Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses.
OBJECTIVE
Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F-->C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F-->C-->R).


METHODS
Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m(2) on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m(2) administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m(2) for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgV(H) genes.


RESULTS
There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F-->C regimen (P = .10).


CONCLUSIONS
Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.
Lamanna
Nicole
N
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
Jurcic
Joseph G
JG
Noy
Ariela
A
Maslak
Peter
P
Gencarelli
Alison N
AN
Panageas
Katherine S
KS
Heaney
Mark L
ML
Brentjens
Renier J
RJ
Golde
David W
DW
Scheinberg
David A
DA
Zelenetz
Andrew D
AD
Weiss
Mark A
MA
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012074:Remission Induction; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine