Split-Dose Rituximab Reduces Side Effects in Patients With High Circulating Lymphocytes

MIAMI BEACH—Patients with hematologic malignancies and high circulating lymphocyte counts are at increased risk for infusion-related side effects after the initial infusion of the anti-CD20 mo-noclonal antibody rituximab (Rituxan), but this problem can be prevented by a stepped-dosing scheme.

At a poster session of the 40th Annual Meeting of the American Society of Hematology (ASH), John C. Byrd, MD, of Walter Reed Army Medical Center, presented findings from six patients who had high circulating lymphocyte counts and infusion-related problems with rituximab.

Dr. Byrd said in an interview with Oncology News International that infusion-related problems are usually associated with the first infusion. “This is apparently because between the first and second infusions of rituximab, the peripheral blood leukocyte count will drop,” he said. “Patients typically can resume treatment the following day with no further problems.”

Rituximab is approved for use in relapsed and previously treated low-grade non-Hodgkin’s lymphoma (NHL). The pivotal trial excluded patients with circulating lymphocyte counts over 5,000/cm³ and/or significant cytopenias.

For patients who are likely to have high circulating tumor cell counts, Dr. Byrd said, “we begin the first infusion with 25 mg/m² of rituximab per hour for 4 hours (100 mg/m² total) in our outpatient clinic. We watch carefully for signs of toxicity, and we do not escalate the dose. Then we send the patient home. The next day we give the rest of the prescribed dose.”

This strategy has been effectively employed in two patients at Walter Reed with no infusion toxicity but clinically significant transient thrombocytopenia, he said.

Six Patients

The study presented at ASH included four cases seen at Walter Reed and the National Naval Medical Center plus two cases that had been reported to IDEC Pharmaceuticals, the manufacturer of rituximab.

Patients in the study had a median age of 67 years (range, 26 to 73). Two patients had B-prolymphocytic leukemia (B-PLL), two patients had chronic lymphocytic leukemia (CLL), one patient had mantle-cell lymphoma, and one patient had transformed non-Hodgkin’s B-cell lymphoma.

All had received prior therapy. All had elevated leukocyte counts as a consequence of blood tumor involvement, bulky adenopathy, and organomegaly.

The unique infusion-related syndrome observed in these six patients included significant bronchospasm and hypoxemia requiring rapid intervention with oxygen and bronchodilators; rigors; chills; and fever, Dr. Byrd said.

Possible Mechanisms of Infusion-Related Syndrome

The infusion-related side effects of rituximab (Rituxan) seen in patients with high circulating tumor cell counts may be a constellation of several events, Dr. John Byrd told Oncology News International.

“From previous work in immunotherapy,” he said, “it is known that when patients have high circulating tumor cell counts, the anti-CD20 antibody (either naked or radiolabeled) attaches to the circulating tumor cells and can be transported to the lung. The tumor cells can immediately be lysed, with release of the cell contents, and this can induce a secondary release of cytokines.”

Infusing the antibody into the circulation also provides an immediate supply of cells to which the antibody can directly bind and a ready supply of complement, which is more available in serum than in nodal and splenic sites, Dr. Byrd suggested. This may facilitate the rapid lysis and reduction of blood counts. Further studies are being done at Walter Reed to address these issues.

The thrombocytopenia seen in the syndrome may be related to the Fc receptor on the antibody. “Thrombocytopenia may occur because platelets bind to the antibody Fc receptor,” he said. “There is also cytokine release, which can cause a transient thrombocytopenia as is seen with interferon-alfa.”

In general, he said, this early thrombocytopenia may be a favorable response and shows that the antibody is working against the tumor cells. “In our clinical trial of rituximab,” he said, “the patients who had the best preliminary responses also had some type of preliminary thrombocytopenia or infusion-related side effects.”

The syndrome was accompanied by a rapid decline in peripheral lymphocytosis and a transient severe thrombocytopenia (less than 25 × 10⁹/L) in patients with baseline platelet counts lower than 100 × 10⁹/L.

At the same time, Dr. Byrd said, patients experienced a rapid drop in circulating tumor cell load and laboratory evidence of rapid tumor lysis, as demonstrated by changes in uric acid, phosphate, calcium, and LDH levels.

Five of the six patients received a second infusion of rituximab, Dr. Byrd reported. Two patients had fever and rigors, one had transient bronchospasm but completed the full dose of therapy, and all five finished either four or eight weekly treatments with rituximab.

Transient tumor responses to rituximab therapy were observed in both patients with prolymphocytic leukemia and in one patient with chronic lymphocytic leukemia.

The Index Case

The index case was a 73-year-old man with a refractory transformed B-cell lymphoma, Dr. Byrd said. He presented with extensive bulky adenopathy, B symptoms requiring steroids for palliation, bone marrow involvement, and lymphocyte count of 76.6/mm³, with abundant cells expressing CD5, CD20 (bright), FMC7, and slg (bright).

Rituximab was considered for this patient because of his lack of response to prior chemotherapy and because of the antibody’s novel mechanism of action and efficacy in large-cell non-Hodgkin’s lymphoma.

A previous patient treated with rituximab had significant infusion-related adverse effects, so Dr. Byrd and his colleagues decided to hospitalize the index patient and to initiate intravenous hydration and alkalinization, along with diphenhydramine, acetaminophen, and continued dexamethasone.

The Initial Infusion

Rituximab was initiated at 25 mg/h, but within 10 minutes the patient developed bronchospasm and dyspnea. Rituximab was promptly discontinued, and bronchodilators were initiated. The symptoms resolved in about 30 minutes.

Two attempts later in the day to restart rituximab therapy at lower infusion rates were unsuccessful despite the addition of corticosteroids and H₂-blockers, and consequently only 100 mg of the planned 700 mg rituximab dose was administered. The white blood cell count was 10.9/mm³ about 12 hours after the rituximab infusion, and chemistry studies showed evidence of tumor cell destruction.

Rituximab infusion was re-initiated the following day and was well tolerated, as were three subsequent infusions.