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Abnormal Cytogenetics at Date of Morphologic Complete Remission Predicts Short Overall and Disease-Free Survival, and Higher Relapse Rate in Adult Acute Myeloid Leukemia: Results From Cancer and Leukemia Group B Study 8461

From the Division of Hematology and Oncology, Department of Internal Medicine, and the Department of Pathology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; CALGB Statistical Center, Durham; Wake Forest University Medical Center, Winston Salem, NC; University of Alabama at Birmingham, Birmingham, AL; North Shore University Hospital, Manhasset, NY; University of Chicago, Chicago, IL

Address reprint requests to Guido Marcucci, the Comprehensive Cancer Center, The Ohio State University, A433B Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210; e-mail: marcucci-1{at}medctr.osu.edu

	ABSTRACT

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PURPOSE: As most patients with acute myeloid leukemia (AML) with morphologic complete remission (CR) ultimately relapse, better predictors for outcome are needed. Recently, Cheson et al suggested using cytogenetic remission (CRc) as part of the criteria for CR. To our knowledge, ours is the first relatively large study evaluating the usefulness of CRc attained immediately following induction chemotherapy.

PATIENTS AND METHODS: We included AML patients treated on Cancer and Leukemia Group B front-line studies with cytogenetic samples obtained at diagnosis and at the first day of documented CR following induction. Patients with abnormal cytogenetics at diagnosis, and normal cytogenetics at CR (NCR; n = 103) were compared with those with abnormal cytogenetics both at diagnosis and at CR (ACR; n = 15) for overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). Cox proportional hazards models determined the prognostic significance of cytogenetics at CR, adjusting for other covariates.

RESULTS: Clinical features were similar for both groups, with the exception of favorable cytogenetics [t(8;21), inv(16)/t(16;16), t(15;17)] at diagnosis, which was more frequent (P = .03) in the NCR group. Median follow-up was 3.1 years (range, 1.0 to 11.4 years). ACR patients had significantly shorter OS (P = .006) and DFS (P = .0001), and higher CIR (P = .0001). In multivariable models, the NCR and ACR groups were predictors for OS (P = .03), DFS (P = .02), and CIR (P = .05). The relative risk of relapse or death was 2.1 times higher for ACR patients than for NCR patients (95% CI, 1.1 to 3.9).

CONCLUSION: Our data suggest that converting to normal karyotype at the time of first CR is an important prognostic indicator and support the use of CRc as a criterion of CR in AML.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Acute myeloid leukemia (AML) is a biologically heterogeneous disease characterized by a clonal accumulation of immature blood cells, which ultimately leads to bone marrow failure.^1,2 The management of AML is complex, and only 30% to 40% of patients treated with chemotherapy are cured.^3,4 Among the clinical and biologic factors used to predict clinical outcome in AML, pretreatment cytogenetics is recognized as one of the most important.^3-6 Clonal chromosomal abnormalities are identified in approximately 55% of adult AML patients, and represent a strong independent predictor for achievement of complete remission (CR), duration of first CR, and survival.⁷ Based on data from large prospective studies, diagnostic cytogenetics has become an essential component of the initial work-up for AML, and cytogenetic results are being incorporated to stratify patients to different consolidation/intensification treatment strategies.^8-14

Attaining CR following induction chemotherapy is also a prerequisite for long-term survival in AML.¹⁵ However, many patients who achieve CR ultimately relapse and die from their disease.¹⁶ To date, widely used definitions of CR have been based solely on cytologic examination of bone marrow (BM) and blood.¹⁷ However, as the rate of relapse after attaining morphologic CR is high, one could conclude that these criteria for CR lack a sufficient predictive value for clinical outcome, and cannot be used to stratify patients into risk-adapted therapeutic subgroups. This problem likely stems from the low sensitivity of morphological examination for detection of residual disease in remission BM samples. In this context, other methods (eg, cytogenetics, flow cytometry, or reverse-transcription polymerase chain reaction [RT-PCR]) that identify significant levels of residual blasts could represent an important step forward for prognostic stratification of patients otherwise deemed in morphological CR.^18-23 In order to improve the predictive value of achieving a CR, a panel of experts has recently suggested using cytogenetic remission (CRc) as part of the remission criteria in AML.²⁴

In contrast to the wealth of data on the clinical importance of cytogenetics at diagnosis,⁵ little is known about the prognostic significance of cytogenetic abnormalities present in BM and/or blood from patients deemed in morphological CR. To date, a few studies have attempted to address this issue, but small numbers of patients evaluated and the heterogeneity of the CR time points analyzed have precluded the establishment of definitive conclusions.^25,26 Therefore, we retrospectively analyzed the clinical outcome of AML patients enrolled on Cancer and Leukemia Group B (CALGB) study 8461 whose BM samples were investigated cytogenetically both at diagnosis and on the first day of morphologic CR following induction chemotherapy. We found that the presence of abnormal metaphase cells at the latter time point has an adverse prognostic effect.

	PATIENTS AND METHODS

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Patients and Cytogenetic Analysis
We identified 183 AML patients enrolled onto the prospective cytogenetic study CALGB 8461²⁷ between February 1986 and September 2002 who achieved CR on front-line CALGB treatment studies and had successful BM cytogenetic analyses both at diagnosis and on the first day of morphologic CR following induction chemotherapy. Three patients who underwent allogeneic stem-cell transplantation (SCT) in first CR off-protocol have been excluded, leaving 180 patients included in this study. All samples were analyzed cytogenetically in CALGB-designated institutional laboratories, reviewed centrally, and accepted. The karyotypes were interpreted according to the International System for Human Cytogenetic Nomenclature.²⁸ To define a karyotype as normal, at least 20 metaphases from BM were analyzed. For samples with clonal abnormalities, analyses with fewer than 20 metaphases were acceptable. At diagnosis, 118 patients had an abnormal karyotype, and 62 had a normal karyotype. Because only one patient in the latter group acquired a clonal chromosome aberration at CR, all analyses were conducted on 118 patients presenting with an abnormal karyotype.

These 118 patients achieved CR on one of the following CALGB treatment protocols: 8525 (n = 8), 8923 (n = 3), 9022 (n = 4), 9191 (n = 9), 9222 (n = 8), 9621 (n = 28), 9710 (n = 18), 9720 (n = 29), or 19808 (n = 11). They constitute a subset of the estimated 748 patients enrolled onto the same protocols who would have been eligible for inclusion in our study, had CR samples been studied cytogenetically in all patients achieving a CR (assuming a success rate of 85% for obtaining adequate cytogenetic results at CR). However, not all patients' samples were analyzed cytogenetically at CR because the earlier protocols did not specifically require such analysis. This study comprises all patients whose BM samples obtained on the first day of morphologic CR were successfully studied cytogenetically and accepted on central karyotype review.

The patients received cytarabine (100 to 200 mg/m²/d for 7 days) and an anthracycline-based induction chemotherapy ± etoposide and ± PSC-833, a multidrug resistance protein modulator, depending on the protocol. Postremission therapy included repeated cycles of cytarabine given in standard (100 mg/m²/d for 5 days), intermediate (400 mg/m²/d for 5 days), or high (3 g/m² bolus every 12 hours on days 1, 3, and 5) doses, alone or in combination with other drugs. A smaller proportion of patients also received interleukin-2, intensification with high-dose etoposide and cyclophosphamide, or autologous SCT, depending on the protocol. The details of therapy for CALGB 8525, 8923, 9022, 9191, 9222, 9621, and 9720 have been previously reported.^29-38 The patients enrolled on 19808 received the same therapy regimen as those on 9621. Patients with t(15;17)(q22;q21) treated on CALGB 9191 were randomly assigned to induction with all-trans-retinoic acid (ATRA) versus cytarabine/daunorubicin, and those in CR after consolidation therapy to maintenance with ATRA versus observation.³⁹ Patients with t(15;17) treated on CALGB 9710 received a combination of ATRA, cytarabine, and daunorubicin as induction therapy, before double random assignment to consolidation with arsenic trioxide followed by daunorubicin and ATRA versus daunorubicin and ATRA alone, and to maintenance with ATRA/methotrexate/6-mercaptopurine versus ATRA alone.

CR was defined as an absolute neutrophil count of 1,500/µL, platelet count of 100,000/µL, no leukemic blasts in the blood nor evidence of extramedullary leukemia, BM with a cellularity of more than 20%, maturation of all three cell lineages, no Auer rods, and less than 5% BM blast cells. Relapse was defined as the reappearance of circulating blasts not attributable to "overshoot" following recovery from myelosuppressive therapy, or 5% blasts in the BM not attributable to another cause, or development of extramedullary leukemia.

Statistical Analysis
All patients were classified according to one of four pretreatment and CR cytogenetic groups: (1) abnormal at diagnosis and normal at CR (NCR), (2) abnormal at both diagnosis and CR (ACR), (3) normal at both diagnosis and CR, and (4) normal at diagnosis and abnormal at CR. Patients with a nonclonal abnormality at CR that had not been present at diagnosis were considered to be normal, whereas patients with a single cell at CR that included an abnormality seen in the diagnostic karyotype were considered to be abnormal. Because group 4 consisted of only one patient, all analyses were restricted to the NCR and ACR groups. Clinical features at presentation were compared. Categoric variables such as sex and race were compared using Fisher's exact test. Continuous variables such as age and WBC count were compared using the Wilcoxon rank sum test. Patients were classified into two cytogenetic risk groups based on their pretreatment cytogenetics. The favorable risk group comprised patients with t(8;21)(q22;q22), inv(16)(p13q22)/t(16;16)(p13;q22), or t(15;17). All other patients were included in the intermediate-/unfavorable-risk group. Comparison of NCR versus ACR groups by cytogenetic risk group was made using Fisher's exact test.

Overall survival (OS) was measured from the date on study, until date of death or date last known alive. Disease-free survival (DFS) was measured from the documented date of CR until date of relapse or death from any cause, whichever occurred first, censoring for patients alive in continuous CR. Kaplan-Meier curves were constructed for OS and DFS comparing the NCR and ACR groups. The log-rank test was performed to determine whether there was a significant difference between the survival curves. Cumulative incidence of relapse (CIR) was also examined to account for competing risks, namely, deaths in CR. Gray's k-sample test comparing the CIR was used to determine whether there was a significant difference in relapse rates between the NCR and ACR groups.⁴⁰

Finally, to adjust for potential confounding covariates, a Cox proportional hazards model was built for OS and DFS, while a multivariable model using Gray's method was built for CIR. A forward variable selection procedure was used in all models to determine whether cytogenetic abnormalities detected at CR remained a significant prognostic factor once other covariates adjusted the model. First, models for each baseline clinical characteristic with the indicator for cytogenetics at CR were fit. The variable reporting the largest likelihood ratio test statistic (OS, DFS) or smallest P-value (CIR) that was also statistically significant was added to the model. The model-building process stopped once the addition of variables was no longer significant at = .05. Once the final model was determined, a global assessment of the proportional hazards assumption was conducted (OS, DFS). Statistical analyses were performed by the CALGB Statistical Center.

	RESULTS

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Of the 180 patients eligible for this study, 62 had a normal karyotype at diagnosis. Of the 62, only one patient, who died in remission 77 days from diagnosis, acquired a clonal chromosome aberration, +mar, at CR. As the goal of this study was to assess the prognostic impact of cytogenetic aberrations present on the first day of morphologic CR, the low rate of aberrant karyotypes at this time point prevented assessment of the intended end points in patients with a normal karyotype at diagnosis. Therefore, all outcome analyses were conducted in 118 patients with an abnormal karyotype at diagnosis.

Among the 118 patients, there were 103 with normal (NCR group), and 15 with abnormal (ACR group) cytogenetics at CR. There were no differences in median age, WBC, percentage of blood blasts, hemoglobin, or platelet counts at diagnosis between the NCR and ACR groups (Table 1). The NCR group had a higher median percentage of BM blasts than the ACR group (68% v 44%; P = .05). In the NCR group, 60 patients (58%) had favorable cytogenetics [t(8;21), inv(16;16) or t(15;17)], compared with four (27%) in the ACR group (P = .03; Table 2). Median time from the date of enrollment onto treatment study to CR was 38 days (range, 13 to 232 days) for the NCR group and 41 days (range, 19 to 60 days) for the ACR group (P = .45). In the NCR group, all patients attained CR within 81 days, except for a 69-year-old patient with prolonged neutropenia following induction who achieved a late CR at day 232. Abnormal karyotypes detected at both diagnosis and CR in the ACR group are presented in Table 3. At CR, 14 of the 15 ACR patients had at least one cytogenetic abnormality identical to those observed at diagnosis. In one patient (patient 4), the clonal abnormality detected at CR was different from that seen at diagnosis

View larger version (16K): [in this window] [in a new window]   Fig 1. Overall survival according to the presence or absence of cytogenetic abnormalities on the first day of complete remission (CR) following induction chemotherapy in acute myeloid leukemia patients with abnormal cytogenetics at diagnosis.

View larger version (16K): [in this window] [in a new window]   Fig 2. Disease-free survival according to the presence or absence of cytogenetic abnormalities on the first day of complete remission (CR) following induction chemotherapy in acute myeloid leukemia patients with abnormal cytogenetics at diagnosis.

When the analysis, including all ACR and NCR patients, acknowledged death as a competing risk, CIR was significantly increased for the ACR group (median, 0.6 v 1.2 years; P = .0001; Fig 3). At 3 years, all patients in the ACR group relapsed, compared with an estimated 61% (SE, 0.05) in the NCR group (Table 4). After 5 years, no further relapses had occurred in the NCR patients. For patients younger than 60 years, CIR was also significantly increased for the ACR group (median, 0.6 v 1.5 years; P < .0001). At 3 years, all patients in the ACR group had relapsed compared with an estimated 57% (SE, 0.07) in the NCR group. At 5 years, no further relapses occurred in the NCR patients.

View larger version (14K): [in this window] [in a new window]   Fig 3. Cumulative incidence of relapse according to the presence or absence of cytogenetic abnormalities on the first day of complete remission (CR) following induction chemotherapy in acute myeloid leukemia patients with abnormal cytogenetics at diagnosis.

	DISCUSSION

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The primary goal of AML treatment is to induce CR, since failure to achieve CR is associated with shorter survival. In 1990, the National Cancer Institute sponsored a workshop to develop a set of standardized diagnostic and response criteria for AML.¹⁷ According to these criteria, CR was defined by adequate BM cellularity (> 20%) with maturation of all cell lineages, less than 5% blasts, and no detectable Auer rods, in addition to 1,500/µL neutrophil and 100,000/µL platelet counts in the absence of circulating blasts. These criteria were based only on morphological analysis.

Unfortunately, the majority of patients who achieve CR by these parameters eventually relapse, suggesting that these criteria do not allow further stratification according to risk for relapse. Because disease recurrence may be a direct consequence of failure to completely eradicate clonogenic cell populations, additional criteria derived from sensitive methodologies identifying residual leukemic cells otherwise not detectable by morphological analysis could improve the predictive value of CR achievement. Thus, another workshop was recently held to redefine CR in AML based on new insights into the biology of the disease, treatments with novel therapeutic agents, and acquisition of more sophisticated analytic methods for diagnosis and follow-up.²⁴ Although the proposed criteria for morphologic CR remained similar to the previous ones, with the exception of lower absolute neutrophil count (> 1,000/µL), no requirements for BM cellularity and a 4-week response duration, for the first time, this panel of experts suggested the potential usefulness of determining cytogenetic remissions (CRc) to improve risk-adapted stratification of patients deemed otherwise in morphologic CR.

Therefore, we conducted a study to investigate the usefulness of cytogenetic analysis performed on the first day of CR as a predictor for clinical outcome. To our knowledge, this is the first relatively large study indicating that the presence of karyotypically abnormal cells in patients deemed in morphologic CR immediately following induction chemotherapy is predictive of a significantly shorter OS and DFS and higher CIR. These results have been validated in a multivariable analysis, where the presence of abnormal cytogenetics at CR was an independent negative predictor for clinical outcome. Notably, as relapse is a function of time from diagnosis, we showed that there was no significant difference in the time of attaining CR between the NCR and ACR groups. Furthermore, a subanalysis restricted to patients with intermediate/unfavorable cytogenetics at diagnosis confirmed these findings, thus excluding a possible bias due to a greater number of patients with favorable cytogenetics at diagnosis included in the NCR group.

Interestingly, 54% of patients included in our analysis had favorable cytogenetics, compared with 46% with intermediate/unfavorable karyotype. These proportions, though initially striking, are not significantly different from those found among all patients with abnormal cytogenetics at diagnosis who achieved CR on one of the CALGB protocols (ie, 49% with favorable v 51% with intermediate/unfavorable cytogenetics). The apparent overrepresentation of cases with favorable cytogenetics may stem from the fact that patients with t(8;21), inv(16)/t(16;16) and t(15;17) as a group not only constitute approximately 36% to 42% of all AML patients with aberrant karyotypes at diagnosis,^8,9,11 but also have the highest CR rates among cytogenetic subgroups.

Three of the four cases with favorable cytogenetics in the ACR group had t(15;17). Two of the three (one with a high WBC [25,000/µL] at diagnosis) did not receive ATRA, a drug shown to improve outcome of t(15;17)-positive patients.³⁹ The fourth patient was a 63-year-old individual with inv(16), who, besides older age, did not present with any known adverse risk factors.

The negative prognostic significance of aberrant karyotypes found during remission was suggested by earlier studies. These analyses, however, were conducted on smaller cohorts of patients and at heterogeneous time points during CR. In a study of 71 patients, Freireich et al²⁵ reported that all 20 patients with abnormal metaphases at varying time points during CR eventually relapsed. Among the remaining 51 patients with normal karyotypes in their CR marrow, only 49% relapsed. Grimwade et al²⁶ reported 19 patients with cytogenetic abnormalities at the time of marrow harvest for possible autologous SCT as intensification treatment. In 8 patients, the detected abnormalities were identical to those found at diagnosis, suggesting persistence of the disease-related clones. Of the eight patients, two died of sepsis during consolidation therapy, whereas five relapsed within 5 to 6.5 months from SCT or BM harvest. The major difference between the aforementioned studies and ours is that our analysis was restricted to cytogenetic investigations performed on the first day of morphologic CR. This substantially reduced the possibility that BM sampling was performed because of clinical features suspicious for early recurrence of disease.

Although cytogenetic analysis appears to be informative in detecting residual disease following induction, it is also labor intensive. Molecular and immunologic technologies have emerged as important complementary modalities for a full evaluation of AML at diagnosis. Several groups have proposed using these sensitive and perhaps less laborious methodologies to detect residual disease in CR.²² RT-PCR, for example, can readily detect fusion transcripts encoded by chimeric genes resulting from chromosome translocations or inversions. Although this strategy has been successful in predicting clinical outcome in PML-RAR–positive acute promyelocytic leukemia, its prognostic use in other molecular subgroups of AML (eg, AML1/ETO fusion in t[8;21], CBFß-MYH11 fusion in inv[16]) has yet to be fully validated.^41-44

Similarly, monitoring of residual disease by immunophenotyping requires further validation.^20,23 A major limitation of this strategy is the instability of AML blast immunophenotype, as evidenced by the presence of immunophenotype changes at relapse in almost all patients.^45-47 The advantage of cytogenetics with respect to RT-PCR and immunophenotyping is that it does not require a prefigured set of primers or monoclonal antibody panels targeting specific fusion transcripts or antigens, respectively. Once metaphases are obtained, any chromosome aberration or aberrations, irrespective of their type and whether they are molecularly characterized or not, can be identified. However, a drawback is a lower level of sensitivity (1:10¹ to 10²) of cytogenetics as compared with RT-PCR (1:10⁴ to 10⁶) and immunophenotyping (1:10² to 10³). The use of molecular cytogenetic methodologies such as metaphase or interphase fluorescence in situ hybridization, in conjunction with conventional cytogenetic analysis, has been advocated to overcome this limitation.^48-52

In conclusion, in line with recent recommendations for redefining CR in AML according to methodologies that quantify levels of leukemia burden beyond the sensitivity of morphologic analysis, we performed the first relatively large study supporting the predictive value of achieving CRc. Our data indicate that converting to a normal karyotype at the time of first CR immediately following induction chemotherapy is an important prognostic indicator for clinical outcome and support further prospective validation of these results in future, larger studies. It should be recognized that it is at present unknown whether prognostic significance of CRc is the same among AML patients sharing an identical, prognostically-relevant chromosome abnormality. Given the remarkable cytogenetic heterogeneity of AML, a collaborative well-planned effort by national and/or international groups is needed to accrue several hundred or even thousands of AML patients necessary to answer this question.

APPENDIX
The following Cancer and Leukemia Group B institutions, principal investigators, and cytogeneticists participated in this study: North Shore University Hospital, Manhasset, NY: Daniel R. Budman and Prasad R.K. Koduru (grant no. CA35279); The Ohio State University Medical Center, Columbus, OH: Clara D. Bloomfield and Nyla A. Heerema (grant no. CA77658); Wake Forest University School of Medicine, Winston-Salem, NC: David D. Hurd and Mark J. Pettenati (grant no. CA03927); Dana-Farber Cancer Institute, Boston, MA: George P. Canellos, Cynthia C. Morton and Paola Dal Cin (grant no. CA32291); Weill Medical College of Cornell University, New York, NY: Scott Wadler and Andrew J. Carroll (grant no. CA07968); Ft. Wayne Medical Oncology/Hematology, Inc, Ft Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; Dartmouth College, NCCC, Dartmouth Medical School, Lebanon, NH: Marc S. Ernstoff and Thuluvancheri K. Mohandas (grant no. CA04326); Mount Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld (grant no. CA04457); Duke University Medical Center, Durham, NC: Jeffrey Crawford and Barbara K. Goodman (grant no. CA47577); University of Alabama at Birmingham: Robert Diasio and Andrew J. Carroll (grant no. CA47545); University of Nebraska Medical Center, Omaha, NE: Margaret A. Kessinger Wegner and Warren G. Sanger (grant no. CA77298); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Michael C. Perry and Tim Huang (grant no. CA12046); SUNY Upstate Medical University, Syracuse, NY: Stephen L. Graziano, and Constance K. Stein (grant no. CA21060); University of California, San Diego, CA: Stephen L. Seagren and Marie Dell'Aquila (grant no. CA11789); Christiana Care Health System, Inc, Newark, DE: Stephen S. Grubbs and Jeanne M. Meck (grant no. CA45418); University of Chicago Medical Center, Chicago, IL: Gini Fleming, Michelle M. LeBeau and Katrin Carlson (grant no. CA41287); University of North Carolina, Chapel Hill, NC: Thomas C. Shea and Kathleen W. Rao (grant no. CA47559); Massachusetts General Hospital, Boston, MA: Michael L. Grossbard, Cynthia C. Morton, and Paola Dal Cin (grant no. CA 12,449); Southern Nevada Cancer Research Foundation—CCOP, Las Vegas, NV: John A. Ellerton and Marie Dell'Aquila (grant no. CA35421); Long Island Jewish Medical Center, Lake Success, NY: Marc Citron and Prasad R.K. Koduru (grant no. CA11028).

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by National Cancer Institute (Bethesda, MD) grants CA77658, CA101140, CA31946, P30CA16058, and K08-CA90469, and the Coleman Leukemia Research Foundation.

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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Submitted March 3, 2004; accepted March 11, 2004.

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