Substituting Liposomal for Free Vincristine in CHOP Could Permit Higher Therapeutic Doses

HOUSTON-Vincristine is efficaciousfor the treatment of aggressiveB-cell non-Hodgkin's lymphoma(NHL), but can have significant neurotoxicityat therapeutic levels. Liposomalvincristine has a longer half-lifeand preferentially greater accumulationin tumor cells and lymph nodesthan free vincristine, allowing the useof higher doses.In an early phase II trial of liposomalvincristine for the treatment ofrelapsed NHL, response rates of 10%for indolent lymphoma and 47% foraggressive lymphoma were observedin 51 patients.[1] Less than 22% ofpatients (11 of 51) reported neurotoxicityafter a median injected doseof 3.8 mg (range, 2.6 to 4.8 mg) and amedian of four injections (range, 1 to12 injections), and all patients withneurotoxicity had previously reportedneuropathy from prior treatmentwith paclitaxel or platinum drugs.Vincristine is a component of thecyclophosphamide (Cytoxan,Neosar), doxorubicin, vincristine(Oncovin), and prednisone (CHOP)chemotherapy regimen. In elderlypatients with diffuse large-B-cell lymphoma,complete response rates of63% have been reported for CHOPalone and 76% for CHOP plus rituximab(Rituxan).[2]Reduced NeurotoxicityLiposomal vincristine has reducedneurotoxicity relative to free vincristine.Substituting liposomal vincristinefor free vincristine as a componentof the CHOP regimen may leadto higher response rates with reducedtoxicity.[3] Maria Rodriguez, MD,and colleagues at The University ofTexas M.D. Anderson Cancer Centerin Houston, tested this hypothesisamong 73 patients with previouslyuntreated aggressive NHL (ASH abstract338).[3]Approximately half of the patientspresented with poor prognostic factors,including 36 patients who wereolder than 60 years of age and 30patients who had International PrognosticFactor Index scores of 2 orhigher.All patients in the study receivedstandard-dose CHOP (cyclophosphamide750 mg/m², doxorubicin 50mg/m², prednisone 100 mg, but substitutingliposomal vincristine 2.0 mg/m² for free vincristine) for 5 days, plussix to eight courses of rituximab (375mg/m²) every 21 days. Among the 66patients who have completed treatment,the response rate was 100%; 62patients had a complete response; 3patients had an unconfirmed completeresponse (negative scan bypositron emission tomography); and1 patient had a partial response. Aftera median follow-up of 12 months, allpatients were alive and only five patientshad relapsed, of whom fourwere over 60 years old.Neuropathy with liposomal vincristinewas mild (grade 0 to 2), andonly 5 of 69 evaluable patients (7%)required dose adjustments because ofneuropathy. Based on these results,the investigators concluded thatCHOP with liposomal vincristinecombined with rituximab is efficaciousand well tolerated, particularlyin elderly patients. The researchersurged the initiation of a randomizedtrial comparing this treatment regimenwith standard CHOP plus rituximabto further evaluate this innovativemodification.

References:

1.

Sarris AH, Hagemeister F, RomagueraJ, et al: Liposomal vincristinein relapsed non-Hodgkin’s lymphomas:early results of an ongoingphase II trial. Ann Oncol 11:69-72,2000.

2.

Coiffier B, Lepage E, Briere J, etal: CHOP chemotherapy plus rituximabcompared with CHOP alone inelderly patients with diffuse large-Bcelllymphoma. N Engl J Med 346:235-242, 2002.

3.

Rodriguez MA, Sarris A, East K,et al: A phase II study of liposomalvincristine in CHOP with rituximabfor patients with untreated aggressiveB-cell non-Hodgkin’s lymphoma(NHL): a safe and effective combination(abstract 338). Blood 100:92a,2002.