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

March 1, 2002

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).

Rituximab (Rituxan), a chimeric human-mouse anti-CD20 antibody, andalemtuzumab (Campath), a humanized rat anti-CD52 antibody, have each shown activity in chronic lymphocyticleukemia (CLL). To test the efficacy and safety of combining both antibodies (upto their approved doses) in relapsed and/or refractory CLL, nine patients (eightmales, 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 cohortreceived alemtuzumab at 3 mg three times per week. The second and third cohortsreceived alemtuzumab at 10 mg and 30 mg, respectively, in a similar fashion. Allhigher-dose cohort patients were treated initially with 3 mg of alemtuzumab andthen escalated to the targeted dose.

All patients received premedication with acetaminophen, antihistamines, andprophylactic antibiotics including fluconazole (Diflucan), acyclovir orvalacyclovir (Valtrex), and trimethoprim and sulfamethoxazole. Ciprofloxacin(Cipro) was given when absolute neutrophil count (ANC) was below 500/µL. Medianage was 66 years (range: 52-73 years). Median white blood cell count was63,900/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 withchlorambucil [Leukeran] with or without prednisone, and two withcyclophosphamide [Cytoxan, Neosar], vincristine, and prednisone), and had alsoprogressed despite purine analog-based therapy (one cladribine [Leustatin] andeight fludarabine [Fludara]). Seven patients had evidence of splenomegaly. Allpatients completed therapy. One patient failed to comply with the follow-upschedule. Treatment was delayed in two patients because of transient centralline-related gram-positive bacteremia.

Grade 2 hypotension developed in three of nine patients after rituximabinfusion and in one patient after alemtuzumab with correction after IV fluidadministration. Grade 3/4 fevers occurred in one and four patients afterrituximab and alemtuzumab infusions, respectively. Grade 2 rigors occurred atthe same frequency after rituximab and alemtuzumab (two patients each). Only onepatient developed dyspnea after the initial infusion of rituximab and resolvedspontaneously. Eight patients had a transient decline in the CD4 count, but noopportunistic infections were observed.

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

CONCLUSION: We conclude that the combination of rituximab and alemtuzumab isfeasible and safe in relapsed and/or refractory CLL patients. Hematologicresponses have been observed in the majority of patients. Currently, we areexploring the same combination but with increased duration of alemtuzumabtherapy. Patients will be treated with rituximab for 4 weeks, and withalemtuzumab for 4 to 12 weeks depending on their initial response. If thisapproach proves to be feasible, incorporating higher doses of rituximab intothis combination could be attempted. Once the feasibility is validated, a phaseII trial will be initiated to better explore efficacy.

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