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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Doxorubicin/analogs & derivatives , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Vidarabine/analogs & derivatives , Adolescent , Child , Cytarabine/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Germany , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Leukemia, Myeloid, Acute/pathology , Male , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Polyethylene Glycols/administration & dosage , Remission Induction , Retreatment , Selection Bias , Survival Rate , Vidarabine/administration & dosage , Young AdultABSTRACT
Mitoxantrone (MIT) has not been studied as a single agent in children with untreated leukemia. The antileukemic activity of MIT in these patients and its activity in relation to clinical and cell biological features is unknown. We studied the in vitro cytotoxicity of MIT, daunorubicin (DNR) and doxorubicin (DOX) in untreated childhood acute lymphoblastic leukemia (ALL, n = 131) and acute nonlymphoblastic leukemia (ANLL, n = 20) samples, using the MTT assay. There were marked interindividual differences in resistance to all three drugs. A strong, significant cross-resistance was found in ALL between MIT, DNR and DOX. All samples of the T-lineage, a prognostically unfavorable immunophenotype, however, were significantly more resistant to DNR and DOX, but not to MIT, than common or pre-B ALL samples. ALL cells from children with a prognostically unfavorable age at diagnosis, especially those < 2 years, showed a relative resistance to all three drugs compared to the intermediate age-group. This was found within all patients, but also within the common or pre-B ALL cases only. Sex, white blood cell count, or FAB type was not related to in vitro drug resistance. None of the three drugs showed an overall preferential activity in ALL or ANLL. We conclude that the in vitro antileukemic activity of MIT, DNR and DOX is related to certain clinical and cell biological features. There were no major differences between the three drugs in antileukemic activity, except that T-ALL samples were more resistant than common or pre-B ALL samples to DNR and DOX, while MIT was equally active in these two immunophenotypes.
