Fludarabine Followed by Alemtuzumab Produces High Response Rates in Previously Untreated CLL

May 1, 2003

This special supplement to Oncology NewsInternational includes updated results ofstudies with anti-CD20 therapy and othertargeted therapies in the treatment oflymphomas, chronic lymphocytic leukemia,and immune thrombocytopenic purpura. Theresults were presented at the American Societyof Hematology 44th Annual Meeting inPhiladelphia, December 6 to 10, 2002.

NEW HYDE PARK, NewYork-Single-agent fludarabine (Fludara)is an active front-line therapyfor chronic lymphocytic leukemia(CLL) and has resulted in overall responserates of 63% to 71%.[1,2]Slightly higher response rates (approximately87%) in previously untreatedpatients with CLL have been reportedfor subcutaneous alemtuzumab(Campath-1H), an anti-CD52monoclonal antibody.[3] As part ofthe ongoing quest to improve responserates for patients with CLL,the Cancer and Leukemia Group B(CALGB) conducted a study usingsequential administration of fludarabinefollowed by alemtuzumab.Kanti R. Rai, MD, of Long IslandJewish Medical Center, Albert EinsteinCollege of Medicine, New HydePark, New York, presented results ofthe phase II trial (ASH abstract772).[4] The primary goal of the studywas to determine the toxicity and responserates of fludarabine plus alemtuzumabin treatment-naive patientswith CLL.Patients were administered fludarabine25 mg/m2 per day intravenouslyfor 5 days and monthly thereafter for4 months. Those who achieved stabledisease or better were then treatedwith a 6-week course of alemtuzumab30 mg three times per week intravenously,with the antibody first given at3 mg, then progressively increased astolerated during the first week, up to30 mg. Patients were also treated withprophylactic trimethoprim-sulfamethoxazoledouble strength (DS)and acyclovir (Zovirax) during andfor 6 months after alemtuzumab therapy.Final response results were evaluated2 months after completion oftherapy.Effective as CombinationA total of 57 patients were enrolledin the trial. One patient died beforeinitiation of fludarabine therapy; safetyand efficacy evaluations are thereforebased on 56 patients. During fludarabinetherapy, 11 patients requiredparenteral antibiotics and/or hospitalizationfor serious infections, and 1patient died of septicemia. After fludarabinetherapy, three (5%) patientsachieved a complete response and 28(50%) achieved a partial response. Ofthe 56 patients who received fludarabine,17 were not treated with alemtuzumabeither because of no response(7 patients) or progressive disease (10patients). Thus, 39 patients receivedalemtuzumab and were evaluable forresponse.The combination of alemtuzumaband fludarabine proved highly effective.The overall response rate among39 patients who received alemtuzumabwas 92% (36 patients), including a36% complete response rate and 56%partial response rate, according toNational Cancer Institute-WorkingGroup 1996 criteria.Among the 56 intent-to-treat patientsenrolled in the study, the completeresponse rate was 25% and thepartial response rate was 40%. Ofthe 12 patients who had stable diseaseafter fludarabine treatment, two(17%) achieved a complete responseafter alemtuzumab therapy. After amedian follow-up of 10 months, 87%of the 56 intent-to-treat patients werestill alive.Improved CMV RecognitionAlemtuzumab infusion reactionswere manageable and in most caseswere limited to grade 1 or 2. Twelvepatients had grade 3 or higher infectionsrequiring parenteral antibioticsor hospitalization.Infection with cytomegalovirus(CMV) occurred in eight patients duringor within 4 months of alemtuzumabtherapy. Complete or partialresolution of CMV occurred in six ofthese patients. Persistent CMV occurredin one patient, and one patientdied. Following the fatality, weeklyqualitative polymerase chain reactionbasedtesting for CMV was initiatedto improve early recognition of CMVand to allow both discontinuation ofalemtuzumab and initiation of antiviraltherapy.These results compare favorablywith those of a similar trial conductedwith sequential fludarabine and ritdarabine,uximab (Rituxan).[5] In that trial, 53previously untreated CLL patients received6 monthly courses of fludarabinefollowed 2 months later withrituximab. The overall response ratewith sequential administration of fludarabineand rituximab was 77% (41patients), including 28% completeand 49% partial response rates (95%confidence interval, 0.66, 0.89).Although these early results withalemtuzumab in combination withfludarabine are encouraging, Dr. Raicautioned that longer follow-up willbe necessary to determine whetheralemtuzumab has a positive influenceon survival in patients who have receivedinitial therapy with fludarabine.

References:

1.

Rai KR, Peterson BL, AppelbaumFR, et al: Fludarabine comparedwith chlorambucil as primarytherapy for chronic lymphocytic leukemia.N Engl J Med 343:1750-1757,2000.

2.

Leporrier M, Chevret S, Cazin B,et al: Randomized comparison of flu-ritdarabine,CAP, and CHOP in 938previously untreated stage B and Cchronic lymphocytic leukemia patients.Blood 98:2319-2325, 2001.

3.

Lundin J, Kimby E, BjorkholmM, et al: Phase II trial of subcutaneousanti-CD52 monoclonal antibody alemtuzumab(Campath-1H) as firstlinetreatment for patients with B-cellchronic lymphocytic leukemia (BCLL).Blood 100:768-773, 2002.

4.

Rai KR, Byrd JC, Peterson BL,Larson RA. A phase II trial of fludarabinefollowed by alemtuzumab (Campath-1H) in previously untreatedchronic lymphocytic leukemia (CLL)patients with active disease: Cancerand Leukemia Group B (CALGB)study 19901 (abstract 772). Blood100:205a-206a, 2002.

5.

Byrd JC, Peterson BL, MorrisonVA, et al: Randomized phase 2 studyof fludarabine with concurrent versussequential treatment with rituximabin symptomatic, untreated patientswith B-cell chronic lymphocytic leukemia:Results from Cancer and LeukemiaGroup B 9712 (CALGB 9712).Blood 101:6-14, 2003.