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Phase I Study of Rituximab and Alemtuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Phase I Study of Rituximab and Alemtuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Rituximab (Rituxan), a chimeric human-mouse anti-CD20 antibody, and alemtuzumab (Campath), a humanized rat anti-CD52 antibody, have each shown activity in chronic lymphocytic leukemia (CLL). To test the efficacy and safety of combining both antibodies (up to their approved doses) in relapsed and/or refractory CLL, nine patients (eight males, one female) were treated with rituximab at 375 mg/m²/wk for four doses (weeks 1, 3, 4, and 5), and alemtuzumab weeks 2 through 5. The first cohort received alemtuzumab at 3 mg three times per week. The second and third cohorts received alemtuzumab at 10 mg and 30 mg, respectively, in a similar fashion. All higher-dose cohort patients were treated initially with 3 mg of alemtuzumab and then escalated to the targeted dose.

All patients received premedication with acetaminophen, antihistamines, and prophylactic antibiotics including fluconazole (Diflucan), acyclovir or valacyclovir (Valtrex), and trimethoprim and sulfamethoxazole. Ciprofloxacin (Cipro) was given when absolute neutrophil count (ANC) was below 500/µL. Median age was 66 years (range: 52-73 years). Median white blood cell count was 63,900/µL (range: 1,500-237,600/µL). Median hemoglobin was 9.8 g/dL (range: 7.0-14.1 g/dL). Median platelet count was 67,000/µL (range: 14,000-429,000/µL).

All patients were previously treated with alkylating agents (seven with chlorambucil [Leukeran] with or without prednisone, and two with cyclophosphamide [Cytoxan, Neosar], vincristine, and prednisone), and had also progressed despite purine analog-based therapy (one cladribine [Leustatin] and eight fludarabine [Fludara]). Seven patients had evidence of splenomegaly. All patients completed therapy. One patient failed to comply with the follow-up schedule. Treatment was delayed in two patients because of transient central line-related gram-positive bacteremia.

Grade 2 hypotension developed in three of nine patients after rituximab infusion and in one patient after alemtuzumab with correction after IV fluid administration. Grade 3/4 fevers occurred in one and four patients after rituximab and alemtuzumab infusions, respectively. Grade 2 rigors occurred at the same frequency after rituximab and alemtuzumab (two patients each). Only one patient developed dyspnea after the initial infusion of rituximab and resolved spontaneously. Eight patients had a transient decline in the CD4 count, but no opportunistic infections were observed.

Eight patients (88%) had a hematologic response in the peripheral blood, since they had significant reduction in their absolute lymphocyte count (median decrease of 95% at the point of maximum response). Six of nine patients had stable adenopathy. Using the criteria recommended by the National Cancer Institute-sponsored working group on CLL, one patient obtained a partial remission that lasted 4 months. All other patients eventually progressed, but two patients did not require therapy until 12 months after completing the protocol. There was no treatment-related mortality.

CONCLUSION: We conclude that the combination of rituximab and alemtuzumab is feasible and safe in relapsed and/or refractory CLL patients. Hematologic responses have been observed in the majority of patients. Currently, we are exploring the same combination but with increased duration of alemtuzumab therapy. Patients will be treated with rituximab for 4 weeks, and with alemtuzumab for 4 to 12 weeks depending on their initial response. If this approach proves to be feasible, incorporating higher doses of rituximab into this combination could be attempted. Once the feasibility is validated, a phase II trial will be initiated to better explore efficacy.

Click here to read Dr. Bruce Cheson's commentary on this abstract.

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