Impact of three courses of intensified CHOP prior to high-dose sequential therapy followed by autologous stem-cell transplantation as first-line treatment in poor-risk, aggressive non-hodgkin's lymphoma: comparative analysis of Dutch-Belgian Hemato-Oncology Cooperative Group Studies 27 and 40.
OBJECTIVE
Timing, appropriate amount, and composition of treatment before high-dose therapy and autologous stem-cell transplantation (ASCT) in patients with poor-risk, aggressive non-Hodgkin's lymphoma (NHL) are still unknown. We conducted two consecutive multicenter phase II trials with up-front, high-dose, sequential chemotherapy and ASCT in poor-risk, aggressive NHL. Both trials had identical inclusion criteria and only differed in amount and duration of induction treatment before ASCT.


METHODS
Between 1994 and 2001, 147 newly diagnosed, poor-risk, aggressive NHL patients, age < or = 65 years with stage III to IV and lactate dehydrogenase (LDH) more than 1.5x upper limit of normal (ULN), entered the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) -27 and HOVON-40 trials. Treatment in HOVON-27 consisted of two up-front, high-dose induction courses followed by carmustine, etoposide, cytarabine, and melphalan plus ASCT in responding patients. In HOVON-40, the same treatment was preceded by three intensified courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).


RESULTS
Patient characteristics in both trials were comparable: 80% had diffuse large B-cell lymphoma, 77% had stage IV disease, and median LDH levels were 3.1x ULN. Complete remission (CR) in both trials was 45% to 51%. Before ASCT, CR was 14% in HOVON-27 versus 28% in HOVON-40 (P = .03). Treatment failure was similar (27%). Four-year survival estimates in HOVON-27 compared with HOVON-40 were overall survival, 21% v 50% (P = .007); event-free survival, 15% v 49% (P = .0001); and disease-free survival, 34% v 74% (P = .008). This different outcome favoring HOVON-40 remained highly significant when correcting for competing risk factors in multivariate analysis.


CONCLUSIONS
In patients with poor-risk, aggressive NHL, addition of intensified CHOP before up-front, high-dose, sequential therapy and ASCT significantly improved the duration of response and survival.
van Imhoff
Gustaaf W
GW
Department of Hematology, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands. g.w.van.imhoff@int.umcg.nl
van der Holt
Bronno
B
Mackenzie
Marius A
MA
Van't Veer
Mars B
MB
Wijermans
Pierre W
PW
Ossenkoppele
Gerrit J
GJ
Schouten
Harry C
HC
Sonneveld
Pieter
P
Steijaert
Monique M C
MM
Kluin
Philip M
PM
Kluin-Nelemans
Hanneke C
HC
Verdonck
Leo F
LF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D012074:Remission Induction; D012307:Risk Factors; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D008942:Mitoxantrone; D011241:Prednisone