Immunotherapy with rituximab following high-dose therapy and autologous stem-cell transplantation for mantle cell lymphoma.
Advanced-stage mantle cell lymphoma (MCL) is a disease for which no curative treatment strategy exists. Results with standard combination chemotherapy, with or without an anthracycline, are disappointing, and new and better therapies are needed. High-dose therapy and autologous stem-cell transplantation (ASCT) have been performed in patients with MCL both up front and at relapse with varying degrees of success. Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) has shown moderate response rates in patients with MCL. It has also been used safely and effectively as an in vivo purge during ASCT for patients with lymphoma. We are currently investigating an aggressive protocol in patients with newly diagnosed, untreated MCL using a combination of two promising therapeutic modalities, high-dose therapy-ASCT and rituximab. Since 1999, 13 patients with newly diagnosed MCL have been enrolled in this phase II clinical trial. CHOP (cyclophosphamide/prednisone/vincristine/doxorubicin) is used as debulking chemotherapy. Stem cells are mobilized with 5 days of granulocyte colony-stimulating factor 10 microg/kg/d, with a single infusion of rituximab 375 mg/m(2) used as an in vivo purge before stem-cell collection by large-volume leukapheresis. The transplant conditioning regimen is cyclophosphamide/carmustine/etoposide. Post-transplant consolidative immunotherapy consists of rituximab 375 mg/m(2), administered as two 4-week cycles at 2 and 6 months post-transplant. So far, 12 patients (7 men/5 women) with a median age of 55 years (range, 41 to 65 years) have been transplanted. Patients were first assessed and then transplanted a median of 40 and 201 days, respectively, from diagnosis. International Prognostic Index at diagnosis was low (n = 3), low-intermediate (n = 8), and high-intermediate (n = 1). A median of six cycles of CHOP was required to debulk tumor sufficiently for transplant. Response to CHOP was 100% with six complete responses, one complete response unconfirmed, and five partial responses. Transplantation was well tolerated. Patients engrafted quickly, with a median of 11.5 days to neutrophil engraftment and 10 days to platelet independence. Patients had modest transfusion requirements, requiring a median of four units of packed red blood cells and two and a half platelet transfusions. Six to 8 weeks post-transplant, six patients were in complete response, four in complete response unconfirmed, and two in partial response. Eight patients have received all eight maintenance rituximab treatments, and four have received only their first cycle. Following rituximab, the two patients in partial response and two in complete response unconfirmed converted to complete response. With a median follow-up of 239 days from transplant (range, 61 to 727 days), all patients remain alive and well with no documented relapses. Samples for molecular monitoring have been drawn from the stem-cell graft, and serially from the peripheral blood and bone marrow of patients at baseline, preapheresis, pretransplant, and post-transplant at 3-month intervals. This data shows that ASCT followed by rituximab immunotherapy is feasible and safe in patients with MCL. Although patient numbers are low and follow-up time is short, preliminary results are encouraging. Rituximab may convert partial responders to complete responders. The durability of responses will be determined with longer follow-up.
Mangel
Joy
J
Advanced Therapeutics Program, Toronto Sunnybrook Regional Cancer Centre, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.
Buckstein
Rena
R
Imrie
Kevin
K
Spaner
David
D
Crump
Michael
M
Tompkins
Kirsty
K
Reis
Marciano
M
Perez-Ordonez
Bayardo
B
Deodhare
Sanjeev
S
Romans
Robert
R
Pennell
Nancy
N
Robinson
Jean B
JB
Hewitt
Karen
K
Richardson
Patricia
P
Lima
Ana
A
Pavlin
Peggy
P
Berinstein
Neil L
NL
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D019940:Genes, bcl-1; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D020522:Lymphoma, Mantle-Cell / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011241:Prednisone / Q000008:administration & dosage; D012074:Remission Induction; D000069283:Rituximab; D014178:Translocation, Genetic; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D014750:Vincristine / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone