Re-induction with L-DNR/FLAG Improves Response after AML Relapse, but not Long-term Survival

Abstract

Background: According to the results of the international study Relapsed AML 2001/01 response was better after re-induction with L-DNR/FLAG (liposomal daunorubicin, fludarabine, cytarabine, G-CSF) compared to FLAG only but survival rate was not improved. However, the findings might be group-specific.

Method: Patient characteristics, actual therapy given and long-term course of the disease in 155 pediatric patients (including non-randomized) with first relapse and 10 primary nonresponders treated in Germany were analyzed.

Results: Overall 4-year survival rates after relapse were similar in the 2 treatment groups L-DNR/FLAG and FLAG (0.43±0.05 vs. 0.47±0.06, p(log-rank)=0.47). The rate of randomization was low (65%) and 5% of the 101 randomized patients changed the treatment arm. Therefore, induction was based in 40% patients on an individual decision with preference for L-DNR/FLAG. There were less patients with favorable cytogenetics and morphology in the L-DNR/FLAG-group (p<0.04). Response to the first re-induction course at day 28 tended to be more unfavorable with FLAG only. In this patient group protocol intensifications were more frequent as compared to the L-DNR/FLAG-group (p=0.07), and late CR could be achieved after intensification in 9/18 poor responding patients.

Conclusion: The initial selection bias of relapse patients with unfavorable risk factors to the disadvantage of the L-DNR/FLAG-group and the more drug- and time-intensive treatment after 1^st re-induction given in the FLAG-group may have nullified the initial beneficial effect of L-DNR containing re-induction therapy and led to similar and relatively favorable survival rates in both treatment groups in Germany.

Zusammenfassung

Hintergrund: Nach den Ergebnissen der internationalen Studie Relapsed AML 2001/01 war das Ansprechen nach Re-Induktion mit L-DNR/FLAG (liposomales Daunorubicin, Fludarabin, Cytarabin, G-CSF) im Vergleich zu FLAG bei den randomisierte Patienten besser, das Überleben war jedoch gleich.

Methode: Daraufhin wurden bei 155 pädiatrischen in Deutschland behandelten Patienten mit ersten Rezidiv und 10 primären Nonrespondern (Nicht-randomisierte eingeschlossen) die Patientencharakteristika, die aktuelle Therapie und die langfristigen Verläufe analysiert.

Ergebnisse: Die 4-Jahres Überlebensraten der 155 Rezidivpatienten waren in den Behandlungsgruppen L-DNR/FLAG und FLAG vergleichbar (0,43±0,05 vs. 0,47±0,06, p(log-rank)=0,47). Die Randomisationsrate war niedrig (101/155=65%), die Art der Induktion basierte bei 40% der Rezi­divpatienten auf einer individuellen Entscheidung, überwiegend zu Gunsten von L-DNR/FLAG. Die L-DNR/FLAG Gruppe enthielt signifikant weniger Patienten mit günstiger Zytogenetik/Morphologie. Das Ansprechen auf die erste Induktion war bei alleiniger FLAG Gabe am Tag 28 tendenziell ungünstiger. In dieser Gruppe waren Protokollintensivierungen häufiger als in der L-DNR/FLAG Gruppe (p=0,07), (9/18 FLAG-Patienten mit schlechtem Ansprechen erreichten noch eine späte CR).

Schlussfolgerung: Insgesamt dürfte der initiale Selektionsbias mit ungünstigen Risikofaktoren zum Nachteil der L-DNR/FLAG Gruppe und die spätere chemotherapeutisch- und zeitintensi­vierte Behandlung in der FLAG Gruppe den anfänglichen Vorteil der L-DNR/FLAG Induktion relativieren und damit die ähnlichen und relativ guten Überlebensraten in beiden Behandlungsgruppen erklären.

Key words

AML relapse - children - re-induction therapy - liposomal daunorubicin - FLAG

Schlüsselwörter

AML Rezidive - Kinder - Re-Induktionstherapie - liposomales Daunorubicin - FLAG

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