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DOI: 10.1055/s-2003-39374
Analyse der Ursachen von Todesfällen im Verlauf der intensiven Anfangschemotherapie in der Studie AML-BFM 93
Analysis of Causes of Death During Intensive Chemotherapy According to Treatment Protocol AML-BFM 93 Unterstützt von der Deutschen KrebshilfePublication History
Publication Date:
02 June 2003 (online)
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Zusammenfassung
Hintergrund: Im Verlauf der AML-Behandlung versterben über 10 % der Patienten nicht unmittelbar an ihrer Leukämie, sondern im Zusammenhang mit der durchgeführten Therapie. Ziel unserer Analyse war es, die Todesursachen und Zusammenhänge mit den jeweiligen Therapiephasen aufzuzeigen, um mögliche Konsequenzen für Therapieempfehlungen zu ziehen. Ergebnisse: Von den insgesamt 471 Protokollpatienten der Studie AML-BFM 93 sind 35 (7 %) vor Therapiebeginn oder innerhalb der ersten 6 Wochen nach Diagnose verstorben, 49 (10 %) erreichten keine vollständige Remission und 18 (4 %) sind nach Erreichen der Remission therapieassoziiert verstorben: Im Vergleich zu früheren Studien konnte die Rate der Frühtodesfälle von 13 % in Studie AML-BFM 78 auf 12 %, 9 % und 7 % (Studien 83, 87 und 93) reduziert werden (p-trend = 0,03). Der Anteil der partiellen und Nonresponder sowie der Patienten, die nach Erreichen der Remission in CCR verstarben, blieb weitgehend unverändert. Infektionen, besonders bakterielle Septitiden und Pilzinfektionen, waren die häufigsten Todesursachen. Ein Kind verstarb an einer Arrhythmie bei bestehendem Syndrom einer inadäquaten ADH-Sekretion. Nach Stammzelltransplantation in 1. Remission sind 7 von 51 Patienten überwiegend GvHD- und/oder infektionsbedingt verstorben. Die genannten infektiösen Komplikationen traten in abnehmender Häufigkeit nach Induktion, HAM, Konsolidierung oder Intensivierung mit HD/VP16 auf. Während und nach Ende der Dauertherapie verstarb jeweils ein Kind in CCR. 14 weitere Patienten, die als Nonresponder gewertet wurden, verstarben im Rahmen der Intensivtherapie (vor Tag 150) überwiegend mit wenigen Blasten und fehlender hämatologischer Rekonstitution. Todesursachen bei diesen Kindern waren überwiegend Septitiden oder invasive Aspergillosen nach HAM oder nach der ersten Phase der Konsolidierung und nur selten ein Progress der Leukämie. Schlussfolgerung: Insgesamt bestätigt diese Analyse, dass die Phase der Aplasie nach der Induktion und den Intensivkursen (HAM, Konsolidierung, HD-ARA-C/VP-16) besonders kritisch hinsichtlich der Infektionsgefährdung zu sehen ist. Konsequenzen sind: (1) Verbesserung der blutungs- und infektionsprophylaktischen sowie -therapeutischen Maßnahmen, (2) risikoadaptierte Therapiefortsetzung, und (3) Konzentrierung von besonders gefährdeten Patienten auf erfahrene Zentren.
Abstract
Background: During intensive chemotherapy for AML, more than 10 % of patients die because of treatment complications but not because of progression of their underlying disease. In order to improve supportive care and to decrease mortality, we analysed the causes of death and their relationship to the cycles of chemotherapy in children undergoing treatment for AML according to the study AML-BFM 93. Results: Thirty-five (7.4 %) of a total of 471 patients treated according to protocol AML-BFM 93 died before or within the first 6 weeks after diagnosis (early death). Fourty-nine patients (10 %) did not achieve remission, and 18 (4 %) died of therapy-related complications after having achieved remission. In comparison to earlier AML-BFM studies, early mortality was reduced from 13 %, 12 %, 9 % (AML-BFM 78, 83, 87) to 7 % (AML-BFM 93, p-trend = 0.03). In contrast, mortality of patients in complete continuous remission (CCR) did not change. Infectious complications, in particular due to bacterial and fungal pathogens, were the main cause of death. One patient died of arrhythmia associated with SIAD. After stem-cell transplantation in first remission, 7 of 51 patients died, mainly because of graft-versus-host-disease and/or infections. The incidence of infectious complications decreased with the number of chemotherapy cycles and was highest during induction therapy. Fatal complications occurred in one patient during maintenance therapy and in one patient thereafter; both patients were in CCR. Another 14 patients died during intensive therapy (before day 150) mostly with a low percentage of blasts, but no haematologic recovery. The cause of death in these children was mainly bacterial infection or invasive aspergillosis, but seldom progression of leukaemia. Conclusion: This analysis confirmed the high incidence of fatal infections in children with AML during chemotherapy-induced severe neutropenia. To increase overall survival in children undergoing therapy for AML, we propose (1) to improve the prophylactic and therapeutic measures for haemorrhage and infections, (2) to continue risk-adapted therapy and (3) to treat high-risk patients in specialised centres only.
Schlüsselwörter
AML im Kindesalter - Toxizität - Todesfälle
Key words
AML in children - toxicity - causes of death
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Prof. Dr. Ursula Creutzig
Pädiatrische Hämatologie/Onkologie, Universität Münster
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48129 Münster
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