an obvious limitation of our study is that patients were treated on different protocols. However, both the incidence of t(8;21) and inv(16) and the rates of death in CR were similar in the sequential CALGB studies included in our analysis (data not shown). This indicates that the differences in outcome reported here were probably not related to the changes in the diagnostic techniques or improvement in the supportive care over time.
We conclude that patients with t(8;21) and inv(16) AML constitute two separate entities clinically, in that they differ with regard to multiple prognostic factors and response to induction and salvage treatments. Notably, for the first time, we show the impact of race on patients with t(8;21) and sex on patients with inv(16). Furthermore, because our data, based on a prolonged follow-up, show that the rates of relapse and long-term survival are still disappointing for both patients with t(8;21) AML and those with inv(16) AML, it is important that future studies identify and target therapeutically the leukemogenic mechanisms accountable for molecular14每16,48每50 and clinical differences between the two cytogenetic groups of CBF AML.
Appendix
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, Mark J. Pettenati, and Wendy L. Flejter (grant No. CA03927); University of Maryland Cancer Center, Baltimore, MD: Martin J. Edelman, Joseph R. Testa, Deana Hallman, Stuart Schwartz, Maimon M. Cohen, and Judith Stamberg (grant No. CA31983); 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, Leonard L. Atkins, and Paola Dal Cin (grant No. CA32291); North Shore University Hospital, Manhasset, NY: Daniel R. Budman and Prasad R. K. Koduru (grant No. CA35279); University of Iowa Hospitals, Iowa City, IA: Gerald H. Clamon and Shivanand R. Patil (grant No. CA47642); Dartmouth College, NCCC, Dartmouth Medical School, Lebanon, NH: Marc S. Ernstoff, Doris H. Wurster-Hill, and Thuluvancheri K. Mohandas (grant No. CA04326); Duke University Medical Center, Durham, NC: Jeffrey Crawford, Sandra H. Bigner, Mazin B. Qumsiyeh, and Barbara K. Goodman (grant No. CA47577); The Ohio State University, Columbus, OH: Clara D. Bloomfield, Karl S. Theil, Diane Minka, and Nyla A. Heerema (grant No. CA77658); University of North Carolina, Chapel Hill, NC: Thomas C. Shea, and Kathleen W. Rao (grant No. CA47559); Weill Medical College of Cornell University, New York, NY: Scott Wadler, Ram S. Verma, Prasad R. K. Koduru, and Andrew J. Carroll (grant No. CA07968); Washington University School of Medicine, St. Louis, MO: Nancy L. Bartlett, Michael S. Watson, Eric C. Crawford, and Jaime Garcia-Heras (grant No. CA77440); SUNY Upstate Medical University, Syracuse, NY: Stephen L. Graziano, Edward J. Hallinan, and Constance K. Stein (grant No. CA21060); Walter Reed Army Medical Center, Washington, DC: Thomas Reid, Rawatmal B. Surana, and Digamber S. Borgaonkar (grant No. CA26806); University of Tennessee Cancer Center, Memphis, TN: Harvey B. Niell and Sugandhi A. Tharapel (grant No. CA47555); Rhode Island Hospital, Providence, RI: William Sikov, Teresita Padre-Mendoza, Hon Fong L. Mark, and Shelly L. Kerman (grant No. CA08025); University of California, San Diego, CA: Stephen L. Seagren, E. Robert Wassman, Ren谷e Bernstein, and Marie L. Dell'Aquila (grant No. CA11789); Christiana Care Health System, Inc., Newark, DE: Stephen S. Grubbs and Digamber S. Borgaonkar (grant No. CA45418); Mount Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld (grant No. CA04457); Roswell Park Cancer Institute, Buffalo, NY: Ellis G. Levine and AnneMarie W. Block (grant No. CA02599); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry, Judith H. Miles, Jeffrey R. Sawyer, and Tim Huang (grant No. CA12046); Ft. Wayne Medical Oncology/Hematology Inc., Ft. Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; University of Chicago Medical Center, Chicago, IL: Gini Fleming, Michelle M. Le Beau, and Katrin M. Carlson (grant No. CA41287); University of Massachusetts Medical Center, Worcester, MA: Pankaj Bhargava, Philip L. Townes, and Vikram Jaswaney (grant No. CA37135); University of Vermont, Burlington, VT: Hyman B. Muss and Elizabeth F. Allen (grant No. CA77406); Massachusetts General Hospital, Boston, MA: Michael L. Grossbard and Leonard L. Atkins (grant No. CA12449); University of Puerto Rico, San Juan, PR: Enrique Velez-Garcia; Long Island Jewish Medical Center, Lake Success, NY: Kanti R. Rai and Prasad R. K. Koduru (grant No. CA11028); University of Minnesota, Minneapolis, MN: Bruce A. Peterson and Diane C. Arthur (grant No. CA16450); University of Nebraska Medical Center, Omaha, NE: Margaret A. Kessinger Wegner and Warren G. Sanger (grant No. CA77298); Columbia-Presbyterian Medical Center, New York, NY: Rose R. Ellison and Dorothy Warburton (CA12011); University of Illinois, Chicago, IL: Lawrence E. Feldman, Maureen M. McCorquodale, and Valerie Lindgren (grant CA74811); Virginia Commonwealth University MB CCOP, Richmond, VA: John D. Roberts and Colleen Jackson-Cook (grant No. CA52784); SUNY Maimonides Medical Center, Brooklyn, NY: Sameer Rafla and Ram S. Verma (grant No. CA25119); Eastern Maine Medical Center, Bangor, ME: Philip L. Brooks and Laurent J. Beauregard (grant No. CA35406); Georgetown University Medical Center, Washington, DC: Edward P. Gelmann and Jeanne M. Meck (grant No. CA77597); McGill Department of Oncology, Montreal, Quebec: J. L. Hutchison and Jacqueline Emond (grant No. CA31809); Western Pennsylvania Hospital, Pittsburgh, PA: Richard K. Shadduck and Gerard R. Diggans.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by National Cancer Institute grants No. CA77658, CA101140, CA31946, P30-CA16058, and K08-CA90469, and by The Coleman Leukemia Research Foundation.
Both G.M. and K.M. contributed equally to this work.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Mayer RJ, Davis RB, Schiffer CA, et al: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896每903, 1994
Lee EJ, George SL, Caligiuri M, et al: Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: Results of Cancer and Leukemia Group B study 9420. J Clin Oncol 17:2831每2839, 1999
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Byrd JC, Ruppert AS, Mr車zek K, et al: 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. J Clin Oncol 22:1087每1094, 2004
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The CALGB Statistical Center and Duke University Medical Center, Durham, NC
North Shore University Hospital, Manhasset, NY
Dana-Farber Cancer Institute, Boston, MA
Wake Forest University School of Medicine, Winston-Salem, NC
University of Chicago, Chicago, IL
Wayne State University School of Medicine, Detroit, MI
University of Alabama at Birmingham, Birmingham, AL
ABSTRACT
PURPOSE: Because both t(8;21) and inv(16) disrupt core binding factor (CBF) in acute myeloid leukemia (AML) and confer relatively favorable prognoses, these cytogenetic groups are often treated similarly. Recent studies, however, have shown different gene profiling for the two groups, underscoring potential biologic differences. Therefore, we sought to determine whether these two cytogenetic groups should also be considered separate entities from a clinical standpoint.
PATIENTS AND METHODS: We analyzed 144 consecutive adults with t(8;21) and 168 with inv(16) treated on Cancer and Leukemia Group B front-line studies. We compared pretreatment features, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) between the two groups.
RESULTS: With a median follow-up of 6.4 years, for CBF AML as a whole, the CR rate was 88%, 5-year OS was 50% and CIR was 53%. After adjusting for covariates, patients with t(8;21) had shorter OS (hazard ratio [HR] = 1.5; P = .045) and survival after first relapse (HR = 1.7; P = .009) than patients with inv(16). Unexpectedly, race was an important predictor for t(8;21) AML, in that nonwhites failed induction more often (odds ratio = 5.7; P = .006) and had shorter OS than whites when certain secondary cytogenetic abnormalities were present. In patients with t(8;21) younger than 60 years, type of induction also correlated with relapse risk. For inv(16) AML, secondary cytogenetic abnormalities (especially +22) and male sex predicted better outcome.
CONCLUSION: When the prognostic impact of race, secondary cytogenetic abnormalities, sex, and response to salvage treatment is considered, t(8;21) and inv(16) AMLs seem to be distinct clinical entities and should be stratified and reported separately.
INTRODUCTION
Nonrandom chromosome abnormalities are identified in approximately 55% of adults with de novo acute myeloid leukemia (AML) and have long been recognized as important independent predictors for clinical outcome.1每6 Translocation (8;21)(q22;q22) and its variants [abbreviated t(8;21)] and inv(16)(p13q22) or t(16;16)(p13;q22) [abbreviated inv(16)] are among the most common cytogenetic aberrations, occurring in approximately 7% and 8% of adults with de novo AML, respectively.6 At the molecular level, t(8;21) and inv(16) result in the creation of the fusion genes RUNX1/CBFA2T1 and CBFB/MYH11 that disrupt the and ? subunits, respectively, of core binding factor (CBF), a heterodimeric transcription factor involved in the regulation of hematopoiesis.7每10 Both cytogenetic groups (collectively referred to as CBF AML) have also been associated with a relatively favorable prognosis compared with patients with normal or adverse karyotypes, and clinical studies have often stratified these patients together, into one favorable-risk prognostic category, and treated them similarly.3,5,6,11每13
However, patients with t(8;21) or inv(16) AML seem to differ with respect to several biologic features. Recently, microarray gene expression profiling studies showed that patients with t(8;21) and inv(16) AML segregated into two14,15 or more16 different groups. This diversity might reflect the morphologic and cytogenetic differences between patients with t(8;21) and those with inv(16) that are evident at diagnosis. Patients with t(8;21) frequently present with the French-American-British (FAB) morphologic subtype M2 and display loss of a sex chromosome (每Y or 每X) and/or deletions of the long arm of chromosome 9 [del(9q)] as secondary cytogenetic changes.3每6,17,18 In contrast, patients with inv(16) are more often diagnosed with the FAB subtype M4Eo and present with this rearrangement as a sole chromosome aberration or with trisomies of chromosomes 22, 8, and 21, if secondary cytogenetic changes are present.3每6,18,19
Hence, the question arises of whether patients with t(8;21) and inv(16) AML should be considered distinct entities on the basis not only of biologic differences but also from a clinical standpoint. To answer this question, we directly compared the differential effect of prognostic features and treatment regimens on long-term outcome of 144 patients with t(8;21) AML with those of 168 patients with inv(16) AML.
PATIENTS AND METHODS
Patients and Cytogenetic Analysis
We identified 312 consecutive adult patients with AML enrolled onto the prospective cytogenetic study Cancer and Leukemia Group B (CALGB) 846120 who had a successful cytogenetic analysis of bone marrow (BM) and/or blood at diagnosis that detected t(8;21) or inv(16). All karyotypes, interpreted according to the International System for Human Cytogenetic Nomenclature,21 were analyzed in CALGB-designated institutional laboratories and confirmed by central review. BM samples underwent central pathology review to confirm diagnosis of AML and FAB morphologic classification.
Patients were enrolled onto one of the CALGB frontline treatment protocols, and signed an IRB-approved, protocol-specific informed consent. Details of the therapeutic schemas for the CALGB protocols have been reported previously.12,13,22每29 Of the 312 enrolled patients, only 303 [139 with t(8;21) and 164 with inv(16)] received treatment and were included in outcome analyses. Of the nine patients excluded, one refused treatment, four died before starting treatment, and four received therapy off-study. The majority of the patients received one of the following induction regimens: (1) cytarabine 200 mg/m2/d x 7 days in combination with daunorubicin 45 mg/m2/d x 3 days (AD) [83 patients with t(8;21) and 98 with inv(16) on CALGB 8221, 8525, 8821, 8923, 9022, 9222] or (2) cytarabine 100 mg/m2/d x 7 days in combination with daunorubicin and etoposide x 3 days ㊣ PSC-833, a multidrug resistance modulator (ADE ㊣ P) [53 patients with t(8;21) and 62 with inv(16) on CALGB 9420, 9621, 9720, 19808]. Only seven remaining patients were assigned to different induction regimens [three patients with t(8;21) and four with inv(16) on CALGB 8321, 8361, 8621, 9120].
As part of consolidation, most patients received cytarabine, according to one of the following doses and schedules: (a) 100 mg/m2/d for 5 days x four courses; (b) 400 mg/m2/d for 5 days x four courses; (c) 3 g/m2 every 12 hours on days 1, 3, and 5 x 3 or 4 courses; or (d) 3 g/m2 every 12 hours on days 1, 3, and 5 x one course followed by consolidation with etoposide/cyclophosphamide (x one course) and diaziquinone/mitoxantrone (x one course).
Definition of Clinical End Points
Complete remission (CR) was defined as recovery of morphologically normal BM and normal blood counts (ie, neutrophils 1500/米L and platelets 100,000/米L) and no circulating leukemic blasts or evidence of extramedullary leukemia. Relapse was defined by 5% BM blasts, circulating leukemic blasts, or development of extramedullary leukemia.30
Overall survival (OS) was measured from the date on study until date of death or date last known alive. Cumulative incidence of relapse (CIR) was measured only in patients who achieved a CR, from the date of CR to date of relapse, death, or date last known alive, in which death in CR was considered a competing risk.
Statistical Analysis
The purpose of the study was to identify and compare prognostic factors for AML patients with t(8;21) and inv(16). Fisher's exact and Wilcoxon rank sum tests compared categoric and continuous variables, respectively. To analyze factors related to the probability of achieving CR and to determine whether cytogenetic group was significant once adjusting for other covariates, logistic regression models were constructed using a limited backward selection procedure. Variables remaining in the model were significant at = .05, unless found to be important confounders, defined by a change in the estimated coefficients of at least 15%. Odds ratios and 95% confidence intervals (CI) were obtained to describe the odds of induction failure for significant prognostic factors.
Estimated probabilities for OS were calculated by the Kaplan-Meier method, and the log-rank test evaluated differences between survival distributions. Estimates of CIR were calculated, and Gray's k-sample test was used to evaluate differences in relapse rates.31
A proportional hazards model was constructed for OS, whereas a multivariable model using Gray's method was constructed for CIR, using a limited backward selection procedure.32 Adjusted survival curves from the proportional hazards and Gray models were generated using average covariate values. Estimates for hazard ratios and corresponding 95% CIs were obtained for each significant prognostic factor. The proportional hazards assumption was checked individually for each variable in the OS model. Appropriate transformations were made for continuous variables with highly skewed distributions.
To assess the prognostic impact of consolidation with high-dose cytarabine (HDAC), patients younger than 60 years who had achieved a CR and were assigned to receive at least one cycle of HDAC were classified according to the assigned consolidation treatment. Because no significant differences in OS (P = .48) or CIR (P = .66) were noted among patients receiving cytarabine 3 g/m2 every 12 hours on days 1, 3, and 5 x three or four courses and those receiving cytarabine 400 mg/m2/d for 5 days x four courses, these patients were pooled together as the "multicourse HDAC" group and compared with patients receiving only a single course of HDAC (ie, 3 g/m2).
All tests of statistical significance were two-sided at an level of .05. The CALGB Statistical Center performed all analyses.
RESULTS
Patients' Clinical Characteristics at Diagnosis
Of 312 patients, 144 had t(8;21) and 168 had inv(16). The two groups differed significantly in several pretreatment characteristics (Table 1). There was a significant association between cytogenetic group and race. Patients with t(8;21) were less frequently white (69% versus 82%; P = .01) and more frequently African American (19% versus 8%) than those with inv(16). Normal metaphases were present more frequently in patients with t(8;21) than in those with inv(16) (47% versus 31%; P = .004) as were secondary chromosome abnormalities (69% versus 35%; P < .001). A summary of the most common secondary chromosomal abnormalities in each cytogenetic group is provided in Table 2.
Complete Remission After Induction
Of the 303 patients who received treatment on CALGB protocols and were assessable for response, 89% with t(8;21) and 87% with inv(16) achieved a CR (Table 3). On multivariable analysis, higher BM blasts (P = .008), older age (P = .01), lower platelets (P = .006), and nonwhite race (P = .005) adversely affected the achievement of CR when the two cytogenetic groups were considered together (Table 4). Most interestingly, race was an adverse factor for t(8;21) in that nonwhite patients in this cytogenetic group had 5.7 times the odds of not achieving a CR compared with the corresponding white population. Of 42 nonwhite patients with t(8;21), four (10%) died with refractory disease and five (12%) with hypoplastic BM after induction compared with only four (4%) and two (2%), respectively, among whites (Table 5). In contrast, for patients with inv(16), race was not a predictor of CR attainment, and the only adverse prognostic factors were hepatomegaly (P = .04) and lower platelets (P = .009; Tables 4 and 5).
Clinical Outcome〞OS and CIR
Estimated 5- and 10-year rates for OS and CIR are summarized in Table 3. With a median follow-up of 6.4 years (range, 0.3 to 19.0 years), patients with t(8;21) showed a trend toward shorter OS compared with patients with inv(16) (median 4.4 versus 7.1 year; P = .19), whereas no significant difference in CIR was observed between the two groups (median not reached versus 2.2 years; P = .60). Importantly, in a multivariable analysis, after adjusting for WBC, age and platelet count, patients with t(8;21) had a significantly shorter OS (Fig 1A) and risk of death 1.5 times higher than risk of death of patients with inv(16) (P = .045, Table 4). In addition to having t(8;21), older age (P < .001) and lower platelets (P = .05) significantly increased the risk of death (Table 4), whereas no significant prognostic factors were identified for CIR.
When the analysis was restricted to patients with t(8;21), older age (P = .05) and lower platelets (P = .05) were associated with a lower survival rate, and a moderate interaction (P = .13) was observed between race and secondary cytogenetics. Thus corresponding results are presented by race (Table 4). The long-term survival for nonwhite patients with t(8;21) and del(9q), those with sole t(8;21), and those with t(8;21) and secondary abnormalities other than del(9q) were 76%, 50%, and 20%, respectively (P = .02; Fig 2A). In contrast, no difference (P = .97) in long-term survival (ie, 40% to 50%) was observed among white patients with t(8;21) and del(9q), sole t(8;21), or t(8;21) with secondary cytogenetic abnormalities other than del(9q) (Fig 2B). Again, there were no significant variables that predicted CIR.
Prognostic factors for OS in patients with inv(16) were older age (P < .001) and lower platelets (P = .01) (Table 4). Furthermore, patients with inv(16) and one or more secondary abnormalities had lower risk of relapse compared with those with sole inv(16) (P = .02), with estimated long-term CIR rates of 42% and 66%, respectively. The favorable impact of secondary abnormalities on decreasing the risk of relapse could largely be attributed to the presence of +22 (Fig 3). This was also confirmed in a multivariable model in which risk of relapse was lower for patients with inv(16) who also had +22 (as the only secondary aberration or with other aberrations) compared with patients who had a sole inv(16) (P = .02; Table 4).
Survival After First Relapse
Despite similar CIR, patients with t(8;21) had a shorter survival than those with inv(16), suggesting an inferior response to salvage treatment. Indeed, survival of patients with t(8;21) after first relapse was significantly shorter than that of patients with inv(16) (median, 0.7 versus 1.2 years; P = .02), with a 5-year postrelapse survival of 14% compared with 34%, respectively (Fig 4A). Cytogenetic type of CBF AML (P = .009) and age (P = .004) were the only pretreatment factors that predicted shorter survival after relapse in a multivariable analysis. The risk of death after relapse was 1.7 times higher (95% CI, 1.1 to 2.6) for patients with t(8;21) than for those with inv(16). Even though there was no significant interaction between the cytogenetic groups and age, when the two cytogenetic groups were analyzed separately, older age significantly correlated with worse survival after relapse only in patients with inv(16) (P = .01). Interestingly, of the 132 patients with CBF who relapsed, 22 were known to have subsequently received an autologous stem cell transplantation (SCT) and 26 an allogeneic SCT. Patients who had received an autologous SCT had a longer survival than those who had received an allogeneic SCT (P = .03), with estimated 5-year postrelapse survival rates of 72% and 35%, respectively (Fig 4B). Because of small numbers, however, it was difficult to assess the benefit of the type of SCT after relapse for the cytogenetic groups individually. Of the patients with t(8;21), only six were known to have received an autologous SCT and 10 an allogeneic SCT. Of the patients with inv(16), 16 were known to have received an autologous and 16 an allogeneic SCT after relapse. A trend for longer survival was observed for those who received an autologous SCT (P = .06).
Outcome of CBF Patients Younger Than 60 Years
We reported previously that patients with CBF AML younger than 60 years who received HDAC postinduction had significantly longer remission.1,33,34 In this work, we expanded our previous studies and sought to determine whether the benefit from HDAC is similar in patients with t(8;21) and those with inv(16). The subsequent analyses comparing multicourse HDAC and single-course HDAC (regimens are described in detail under Statistical Analysis) were first conducted for all CBF AML patients and then, separately, for the t(8;21) and inv(16) groups (Tables 6 and 7).
Patients in the two consolidation groups, multicourse HDAC (n = 149) and single-course HDAC (n = 48), had similar presenting features at diagnosis (data not shown). Three patients who received off protocol SCT in first CR were excluded. It is noteworthy that 15 patients, 10 with t(8;21) and five with inv(16), in the multicourse HDAC group died in CR, whereas none of the patients in the single-course HDAC group did (P = .02). Nevertheless, with a median follow-up of 5.7 years (range, 0.3 to 19.0 years), patients with CBF assigned to multicourse HDAC were less likely to relapse (P < .001) (Fig 5A). The favorable impact of multicourse HDAC on outcome was also observed for both patients with t(8;21) (Fig 5B) and those with inv(16) (Fig 5C), when they were evaluated separately. The estimated 5- and 10-year rates of survival and CIR are summarized in Table 6.
To evaluate whether there was a difference in outcome between cytogenetic groups and/or consolidation regimens after adjusting for other variables, multivariable models were constructed. The variables included in the final models for CIR are summarized in Table 7. In CBF patients, multicourse HDAC reduced the risk of relapse (P < .001) compared with single-course HDAC. Patients with t(8;21) had a shorter survival (P = .008) (Fig 1B) with an estimated risk of death 2.0 times (95% CI, 1.2 to 3.4) higher than patients with inv(16); patients receiving HDAC consolidation survived longer, but not significantly so (P = .22) (Table 6).
When patients with t(8;21) and those with inv(16) were considered separately (Table 7), consolidation with multicourse HDAC reduced the risk of relapse in both cytogenetic groups when adjusting for other variables (P < .001 for both). Other factors that reduced the risk of relapse in patients with t(8;21) were AD induction therapy and lower platelets. Among the patients with inv(16), sex and secondary chromosome abnormalities were factors affecting CIR. Men had approximately half the risk of relapse compared with women (P = .006; Fig 6), and patients with +22 (P = .001) or other secondary cytogenetic abnormalities (P = .03) had a significantly lower risk of relapse than those with sole inv(16). No predictors for survival were identified for either patients with t(8;21) or those with inv(16).
DISCUSSION
Previous studies have evaluated the prognostic and clinical characteristics of patients with t(8;21) and inv(16) AML,17每19 but rarely have these two cytogenetic groups been compared directly.18 In the present study, one of the largest analyses of CBF AML reported so far and, to our knowledge, that with the longest follow-up, we show for the first time that after controlling for confounding variables, patients with t(8;21) have a significantly worse outcome than those with inv(16), despite similar treatment. Although the basis for such a difference remains to be fully elucidated, a dissimilar response to salvage therapies after relapse seems to be an important factor. In our study, patients with t(8;21) had a significantly shorter survival after relapse than those with inv(16). Similar results were also shown in a previous report by Schlenk et al.18 Interestingly, in our study, for relapsed inv(16) AML, autologous SCT seemed to be equally if not more effective treatment than allogeneic SCT. However, this observation should be confirmed prospectively in a larger patient population. Likewise, more patients with t(8;21) should be assessed to determine the effectiveness of autologous versus allogeneic SCT in relapsed patients with this translocation.
A novel finding of the current analysis was the prognostic impact of race.17每19 We have already reported a higher number of nonwhites among patients with t(8;21) than among those with inv(16).35 In the current analysis, we show for the first time that the nonwhite patients with t(8;21) also had higher odds of failing induction therapy compared with the corresponding white patient population. The reasons for such a disparity are unknown. Treatment outcomes could vary among distinct race or ethnic groups because of social issues such as unequal access to health care and compliance. For patients treated on the same protocols, however, these differences in outcome might reflect a true biologic diversity resulting in a more resistant disease and/or higher susceptibility to drug toxicity. Thus, future trials should pursue microarray and pharmacogenomic studies to define distinct patterns of gene activation or repression that might elucidate the molecular bases for different outcomes among racial subpopulations of patients with CBF AML and perhaps allow adjustments of the treatment approaches accordingly.36,37 Similar considerations are applicable to sex. In our subanalysis of patients with inv(16) younger than 60 years, women were significantly more likely to relapse than the corresponding male population, after controlling for other variables, a finding thus far not reported by others.
Patients with CBF AML can also be subdivided with regard to secondary cytogenetic abnormalities accompanying t(8;21) or inv(16). Our study confirms earlier observations that the incidence of secondary cytogenetic aberrations is significantly higher in t(8;21) than in inv(16) AML and that the distribution of specific secondary aberrations differs between patients with t(8;21) and those with inv(16).2每4,6,38,39 Previous studies by others3,38每45 and us6 also reported that the presence of these secondary aberrations did not negatively affect the prognosis in either cytogenetic group. In the current study, however, we showed for the first time a possible interaction between race and secondary cytogenetic abnormalities in patients with t(8;21). In fact, nonwhites with t(8;21) and secondary cytogenetic abnormalities other than del(9q) had shorter survival compared with nonwhites presenting with sole t(8;21) or t(8;21) with del(9q). In contrast, among white patients with t(8;21), neither del(9q), suggested previously to confer poor prognosis,46 nor loss of the Y chromosome, reported to bestow favorable47 and poor18 prognosis in single studies, affected clinical outcome. Importantly, we also report that patients with inv(16) and secondary +22 were less likely to relapse than those with sole inv(16). Our data are consistent with recent results of the German AML Intergroup study, in which secondary +22 was the only prognostic variable for longer relapse-free survival in adults with inv(16) aged 60 years.18 Further investigation is required to confirm these results and define the molecular basis for the differences in outcome determined by the presence or absence of these specific secondary abnormalities.
Although we did not confirm high WBC17,18 or WBC index18 as adverse predictors for clinical outcome in patients with t(8;21), we showed that older age negatively affected survival in both cytogenetic groups, in agreement with some,17 but not all,19 previous reports. However, when the analysis was limited to patients younger than 60 years, age ceased to be a prognostic factor within t(8;21) and inv(16) groups. Although a direct comparison between younger patients and those 60 years or older was not possible because of differences in postinduction therapies and the limited number of older patients, it is possible that worse outcome of older patients is related to the less aggressive treatment they received compared with the younger patients. With improvements of comorbidity management and supportive care, it is likely that intensive chemotherapeutic regimens, including consolidation with multicourse HDAC, can be adequately tolerated by older patients with AML. Therefore, we propose that future treatment studies adopt similar criteria of eligibility and treatment approaches for all patients with t(8;21) or inv(16) AML regardless of age.
Administration of consolidation with multicourse HDAC in patients younger than 60 years decreased the relapse rate; surprisingly, however, this did not translate into a more favorable survival in both cytogenetic groups. Although the reasons for this observation require further investigation, it is possible that in inv(16) AML, a favorable impact of the multicourse HDAC consolidation on survival was somewhat attenuated by the poorer outcome of patients (n = 10) in this consolidation group who had relapsed and were treated with salvage allogenic SCT compared with that of the corresponding patients (n = 4) in the single-course HDAC group (data not shown). Another surprising finding of our study in this younger subset of patients was that the type of induction treatment seemed to affect the two cytogenetic groups differently. The risk of relapse of patients with t(8;21) treated with AD seemed lower than that of patients who received ADE ㊣ P, whereas no significant differences in outcome were observed in patients with inv(16). Whether these results are related to the addition of etoposide and/or PSC-833 to the AD combination or to the lower dose of cytarabine (100 mg/m2) included in ADE ㊣ P compared with that in AD (200 mg/m2) remains unknown. However, because relatively few patients were included in this subanalysis, the superiority of AD compared with ADE ㊣ P requires confirmation in a prospective randomized study.
As in other similar reports,17每19 an obvious limitation of our study is that patients were treated on different protocols. However, both the incidence of t(8;21) and inv(16) and the rates of death in CR were similar in the sequential CALGB studies included in our analysis (data not shown). This indicates that the differences in outcome reported here were probably not related to the changes in the diagnostic techniques or improvement in the supportive care over time.
We conclude that patients with t(8;21) and inv(16) AML constitute two separate entities clinically, in that they differ with regard to multiple prognostic factors and response to induction and salvage treatments. Notably, for the first time, we show the impact of race on patients with t(8;21) and sex on patients with inv(16). Furthermore, because our data, based on a prolonged follow-up, show that the rates of relapse and long-term survival are still disappointing for both patients with t(8;21) AML and those with inv(16) AML, it is important that future studies identify and target therapeutically the leukemogenic mechanisms accountable for molecular14每16,48每50 and clinical differences between the two cytogenetic groups of CBF AML.
Appendix
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, Mark J. Pettenati, and Wendy L. Flejter (grant No. CA03927); University of Maryland Cancer Center, Baltimore, MD: Martin J. Edelman, Joseph R. Testa, Deana Hallman, Stuart Schwartz, Maimon M. Cohen, and Judith Stamberg (grant No. CA31983); 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, Leonard L. Atkins, and Paola Dal Cin (grant No. CA32291); North Shore University Hospital, Manhasset, NY: Daniel R. Budman and Prasad R. K. Koduru (grant No. CA35279); University of Iowa Hospitals, Iowa City, IA: Gerald H. Clamon and Shivanand R. Patil (grant No. CA47642); Dartmouth College, NCCC, Dartmouth Medical School, Lebanon, NH: Marc S. Ernstoff, Doris H. Wurster-Hill, and Thuluvancheri K. Mohandas (grant No. CA04326); Duke University Medical Center, Durham, NC: Jeffrey Crawford, Sandra H. Bigner, Mazin B. Qumsiyeh, and Barbara K. Goodman (grant No. CA47577); The Ohio State University, Columbus, OH: Clara D. Bloomfield, Karl S. Theil, Diane Minka, and Nyla A. Heerema (grant No. CA77658); University of North Carolina, Chapel Hill, NC: Thomas C. Shea, and Kathleen W. Rao (grant No. CA47559); Weill Medical College of Cornell University, New York, NY: Scott Wadler, Ram S. Verma, Prasad R. K. Koduru, and Andrew J. Carroll (grant No. CA07968); Washington University School of Medicine, St. Louis, MO: Nancy L. Bartlett, Michael S. Watson, Eric C. Crawford, and Jaime Garcia-Heras (grant No. CA77440); SUNY Upstate Medical University, Syracuse, NY: Stephen L. Graziano, Edward J. Hallinan, and Constance K. Stein (grant No. CA21060); Walter Reed Army Medical Center, Washington, DC: Thomas Reid, Rawatmal B. Surana, and Digamber S. Borgaonkar (grant No. CA26806); University of Tennessee Cancer Center, Memphis, TN: Harvey B. Niell and Sugandhi A. Tharapel (grant No. CA47555); Rhode Island Hospital, Providence, RI: William Sikov, Teresita Padre-Mendoza, Hon Fong L. Mark, and Shelly L. Kerman (grant No. CA08025); University of California, San Diego, CA: Stephen L. Seagren, E. Robert Wassman, Ren谷e Bernstein, and Marie L. Dell'Aquila (grant No. CA11789); Christiana Care Health System, Inc., Newark, DE: Stephen S. Grubbs and Digamber S. Borgaonkar (grant No. CA45418); Mount Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld (grant No. CA04457); Roswell Park Cancer Institute, Buffalo, NY: Ellis G. Levine and AnneMarie W. Block (grant No. CA02599); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry, Judith H. Miles, Jeffrey R. Sawyer, and Tim Huang (grant No. CA12046); Ft. Wayne Medical Oncology/Hematology Inc., Ft. Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; University of Chicago Medical Center, Chicago, IL: Gini Fleming, Michelle M. Le Beau, and Katrin M. Carlson (grant No. CA41287); University of Massachusetts Medical Center, Worcester, MA: Pankaj Bhargava, Philip L. Townes, and Vikram Jaswaney (grant No. CA37135); University of Vermont, Burlington, VT: Hyman B. Muss and Elizabeth F. Allen (grant No. CA77406); Massachusetts General Hospital, Boston, MA: Michael L. Grossbard and Leonard L. Atkins (grant No. CA12449); University of Puerto Rico, San Juan, PR: Enrique Velez-Garcia; Long Island Jewish Medical Center, Lake Success, NY: Kanti R. Rai and Prasad R. K. Koduru (grant No. CA11028); University of Minnesota, Minneapolis, MN: Bruce A. Peterson and Diane C. Arthur (grant No. CA16450); University of Nebraska Medical Center, Omaha, NE: Margaret A. Kessinger Wegner and Warren G. Sanger (grant No. CA77298); Columbia-Presbyterian Medical Center, New York, NY: Rose R. Ellison and Dorothy Warburton (CA12011); University of Illinois, Chicago, IL: Lawrence E. Feldman, Maureen M. McCorquodale, and Valerie Lindgren (grant CA74811); Virginia Commonwealth University MB CCOP, Richmond, VA: John D. Roberts and Colleen Jackson-Cook (grant No. CA52784); SUNY Maimonides Medical Center, Brooklyn, NY: Sameer Rafla and Ram S. Verma (grant No. CA25119); Eastern Maine Medical Center, Bangor, ME: Philip L. Brooks and Laurent J. Beauregard (grant No. CA35406); Georgetown University Medical Center, Washington, DC: Edward P. Gelmann and Jeanne M. Meck (grant No. CA77597); McGill Department of Oncology, Montreal, Quebec: J. L. Hutchison and Jacqueline Emond (grant No. CA31809); Western Pennsylvania Hospital, Pittsburgh, PA: Richard K. Shadduck and Gerard R. Diggans.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by National Cancer Institute grants No. CA77658, CA101140, CA31946, P30-CA16058, and K08-CA90469, and by The Coleman Leukemia Research Foundation.
Both G.M. and K.M. contributed equally to this work.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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