1 Cattedra di Ematologia, Università Cattolica S. Cuore, Rome; 2 Dipartimento di Biotecnologie cellulari ed Ematologia, Università "La Sapienza", Rome; 3 Centro Dati GIMEMA Dipartimento di Biotecnologie cellulari ed Ematologia, Università "La Sapienza", Rome; 4 Dipartimento di Epidemiologia e Biostatistica Istituto Superiore di Sanità, Rome; 5 U.O.A. di Ematologia, Ospedale SS: Antonio e Biagio, Alessandria; 6 Ematologia, Ospedale Generale Regionale, Bolzano; 7 Divisione di Ematologia, Ospedale Oncologico "A. Businco", Cagliari; 8 Divisione di Ematologia, Ospedale Regionale "A. Pugliese", Catanzaro; 9 Divisione di Ematologia, Policlinico di Careggi, Firenze; 10 Dipartimento di Scienze Mediche, Oncologiche e Radiologiche, Sezione di Medicina Interna, Oncologia ed Ematologia, Modena; 11 Sezione di Ematologia Clinica, Ospedale "S. Francesco", Nuoro; 12 Divisione di Ematologia, Ospedale "S. Carlo", Potenza; 13 Cattedra di Ematologia, Università di Tor Vergata, Rome, Italy
* Correspondence to: Professor L. Pagano, Department of Haematology, Catholic University, Largo Francesco Vito 1, I-00168 Roma, Italy. Tel: +39-0630154180; Fax: +39-063051343; Email: lpagano{at}rm.unicatt.it
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Abstract |
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Patients and methods: In a multicentre setting, a prospective non-concurrent analysis was performed on 2513 new AML patients, aged 1278 years, consecutively enrolled in EORTC-GIMEMA trials between 1987 and 2001. Thirty-eight patients with sAML were identified and compared with a group of 114 de novo AML patients matched according to age, FrenchAmericanBritish criteria, white blood cell count at diagnosis, trial and time of diagnosis of AML. Induction treatment response, disease-free survival (DFS), duration and overall survival (OS) were evaluated in the two groups.
Results: Comparing the complete remission (CR) rate between 38 sAML patients and 114 de novo AML patients, selected according to the previously reported criteria, we observed no difference in the CR rates [25/38 (66%) versus 66/114 (58%); Pearson 2 0.7393, P=0.390] as well as no differences while comparing the DFS and the OS between the two groups.
Conclusion: The results of this study suggest that sAML patients are characterised by a good performance status permitting their recruitment in conventional trials without a previous myelodysplastic phase. Similar to de novo AML patients, sAML patients show good response to treatment and the possibility of cure.
Key words: secondary acute myeloid leukaemia, treatment
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Introduction |
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The clinical course of sAML is considered progressive and relatively resistant to conventional therapies used for AML arising de novo [5, 6
]. Only a few studies demonstrated good results with a standard induction therapy in sAML, with a favourable cytogenetic pattern [7
9
].
Although many studies concerning treatment response and prognosis of sAML are available, a cooperative study analysing secondary versus homologous de novo AML is still lacking.
In this study, we analysed the outcome of patients with sAML compared with de novo AML in patients treated with standardised chemotherapy according to GIMEMA protocols during a 14-year period.
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Materials and methods |
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The medical records of patients with sAML were reviewed.
As requested from the inclusion criteria in the EORTC-GIMEMA trials, only patients who had no evidence of recurrence of their prior malignancy at the time of sAML were included in the present study. The exclusion criteria also included patients with a myelodysplastic phase lasting more than 6 months before diagnosis of AML, as well as all cases of AML onset after a myeloproliferative malignancy. The following parameters were evaluated: demographic data, white blood cells (WBC), haemoglobin and platelet count at diagnosis of sAML, a previous myelodysplastic phase in the 6 months before sAML diagnosis, morphological, immunophenotypic, cytogenetic studies performed at the onset of sAML, complete remission (CR) achievement, disease-free survival (DFS) duration and overall survival (OS) from AML diagnosis. Further, additional information regarding PM, such as type and date of onset of PM, treatment performed for PM (chemotherapy, radiotherapy, surgery) and latency between PM and sAML, was investigated.
Treatment
Patients with sAML were identified from the GIMEMA database of patients entered in the following clinical trials for previously untreated AML: EORTC-GIMEMA AML 8A and 8B, EORTC-GIMEMA AML 10 and EORTC-GIMEMA AML 13. Data on the treatment schedule of each trial have already been reported [1013
].
Statistical analysis
Because of the limited number of sAML cases, and in order to adjust for possible confounding factors, we preferred the use of matching rather than regression techniques. Patients with sAML were matched with de novo AML according to age, FrenchAmericanBritish (FAB) criteria, WBC count at AML diagnosis, trial and time of diagnosis of AML.
A case-matched study with sAML/de novo AML ratio of 1:3 was chosen. When there were more than three possible matches for each sAML patient, the cases with the date of diagnosis closest to that of the sAML cases were selected.
A cytogenetic study was available only in a limited number of cases so that a comparison for cytogenetic risk category was not possible. A comparison was made between sAML patients in whom a cytogenetic pattern was known (12 cases) and de novo AML patients belonging to the same risk category who presented all the previous reported matching criteria.
The following parameters were compared: induction treatment response, DFS duration and OS.
The characteristics of the study groups were compared by 2-test when categorical and by the non-parametric MannWhitney U-test when continuous. The KaplanMeier method was used to analyse survival; the comparison of survival between groups was performed by the log-rank test.
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Results |
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At diagnosis of sAML all patients presented a good performance status. According to the World Health Organization (WHO) classification [14], 28 patients were classified as grade 0 and 10 patients as grade 1.
In the majority of cases the PM was breast cancer (10 pts) or Hodgkin's lymphoma (nine pts); altogether these malignancies represented 50% of all cases.
In Table 1 the type of PM and the primary treatment administered are reported and in Table 2 the peculiar features of sAML and de novo AML considered for the study are shown.
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All patients received chemotherapy and/or radiotherapy; among 15 patients treated with chemotherapy alone, nine patients received alkylating agents, combined with epipodophyllotoxins in three cases, and three patients were treated with different chemotherapy protocols. Of 14 patients treated with chemotherapy and radiotherapy, all received alkylating agents, with only one associated with epipodophyllotoxins. Therefore, 26 of 29 patients received alkylating agents and/or epipodophyllotoxins. The remaining nine patients were treated with radiotherapy only.
Cytogenetic analysis was performed in only 12 sAML patients (32%). In seven patients a normal karyotype was detected, with three patients showing a complex karyotype, while abnormalities of chromosome 5 or 7 were present in two patients.
Remission duration and OS
Twenty-five out of 38 patients with sAML achieved CR (66%); six died in induction while seven were resistant (Table 3). Patients who achieved CR continued their therapeutic programme in the EORTC-GIMEMA trial in which they were included. Eight patients underwent stem cell transplantation (SCT) (four allogeneic and four autologous). The median remission duration among patients achieving CR was 14.7 months with a range of 0.07159.1 months.
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The actuarial KaplanMeier curve at 5 years showed an OS of 19% and at 10 years of 15.2% (Figure 2).
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None of the patients presented a relapse of the primary malignancy.
Comparison between sAML and AML enrolled in GIMEMA trials
Comparing the CR rate between 38 sAML and 114 de novo AML patients, selected according to the previously reported criteria, we observed no difference [25/38 (66%) versus 66/114 (58%); Pearson 2 0.7393, P=0.390]. No differences were observed when comparing the DFS (Figure 1) and the OS between the two groups (Figure 2).
To verify that the data on DFS and OS of the 114 cases of de novo AML patients selected as controls would be effectively representative of the whole population of sAML patients, these data were compared with those of the whole population of de novo AMLs. No significant differences were observed.
Comparing sAML and de novo AML patients according to the cytogenetic pattern, we observed no differences in CR rate, DFS and OS.
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Discussion |
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Note that the proportion of secondary acute leukaemias is increasing and is related to the widespread use of radio-chemotherapy, increased survival of patients treated for neoplasia and ageing of the population [15, 16
].
The treatment strategies of sAML have been considered until now as a separate entity and different therapeutic regimens have been employed. Preliminary studies reporting a CR rate ranging from 0% to 10% [17] were published in the 1980s. The high failure rates during that period can probably be explained by the exclusion of these patients from the current chemotherapy regimens, in favour of non-intensive approaches such as vitamins, immunosuppressive agents and steroids. During the 1990s, an initial goal was obtained by conventional induction schemes: CR rates averaged from 15% to 75%, but no advances were registered for DFS and OS [18
24
].
Thus, the real challenge in the treatment of sAML appeared not in achieving CR, but maintaining such a response and obtaining a prolonged OS.
In order to improve these disappointing results, some studies suggested the use of high-dose chemotherapy (i.e. cytosine arabinoside) in some cases by adding growth factors to shorten the duration of neutropaenia and decrease infections. The results did not show any improvement in DFS and OS duration [25, 26
]. The higher failure rate was explained by a higher intrinsic biologic drug resistance of the leukaemic clone.
Recent reports showed that allogeneic SCT after intensive chemotherapy should be considered the treatment of choice for younger patients with a compatible sibling, when minimum requirements are met, namely age younger than 40 years, low peripheral and medullar blasts count [27, 28
]. In a recent experience of the European Bone Marrow Transplantation Group, 58 patients with de novo AML and 21 sAML were submitted for autologous stem cell transplantation. The actuarial 2-year survival, DFS, relapse rate and transplant-related mortality of patients with sAML were not statistically different from those of patients with de novo AML [29
].
However, this procedure can be performed only on a small proportion of patients with sAML, because they are, in the majority of cases, too old, and frequently unable to tolerate conventional myeloablative regimens.
In our prospective study, we wished to evaluate the outcome in a selected subset of patients with sAML considered eligible for an aggressive antileukaemic approach and therefore enrolled in conventional trials.
In fact the proportion of sAML included in the present series is 1.5% of the AML population, thus lower than that observed during the same period in patients registered by the GIMEMA Acute Leukemia Archive (6%) [4
]. This relevant discrepancy has various causes: one of these is that the median age of sAML enrolled in the Archive was 63 years [4
], while the criteria of inclusion in the therapeutic trials considered in the present study included all patients aged up to 60 years. Another parameter that could cause a non-eligibility of sAML for aggressive treatments was the worse performance status, either related to age, or due to frequent multiple concomitant medical problems related to previous exposure to chemotherapeutic agents. Furthermore, according to GIMEMA protocols, no AML patient, de novo or secondary, with previous prolonged myelodysplasia was enrolled in any trials, so that all these criteria markedly reduced the number of sAML patients considered eligible for an aggressive treatment.
Recently, Rowe [30] emphasised that the prognosis of sAML is absolutely similar to that of de novo AML with corresponding cytogenetic risk. He pointed out that this prognostic similarity also persists when patients are stratified based on other factors such as morphology, immunophenotype and multidrug resistance profile (MDR). This opinion was confirmed by Kern et al. [31
].
In addition, at present, no specific treatment strategies for sAML have demonstrated a higher activity versus standard therapy. This observation was also confirmed by a GIMEMA study on secondary acute promyelocytic leukaemia (sAPL). In fact, when sAPL patients enrolled in the AIDA trial, were compared with de novo APLs, no difference in remission rate or in general outcome was observed [32]. These data were subsequently confirmed by a cooperative FrenchSpanish study [33
].
We evaluated the outcome of sAML compared with de novo AML in patients treated with the same approach. None of our patients presented activity of the previous malignancy at the time of sAML and, according to WHO criteria, presented a good performance status that allowed the inclusion in a conventional therapeutic trial.
No differences were found in the CR rate, or in DFS and OS, between the two groups even after prolonged follow-up. Furthermore, the outcome was not influenced by the kind of previous malignancy or by the cytogenetic pattern at the onset of sAML.
The lack of cytogenetic data in two-thirds of our patients certainly represents a limit of our evaluation; however, in the risk analysis we analysed the cohort of patients separately, comparing them with de novo AML cases in which the cytogenetic profile was available with corresponding cytogenetic risk. The CR rate, OS and DFS did not differ in the two groups. Remarkably, only five of 12 sAML patients for whom cytogenetic analysis was available showed an unfavourable karyotype and, in particular, only two of them presented abnormalities of chromosome 5 or 7, a lower proportion than expected, also considering that 24 patients received alkylating agents previously.
It is well known that a myelodysplastic phase generally worsens the outcome of AML. The absence of a myelodysplastic phase could influence markedly the outcome in our series. In fact, a recent report by Goldstone et al. [34] on a large population of AML patients enrolled in the metabolic clearance rate AML 10, 11 and 12 trials, demonstrated that patients with sAML had a worse prognosis irrespective of cytogenetics or age, but sAML patients were in more than 50% of cases post-MDS AML.
Thus, the patients with de novo AML and sAML whom we enrolled before starting chemotherapy presented identical possibility of cure. The possible influence of the toxicity due to the drugs used for the treatment of the first malignancy must be considered apart.
The results of our study, based on a large group of patients and on a prolonged follow-up, demonstrated that a selected group of sAML patients, characterised by a good performance status and by the absence of previous myelodysplasia, present similar chances of cure to de novo AML.
Acknowledgements
This work was supported in part by a grant from the Ministry of University and Technological Research (MURST) of Italy.
Received for publication August 24, 2004. Accepted for publication September 22, 2004.
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