|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Prognostic Significance of Partial Tandem Duplications of the MLL Gene in Adult Patients 16 to 60 Years Old With Acute Myeloid Leukemia and Normal Cytogenetics: A Study of the Acute Myeloid Leukemia Study Group UlmByFrom the Department of Internal Medicine III, University of Ulm, Ulm, and Deutsches Krebsforschungszentrum, Heidelberg, Germany. Address reprint requests to Hartmut Döhner, Department of Internal Medicine III, Robert-Koch-Straße 8, 89081 Ulm, Germany; email: hartmut.doehner{at}medizin.uni-ulm.de
PURPOSE: To evaluate the incidence and clinical significance of partial tandem duplications (PTDs) of the mixed lineage leukemia (MLL) gene in a large series of newly diagnosed adult patients (16 to 60 years old) with acute myeloid leukemia (AML) intensively treated within the multicenter treatment trials AML-HD93 and AML-HD98A. PATIENTS AND METHODS: Identification of MLL PTD was performed centrally using Southern blot analysis in pretreatment samples from 525 of 683 assessable patients. PTD was confirmed by polymerase chain reaction (PCR) and sequencing of the PCR products. RESULTS: MLL PTD was identified in none of the 129 patients with t(8;21), inv(16), and t(15;17); in 19 (7.7%) of 247 patients with normal karyotype; and in 10 (8.5%) of 119 patients with all other abnormalities, with 30 cases of t(11q23) excluded. In the group of patients with a normal karyotype, there was no difference in the presenting clinical features between the PTD-positive and the PTD-negative cases. Sixteen (89%) of the 18 assessable PTD-positive patients and 158 (78%) of the 203 PTD-negative patients achieved a complete remission. After a median follow-up time of 19 months, 11 of the 16 PTD-positive patients relapsed compared with 54 of the 158 PTD-negative patients; the median remission durations of the PTD-positive and the PTD-negative groups were 7.75 months and 19 months, respectively (P < .001). Multivariate analysis identified the MLL PTD status as the single prognostic factor for remission duration. CONCLUSION: Within the subgroup of young adult AML patients with normal karyotype, MLL PTD is associated with short remission duration.
AT THE CYTOGENETIC level, clonal chromosome aberrations are identified in approximately 50% of all patients with de novo adult acute myeloid leukemia (AML).1 These chromosomal abnormalities provide important insights into the genes involved in the pathogenesis of leukemia. Clinically, chromosome aberrations are one of the most important prognostic factors in AML.1-4 This prognostic information is increasingly being used for treatment decisions, eg, whether a patient is assigned to an intense therapy such as bone marrow (BM) or blood stem-cell transplantation or to a less intense regimen. The remaining half of the patients lack microscopically visible chromosome aberrations. For this clinically heterogeneous group of patients, prognostic markers are warranted for establishing risk-adapted therapy. Rearrangement of the mixed lineage leukemia (MLL) gene detected by Southern blot analysis was the first molecular marker described in patients with AML and normal cytogenetics.5 The MLL gene is frequently involved in translocations that occur in AML and in acute lymphoblastic leukemia (ALL).6 The gene is located in chromosome band 11q23 and covers a genomic region of approximately 100 kb of DNA. The majority of the translocation breakpoints cluster in an 8.3-kb region (breakpoint cluster region) that is represented by exons 5 to 11.5-7 The molecular rearrangement identified by Strout et al8 in patients with normal cytogenetics is a tandem duplication of an internal portion of the MLL gene that spans exons 2 to 6 or exons 2 to 8 in most of the cases. This partial tandem duplication (PTD) was detected in approximately 10% of AML with normal cytogenetics and in 90% of AML exhibiting trisomy 11 (+11) as sole chromosome abnormality.5,9 By dosage analysis, it was shown that in the cytogenetically normal cases and in the cases with +11, only one chromosome 11 contained the mutated allele.10 In another study performed by Strout et al,11 the molecular mechanisms responsible for this gene rearrangement were analyzed. In this study, the fusion breakpoints were identified and located in Alu elements. Their data support the hypothesis that a recombination event between homologous Alu sequences might be responsible for the development of the PTD. Nevertheless, the pathogenetic relevance of this gene rearrangement in AML is still not clear. This is demonstrated by two studies published by Marcucci et al12 and Schnittger et al.13 Using nested reverse transcriptase polymerase chain reaction (RT-PCR), both groups detected PTD of the MLL gene with a different frequency in peripheral blood (PB) and BM of healthy donors. Recently, Caligiuri et al14 analyzed 98 patients with de novo AML and normal karyotype for PTD of the MLL gene by Southern blot analysis and single-round RT-PCR. In this study, 11 (11%) of 98 patients showed a PTD. Correlation of these molecular findings with clinical features such as age, sex, French-American-British (FAB) subtype, WBC count, and percentage of BM blasts was not significantly different between the patients with or without PTD. However, the PTD-positive patients who achieved complete remission (CR) had a statistically significant shorter CR duration (7.1 months) compared with the PTD-negative patients (23.2 months). In another study, eight patients with trisomy 11 and 387 unselected patients with de novo and secondary AML were screened for MLL PTD by single-round RT-PCR.15 In this study, the incidence of MLL PTD was lower than previously reported, but in accordance with the findings of Caligiuri et al,14 PTD of the MLL gene was associated with an unfavorable prognosis. One drawback of these studies is that they were performed in patient series highly heterogeneous with respect to treatment and age. The objective of this study was to evaluate the incidence and clinical significance of MLL PTD in a large prospective series of newly diagnosed adult patients (16 to 60 years old) with AML treated within the multicenter treatment trials AML-HD93 and AML-HD98A of the AML Study Group Ulm.16
Patients Between July 1993 and November 2001, 745 adult patients (16 to 60 years old) with AML, de novo or secondary after a primary malignancy, were entered onto the multicenter treatment trials AML-HD93 (246 patients, July 1993 to January 1998) and AML-HD98A (499 patients, February 1998 to November 2001). The ongoing treatment trial AML-HD98A also includes patients with refractory anemia with excess of blasts in transformation and AML after myelodysplastic syndrome. The median age of the patients was 46.8 years (range, 16 to 60 years). For the diagnosis of AML, standard FAB morphologic and cytochemical criteria were used.17 Informed consent was obtained from all patients. In 62 of the 745 patients, no adequate karyotype was obtained. These patients were considered nonassessable for analysis. For the remaining 683 patients, the only criterion used to include or exclude patients was the availability of BM or PB samples from diagnosis for Southern blot analysis of the MLL gene: the analysis could be performed in pretreatment samples from 129 of 174 patients with t(8;21), inv(16), t(15;17); from 247 of 303 patients with normal karyotype; and from 149 of 206 patients with all other abnormalities.
Therapy of Patients With Normal Cytogenetics The second consolidation therapy differed among the two trials: in AML-HD93, patients 16 to 54 years of age were assigned to one cycle according to the S-HAM protocol (cytarabine 3 g/m2 bid IV on days 1, 2, 8, and 9; and mitoxantrone 10 mg/m2 IV on days 3, 4, 10, and 11); patients 55 to 60 years of age received the less intense HAM regimen. In AML-HD98A, the patients were randomized to either HAM or high-dose therapy (total-body irradiation [TBI]/cyclophosphamide or busulfan/cyclophosphamide) followed by autologous hematopoietic stem-cell transplantation. In both trials, patients were assigned to allogeneic stem-cell transplantation, if an HLA-compatible donor was available.
Cytogenetic and Molecular Cytogenetic Analysis
Analysis of MLL Rearrangements Southern blot analysis. To be considered PTD-positive, DNA from the diagnostic BM/PB sample had to show an MLL rearrangement by Southern blot analysis. Eight to 10 µg of genomic DNA were digested with HindIII and/or BamHI. The digests were first hybridized with a 0.74-kb BamHI cDNA fragment covering the breakpoint cluster region represented by exons 5 to 11, stripped, and than hybridized to the SAS1 probe.6,21 The SAS1 probe is a 289-bp DNA probe derived from a XhoI/HindIII fragment of intron 1 of the MLL gene by PCR. Using a HindIII or BamHI digestion of DNA, the SAS1 probe detects rearrangements of MLL that occur when PTD involves a region of intron 1 immediately 5' of exon 2.14 Southern blotting, probe radiolabeling, and autoradiography were performed by standard techniques. Exons of the MLL gene were described using the old nomenclature.22,23 RT-PCR. Primer sets, sequences, location of the primers, and PCR conditions for amplification were published previously.9,21 Single-round RT-PCR with outside primers located in exon 5 (sense) and exon 3 (antisense) was used for amplification of the partially duplicated MLL fusion transcript. PCR products were analyzed by electrophoresis on a 2% agarose gel. To determine the extent of the duplication and to identify the involved exons, all PCR products were sequenced after purification using the QIAquick PCR purification kit (Qiagen). Genomic XL-PCR. Long-range genomic amplification (XL-PCR) with primers from exon 6 and exon 2 was performed using the GeneAmp XL-PCR kit (Perkin Elmer, Weiterstadt, Germany) following the manufacturer‘s instructions.9,21 DNA sequencing and sequence analysis. Approximately 100 ng of purified RT-PCR product was directly sequenced with 3.0 pmol of forward or reverse primer using the ABI Ready Reaction Dye Terminator Cycle Sequencing Kit (Applied Biosystems, Weiterstadt, Germany). Cycle sequencing reaction consisted of an initial denaturation step at 96°C for 45 seconds, 25 cycles at 96°C for 15 seconds, 54°C for 10 seconds, and 60°C for 4 minutes. Sequencing was performed on an ABI PRISM 310 Genetic Analyzer (Applied Biosystems) and sequence analysis (BLAST/dbEST) was performed using the National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov/).
Statistical Analysis
Molecular Genetic Analysis Patient samples were available for 525 (BM, n = 270; PB, n = 255) of the 683 AML patients assessable for this study: for 129 of 174 patients with t(8;21), inv(16), or t(15;17); for 247 of 303 patients with normal karyotype; and for 149 of 206 patients with all other chromosome aberrations, including 30 of 40 patients with t(11q23). None of the 129 patients with t(8;21), inv(16), or t(15;17) exhibited a MLL rearrangement. Of the 119 patients with all other chromosome abnormalities (the 30 patients with t(11q23) excluded), 10 patients (8.5%) were PTD-positive: three patients each had trisomy 11q within a complex karyotype (unique patient number [UPN] 93-16, 93-83, and 98A-182); trisomy 8 as the sole aberration (UPN 98A-146, 98A-450, and UPN 98A-460); one patient had deletion 7q (UPN 98A-489); and one patient each had trisomy 21 as the sole aberration (UPN 93-209), deletion 20q as the sole aberration (UPN 98A-345), and a marker chromosome (UPN 98A-26). Among the 22 patients with total or partial trisomy or tetrasomy 11, only three patients (UPN 93-16, 93-83, and 98A-182) were PTD-positive. In 19 of the 22 patients, trisomy or tetrasomy 11 was part of a complex karyotype, in one patient it was an abnormality secondary to a t(15;17), in one patient it was secondary to inv(16), and in the remaining patient tetrasomy 11 resulted from two unbalanced translocations. There was no trisomy 11 as the sole aberration in this series. Of the 247 patients exhibiting a normal karyotype, a rearranged MLL gene in HindIII and/or BamHI digests after hybridization with the 0.74-kb BamHI cDNA fragment was detected in 19 patients (7.7%; 95% confidence interval, 4.79% to 11.48%). The MLL rearrangement was represented by a single additional band (Fig 1). In eight (UPN 93-95, 93-124, 93-198, 93-205, 93-211, 98A-4, 98A-85, and 98A-218) of the 19 positive patients, PB was used for Southern blot analysis. In these patients, the blast counts ranged between 0% (UPN 93-95) and 87%.
Hybridization using the SAS1 probe identified the rearrangement in 19 of the 29 patients, indicating that the PTD had involved a region of intron 1 immediately 5' of exon 2 (Table 1). Additional material for single-round RT-PCR was available in 25 of the 29 PTD-positive patients, and PTD of the MLL gene was confirmed by sequencing of the PCR product (Fig 2): 18 patients (Table 1) showed a duplication that spanned exons 2 to 6, in three patients (UPN 98A-182, 98A-460, and 98A-470) differentially spliced transcripts of exons 2 to 8 and exons 2 to 7 were identified, in two patients (UPN 93-211 and 98A-189) the duplication of MLL involved exons 2 to 8, in one patient (UPN 93-116) exons 2 to 7 were duplicated, and in one patient (UPN 98A-26) a duplication of exons 4a to 6 was detected (Table 1). In 20 patients analyzed (Table 1), the MLL rearrangement was also diagnosed at the genomic level using XL-PCR. In one patient (UPN 93-75), the rearrangement of MLL could only be identified by Southern blot analysis using the BamHI cDNA probe. Hybridization with the SAS1 probe and genomic XL-PCR were negative. In this patient, no RNA was available for single-round RT-PCR. However, a negative result with the SAS1 probe does not exclude MLL PTD because fusion breakpoints might be located further 5' of intron 1. In these cases, genomic XL-PCR will result in large PCR products that are difficult to amplify. Hybridization with the SAS1 probe and genomic XL-PCR were negative in seven more patients (UPN 93-116, 93-186, 98A-26, 98A-182, 98A-199, 98A-460, and 98A-470) and the internal tandem duplication was confirmed by single-round RT-PCR and DNA sequencing (Table 1).
Correlation of Molecular Findings With Clinical Features in AML With Normal Karyotype Correlation of MLL PTD with clinical parameters was restricted to the group of patients with a normal karyotype; clinical data for statistical analysis were available in 221 patients including 18 PTD-positive patients (for one PTD-positive patient, no clinical data were available). There were no significant differences in the presenting clinical features such as age, sex, FAB subtype, WBC count, serum lactate dehydrogenase level, extramedullary manifestations, and BM blasts between the PTD-positive and the PTD-negative groups (Table 2). There was no significant difference in response to intensive double-induction therapy between the two groups (P = .74): 158 (78%) of 203 PTD-negative and 16 (89%) of 18 PTD-positive patients achieved a CR; 33 (16%) of 203 PTD-negative and two (11%) of 18 PTD-positive patients were refractory to the first cycle of ICE; 12 (6%) of 203 PTD-negative and none of the PTD-positive patients died during the phase of double-induction therapy (early death).
Survival Analysis Of the 16 PTD-positive patients who entered CR after double-induction therapy, one patient was lost to follow-up and the remaining 15 patients received intensive consolidation treatment. All 15 patients received the first consolidation therapy with HAM (cumulative dosage of cytarabine, 18 g/m2). Two patients relapsed before receiving the assigned second consolidation HAM and autologous PB stem-cell transplantation, respectively. Of the remaining 13 patients, eight patients received HAM (n = 6) or S-HAM (n = 2) (cumulative dosages of cytarabine, 18 g/m2 and 24 g/m2, respectively); two patients had autologous PB stem-cell transplantation after high-dose therapy with TBI and cyclophosphamide; and three patients had allogeneic PB stem-cell transplantation from an HLA-identical sibling after myeloablative therapy in one (TBI and cyclophosphamide), and less intense conditioning with fludarabine, cyclophosphamide, idarubicin, and etoposide in two patients (Table 3).29
Of the 158 PTD-negative patients who achieved CR, 88 received high-dose cytarabine-based consolidation, 20 had autologous transplantation, and 27 had allogeneic transplantation; three patients relapsed before receiving the second consolidation, and another 19 patients are still earlier in the treatment plan. After a median follow-up time of 19 months, 11 of 16 PTD-positive patients have relapsed, compared with 54 of 158 PTD-negative patients; the median remission durations of the PTD-positive and the PTD-negative patients were 7.75 months and 19 months, respectively (P < .001). The difference between the remission duration curves was statistically significant (P = .02) (Fig 3).
Only two PTD-positive patients (UPN 93-198 and UPN 98A-4), the ones with the longest duration of first CR (693 and 482 days, respectively), achieved a second CR after treatment with two cycles of idarubicin, fludarabine, cytarabine, and granulocyte colony-stimulating factor; both patients are in continuous second CR after myeloablative therapy and stem-cell transplantation from a matched unrelated donor. The median survival times of the PTD-positive and PTD-negative patients were 13.4 months and 20.8 months, respectively. There was no significant difference between the two survival curves (P = .427) (Fig 4).
The Cox proportional hazards regression model was used to identify differences in remission duration caused by prognostic factors. As possible prognostic factors, MLL PTD status, WBC count, serum lactate dehydrogenase level, age, and remission status after the first cycle of ICE were included in the regression model. The model identified the MLL PTD status as the single prognostic factor with a hazard ratio of 3.595 (95% confidence interval, 1.8 to 7.1; P < .001).
In this study, we analyzed BM or PB samples from a large prospective series of newly diagnosed patients with de novo or secondary AML entered onto two consecutive treatment trials of the AML Study Group Ulm for PTD of the MLL gene. The only limiting factor for the study was the availability of sufficient material to perform Southern blot analysis, and the analyses could be performed in 525 of the assessable 683 patients. In contrast to the previously published studies,14,15 this study is the first to evaluate the incidence and in particular the prognostic significance of MLL PTD within a large group of patients homogeneous with respect to age (young adults, 16 to 60 years of age) and to treatment; that is, all patients received intensive double-induction therapy followed by two cycles of intensification therapy including significant cumulative dosages of high-dose cytarabine combined with mitoxantrone. Southern blot analysis was performed using a cDNA probe that identifies all rearrangements that occur within the breakpoint cluster region of the MLL gene. In the group of patients with normal cytogenetics, MLL PTD was found in 7.7% of the cases. This percentage is comparable to those published by Caligiuri et al14 and Schnittger et al15 reporting an incidence of MLL PTD of 11% (11 of 98 patients) and 6% (six of 105 patients) in the subgroup of patients with normal cytogenetics, respectively. None of the 129 patients in our series exhibiting the prognostically favorable chromosome abnormalities t(8;21), inv(16), or t(15;17) had an MLL PTD. In the remaining subgroup of 119 patients with all other abnormalities (excluding 30 patients with 11q23 translocations), 10 patients (8.5%) were PTD-positive. Again, this figure is comparable to that published in a previous study.15 In our series, only three of the 22 patients with trisomy or tetrasomy 11q were PTD-positive. These data are somewhat at variance with those published by Caligiuri et al9; this study showed a close correlation of MLL PTD with trisomy 11, with 10 of 11 patients with trisomy 11 being PTD-positive. In contrast to the latter study, in none of our patients did trisomy or tetrasomy 11q represent the sole abnormality, but in all but three patients it occurred within a complex karyotype. On the basis of these data, one might speculate that trisomy 11 has a different molecular genetic basis depending on whether it occurs as a single abnormality or as one of multiple aberrations. The molecular texture of the gene duplication is consistent with previous studies, with exons 2 to 6 being the most frequently duplicated segment. In all cases where sufficient material was available, the rearrangement as detected by Southern blot analysis was confirmed by single-round RT-PCR. In all cases, sequence analysis revealed that the unique fusion product keeps in frame and thus will be translated into a full-length protein. The correlation of the molecular genetic findings with clinical outcome was restricted to the patients exhibiting a normal karyotype, and it demonstrates that MLL PTD is associated with an inferior outcome in this subgroup of patients. Analogous to the study by Caligiuri et al,14 there was no difference in the presenting clinical features between the MLL PTD-positive and the MLL PTD-negative patients; furthermore, the response to double-induction therapy was not different between the MLL PTD-positive and the MLL PTD-negative group, with a CR rate of 89% (16 of 18 patients) and 78% (158 of 203 patients), respectively. However, of the 16 MLL PTD-positive patients who achieved a CR, 11 have relapsed, compared with only 54 of the 158 MLL PTD-negative patients. The relapses in the MLL PTD-positive patients occurred despite intensive consolidation treatment (Table 3): of the eight patients who received two cycles of a high-dose cytarabine-based regimen with cumulative dosages of 36 to 42 g/m2, six have relapsed; of the two patients receiving autologous transplantation, one has relapsed; and of the three patients who had allogeneic transplantation, two have relapsed. In the latter group, the two relapses occurred in the two patients who had less intense conditioning because of their age (59 and 60 years). Thus, one important message from our study is that the treatment as given on our protocol, which included a high cumulative dosage of high-dose cytarabine in consolidation therapy, cannot be recommended to this subgroup of patients. In contrast to previous published studies that show a similar negative prognostic impact of MLL PTD,14,15 the results from our study are derived from a group of homogeneously treated younger adult patients, and they provide an answer to the impact of a specific consolidation therapy, that is, high-dose cytarabine consolidation, which is currently considered as the best conventional treatment option in patients up to the age of 60 years. In our series, only two of the 11 patients who relapsed achieved a second CR. Not surprisingly, these patients had by far the longest duration of first CR, and both patients are in continuous second CR after myeloablative therapy and allogeneic transplantation from a matched unrelated donor. As long as no molecularly targeted therapy is available for leukemias with MLL PTD, allogeneic transplantation from related or unrelated donors, including experimental conditioning regimens, should be carefully evaluated for this subgroup of patients.30
Supported by Leukemia Society of America grant no. 6599-01, Medical Faculty of the University of Ulm grant no. P.672, and Bundesministerium für Bildung und Forschung grant no. 01GI9981. We thank all participating centers of the AMLSG ULM for providing patient samples, Claudia Liebisch for excellent technical assistance, and Matthew P. Strout, MD, Comprehensive Cancer Center, Ohio State University, for providing the SAS1 probe, and Prof Michael J. Thirman, University of Chicago, for providing the 0.74-kb BamHI fragment.
1. Mrózek K, Heinonen K, Bloomfield CD: Clinical importance of cytogenetics in acute myeloid leukaemia. Best Pract Res Clin Haematol 14: 19-47, 2001[Medline]
2. Bloomfield CD, 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
3. 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 Leukemia Working Parties. Blood 92: 2322-2333, 1998
4. Slovak ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 96: 4075-4083, 2000
5. Caligiuri MA, Schichmann SA, Strout MP, et al: Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res 54: 370-373, 1994
6. Thirman MJ, Gill HJ, Burnett RC, et al: Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 translocations. N Engl J Med 329: 909-914, 1993 7. Gu Y, Nakamura T, Alder H, et al: The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71: 701-708, 1992[CrossRef][Medline] 8. Strout MP, Marcucci G, Caligiuri MA, et al: Core-binding factor (CBF) and MLL-associated primary acute myeloid leukemia: Biology and clinical implications. Ann Hematol 78: 251-264, 1999[CrossRef][Medline]
9. Caligiuri MA, Strout MP, Schichmann SA, et al: Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11. Cancer Res 56: 1418-1425, 1996
10. Caligiuri MA, Strout MP, Oberkircher AR, et al: The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome. Proc Natl Acad Sci U S A 94: 3899-3902, 1997
11. Strout MP, Marcucci G, Bloomfield CD, et al: The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia. Proc Natl Acad Sci U S A 95: 2390-2395, 1998
12. Marcucci G, Strout MP, Bloomfield CD, et al: Detection of unique ALL1 (MLL) fusion transcripts in normal human bone marrow and blood: Distinct origin of normal versus leukemic ALL1 fusion transcripts. Cancer Res 58: 790-793, 1998
13. Schnittger S, Wörmann B, Hiddemann W, et al: Partial tandem duplication of the MLL gene are detectable in peripheral blood and bone marrow of nearly all healthy donors. Blood 92: 1728-1734, 1998
14. Caligiuri MA, Strout MP, Lawrence D, et al: Rearrangement of the ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 58: 55-59, 1998 15. Schnittger S, Kinkelin U, Schoch C, et al: Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavourable subset of AML. Leukemia 14: 796-804, 2000[CrossRef][Medline] 16. Döhner H, Fischer K, del Valle F, et al: Stratification of postremission therapy in adult acute myeloid leukemia according to the karyotype: First results of the AML HD93 multicenter treatment trial. Blood 90: 584a, 1997 (suppl 1)
17. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 103: 620-625, 1985 18. Mitelman F (ed): ISCN (1995): An International System for Human Cytogenetic Nomenclature. Basel Switzerland, Karger, 1995
19. Fischer K, Scholl C, Sàlat J, et al: Design and validation of DNA probe sets for a comprehensive interphase cytogenetic analysis of acute myeloid leukemia. Blood 88: 3962-3971, 1996
20. Fröhling S, Skelin S, Liebisch C, et al: Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. J Clin Oncol 20: 2480-2485, 2002
21. Schichman SA, Caligiuri MA, Yansong G, et al: ALL-1 partial duplication in acute leukemia. Proc Natl Acad Sci U S A 91: 6236-6239, 1994 22. Tkachuk DC, Kohler S, Cleary ML: Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71: 691-700, 1992[CrossRef][Medline]
23. Parry P, Malek D, Mark B, et al: Structure and expression of the human trithorax-like gene 1 involved in acute leukemias. Proc Natl Acad Sci U S A 90: 4738-4742, 1993 24. Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8: 813-819, 1990[Abstract] 25. Korn EL: Censoring distributions as a measure of follow-up in survival analysis. Stat Med 5: 255-260, 1986[Medline] 26. Kaplan EL, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc 47: 457-481, 1958[Medline] 27. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719-748, 1959[Medline] 28. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-220, 1972 29. Schlenk RF, Hartmann F, Hensel M, et al: Less intense conditioning with fludarabine, cyclophosphamide, idarubicin and etoposide (FCIE) followed by allogeneic unselected peripheral blood stem cell transplantation in elderly patients with leukemia. Leukemia 16: 581-586, 2002[CrossRef][Medline]
30. Bunjes D, Buchmann I, Duncker C, et al: Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: Results of a phase I-II study. Blood 98: 565-572, 2001 Submitted September 20, 2001; accepted April 29, 2002.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
