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Treatment of Secondary Acute Myeloid Leukemia

Department of Hematology, La Sapienza University and Catholic Universities, Rome, Italy

To the Editor:

In a recent issue, Kern et al reported the experience of the German Cooperative Group on the treatment of therapy-related acute myeloid leukemia (tAML), concluding that these patients should be treated as "de novo" AML. The most important prognostic parameter was the cytogenetic pattern, while being a "therapy related disease" itself does not retain a specific negative prognostic significance.¹

We want to add the experience of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) in the treatment of tAML. We analyzed the outcome of patients with tAML in comparison with de novo AML in patients treated with standardized chemotherapy according to four consecutive trials for previously untreated AML conducted during the period January 1987 to January 2001 by the GIMEMA cooperative group. The study population comprised more than 2,000 adult patients with newly diagnosed AML; only patients who had no recurrence of their prior malignancy at the time of tAML were included in the analysis. Thirty-eight patients were treated with chemoradiotherapy and subsequently developed tAML (1.5%). In a case-matched study, three cases of de novo AML, comparable for age, French-American-British criteria, WBC count at AML diagnosis, trial, and time of diagnosis were chosen for each tAML case. Cytogenetic study was available only in a limited number of cases (12 patients), and a comparison was made between tAML patients in whom cytogenetic pattern was known, with de novo AML patients belonging to the same risk category and respective to all the previously reported matching criteria. tAML occurred after a median latency of 38 months from primary malignancy. None of the patients with tAML had a previous myelodysplastic phase. Sixty-six percent of patients with tAML achieved compete response (CR), 16% died in induction, and 18% were resistant. The actuarial Kaplan-Meier projection at 5 years showed a disease-free survival (DFS) of 35%. The median overall survival (OS) for all patients was 11.4 months. The actuarial Kaplan-Meier curve showed an OS of 19% at 5 years, and of 15.2% at 10 years. Comparing the CR rate between 38 tAML and 114 de novo AML patients selected according to the previously reported criteria, no difference was observed (66% v 58%; Pearson ² = 0.7393; P = .390), and no difference was observed comparing the DFS and the OS between the two groups.

In a recent experience of the European Bone Marrow Transplantation Group the actuarial 2-year survival, DFS, relapse rate, and transplant-related mortality of patients with tAML were not statistically different from those of patients with de novo AML.² However, this procedure can really be performed in only a small proportion of patients with tAML, because they are, in the majority of cases, too old for the procedure and are frequently unable to tolerate conventional myeloablative regimens. Recently, Rowe³ emphasized that the prognosis of the tAML is absolutely similar to that of de novo AML with corresponding cytogenetic risk. This observation was also confirmed by a GIMEMA study on secondary acute promyelocytic leukemia that presented no difference in remission rate when compared with de novo acute promyelocytic leukemia enrolled in the AIDA (All-trans-retinoic acid plus Idarubicin) trial.⁴

Furthermore, no specific treatment strategies for tAML demonstrated a higher activity with respect to standard therapy. The lack of cytogenetic data in our patients surely represents a limit of our evaluation; however, in the risk analysis, we separately analyzed the cohort of patients, 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 between the two groups. It is noteworthy that in none of our tAML patients was a previous myelodysplasia reported. It is well known that a myelodysplastic phase generally worsens the outcome of AML, above all in tAML. The absence of an myelodysplastic phase could influence the results of treatment in our series. In fact, a recent report by Goldstone et al⁵ on a large population of AML patients enrolled in the MRC AML 10-11-12 trials, demonstrated that those patients with tAML had a worse prognosis and were in more than 50% of cases of postmyelodysplastic AML.

The results of this study and the above considerations, together with the data reported by Kern et al,¹ support the evidence that tAML patients usually have a worse prognosis frequently because of older age, lower performance status, and higher comorbidity, frequently associated with unfavorable cytogenetic profile with respect to de novo AML. Therefore, the secondary nature of the disease should not itself be considered an adverse factor, and the therapeutic strategy should be defined considering the conventional risk factor combination, similar to the de novo AML cases.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Kern W, Haferlach T, Schnittger S, et al: Prognosis in therapy-related acute myeloid leukemia and impact of karyotype. J Clin Oncol 22:2510-2511, 2004[Free Full Text]

2. Runde V, De Witte T, Arnold R, et al: Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: Early transplantation is associated with improved outcome—Chronic Leukemia Working Party of the European Group of Blood and Marrow transplantation. Bone Marrow Transplant 21:255-261, 1998[CrossRef][Medline]

3. Rowe JM: Therapy of secondary leukemia. Leukemia 16:748-750, 2002[CrossRef][Medline]

4. Pulsoni A, Pagano L, Lo Coco F, et al: Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: The GIMEMA experience. Blood 100:1972-1976, 2002[Abstract/Free Full Text]

5. Goldstone AH, Burnett AK, Avivi I, et al: Secondary acute myeloid leukemia has a worse outcome than de novo AML, even taking into account cytogenetics and age: AML 10, 11, 12 MRC Trials. Blood 100:88a, 2002 (abstr 322)

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• Prognosis in Therapy-Related Acute Myeloid Leukemia and Impact of Karyotype
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