Significant dose Escalation of Idarubicin in the treatment of aggressive Non- Hodgkin Lymphoma leads to increased hematotoxicity without improvement in efficacy in comparison to standard CHOEP-14: 9-year follow up results of the CIVEP trial of the DSHNHL.
BACKGROUND
Dose escalation and modification of CHOP has improved the prognosis of patients with aggressive lymphoma; even in the rituximab era, dose escalation for high-risk patients is exploited and frequently limited by drug toxicity. Idarubicin (Id) is a 4-demethoxy anthracycline analogue of daunorubicin with activity against lymphoma and has been reported to cause less cardiotoxicity than other anthracylines. The aim of this study was to replace doxorubicine with idarubicin in the CHOEP regimen and to find the maximum tolerable dose (MTD) of idarubicin based on hematotoxicity.


METHODS
Between 11/96 and 09/98, 64 patients (pts) aged 18-75 yrs (pts. 18-60, LDH not elevated, >60 years all risk groups) with newly diagnosed aggressive lymphoma received 6 cycles of CIVEP-14 with an escalating dose of idarubicin, consisting of idarubicin (11-16 mg/m(2) d1) and standard doses of cyclophosphamide, vincristine, etoposide, and prednisone with G-CSF support.


RESULTS
55 pts (median age 56 yrs) were evaluable for a final analysis with a median observation time of 9.3 years. The CR-rate was 77.4% ; the 5 and 8-year-EFS rates were 46.4% (95%CI 32.5-60.3%) and 43.5% (29.4-57.6%), respectively, and the 5- and 8 yr OS rates were 64.6% (51.7-77.5%) and 59.9% (46.4-73.4%). 14/55 patients have died due to lymphoma progression, and 2/55 patients (3.6%) due to treatment related toxicity, 4/55 due to other causes (3 infections, 1 acute heart failure). In a matched pair analysis comparing CHOEP-14 and CIVEP-14, CIVEP-14 had a higher hematotoxicity with no significant differences in the event free and overall survival for the two regimens.


CONCLUSIONS
Thus, idarubicin cannot be used instead doxorubicin even if its dose is escalated to achieve similar hematotoxicity. Doxorubicin remains the standard anthracycline for the treatment of aggressive NHL.
Department of Hematology and Oncology, Georg August University, 37099 Göttingen, Germany.
Karin
K
Hohloch
Department Internal Medicine I, University of Saarland, 66421 Homburg/Saar, Germany.
Carsten
C
Zwick
Institue for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
Marita
M
Ziepert
Institue for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
Dirk
D
Hasenclever
Department of Hematology, St Bernward Hospital, 31134 Hildesheim, Germany.
Ulrich
U
Kaiser
Department of Internal Medicine I, University of Köln, 50937 Köln, Germany.
Andreas
A
Engert
Department of Hematology, City Hospital Fulda, 36043 Fulda, Germany.
Heinz-Gert
HG
Höffkes
Department of Hematology and Oncology, University Hospital, 01307 Dresden, Germany.
Frank
F
Kroschinsky
Department of Hematology and Oncology, University Hospital, 48149 Münster, Germany.
Rolf
R
Mesters
Institute of Pathology, Medical University of Lübeck, 23538 Lübeck, Germany.
Andreas C
AC
Feller
Institue for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
Markus
M
Löffler
Department of Hematology and Oncology, Georg August University, 37099 Göttingen, Germany.
Lorenz
L
Trümper
Department Internal Medicine I, University of Saarland, 66421 Homburg/Saar, Germany.
Michael
M
Pfreundschuh
Aggressive B-cell lymphoma; Anthracycline; Dose escalation; Toxicity