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Combination Chemo-Rituximab Therapy Raises CLL Response Rates

Combination Chemo-Rituximab Therapy Raises CLL Response Rates

SAN FRANCISCO—A regimen combining the monoclonal antibody rituximab (Rituxan) with fludarabine (Fludara) and cyclophosphamide may become the standard treatment for patients with chronic lymphocytic leukemia (CLL). That projection is based on preliminary findings from a phase II trial of 56 previously untreated patients with advanced CLL presented at the American Society of Hematology annual meeting.

Complete remission rates with chlorambucil, the traditional therapy for CLL, have been under 5%, said Michael J. Keating, MD, professor of medicine, M.D. Anderson Cancer Center.

While fludarabine (introduced in the mid-1980s) brought the complete response rate up to 30%, that advance did not translate into long-term survival. "No one was cured of disease, and we needed to get above 50% complete responses before there would be any prospect of patients with cancer being cured," Dr. Keating said.

When research showed that fludarabine inhibited an important resistance mechanism for alkylating agents, it was combined with the most "user-friendly" alkylating agent, cyclophosphamide, and the result was that the FC combination produced complete response rates of 40% to 45%, Dr. Keating said.

Initially, rituximab was overlooked in CLL, because the partial response rate in the pivotal trial of lymphocytic lymphoma (the lymphoma counterpart of CLL) was only 12%. Based on the insight that rituximab’s short half-life might require higher doses, investigators increased doses sixfold without side effects and achieved partial response rates of about 75%.

"That convinced us that rituximab would be active in CLL," Dr. Keating told ONI in an interview. He said that the researchers had a hunch that fludarabine would make cells more susceptible to chemotherapy, and that, plus some evidence that fludarabine would decrease resistance proteins to rituximab, led to the current trial with the three-drug (FCR) regimen.

The study included 68 patients with previously untreated progressive or advanced CLL given FC (fludarabine 25 mg/m2, cyclophosphamide 250 mg/m2) daily for 3 days for 6 courses every 4 weeks plus rituximab 375 mg/m2 on day 1 of course 1 and 500 mg/m2 on day 1 of courses 2 to 6.

The patients, Dr. Keating noted, were younger than a typical CLL population (median, 58 years). Forty percent were Rai stage III-IV, and the median white blood cell count was 111 × 103/mL. Fifty-six patients were evaluable for response.

Study Results

In the ongoing trial, for patients completing 3 courses (n = 21), complete response is 14% and nodal partial response is 29%. For those completing 6 courses (n = 35), complete response is 57% and nodal partial response is 20% (see Table). The overall response rate for the latter group is 94%.

"The initial data from this study suggest that the addition of rituximab to fludarabine and cyclophosphamide leads to a complete response rate that is clinically significantly higher than we have been able to achieve with chemotherapy alone," Dr. Keating said.

He noted also that "in 71% of patients, we are currently unable to find any CLL cells using the PCR [polymerase chain reaction] technique—which can identify one cell in half a million."

The addition of rituximab to FC did not appear to cause a clinically significant increase in adverse events, compared with those seen with FC alone. The most commonly reported adverse event, neutropenia, led to an FC dose reduction in 21% of patients.

Nausea was reported in 21% of patients, vomiting in 7%, and infections in 13% (pneumonia 1.1%, septicemia 1.9%, fever of unknown cause 4.2%, herpes 1.5%, soft tissue 4.2%). No opportunistic infections were reported.

During the first rituximab infusion, 61% of patients experienced grade 1-2 and 14% experienced grade 3-4 toxicities. Infusion-related events were uncommon in subsequent courses of rituximab. Tumor lysis was noted in five patients before allopurinol prophylaxis was initiated. After six courses, all responders except two partial responders had less than 5% CD5 and CD19 coexpressing lymphocytes in the marrow (median, 0.8%).

"With this protocol we have improved our complete response rate, we haven’t increased toxicity, and we have the best quality remissions that have been reported in CLL—apart from transplantation—which is clearly a risky procedure to go through," Dr. Keating said. He stated furthermore that with 90 patients currently enrolled in the trial, response rates remain consistent "across the board."

"So this is virtually becoming our new standard of treatment," Dr. Keating said, noting that the new task is to build on the FCR success.

Next year, trials of antisense will be launched among patients with bcl-2, an immortalizing protein that in CLL is almost always upregulated dramatically. Antisense will be given prior to the FCR combination, Dr. Keating said, to see if "we can shut down the bcl-2 protein" and make cells more susceptible to chemotherapy.

 
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