We studied the impact of cytogenetics and kind of induction/consolidation therapy on 848 adult acute myeloid leukemia (AML) patients (age 15–83). The patients received three types of induction/consolidation regimen: standard (daunorubicin and cytosine arabinoside (3/7); two cycles); intensive (idarubicin, cytosine arabinoside and etoposide (ICE), plus mitoxantrone and intermediate-dose Ara-C (NOVIA)); and low-dose (low-dose cytosine arabinoside). CR patients under 60 years of age, if an HLA-identical donor was available received allogeneic stem cell transplantation (allo-SCT); otherwise, as part of the program, they underwent autologous (auto)-SCT. CR rates significantly associated with ‘favorable’ (inv(16), t(8;21)), ‘intermediate’ (‘no abnormality’, abn(11q23), +8, del(7q)) and ‘unfavorable’ (del (5q), −7, abn(3)(q21q26), t(6;9), ‘complex’ (more than three unrelated cytogenetic abnormalities)) karyotypes (88% vs65% vs 36%, respectively; P = 0.0001). these trends were confirmed in all age groups. on therapeutic grounds, intensive induction did not determine significant increases of cr rates in any of the considered groups, with respect to standard induction. low-dose induction was associated with significantly lower cr rates. considering disease-free survival (dfs), multivariate analysis of the factors examined (including karyotype grouping) showed that only age >60 years significantly affected outcome. However, in cases where intensive induction was adopted, ‘favorable’ karyotype was significantly related to longer DFS (P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction. Patients receiving allo-SCT had significantly longer DFS (P = 0.005); in particular, allo-SCT significantly improved DFS in the ‘favorable’ and ‘intermediate’ groups (P = 0.04 and P = 0.048, respectively). In conclusion our study could provide some guidelines for AML therapy: (1) patients in the ‘favorable’ karyotype group seem to have a longer DFS when treated with an intensive induction/consolidation regimen, adopted before auto-SCT instead of standard induction; this underlines the importance of reinforcement of chemotherapy, not necessarily based on repeated high-dose AraC cycles. Allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment; (2) patients in the ‘intermediate’ karyotype group should receive allo-SCT; (3) patients in the ‘unfavorable’ karyotype group should be treated using investigational chemotherapy, considering that even allo-SCT cannot provide a significantly longer DFS, but only a trend to a better prognosis.
There is considerable debate on how the outcome of acute myeloid leukemia (AML) patients can best be improved.1,2,3,4,5 Until recently, treatment was based on a standard two-drug induction phase followed by various post-remission options, the intensity of which depended on the patient's age and eligibility for stem cell transplantation (SCT).3,4,5,6 Allogeneic (allo)-SCT is still generally considered the best option for patients with an HLA-identical donor. However, there is little agreement as to whether intensification of either induction or consolidation treatment can influence the duration of remission and survival.7,8 This situation may stem from the lack of diversified treatment schemes that take into account the biological heterogeneity of AML.9 Much effort has been made to identify prognostic factors. The FAB classification identifies the acute promyelocytic leukemia (APL) subtype (M3) of AML, which displays unique clinical features and marked sensitivity to all trans-retinoic acid and conventional chemotherapy based on anthracyclines.10,11 In addition, distinct trends have been found in the outcome of other AML subtypes, such as minimally differentiated (M0) AML and megakaryoblastic (M7) AML with trilineage myelodysplasia.12,13 Nevertheless, with the exception of APL, the FAB groupings seem to have little clinical relevance for initial therapeutic stratification. The most significant patient variable appears to be age, with older patients having a worse prognosis. The presence of a prior bone marrow disorder is also thought to affect outcome,14 whereas the value of the overall mass of leukemia, defined as the number of blasts or leukocytes, is still disputed.15 Taken together, these parameters are insufficient to identify the eventual outcome of many patients.
Cytogenetics is increasingly considered to be a relevant predictor of response to chemotherapy and clinical outcome.15,16,17,18 Two large multicenter studies19,20 have recently indicated that varying clinical outcomes can be predicted by detection at diagnosis of blasts of ‘unfavorable’, ‘intermediate’ or ‘favorable’ karyotype. One way of improving treatment strategy could be tailored induction and post-remission therapy based on genetic prognostic factors. Therapeutic trials are now being initiated to investigate different post-remission options on the basis of karyotype.16,19,21 Another issue that needs to be clarified is the impact of varying intensities of induction treatment on remission duration and survival.22,23,24
We thus retrospectively studied a non-randomized group of 848 AML patients enrolled and treated from 1990 to 1997 in 11 Italian centers, for whom cytogenetic analysis was available. We examined the impact of the most frequent cytogenetic abnormalities on complete remission (CR) rate and disease-free survival (DFS). We also observed the potential role of cytogenetics and other major prognostic factors with respect to standard, intensive and low-dose induction/ consolidation therapy.
Materials and methods
We reviewed 848 previously untreated AML (non-APL) patients over 15 years of age, diagnosed from January 1990 to December 1997 in 11 Italian institutions, for whom treatment response and survival duration data were available, as well as cytogenetic analysis at diagnosis. Clinical characteristics are reported in Table 1A. For the purpose of statistical analysis, the patients were subdivided into two age groups: ⩽60 years (n = 615) and >60 years (n = 233). The morphological diagnosis of AML was determined by conventional morphological criteria, according to the FAB classification.25 Patients with diagnosis of APL were not included in the study as they were treated according to a specifically tailored protocol. Criteria for CR were normocellular bone marrow with normal hematopoiesis and <5% blast cells, with concomitant normal peripheral counts and no signs of extramedullary leukemia. DFS was considered as the interval between documentation of CR and first evidence of relapse.
Bone marrow for cytogenetic analysis was cultured according to standard methods. Twenty or more cells were fully analyzed to exclude clonal abnormalities, which were defined in accordance with the International System for Human Cytogenetic Nomenclature (ISCN) guidelines.26 For patients with a detectable clonal abnormality, at least 10 metaphases were examined to exclude secondary changes in accordance with national guidelines for clinical cytogenetics.27 Complex karyotype was defined as the presence of a clone with more than three unrelated cytogenetic abnormalities. The 848 patients for whom successful cytogenetic detection data were available corresponded to 82% of the 1034 cases of AML observed in the period. Herein we consider separately the categories of abnormalities found in at least 10 patients (Table 1B). In these analyses, each case was defined by the primary abnormality, as previously described,19 and was counted only once.
The participating centers all employed three types of induction/consolidation regimen: intensive, standard and low dose. As there was no demonstration of an advantage of either protocol, the centers were free to adopt, as center policy, the intensive or the standard induction/consolidation regimens. Briefly, intensive regimen consisted of induction with idarubicin (10 mg/m2 i.v. push per day on days 1, 3, 5), cytosine arabinoside (100 mg/m2/day in continuous infusion on days 1–10, preceded at the start of infusion by 100 mg bolus injection) and etoposide (100 mg/m2/day i.v. on days 1 to 5) (ICE); patients who achieved CR after ICE received high-dose NOVIA consolidation: cytosine arabinoside 500 mg/m2/twice a day on days 1–6; mitoxantrone 12 mg/m2/day on days 1–4. Standard therapy comprised daunorubicin (45 mg/m2 i.v. bolus on days 1–3) and cytosine arabinoside (200 mg/m2 in continuous infusion on days 1–7, preceded at the start of infusion by 100 mg bolus injection), based on the 3/7 scheme; patients who achieved CR received a second 3/7 scheme. The low-dose therapy was administered to patients older than 70 years. It consisted of cytosine arabinoside 15 mg/m2/12 h (subcutaneous injection) on days 1–12, administered twice.
Up to 55 years of age allo-SCT was performed, when an HLA matched donor was available. Up to 60 years of age, consolidation was reinforced by autologous (auto)-SCT whenever the performance status was considered adequate. After 60 years of age, post-consolidation treatment was only occasionally administered.
The last analysis was in August 1999. Patients who died in CR or who were lost to follow-up were considered censored observations at the time point when they were last observed. Events were relapse or death. DFS was calculated according to the Kaplan–Meier estimate.28 Comparison between the DFS curves was conducted by the log-rank test according to Peto et al.29 Analysis was performed using the BMDP Statistical Software 1990 Edition. Two-sided P values were used throughout. P values were considered significant when <0.05.
Incidence of specific cytogenetic abnormalities
The frequency of the most common cytogenetic abnormalities detected at diagnosis are presented in Table 1B.
CR rates with respect to karyotype, therapy and other factors
Inv(16) and t(8;21) were associated with particularly high CR rates (91% and 86%, respectively). Abnormalities associated with extremely poor CR rates were abn(3)(q21q26), complex karyotype and del(5q) (CR rates 28%, 30% and 37%, respectively). Intermediate CR levels were found in the remaining categories: eg abn(11q23): 62% CR; no karyotypic abnormality: 69% CR; +8: 65% CR; del(7q): 62% CR. These findings are in line with the ‘unfavorable’, ‘intermediate’ and ‘favorable’ risk groups already reported.19,20 As can be seen from Table 2, CR rates significantly associated with the three groups (P = 0.0001). As regards therapy, intensive induction, with respect to standard induction, did not determine significant increases of CR rates in any of the three major karyotype groups, with the exception of the whole ‘intermediate’ group; the latter result, however, was not found among patients in the ‘intermediate’ karyotype group ⩽60 years (data non shown).
Impact of cytogenetic abnormalities and kind of therapy on survival
Overall DFS is reported in Figure 1. The DFS with respect to the three karyotype groups is reported in Figure 2. Univariate analysis showed longer DFS in the ‘favorable’ karyotype group with respect to the ‘unfavorable’ one (P = 0.001) as well as in the ‘intermediate’ group with respect to the ‘unfavorable’ one (P = 0.03). Nevertheless, multivariate analysis showed that up to 60 years of age DFS did not significantly differ among the three different karyotype groups. Among the other prognostic factors examined at diagnosis (FAB subgroup, number of leukocytes, sex, organomegaly, or age), the only ones that influenced DFS at univariate analysis were organomegaly and age >60 years (P = 0.0001) (Figure 3).
Concerning AML patients aged between 14 and 60 years, the type of induction therapy (low-dose, standard or intensive) significantly influenced DFS in certain karyotype subgroups (Figures 4–8). The ‘favorable’ karyotype group performed significantly better in terms of DFS when intensive induction with ICE was adopted (Figure 4; P = 0.04). This was mainly due to the favorable outcome of t(8;21) patients treated with intensive induction (DFS at 5 years: 80% intensive vs 14% standard; P = 0.003; Figure 5). By contrast, patients with inv(16) showed over 40% DFS in both therapeutic arms. In the ‘intermediate’ karyotype group, the type of induction therapy was not significantly associated with DFS. This was confirmed when the different karyotypic subgroups (eg ‘normal’ karyotype, abn(11q23), +8, del(7q), ‘other numerical’, ‘other structural’) were analyzed separately. The same applied in the ‘unfavorable’ karyotype group. However, in this group, a trend in favor of intensive therapy was observed, but, probably due to the relatively low number of patients, this did not reach significance. The number of cases receiving auto-SCT (n = 154) were comparable after the two types of induction.
Overall, patients receiving allo-SCT had significantly longer DFS (P = 0.005; Figure 6). In addition, allo-SCT was associated with significantly better DFS in patients in the ‘favorable’ and ‘intermediate’ karyotype groups (Figures 7 and 8; P = 0.04 and P = 0.048, respectively), independently of the kind of induction/consolidation therapy used. As regards the ‘unfavorable’ group, the DFS was longer after allo-SCT, but due to the small number of patients, this trend could not reach significance.
Cytogenetics is now considered one of the most valuable prognostic determinants in AML. However, many of the studies on which this convinction is based were limited by relatively small sample size or varying therapeutic approaches. This has led to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. Two large multicenter studies,19,20 in which cytogenetics was available for the majority of the enrolled patients, have indicated a correlation between clinical outcome and detection at diagnosis of AML blasts of ‘unfavorable’, ‘intermediate’ and ‘favorable’ karyotype. It has been suggested that patients bearing favorable cytogenetic abnormalities could be spared highly toxic and life-threatening approaches such as allo-SCT, as they could achieve long-term remission with chemotherapy alone.19,20,21,22,23,24,25,26,27,28,29,30,31,32
A second point that needs to be clarified is the impact of induction/consolidation treatment on remission duration and survival. In the effort to improve results, the standard two-drug induction approach has been varied many times in the last 15 years as regards intensity, duration and combination.33,34,35,36 Addition of a third drug has resulted in contradictory effects. However, employment of high-dose cytarabine seems to improve outcome,7,8,21,24,37,38,39 without affecting the remission rates. This suggests that high-dose cytarabine provides a better quality of remission. The prolongation of induction with cytarabine treatment for 10 instead of 7 days is now a widely used strategy, although the possible superiority of this schedule has yet to be demonstrated in a randomized trial. Moreover, the best type of induction and consolidation treatment for patients with different cytogenetic characteristics has still to be determined.
In the present study, in a relatively large series of consecutive AML patients, we assessed the possible impact of the stratification of patients into three karyotype risk groups. Our results suggest that this stratification has a significant prognostic value in univariate analysis, especially in certain karyotype subgroups. However, this stratification seems somewhat limited analyzing data in multivariate analysis. As expected, CR rates turned out to be significantly higher in the ‘favorable’ group than in the ‘intermediate’ and ‘unfavorable’ group, and also in the ‘intermediate’ group as compared with the ‘unfavorable’ one. These trends were apparently independent of the use of intensive induction. Low-dose induction was associated with significantly lower overall CR rates with respect to those obtained with the intensive or standard forms. Considering DFS, only age >60 years was related to significantly poorer outcome. None of the other prognostic factors examined at diagnosis (including the three karyotypic subgroups) was independently related to significant differences in DFS. The negative impact of age on DFS may be related to the more frequent incidence of ‘unfavorable’ karyotypes in the elderly and to the generally poor performance status at diagnosis, which often prohibits the use of intensive chemotherapy schemes. These findings provide further evidence of the limitations of the currently available prognostic factors at diagnosis (including karyotype grouping), and highlight the need for more powerful indicators.
When the impact of the different therapies was considered, the ‘favorable’ subgroup turned out to be significantly related to longer DFS if intensive induction/consolidation was adopted. This finding appears to be specifically due to the favorable outcome of t(8;21) patients when treated with the intensive induction/consolidation regimen, whereas the DFS of inv(16) patients seemed to be unaffected by the kind of therapy employed. A favorable outcome, in t(8;21) cases, could thus be related not only with the number of repeated cycles of high-dose AraC as previously reported,40 but with alternative intensive chemotherapy schedules as well. In the ‘intermediate’ subgroup, intensive induction did not appear to improve DFS with respect to standard induction. On the other hand, use of intensive induction in the ‘unfavorable’ subgroup appeared to be associated with somewhat better DFS.
As regards the contribution of allo-SCT, this procedure seemed to exert a positive influence on DFS both in the ‘favorable’ and ‘intermediate’ karyotype group, independent of the kind of induction/consolidation therapy used, whereas we did not observe a significant different in the ‘unfavorable’ subgroup. Thus, whether or not survival improvements observed after allo-SCT reflect more effective therapy or represent patient selection still remains unclear.
These results seem to suggest that the prognostic value of karyotype groupings is somewhat limited. It is true that our findings derive from a retrospective study, albeit of a large series of consecutive patients treated with standardized therapeutic protocols. Furthermore, it could be argued that the use of auto-SCT affected the relative DFS with respect to specific abnormalities, even though the percentage of patients who underwent this procedure was similar in the three karyotype groups. However, among patients carrying t(8;21) the influence of auto-SCT seems to have been negligible. Our findings underline the validity of adopting intensive induction/ consolidation therapy without recourse to allo-SCT in patients with t(8;21) alteration.
In conclusion, our study shows that karyotype abnormalities do not influence the outcome of AML patients in multivariate analysis. However, it is evident that karyotype has a predictive value on CR rates and DFS in univariate analysis. Thus, it may provide some guidelines for AML therapy. In the ‘favorable’ karyotype group, the duration of DFS in t(8;21) patients appears to be favorably influenced by an intensive induction/consolidation regimen adopted before auto-SCT instead of standard induction, underlining the importance of a reinforcement of chemotherapy, not necessarily based on repeated high-dose Ara-C cycles; allo-SCT, independently of induction/consolidation therapy, should be considered an alternative treatment, able to determine equivalent results if compared to the previous approach. Inv(16) patients have a similar good prognosis, which does not seem to be influenced by the kind of induction/consolidation regimen adopted. Patients in the ‘intermediate’ karyotype group should receive allo-SCT whereas patients in the ‘unfavorable’ karyotype group should be treated using investigational chemotherapy, considering their poor prognosis when any other conventional therapy is used.
Bloomfield CD, Baer MR, Herzig GP . Acute myeloid leukemia in adults: an update Educational Sessions of the Second EHA 1996 1–7
Bloomfield CD, Shuma C, Regal L, Philip PP, Hossfeld DK, Hagemejier AM, Garson OM, Peterson BA, Sakurai M, Alimena G, Berger R, Rowley JD, Ruutu T, Mitelman F, Dewald GW, Swansbury J . Long-term survival of patients with acute myeloid leukemia Cancer 1997 80: 2191–2198
Berman E . Recent advances in the treatment of acute leukemia Curr Opin Hematol 1997 4: 256–260
Rowe JM, Tallman MS . Intensifying induction therapy in acute myeloid leukemia: has a new standard of care emerged? Blood 1997 90: 2121–2126
Mandelli F, Petti MC, Lo Coco F . Therapy of acute myeloid leukemia: towards a patient-oriented, risk-adapted approach Haematologica 1998 83: 1015–1023
Bassan R, Barbui T . Remission induction therapy for adults with acute myelogenous leukemia: towards the ICE age? Haematologica 1995 80: 82–90
Bishop JF . Does it matter how remission is achieved in acute leukemia? Leukemia 1996 10 (Suppl. 1): S7–S9
Bishop JF . Approaches to induction therapy with adult acute myeloid leukemia Acta Haematol 1998 99: 133–137
Towards an increasingly molecularly-based . Patient-oriented treatment of acute myeloid leukemia. Editorial Haematologica 1996 81: 1–2
Warrel RP Jr, de The H, Wang ZY, Degos L . Acute promyelocytic leukemia N Engl J Med 1993 329: 177–189
Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, Willemze R, Muus P, Pelicci PG, Biondi A, Lo Coco F . Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy Blood 1997 90: 1014–1024
Venditti A, Del Poeta G, Buccisano F, Tamburini A, Cox MC, Stasi R, Bruno A, Aronica G, Maffei L, Suppo G, Simone MD, Forte L, Cordero V, Postorino M, Tufilli G, Isacchi G, Masi M, Papa G, Amadori S . Minimally differentiated acute myeloid leukemia (AML-M0): a distinct clinico–biologic entity with poor prognosis Ann Hematol 1996 72: 208–215
Tallman MS, Neuberg D, Bennet JM, Francois CJ, Paietta E, Wiernik P, Dewald G, Cassileth PA, Oken MM, Rowe JM . Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience Blood 2000 96: 2405–2411
Dassoneville L, Bailly C . Chromosome translocation and leukemias induced by inhibitors of topoisomerase II anticarcinogenetic drugs Bull Cancer 1998 85: 254–261
Van Putten WLJ on behalf of the AML Collaborative Group . Prognostic factors in AML Blood 1997 90 (Suppl. 1): 283-1(Abstr.)
Buchner T, Hiddemann W, Wormann B, Loffler H, Gassmann W, Haferlach T, Fontasch C, Hossfeld D, Maschmeyer G, Lengfelder E, Aul C, Heyll A, Ludwig W-D, Sauerland M-C, Heinecke A . Therapeutic outcome in AML is mainly determined by cytogenetics, LDH in serum, early response and, in poor risk subgroup, by intensified induction treatment Blood 1997 90 (Suppl. 1): 307-IX (Abstr.)
Dastigue N, Payen C, Lafage-Pochitaloff M, Bernard P, Leroux D, Huguet-Rigal F, Stoppa AM, Marit G, Molina L, Michallet M, Maraninchi D, Attal M, Reiffers J . Prognostic significance of karyotype in de novo adult acute leukemia Leukemia 1995 9: 1491–1498
Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, McCredie KB, Gehan EA, Freireich EJ . Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome Leukemia 1988 2: 403–412
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A on behalf of the Medical Research Council Adult and Children's Leukaemia Working Parties . The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML10 Trial Blood 1998 92: 2322–2333
Leith PC, Kopecky KJ, Godwin J, McConnel T, Slovak ML, Chen I M, Head DR, Appelbaum F, Willman CL . Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group Study Blood 1997 89: 3323–3329
Dohner H, Fisher K, Del Valle F, Hartmann F, Pralle H, Fisher JT, Gunzer U, Pezzuto A, Weber W, Grimminger W, Preiss J, Haas R, Schlenk R . Stratification of postremission therapy in adult acute myeloid leukemia according to the karyotype. First result of the AML HD93 multicenter treatment trial Blood 1997 90 (Suppl. 1): 2598 (Abstr.)
Preisler H, Davis RB, Kirshner J, Dupre E, Richards F, Hoagland HC, Kopel S, Levy RN, Carey R, Schulman P, Gottlieb AJ, McIntre OR and the Cancer and Leukemia Group B . Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study Blood 1987 69: 1441–1449
Berman E . Chemotherapy in acute myeloid leukemia: high dose, higher expectations? J Clin Oncol 1995 13: 1–4
Weick JW, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M . A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study Blood 1996 88: 2841–2851
Bennet JM, Catovsky DM, Daniel MT . Proposals for the classification of acute leukaemias Br J Haematol 1977 33: 451–458
Mitelman F . ISCN. An international system for human cytogenetic nomenclature Karger: Basel 1995
Testoni N, Borsaru G, Martinelli G, Carboni C, Ottaviani E, Pelliconi S, Ricci P, Pastano R, Visani G, Zaccari A, Tura S . 3q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features Haematologica 1999 84: 690–694
Kaplan EL, Meier P . Non-parametric estimation from incomplete observation J Am Stat Assoc 1958 53: 457–481
Peto R, Pike MC, Armitage ME Breslow NE, Cox DR, Howard SW, Mantel N, McPherson K, Peto J, Smith PG . Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Part II. Analysis and examples Br J Cancer 1977 35: 1–39
Ferrant A, Doyen C, Delannoy A, Straetmans N, Martiat P, Mineur P, Bosly A, Van Den Berghe H, Michaux JL . Karyotype in acute myeloblastic leukemia: prognostic significance in a prospective study assessing bone marrow transplantation in first remission Bone Marrow Transplant 1995 15: 685–690
Ferrant A, Labopin M, Frassoni F, Prentice HG, Cahn JY, Blaise D, Reiffers J, Visani G, Sanz MA, Boogaerts MA, Lowenberg B, Gorin NC . Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation Study Blood 1997 90: 2931–2938
Wheatley K, Burnett AK, Goldstone AH, Gray RG, Hann IM, Harrison IM, Harrison CJ, Rees JK, Stevens RF, Walker H . A simple, robust, validated and higly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial Br J Haematol 1999 107: 69–79
Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci A A, Omura GA, Gerber MC, Banks PLC . A phase III trial comparing idarubicin and daunorubicin with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Group Study J Clin Oncol 1992 10: 1103–1111
Rowe JM, Andersen JW, Mazza JJ, Bennet JM, Paietta E, Hayes FA, Oette D, Cassileth PA, Stadtmauer EA, Wiernick PH . A randomized placebo-controlled phase III study of granulocyte–macrophage colony stimulating-factor in adult patients (>55 years of age) with acute myelogenous leukemia: a study of the Eastern Oncology Cooperative Group (E1490) Blood 1995 86: 457–462
Lowenberg B, Suciu S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R, Dekker AW, Bernema ZN, Thyss A, Van der Lelie J, Sonnevald P, Visani G, Fillet G, Hayat M, Hagemeijer A, Solbu G, Zittoun R . Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy. The value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: a final report of the Leukemia Cooperative Group of the European Organization for the research and treatment of cancer and the Dutch–Belgian Hemato–Oncology Cooperative Hovon Group Randomized Phase III Study AML-9 J Clin Oncol 1998 16: 872–881
Willman CL . Immunophenotyping and cytogenetics in older adults with acute myeloid leukemia: significance of expression of multidrug resistance gene-1 (MDR1) Leukemia 1996 10 (Suppl. 1): S33–S35
Schiller G, Gajewski J, Territo M, Nimer S, Lee M, Belin T, Champlin R . Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia Blood 1992 80: 2977–2982
Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E . Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B N Engl J Med 1994 331: 896–903
Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, Patil SR, Davey FR, Berg DT, Schiffer CA, Arthur DC, Mayer RJ . Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype Cancer Res 1998 58: 4173–4179
Byrd JC, Dodge RK, Carroll A, Baer MR, Edwards C, Stamberg J, Qumsiyeh M, Moore JO, Mayer RJ, Davey F, Schiffer CA, Bloomfield CD . 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 1999 17: 3767–3775
This work was supported in part by MURST ex 40% (S Tura) and FONDI ex 60% (S Tura).
About this article
Case Reports in Hematology (2019)
Integrating resistance functions to predict response to induction chemotherapy in de novo acute myeloid leukemia
European Journal of Haematology (2019)
Expert Review of Hematology (2018)
Relapse and survival after transplantation for complex karyotype acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and the University of Texas MD Anderson Cancer Center