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© 2002 American Society for Clinical Oncology Favorable Impact of the t(9;11) in Childhood Acute Myeloid LeukemiaByFrom the Departments of Hematology-Oncology, Pathology, and Biostatistics, St Jude Children’s Research Hospital; and Department of Pediatrics, University of Tennessee, Memphis, College of Medicine, Memphis, TN. Address reprint requests to Frederick G. Behm, MD, Department of Pathology, St Jude Children’s Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; email: fred.behm{at}stjude.org
PURPOSE: To determine the impact of MLL rearrangements on the outcome of children with acute myeloid leukemia (AML). PATIENTS AND METHODS: We analyzed the clinical and biologic features of 298 infants and children with primary AML treated on four consecutive institutional clinical trials. The Kaplan-Meier method was used in survival analysis and the Cox proportional-hazards model was used to analyze the effect of potential prognostic factors on event-free survival (± 1 SE). RESULTS: Molecular studies of 152 cases detected 42 with MLL rearrangements. The karyotypes of these 42 revealed the t(9;11) (15 cases), abnormalities of chromosomes 10 and 11 (nine cases), the t(11;19) (four cases), other abnormalities of 11q23 (seven cases), and miscellaneous rearrangements (seven cases). Among these 42 patients, the 15 whose leukemic cells carried the t(9;11) had a better outcome (66% ± 15%) than the other 27 (25.9% ± 11.2%; P = .004). Cases with the t(9;11) were also characterized by M5 AML morphology (21 of 23 cases). Of the 63 patients with M5 AML, the 21 whose leukemic cells demonstrated the t(9;11) had a better outcome (71.1% ± 11%) than the other 42 (25.8% ± 7.9%; P = .0004). The only independent factors indicating a favorable prognosis were presenting leukocyte count less than 50 x 109/L (relative risk of relapse, 0.73; 95% confidence interval, 0.55 to 0.97; P = .03) and the t(9;11) (relative risk of relapse, 0.32; 95% confidence interval, 0.16 to 0.64; P = .002). CONCLUSION: We conclude that the t(9;11) is the most favorable genetic factor for patients with AML treated at our institution.
RECENT STUDIES HAVE confirmed the prognostic importance of the leukemic karyotype in adults and children with acute myeloid leukemia (AML).1-4 For example, these studies have demonstrated that the t(8;21) and inv(16) are associated with a favorable outcome. Leukemias containing the t(8;21) or inv(16), sometimes referred to as core-binding factor (CBF) AML because the abnormal gene products in these cases disrupt CBF, respond well to therapy that incorporates high-dose cytarabine.2,5 In some studies, patients whose leukemic cells contain abnormalities of 11q23 appear to have an intermediate or poor outcome.1,3 Although one report showed that patients whose leukemic cells contained the t(9;11) have an outcome as poor as those whose leukemic cells contain other 11q23 alterations,3 other studies have suggested that the t(9;11) may in fact confer a good prognosis.6-9 We previously suggested that pediatric patients with AML whose leukemic cells contained the t(9;11) have a favorable outcome when treated with epipodophyllotoxin-based regimens; however, this report included only nine such patients.7 More recently, we demonstrated that the t(9;11) independently predicted a good outcome for infants with AML.10 We now report the cytogenetic and molecular findings for 298 pediatric patients with AML treated on four consecutive institutional protocols, with emphasis on the t(9;11) and other 11q23 abnormalities.
Two hundred ninety-eight patients with newly diagnosed primary AML were treated on four consecutive clinical trials at this institution: AML-80 (1980 to 1983), AML-83 (1983 to 1987), AML-87 (1987 to 1991), and AML-91 (1991 to 1997). On the AML-80 protocol, children were treated with three cycles of induction chemotherapy (two courses of daunomycin and cytarabine and one course of etoposide and 5-azacytidine) followed by allogeneic bone marrow transplantation or sequential chemotherapy.11 The AML-83 regimen introduced etoposide and cytarabine as the initial induction course, followed by daunomycin, cytarabine, and thioguanine and etoposide and 5-azacytidine induction cycles, and then 16 cycles of continuation therapy.12 Children on the AML-87 protocol received individualized doses of etoposide and cytarabine during an intensive six-cycle chemotherapy regimen.13 Finally, AML-91 evaluated 2-chlorodeoxyadenosine as initial therapy, followed by daunomycin, cytarabine, and etoposide induction and autologous or allogeneic transplantation as postremission therapy.14 Written informed consent was obtained from patients, parents, or legal guardians, as appropriate, and all studies (therapeutic and diagnostic) were approved by the institutional review board. Diagnoses were made on the basis of standard techniques, and cases were classified morphologically according to the French-American-British (FAB) criteria. Cytogenetic analysis was performed as previously described.15 Cytogenetic and FAB data were available for 295 cases. Southern blot determination of MLL gene status and reverse transcriptase polymerase chain reaction (RT-PCR) detection16,17 of the AML1-ETO, CBFß-MYH11, and PML-RAR  fusion transcripts were performed in 152 cases. For estimates of event-free survival (EFS), an event was defined as relapse, disease progression, or death from any cause. The median follow-up for all patients was 2 years (range, 0.0 to 19.6 years), whereas the median follow-up for patients remaining in first complete remission was 11.3 years (range, 2.3 to 19.6 years). The date of first event was used in calculating EFS. Patients who did not achieve complete remission were assigned an EFS value of zero. Time was censored at the last follow-up visit if no failure was observed. The Kaplan-Meier method was used in survival analysis, and the log-rank test was used for comparisons between survival distributions. The Cox proportional hazards model was used to analyze the effect of potential prognostic factors on EFS. All variables significant at the 0.10 level were entered into the multiple regression model. When the parsimonious model was developed, variables were removed if they were not significant at the level of 0.05 on the basis of the likelihood ratio test. Because overall outcome did not differ significantly between protocols, results were not stratified by treatment protocol.
One hundred sixty-one (54%) male and 137 (46%) female patients were included in this analysis (Table 1). Although the sex of patients was not a prognostically significant variable, a low leukocyte count at the time of diagnosis was associated with a favorable outcome (P = .02) (Fig 1). There was also a statistically significant difference in outcome according to FAB subtypes (P = .002) (Table 1). The greatest contribution to this difference was made by the poor prognosis of patients with the FAB M7 subtype of AML; when FAB M7 cases were excluded from the analysis, there was no significant difference in outcome between the other subtypes (P = .21). The 20 cases with FAB M7 subtype included three children with Down syndrome.18
Among the 295 patients with AML for whom cytogenetic data were available, the most common recurrent abnormalities were the t(8;21)(q22;q22) (40 cases), the t(9;11)(p22;q23) (23 cases), other 11q23 abnormalities (21 cases), inv(16) (18 cases), and the t(15;17)(q22;q12 to 21) (14 cases). Molecular studies were performed for 152 cases. Twenty-five cases (16%), all of which contained the t(8;21), expressed the AML1-ETO fusion transcript. Eleven of the 18 cases with inv(16) were tested by RT-PCR: nine expressed CBFß-MYH11, but two cases showed no detectable fusion transcript. In addition, one case positive for the CBFß-MYH11 fusion transcript displayed no cytogenetic evidence of inv(16). Of the 152 cases studied by molecular techniques, 42 had rearrangements of the MLL gene (Tables 2 and 3). Among the 23 cases with t(9;11), all 15 that were analyzed molecularly demonstrated MLL gene rearrangements. Thirteen of these 15 cases had simple t(9;11) translocations, whereas two cases contained complex translocations: t(5;9;11)(q33;p22;q23) in patient no. 18 and t(7;9;11)(p15;p21;q23) in patient no. 21. By conventional cytogenetics, the t(9;11) was observed as the sole chromosomal abnormality in 10 of the 23 cases. One other case had a der(9)t(9;11). Additional numeric chromosomal abnormalities observed included three cases with a +8, and one case each with a +X, +1, +6, and +21. Seven cases had additional random structural chromosomal abnormalities. Of the 27 cases without the t(9;11) but with MLL gene rearrangements, only 14 had karyotypes that were initially interpreted as demonstrating 11q23 abnormalities (Table 2). The remaining 13 cases included three that were initially reported as having normal karyotypes (patient nos. 33, 55, and 56). Reevaluation detected the t(10;11)(p15;q23) in three metaphase spreads from the leukemic cells of patient no. 33. One case (patient no. 51) had multiple markers, one of which was initially interpreted as an inv(16) that may have been formed by the missing chromosome 11 or 16. In addition, six cases (patient nos. 24 to 29) had other abnormalities of chromosome arm 11q that are now recognized to be due to an inversion of 11q23, two cases had other abnormalities of chromosome 11 (patient nos. 52 and 54), and two cases had abnormal karyotypes not involving chromosome 11 (patient nos. 50 and 53) (Table 2). On the basis of the reviewed karyotypes, AML cases containing MLL rearrangements or 11q23 abnormalities but lacking the t(9;11) can be placed into four subgroups: abnormalities of chromosomes 10 and 11 (11 cases), the t(11;19) (four cases), other abnormalities of 11q23 (11 cases), and no abnormalities of 11q23 (seven cases).
There was no significant difference in outcome (P = .29) (Fig 2) between cases with rearranged MLL and those with germ-line MLL (5-year EFS estimates ± 1 SE, 40.2% ± 9.8% v 26.9% ± 4.8%). Patients whose cells demonstrated the t(9;11) were young (median age, 2.1 years; range, 0.6 to 16.5 years), had low leukocyte counts at the time of diagnosis (median, 9.4 x 109/L; range, 0.8 x 109 to 159 x 109/L), and were more likely to have FAB M5 AML than other subtypes (21 of 23 cases) (Tables 3 and 4). In addition, patients with AML containing the t(9;11) had a better outcome (5-year EFS estimate, 64.9% ± 11.1%) than patients in all other cytogenetic or molecular subgroups (P = .003) (Table 1). Notably, patients with inv(16) or the t(8;21) had intermediate outcomes; the 5-year EFS estimate for patients with inv(16) was 36.1% ± 10.9%, whereas that for patients with the t(8;21) was 32.5% ± 7.4%. Of the 63 patients with M5 AML, the 21 whose leukemic cells demonstrated the t(9;11) had a better outcome (5-year EFS estimate, 71.1% ± 11%) than did the 42 whose leukemic cells lacked this translocation (25.8% ± 7.9%; P = .0004) (Fig 3). Interestingly, remission was not achieved in either of the cases of non-M5 AML (one M4 and one M7) that contained the t(9;11).
The 33 patients whose leukemic cells had MLL rearrangements or 11q23 abnormalities but did not demonstrate the t(9;11) (Table 2) had the following FAB AML subtypes: M5 (18 cases), M4 (seven cases), M7 (four cases), M2 (two cases), M0 (one case), and M1 (one case). These patients had a median age of 2.3 years (range, 0.003 to 20.73 years) and a median leukocyte count at the time of diagnosis of 36 x 109/L (range, 2.2 x 109 to 751 x 109/L) (Tables 3 and 4). Moreover, the outcome of this group of patients was worse (5-year EFS estimate, 24.2% ± 9.4%) than that of the 23 patients whose leukemic cells had the t(9;11) (64.9% ± 11.1%; P = .00075) (Fig 4).
The Cox proportional hazards model identified leukocyte count less than 50 x 109/L at the time of diagnosis (relative risk of relapse, 0.73; 95% confidence interval, 0.55 to 0.97; P = .03) and the presence of the t(9;11) (relative risk of relapse, 0.32; 95% confidence interval, 0.16 to 0.64; P = .002) as the only independent factors associated with a favorable outcome in this analysis.
The findings of this study demonstrate that a low leukocyte count at the time of diagnosis and the presence of the t(9;11) are associated with a favorable prognosis for pediatric patients with AML treated on four consecutive protocols at our institution. However, patients with CBF AML had only intermediate outcomes. These results differ from those of other reports that suggest a favorable outcome for CBF AML.1-3,5 An analysis of 1,612 patients with AML treated on the Medical Research Council AML 10 trial found that 61% of patients whose leukemic cells contained inv(16) and 69% of patients whose leukemic cells contained the t(8;21) remain alive 5 years after diagnosis.1 The Pediatric Oncology Group recently reported 4-year EFS estimates of 58% for patients whose leukemic cells contained inv(16) and 45% for patients whose leukemic cells contained the t(8;21).3 In addition, Bloomfield et al2 demonstrated that patients with CBF AML had a better outcome than all other patients and had a particularly good outcome when treated with high-dose cytarabine. In that study, the impact of high-dose cytarabine was most dramatic for patients with CBF AML. The results of a subsequent study showed that among patients whose leukemic cells contained the t(8;21), those who received multiple courses of high-dose cytarabine had an even better outcome than those who received only one cycle of this agent.5 The relatively poor outcome of patients with CBF AML in the present report may be attributable, in part, to the fact that our treatment regimens did not include high-dose cytarabine. However, the prognosis for patients with AML whose leukemic cells contain inv(16) has greatly improved at our institution in recent years.19 In a previous report, we suggested that patients with AML whose leukemic cells contained the t(9;11) have a favorable prognosis; only two of nine patients experienced a relapse.7 In the current study of 23 such patients (including the nine previously reported) treated on four consecutive protocols, we have confirmed this good outcome and have shown that the t(9;11) is the most important prognostic factor overall. The t(9;11) was seen primarily in FAB M5 AML, but patients whose leukemic cells demonstrated this translocation had a better outcome than did other patients with M5 AML. In addition, patients whose leukemic cells contained the t(9;11) had a better outcome than patients whose leukemic cells contained other 11q23 abnormalities. Although several other reports also suggest a favorable outcome for patients with AML whose leukemic cells contain the t(9;11),6,7,9 an analysis by the Pediatric Oncology Group showed no difference in outcome between these patients and those whose leukemic cells contain other 11q23 alterations; the prognosis for both groups was quite poor.3 In the largest study to date, a collaborative analysis of 108 patients with AML whose leukemic cells contained the t(9;11), age and leukocyte count at the time of diagnosis were important predictors of outcome. This finding indicates that patients with AML whose leukemic cells contain the t(9;11) do not form a homogeneous group.20 In that study, infants fared quite poorly: 10 of 14 suffered an adverse event. In contrast, we have shown that infants with AML whose leukemic cells contain the t(9;11) have a favorable outcome (5-year EFS estimate, 70% ± 16%).10 The favorable outcome of older children and infants with AML whose leukemic cells contain the t(9;11) may reflect the use of epipodophyllotoxins, agents known to be effective against M5 leukemia,21,22 and of 2-chlorodeoxyadenosine, which was particularly effective against M5 AML in our recent clinical trial.14 It is interesting to note that primary AML cases with t(9:11) and monocytic morphology respond well to epipodophyllotoxins, agents known to induce secondary AML cases that often have monocytic morphology and the t(9;11), but that respond poorly to therapy.23 Unlike the t(9;11), which was associated with a favorable prognosis, other 11q23 abnormalities or MLL gene rearrangements were associated with a poor outcome; these findings confirmed those of previous reports.1,3 In the present study, we retrospectively compared molecular techniques with classic cytogenetic analysis in detecting the common abnormalities of childhood AML. All karyotypically identified cases containing the t(8;21), the t(15;17), or the t(9;11) were subsequently confirmed by RT-PCR or Southern blot analysis to have the predicted molecular lesions. No additional cases with these rearrangements were detected by molecular studies alone. However, two cases containing inv(16) showed no detectable CBFß-MYH11 fusion transcript, and one case with the CBFß-MYH11 fusion transcript lacked cytogenetic evidence of inv(16). Finally, molecular studies were most useful in detecting cases with rearrangements of the MLL gene. Nearly half of these cases initially lacked cytogenetic evidence of 11q23 alterations (Table 3). However, with our current awareness of the spectrum of 11q23 abnormalities, few of these cases would be undetected by cytogenetic analysis. The fluorescent in situ hybridization studies available for the detection of MLL rearrangements not only complement conventional cytogenetics but also limit the use of Southern blot analysis to cases in which findings remain equivocal after conventional tests.24 Among cases with rearrangements of MLL, the t(9;11) was the most common abnormality, occurring in 15 of 42 cases. Alterations involving chromosome arms 10p and 11q were observed in 10 of the 42 cases and in one additional case that was not analyzed by molecular methods. Six of the 11 cases with rearrangements of chromosomes 10 and 11 demonstrated an ins(10;11)(p13;q23q13) and probably harbored MLL-AF10 fusions.25-28 Although the t(10;11) may also fuse AF10 to CALM in both acute lymphoblastic leukemia and AML,27,29,30 the presence of MLL rearrangements in our cases suggests the formation of the MLL-AF10 fusion. Four cases had breakpoints at 10p11.2, the site of the ABI-1 gene, which is fused to MLL by the t(10;11)(p11.2;q23).31 The other two cases contained nonrecurrent abnormalities of chromosomes 10 and 11. Although a recent study showed that 15 patients with AML whose leukemic cells contained the t(10;11)(p12;q23) were more likely to have FAB M5a AML, to be younger, and to have a better outcome than patients whose leukemic cells contained other 11q23 abnormalities,32 other reports suggest a poor outcome for this group of patients.27 The small number of patients in our study precludes any statistical comparisons of outcome between patients with AML whose leukemic cells contain the t(10;11) and those whose leukemic cells contain other 11q23 subgroups, but the fact that only four of 11 patients remain in complete remission suggests an intermediate prognosis. In summary, the treatment regimens used previously at our institution have resulted in an excellent outcome for patients with AML whose leukemic cells contain the t(9;11). Our current protocol, which uses risk-adapted therapy, attempts to maintain this result while improving the prognosis for patients with other genetic subgroups of AML. We also incorporate molecular screening for all patients; this testing should result in better genetic classification, especially for patients with MLL gene rearrangements.
Supported in part by grant nos. CA-20180 and P01 CA-71907, and Cancer Center Support (CORE) grant no. P30 CA-21765 from the National Institutes of Health, Bethesda, MD, by a Center of Excellence grant from the state of Tennessee, and by the American Lebanese Syrian Associated Charities. We thank Flo Witte for expert editorial review; K. Juneau and A. Stone for assistance in data collection; and K. Williams, P. Wescott, and M. Jaynes for technical assistance.
1. Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial—The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 92: 2322-2333, 1998
2.
Bloomfield CD, Lawrence D, Byrd JC, et al: Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58: 4173-4179, 1998
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Raimondi SC, Chang MN, Ravindranath Y, et al: Chromosomal abnormalities in 478 children with acute myeloid leukemia: Clinical characteristics and treatment outcome in a cooperative Pediatric Oncology Group study-POG 8821. Blood 94: 3707-3716, 1999 4. Chang M, Raimondi SC, Ravindranath Y, et al: Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): Univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) study 8821. Leukemia 14: 1201-1207, 2000[CrossRef][Medline]
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Byrd JC, Dodge RK, Carroll A, et al: Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered. J Clin Oncol 17: 3767-3775, 1999
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Mrozek K, Heinonen K, Lawrence D, et al: Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: A Cancer and Leukemia Group B study. Blood 90: 4532-4538, 1997
7.
Kalwinsky DK, Raimondi SC, Schell MJ, et al: Prognostic importance of cytogenetic subgroups in de novo pediatric acute nonlymphocytic leukemia. J Clin Oncol 8: 75-83, 1990 8. Sandoval C, Head DR, Mirro J Jr, et al: Translocation t(9;11)(p21;q23) in pediatric de novo and secondary acute myeloblastic leukemia. Leukemia 6: 513-519, 1992[Medline] 9. Martinez-Climent JA, Lane NJ, Rubin CM, et al: Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo. Leukemia 9: 95-101, 1995[Medline] 10. Pui CH, Raimondi SC, Srivastava DK, et al: Prognostic factors in infants with acute myeloid leukemia. Leukemia 14: 684-687, 2000[CrossRef][Medline] 11. Dahl GV, Kalwinsky DK, Mirro J Jr, et al: Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission. J Clin Oncol 8: 295-303, 1990[Abstract]
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Krance RA, Hurwitz CA, Head DR, et al: Experience with 2-chlorodeoxyadenosine in previously untreated children with newly diagnosed acute myeloid leukemia and myelodysplastic diseases. J Clin Oncol 19: 2804-2811, 2001 15. Williams DL, Harris S, Williams KJ, et al: A direct bone marrow chromosome technique for acute lymphoblastic leukemia. Cancer Genet Cytogenet 13: 239-257, 1984[CrossRef][Medline]
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Downing JR, Head DR, Curcio-Brint AM, et al: An AML1/ETO fusion transcript is consistently detected by RNA-based polymerase chain reaction in acute myelogenous leukemia containing the (8;21)(q22;q22) translocation. Blood 81: 2860-2865, 1993
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Athale UH, Razzouk BI, Raimondi SC, et al: Biology and outcome of childhood acute megakaryoblastic leukemia: A single institution’s experience. Blood 97: 3727-3732, 2001 19. Razzouk BI, Raimondi SC, Srivastava DK, et al: Impact of treatment on the outcome of acute myeloid leukemia with inversion 16: A single institution’s experience. Leukemia 15: 1326-1330, 2001[CrossRef][Medline] 20. Swansbury GJ, Slater R, Bain BJ, et al: Hematological malignancies with t(9;11)(p21-22;q23): A laboratory and clinical study of 125 cases—European 11q23 Workshop participants. Leukemia 12: 792-800, 1998[CrossRef][Medline]
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Odom LF, Gordon EM: Acute monoblastic leukemia in infancy and early childhood: Successful treatment with an epipodophyllotoxin. Blood 64: 875-882, 1984 22. Nishikawa A, Nakamura Y, Nobori U, et al: Acute monocytic leukemia in children: Response to VP-16-213 as a single agent. Cancer 60: 2146-2149, 1987[CrossRef][Medline] 23. Pui CH, Relling MV: Topoisomerase II inhibitor-related acute myeloid leukaemia. Br J Haematol 109: 13-23, 2000[CrossRef][Medline] 24. Mathew S, Behm F, Dalton J, et al: Comparison of cytogenetics, Southern blotting, and fluorescence in situ hybridization as methods for detecting MLL gene rearrangements in children with acute leukemia and with 11q23 abnormalities. Leukemia 13: 1713-1720, 1999[CrossRef][Medline]
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Dreyling MH, Schrader K, Fonatsch C, et al: MLL and CALM are fused to AF10 in morphologically distinct subsets of acute leukemia with translocation t(10;11): Both rearrangements are associated with a poor prognosis. Blood 91: 4662-4667, 1998
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Tanabe S, Bohlander SK, Vignon CV, et al: AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10; 11)(p12;q23q12). Blood 88: 3535-3545, 1996 29. Bohlander SK, Muschinsky V, Schrader K, et al: Molecular analysis of the CALM/AF10 fusion: Identical rearrangements in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma patients. Leukemia 14: 93-99, 2000[CrossRef][Medline] 30. Carlson KM, Vignon C, Bohlander S, et al: Identification and molecular characterization of CALM/AF10 fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia. Leukemia 14: 100-104, 2000[CrossRef][Medline]
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Taki T, Shibuya N, Taniwaki M, et al: ABI-1, a human homolog to mouse Abl-interacter 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). Blood 92: 1125-1130, 1998 32. Lillington DM, Young BD, Berger R, et al: The t(10;11)(p12;q23) translocation in acute leukaemia: A cytogenetic and clinical study of 20 patients—European 11q23 Workshop participants. Leukemia 12: 801-804, 1998[CrossRef][Medline] Submitted August 1, 2001; accepted February 15, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
