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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-02-0532.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From Ludwig-Maximilians-University, University Hospital
Grosshadern, Department of Internal Medicine III, Muenchen,
Germany; Department of Internal Medicine III, St.
Marien-Krankenhaus, Siegen, Germany; and Department of
Biostatistics and Department of Internal Medicine A, Westfälische
Wilhelms-University, Muenster, Germany.
Risk assessment in acute myeloid leukemia (AML) using
pretreatment characteristics may be improved by incorporating
parameters of early response to therapy. In the 1992 trial of the
German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age
(median, 53 years) with de novo AML entered the trial and were
evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either
maintenance therapy or S-HAM consolidation. Cytogenetics were
favorable, intermediate, unfavorable and not available in 10.0%,
48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean ± SD, 18.6 ± 28.5%).
Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia
(PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were
18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to
CR rate (P < 0.0001), PL rate
(P < 0.0001), OS (P < 0.0001), EFS
(P < 0.0001), and RFS (P = 0.0049).
Multivariate analyses identified the following parameters to be
associated with the respective end points. CR rate: day 16 blasts
(P < .0001), age (P = .0036), and LDH
(P = .0072); OS: unfavorable cytogenetics (P < .0001), day 16 blasts (P < .0001),
age (P < .0001), and LDH (P = .0040); EFS:
unfavorable cytogenetics (P < .0001), LDH
(P < .0001), day 16 blasts (P < .0001),
and age (P = .0061); RFS: unfavorable cytogenetics
(P < .0001), LDH (P < .0001), and day 16 blasts (P = .0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR.
(Blood. 2003;101:64-70) Treatment of patients with newly diagnosed acute
myeloid leukemia (AML) has improved during the past decades due to the
intensification of induction and postremission chemotherapies and due
to the incorporation of autologous and allogeneic transplantation
procedures into the first-line management of the disease. Long-term
remissions, however, are achieved in a quarter of patients
only.1 The prognosis of patients with AML can be estimated
based on several patient-specific and disease-related factors among
which karyotype abnormalities have the most important independent
impact.2,3 Thus, most patients with CBF leukemias
including AML associated with t(8;21) and with inv(16)/t(16;16) achieve
long-lasting remissions, while in cases with abnormalities of
chromosomes 5 and 7 and with complex aberrant karyotypes in particular,
the median survival amounts to a few months only. Despite the use of
additional prognostic factors such as age and history of preceding
hematologic diseases for stratification models, the prognosis of
patients within the respective subgroups remains quite heterogeneous
and, thus, the prognosis of an individual patient cannot yet be
estimated accurately.
To this end a vigorous assessment of treatment effects may further help
to define the prognosis of the individual patient and to possibly adapt
the intensity of the antileukemic therapy to be applied. Thus, the
early quantification of therapy-induced cytoreduction in leukemic bone
marrow has been shown to highly correlate with the response to
induction therapy in a cohort of patients with newly diagnosed
AML.4 Trying to further define the prognosis in individual
patients, the quantification of minimal residual disease (MRD) by
molecular markers was assessed. However, this approach is limited to
cases of AML associated with specific genetic changes such as the
translocation PML/RAR In contrast, the early assessment of treatment response of AML has not
yet been studied in larger series of AML patients. In childhood acute
lymphoblastic leukemia, a rapid decline of leukemic blasts was
identified as the most important prognostic factor.18 In
AML, however, parameters of responsiveness identified to have a major
importance were restricted mainly to the rapidity of achievement of
remission19,20 or the achievement of remission by 1 course
only,21 while early response to therapy as assessed by
residual leukemic bone marrow blasts during aplasia has been shown to
have major prognostic impact in 2 reports only.2,22 Thus,
the current analysis was aimed at defining the impact of the level of
bone marrow blasts 1 week after the end of the first course of
induction therapy on the prognosis of patients with de novo AML of all
ages treated within the 1992 trial of the German AML Cooperative Group.
Patients
Antileukemic therapy
Induction.
For remission induction, patients were treated according to the double
induction strategy as previously published, with the second course
starting on day 21 irrespective of response of the disease to the first
course.2 The first course consisted of the TAD combination
with standard-dose cytosine arabinoside 100 mg/m2/d
continuous infusion on days 1 and 2, 100 mg/m2
every 12 hours intravenously as a 1-hour infusion on days 3 to 8, daunorubicin 60 mg/m2 intravenously as a 1-hour infusion on
days 3 to 5, and oral thioguanine 100 mg/m2 every 12 hours
on days 3 to 9.24 The second course was HAM with high-dose
AraC 3 g/m2 (1 g/m2 in patients aged 60 years
and older) every 12 hours intravenously as a 3-hour infusion on
days 1 to 3 and mitoxantrone 10 mg/m2 intravenously as a
1-hour infusion on days 3 to 5.25 The HAM course was
scheduled to be started on day 21 unless patients had severe
life-threatening nonhematologic toxicity, in case of which chemotherapy
was postponed until resolution of toxicity. The second course of the
double induction therapy was applied to patients older than 60 years
only if they had residual leukemic blasts of 5% or more in the bone
marrow on day 16 (ie, 1 week after completion of the first course).
Consolidation.
Consolidation therapy consisted of 1 course of TAD, which was applied 2 to 4 weeks after achievement of complete remission. Patients with
HLA-identical sibling donors subsequently underwent allogeneic bone
marrow or peripheral blood stem cell transplantation. All other
patients received further treatment according to the randomization
performed at study entry. Patients were randomized up-front to 3 years
of myelosuppressive maintenance therapy or to a second course of
intensive consolidation therapy following TAD consolidation, respectively.
Maintenance.
Maintenance therapy was applied every 4 weeks and consisted of AraC 100 mg/m2 every 12 hours subcutaneously on days 1 to 5 in
combination with either daunorubicin 45 mg/m2 on days 2 and
3 (courses 1, 5, 9, etc), thioguanine 100 mg/m2 every 12 hours on days 1 to 5 (courses 2, 4, 6, etc), or cyclophosphamide 1 g/m2 on day 3 (courses 3, 7, 11, etc).20,26
Treatment was delayed and doses were reduced for hematologic toxicity
according to predefined criteria. Upon achievement of a cumulative dose
of daunorubicin of 540 mg/m2, daunorubicin was replaced by thioguanine.
Second course of consolidation.
The second course of consolidation therapy consisted of the sequential
high-dose AraC and mitoxantrone (S-HAM) combination27 and
was applied 4 to 6 weeks after recovery from hematologic toxicity following TAD consolidation. S-HAM consisted of high-dose AraC (HDAraC) as a 3-hour infusion every 12 hours on days 1, 2, 8, and 9. The dose per application of HDAraC was 1 g/m2 in patients
younger than 60 years and 500 mg/m2 in older patients.
Mitoxantrone at 10 mg/m2 was applied as a 1-hour infusion
on days 3, 4, 10, and 11.
Diagnostics
Cytomorphology.
Cytomorphologic assessment was based on May-Grünwald-Giemsa
stains, myeloperoxidase reaction, nonspecific esterase using Cytogenetics.
Cytogenetic analyses were performed centrally according to standard
protocols. Cytogenetic data were classified according to the
International System for Human Cytogenetic Nomenclature (ISCN).33 Patients were classified into 3 subgroups based
on cytogenetics: the group associated with a favorable prognosis included AML with t(8;21), inv(16), or t(16;16); the
unfavorable-prognosis group contained AML with aberrations of
chromosomes 5 or 7, aberrations of 11q23 or 17p, inv(3), t(3;3), or
with a complex aberrant karyotype; the group associated with an
intermediate prognosis included AML with other karyotype aberrations as
well as AML with a normal karyotype.
Study parameters
Survival was measured by the time from inclusion into the AML Cooperative Group (AMLCG) 1992 study to death, and event-free survival (EFS) was measured by the time from inclusion into the study to death, documentation of persistent leukemia, or relapse, respectively. Relapse-free survival (RFS) was measured by the time from achievement of CR to relapse or death during CR. Freedom from relapse was measured by the time from achievement of CR to relapse. Estimates of time-dependent variables were calculated by the Kaplan-Meier method.35 Patients receiving bone marrow transplantation were censored at the time of transplantation. Statistics Univariate and multivariate analyses were performed to evaluate the dependence of the variables CR, persistent leukemia, survival, EFS, and RFS on day 16 blasts as a continuous variable as well as on pretreatment factors that were previously shown to have independent prognostic significance on a similar population (favorable/intermediate/unfavorable cytogenetics as dichotomous covariates; age and lactate dehydrogenase [LDH] as continuous covariates).32Univariate and multivariate analyses were performed for time-dependent variables by a proportional hazards model and for dichotomous variables by a logistic regression model using SAS 6.12.36 All P values reported are 2-sided. Because the application of the second course of double induction therapy to patients older than 60 years was dependent on achievement of fewer than 5% day 16 blasts, these analyses were performed for the total study population as well as for patients younger than 60 years only to prove the significance of the results in a most homogeneously treated group. Study conduct Prior to therapy all patients gave their informed consent for participation in the current evaluation after having been advised about the purpose and investigational nature of the study as well as of potential risks. The study design adhered to the declaration of Helsinki and was approved by the ethics committees of the participating institutions prior to its initiation.
Patients A total of 787 patients with AML were entered into the German AML Cooperative Group 1992 Trial between December 1992 and May 1999, 449 of whom are fully evaluable for the present analysis. In 152 patients the day 16 marrow was not available due to early death (n = 50) or due to lack of assessment because of reasons not specified (n = 102). In a further 186 patients the bone marrow evaluation at diagnosis had not been centrally reviewed, and these cases are not included in the present analysis. The patients' ages ranged from 16 to 76 years (median, 53 years), and the ratio of male-to-female was 1.02:1.00 (Table 1). Cytogenetic data were available from 321 of 449 patients (71.5%) and were rated favorable in 45 (10.0%) cases, prognostically intermediate in 217 (48.3%), unfavorable in 59 (13.1%), and were not available in 128 (28.5%). The amount of residual leukemic blasts in the bone marrow on day 16 blasts ranged from 0% to 100% (median, 5%; mean ± SD, 18.6% ± 28.5%). The distribution of the percentages of day 16 blasts is shown in Figure 1. AML subtypes according to the FAB classification are listed in Table 1. LDH in serum ranged from 98 U/L to 5220 U/L (median, 422 U/L).
Treatment outcome Of all 449 patients, 326 (72.6%) achieved CR, 79 (17.6%) had persistent leukemia, and 44 (9.8%) died from hypoplastic deaths. The median overall survival (OS) was 18 months (28.4% at 5 years), the median EFS was 9 months (21.6% at 5 years), and the median RFS was 15 months (30.1% at 5 years).Prognostic impact of day 16 bone marrow blasts Univariate analyses.
For the total study population, the percentage of day 16 blasts as a
continuous variable significantly influenced both response rates and
long-term outcome (Table 2). Even in
patients having achieved CR, the percentage of day 16 blasts had impact
on the prognosis and was significantly associated with the durations of
RFS (P = .0049) and of OS (P = .0068).
Multivariate analyses.
The day 16 blasts were entered into a multivariate model in addition to
previously defined independent prognostic factors
Analyses in cytogenetically defined subgroups.
Within the cytogenetically defined subgroups of patients with
prognostically intermediate and unfavorable karyotypes, respectively, day 16 blasts as a continuous variable were significantly associated with CR rate, rate of persistent leukemia, OS, and EFS (Table 5). There were no associations between
the respective end points and the day 16 blasts within the group of
patients with favorable cytogenetics. As depicted in Figures
3 and 4,
81 of 217 patients out of the group with prognostically intermediate
karyotypes have 10% or more day 16 blasts. The prognosis of these
patients is most similar to those cases with prognostically unfavorable
karyotypes and fewer than 10% day 16 blasts. In addition, 29 of 59 patients out of the group with prognostically unfavorable karyotypes
have 10% or more day 16 blasts and are prone to a particularly
dismal prognosis.
Analysis of patients younger than 60 years only.
In patients younger than 60 years who were treated with both courses of
double induction therapy independent of the percentage of day 16 blasts, the prognostic significance of day 16 blasts was proved. Thus,
the day 16 blasts as a continuous variable were highly correlated with
response to therapy as well as long-term outcome in univariate analyses
(Table 6) and prove to be of independent and major prognostic significance for all end points in multivariate analyses (Table 7).
Despite the use of stratification models for the treatment of patients with AML that are based mainly on pretherapeutic prognostic parameters such as cytogenetics and age, the prognosis of patients within the respective groups remains heterogeneous. In contrast, the early assessment of response to therapy represents an in vivo assessment of chemosensitivity and may be a powerful tool to delineate the prognosis in individual patients, as has been demonstrated for childhood acute lymphoblastic leukemias and osteosarcomas.18,37 As a consequence, this measure may be implemented into treatment decision strategies. Accordingly, to improve the stratification models used in AML, the current study aimed at defining therapy-dependent prognostic parameters. Along this line, the amount of residual leukemic blasts 1 week after the end of the first course of induction therapy (ie, on day 16) proved to be of major prognostic significance with regard to all analyzed end points independently of previously defined pretherapeutic prognostic parameters. Thus, highly significant correlations exist between day 16 blasts and CR rate, rate of persistent leukemia, OS, EFS, and RFS. As might have been anticipated, day 16 blasts were the factor having the strongest association with the CR rate and with the rate of persistent leukemia. In contrast, with regard to end points reflecting the long-term outcome (ie, OS, EFS, and RFS), unfavorable cytogenetics was the most important factor. However, day 16 blasts still had independent prognostic significance. In particular, the influence of day 16 blasts was not limited to the initial treatment phase but was also demonstrated for the long-term outcome. Thus, besides the influence on OS and EFS, both being closely connected with the CR rate, day 16 blasts also affected the outcome of patients having achieved a CR as demonstrated by the independent impact on the RFS. Furthermore, univariate and multivariate analyses limited to patients younger than 60 years who were uniformly treated by 2 courses of double induction therapy irrespective of response to the first course proved the significant correlation of day 16 blasts with all end points analyzed as well as the independent prognostic significance of day 16 blasts. These results are in accordance with analyses performed during a previous trial of the German AMLCG demonstrating an independent prognostic significance of day 16 blasts on OS and on RFS in patients 16 to 60 years of age.2 The present analyses are based on a large study population with no upper age limit (median age, 53 years). Besides the diagnosis of de novo AML there were no further limitations to the eligibility of the patients. Thus, the distribution of cytogenetically defined subgroups rather reflects the pattern observed in population-based analyses38,39 and suggests that the prognostic significance of day 16 blasts applies generally to patients with de novo AML. In fact, analyses within cytogenetically defined subgroups confirm the importance of day 16 blasts. The day 16 blasts had no impact on the outcome of patients with favorable karyotype abnormalities; however, due to the overall superior outcome of these patients, the identification of an additional prognostic parameter is rather unlikely. Underlining the importance for the patients with de novo AML in general, the day 16 blasts were significantly associated with all analyzed end points within both the prognostically intermediate and the prognostically unfavorable subgroups. Thus, even in the group of 59 patients with unfavorable cytogenetics the prognosis was heterogeneous and was related to day 16 blasts not only with regard to the CR rate (P = .0034) but also with regard to OS and EFS (P = .0418 and P = .0061, respectively). Previous analyses dealing with the leukemic cell mass have focused on the prognostic relevance of the white blood cell (WBC) count at presentation of the patients. However, only limited efforts were made to characterize the dynamics of their elimination. Thus, a hyperleukocytosis has been identified to be associated with a higher early death rate and an inferior OS.40-44 These associations have been confirmed in some multivariate analyses.45-48 In contrast, there are only a few studies addressing issues similar to those in the present analysis. The rapidity of achievement of CR has been identified to influence the patients' outcome in 2 studies. Thus, it was demonstrated that patients achieving a CR within 30 days of the start of antileukemic therapy had a superior remission duration compared with other patients (n = 156; P = .017).20 Similarly, there was a strong inverse correlation between time to achievement of CR and RFS (n = 1101; P < .001), and a duration to achievement of CR of more than 50 days was associated with a long-term outcome resembling that of patients with resistant disease, while other patients had a strikingly superior outcome (n = 1101).19 The present data are in agreement with those reported from the Medical Research Council (MRC) AML 10 trial49 where the response to the first course of induction therapy has been identified as an independent prognostic factor in a large study population of 1711 patients up to 55 years of age. The MRC therefore incorporated early response together with cytogenetics into a prognostic test discriminating 3 subgroups with highly differing outcomes.21 In the MRC AML 10 trial, the response had been categorized into 3 groups according to bone marrow blast counts of fewer than 5%, 5% to 15%, and more than 15% as assessed 2 weeks after completion of induction therapy. As in the present analysis, these categories did not influence the outcome of patients with prognostically favorable cytogenetics but affected the outcome of patients within both the intermediate and unfavorable groups. Based on the current data, the day 16 blasts represent a highly independent and sensitive prognostic factor and may be used for the stratification of treatment early enough before the second course of a double induction regimen. Clearly, this parameter allows the refinement but not the replacement of the most important system for a prognostically based classification of patients with AML (ie, the grouping according to karyotype abnormalities).3,33,50 The monitoring of early reduction of the leukemic cell burden may be further improved by methods more sensitive and reproducible than cytomorphology, such as immunopenotyping using multiparameter flow cytometry.51,52 Both methods are applied in parallel within the ongoing trial of the German AMLCG to accomplish a comparative analysis. Appendix: Centers participating in the German AML Cooperative Group University Hospital Aachen: T. H. Ittel; University Hospital Berlin-Buch: W. D. Ludwig; University Hospital Berlin-Steglitz: E. Thiel; Krankenhaus Neukölln, Berlin: A. Grüneisen; Franziskus-Hospital Bielefeld: H. J. Weh; Zentralkrankenhaus St. Jürgens, Bremen: U. Kubica; Krankenhaus Düren: J. Karow; University Hospital Düsseldorf: C. Aul; St.-Antonius-Hospital Eschweiler: R. Fuchs; University Hospital Göttingen: W. Hiddemann; Städtisches Krankenhaus Gütersloh: R. Depenbusch; Katholisches Krankenhaus Hagen: H. Eimermacher; Städtisches Krankenhaus Martha-Maria, Halle: U. Haak; Allgemeines Krankenhaus Altona, Hamburg: D. Braumann; Evangelisches Krankenhaus Hamm: A. Grote-Metke; Kreiskrankenhaus Herford: U. Schmitz-Hübner; Städtische Kliniken Kassel: W. D. Hirschmann; University Hospital Kiel: H. Löffler; University Hospital Köln: P. Staib; Städtische Krankenanstalten Krefeld: M. Planker; Dreifaltigkeits-Hospital Lippstadt: K. A. Jost; Städtisches Krankenhaus Süd, Lübeck: H. Bartels; Klinikum der Stadt Ludwigshafen: M. Baldus; University Hospital Mannheim: E. Lengfelder; Krankenhaus Maria Hilf, Mönchengladbach: H. E. Reis; University Hospital Münster: T. Büchner; Paracelsusklinik Osnabrück: O. M. Koch; Städtisches Krankenhaus Osnabrück: T. Hegge; University Hospital Regensburg: A. Reichle; Klinikum Landeshauptstadt Wiesbaden: H. G. Fuhr; St-Willehad-Hospital Wilhelmshaven W. Augener; Heinrich-Braun-Krankenhaus Zwickau: G. Schott.
Submitted February 21, 2002; accepted June 19, 2002.
Prepublished online as Blood First Edition Paper, June 28, 2002; DOI 10.1182/blood-2002-02-0532.
A complete list of the members of the German AML Cooperative Group appears in the "Appendix."
W.K. and T.H. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Wolfgang Kern, Ludwig-Maximilians-University, University Hospital Grosshadern, Department of Internal Medicine III, 81366 Muenchen, Germany; e-mail: wolfgang.kern{at}med3.med.uni-muenchen.de.
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Top
Abstract
Introduction
in acute promyelocytic leukemia. In
these cases, a persisting or recurring positivity for the transcript
during remission and the detection of a distinct level of the
transcript following consolidation therapy, respectively, are
associated with an increased risk of relapse.
that is, unfavorable
cytogenetics, intermediate cytogenetics, favorable cytogenetics, age
(continuous variable), and LDH (continuous variable).
/MYH11 fusion transcripts in patients with inv(16) acute myeloid leukemia after allogeneic bone marrow or peripheral blood progenitor cell transplantation.
Bone Marrow Transplant.
1998;21:159-166