Fludarabine/Mitoxantrone/Rituximab Effective in NHL

February 1, 2002

ORLANDO-In advanced-stage low-grade non-Hodgkin’s lymphoma (NHL), a regimen of fludarabine (Fludara) plus mitoxantrone (Novantrone) followed by rituximab (Rituxan) is highly effective and well tolerated, according to study results presented at the 43rd Annual Meeting of the American Society of Hematology (ASH abstract 2534).

ORLANDO—In advanced-stage low-grade non-Hodgkin’s lymphoma (NHL), a regimen of fludarabine (Fludara) plus mitoxantrone (Novantrone) followed by rituximab (Rituxan) is highly effective and well tolerated, according to study results presented at the 43rd Annual Meeting of the American Society of Hematology (ASH abstract 2534).

There is no known cure for the low-grade non-Hodgkin’s lymphomas, a group of lymphoproliferative malignancies with a survival of 6 to 8 years. The rationale for the three-agent approach, said Stephanie Gregory, MD, Rush-Presbyterian-St. Lukes Medical Center, Chicago, is that the combination of fludarabine and mitoxantrone has previously been shown to be effective in the disease, both as frontline therapy and for patients who have failed prior therapy.

The strategy aims to induce remission with the combination and then to consolidate response by eradicating residual disease with the anti-CD20 monoclonal antibody rituximab.

Dr. Gregory undertook a phase II study to evaluate the safety and efficacy of the combination. Twenty-nine previously untreated low-grade NHL patients (Karnofsky performance status greater than 70%) have completed treatment. They received mitoxantrone 12 mg/m² on the first day of each 28-day cycle plus fludarabine 25 mg/m² on days 1 to 3.

After four cycles, those with a complete response received 375 mg/m² of rituximab weekly for 4 weeks. Partial responders received two further cycles of fludarabine and mitoxantrone, followed by rituximab for 4 weeks.

Shorter Regimen

To reduce toxicity, the study chemotherapy regimen was shorter than has been conventionally given, Dr. Gregory told ONI. "Instead of the standard 5 days of fludarabine at 25 mg/m², we have been able to cut it down to 3 days per week. Also, instead of treating these patients for 8 to 10 cycles, we have tried to get a quick response with 4 to 6 months of treatment, rather than 9 months plus a maintenance regimen," she said.

Dr. Gregory noted further that in the event of severe neutropenia/neutropenic fever, or infection requiring antibiotics, patients received sargramostim (GM-CSF, Leukine, Prokine). Oral allopurinol was given to patients with bulky disease, at the discretion of the investigator.

Four of eight patients with small lymphocytic lymphoma discontinued early because of neutropenia (1), pneumonia (1) and progressive disease (2). Another patient was lost to follow-up.

Among 24 patients evaluable for response, there were 10 complete responses and 12 partial responses. All of the 12 partial response patients achieved their response during fludarabine/mitoxantrone chemotherapy.

Of the 10 complete response patients, 7 achieved a complete response during chemotherapy and 2 achieved a partial response during chemotherapy and converted to complete response during rituximab therapy. One additional patient achieved a partial response during rituximab therapy and reached complete response at 9 months of follow-up. Five of six complete response patients with prolonged follow-up remain in remission with durations of 14 to 24 months.

"We found that even if after 6 months, some of the patients have not achieved a complete response, by then putting them into the monoclonal antibody treatment, some go into complete remission—which shows that you don’t have to overwhelm them with chemotherapy to get a complete response," Dr. Gregory said.

She also observed that the patients who had high baseline beta-2 microglobulin levels went on to progressive disease.

Four patients were discontinued due to toxicity during the first four cycles, and two discontinuations for progressive disease occurred at cycles 2 and 6. Nonhematologic toxicities were generally mild, and hematologic toxicities were comprised mostly of grade 1-2 neutropenia. Grade 3-4 cytopenia caused discontinuation of therapy in three cases and postponement of therapy in two. Other postponements were attributed to infection (1), rigors (1), dehydration with fever (1), and, during rituximab therapy, hypotension (1).

"It is an easy outpatient regimen," Dr. Gregory said, noting also that she had not seen any of the severe cytotoxicity, progressive neutropenia, and hemolytic anemias reported in other trials of fludarabine. "Maybe it is the shortened regimen, the fact that we are giving only 3 days and not 5 days of chemotherapy," she speculated. Extended trials of the combination regimen will evaluate for molecular remission and will test maintenance therapy with rituximab monotherapy over 6 months.