Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma.

The cell cycle regulatory protein cyclin D1, which is over-expressed in 95-100% of mantle cell lymphomas (MCL), is a potential therapeutic target. Flavopiridol inhibits the cyclin-dependent kinase (CDK)4-cyclin D1 complex and induces apoptosis in lymphoma cell lines. Previous phase I clinical studies had demonstrated that this drug could be safely administered in humans, prompting further evaluation of flavopiridol as a single agent in MCL. Ten patients with relapsed or refractory MCL, who had received one prior chemotherapy regimen, were treated with flavopiridol 50 mg/m2/day given as a 72 h continuous intravenous infusion every 14 days. Treatment was well tolerated, and only one patient developed grade III-IV non-hematologic toxicity. However, there were no clinical responses; despite therapy, three patients maintained stable disease, and seven patients demonstrated progressive disease within two months. In relapsed and refractory MCL, flavopiridol is ineffective as a single agent given by 72 h continuous infusion at 50 mg/m2/day. Recent in vitro studies using human plasma suggest that higher plasma drug levels may be necessary to achieve clinical efficacy. In vitro studies of flavopiridol indicate that the agent is synergistic with DNA-damaging compounds. Further investigation into flavopiridol as a clinical agent should focus on alternative dosing schedules and the compound's potential use in combination chemotherapeutic regimens.

Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival.

PURPOSE: To evaluate the efficacy of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) induction therapy in patients with newly diagnosed mantle-cell lymphoma (MCL). PATIENTS AND METHODS: From March 1997 to May 1999, 40 previously untreated patients with stage II through IV MCL were treated with six cycles of rituximab and CHOP chemotherapy in a phase II trial. Pretreatment and interval peripheral-blood (PB) and bone marrow (BM) specimens were also analyzed by polymerase chain reaction (PCR) for tumor-specific BCL-1/immunoglobulin H (IgH) translocations and clonal IgH rearrangements. Study end points included clinical and molecular response rates and long-term progression-free survival (PFS). RESULTS: Forty-eight percent of patients achieved a complete response (CR)/CR unconfirmed (CRu), and 48% of patients obtained a partial response (PR). However, 28 of the 40 patients have already relapsed or developed progressive disease with a median PFS of 16.6 months. Twenty-five patients had PCR-detectable BCL-1/IgH or clonal IgH products in PB or BM at diagnosis. Nine of the 25 informative patients had no evidence of PCR-detectable disease in PB or BM after rituximab and CHOP therapy. However, patients who achieved molecular remissions in PB or BM had PFS similar to patients without molecular remissions (16.5 v 18.8 months, P =.51). CONCLUSION: Favorable clinical and molecular response rates associated with rituximab and CHOP chemotherapy do not translate into prolonged PFS in MCL. Nevertheless, rituximab and combination chemotherapy may transiently clear PB or BM of detectable tumor cells, prompting additional consideration of antibody-based in vivo purging in subsequent clinical trials.