Subcutaneous Alemtuzumab May Be as Effective as Intravenous But With Fewer Severe Complications

PHILADELPHIA-In patientswith chronic lymphocytic leukemia(CLL), the standard regimen for intravenousalemtuzumab (Campath-1H), an anti-CD52 monoclonal antibody,is associated with systemic sideeffects including hypotension, rigors,fever, shortness of breath, bronchospasm,chills, and rash, which requirepretreatment with antihistamines andacetaminophen to ameliorate.[1] Recently,a phase II trial among 41 patientsdemonstrated that subcutaneousadministration of alemtuzumabis effective (87% overall response rate)and appears to reduce the incidenceand severity of some of these adverseevents.[2] Two independent studiespresented at the American Society ofHematology 2002 Annual Meetingtested the efficacy and safety of subcutaneousalemtuzumab in patients withCLL.[3-5]Comparable Blood LevelsGeoff Hale, PhD, and colleagues atthe University of Oxford and otherinstitutions in the United Kingdom,the United States, and Sweden, evaluatedwhether therapeutic serum levelsof alemtuzumab could be achievedvia subcutaneous injection and whetherthis route of administration wouldlead to a higher frequency of antiglobulinresponses (ASH abstracts 777 and5011).[3,4]The 30 patients with fludarabinerefractoryCLL in the IV group weregiven the standard IV protocol of alemtuzumab(CAM213), escalating dosesfrom 3, to 10, to 30 mg during week1 and giving 30 mg three times perweek thereafter for up to 12 weeks.Additionally, 20 patients with previ-ously untreated CLL in the SC groupwere administered the same doses ofalemtuzumab via SC injection for upto 18 weeks.Blood samples were collectedweekly, before and after dose administration,to determine the free serumlevels of alemtuzumab and the presenceor absence of anti-alemtuzumabantibodies. In the IV group, themean maximum serum level of alemtuzumabwas 10.7 μg/mL (range, 2.8to 26.4 μg/mL) and the mean troughconcentration (48 hours) was 5.4 μg/mL (range, < 0.5 to 18.3 μg/mL).In the SC group, peak serum levelsof alemtuzumab were comparable totrough levels of alemtuzumab in theIV group (mean, 5.4 μg/mL; range,0.6 to 24.8 μg/mL). In the SC group,significantly more time was requiredfor patients to achieve an antibodylevel of 1 μg/mL than for the IV group,requiring a mean cumulative dose of551 mg alemtuzumab (range, 146 to1,106 mg), compared with a meancumulative dose of 90 mg (range, 13to 316 mg) for the IV group. Dr. Haleand his colleagues speculate that thismight be secondary to more effectivebinding of alemtuzumab to the tumorcells in the SC group.[3]Antiglobulin ResponsesTo detect antiglobulin responsesto alemtuzumab, Professor Hale'sgroup used a validated enzyme-linkedassay with a lower limit of detection ofapproximately 0.5 μg/mL. In the IVgroup, no patient had anti-alemtuzumabantibodies detectable by thismethod. In the SC group, one patienthad a weak, transient response in asingle sample taken 14 days after thelast dose of alemtuzumab, and onepatient had a strong idiotype-specificresponse high enough to neutralizetherapeutic doses of alemtuzumab.In fact, this patient had no detectablefree serum alemtuzumab and was theonly patient in the SC group to demonstrateno response from alemtuzumabtherapy. Most other patientsadministered alemtuzumab subcutaneouslydemonstrated measurableclinical benefit.Although these results are encouraging,Dr. Hale cautions against drawinga direct comparison between efficacyin the SC group and that in the IVgroup, as the SC patients were previouslyuntreated. Interestingly, in theIV group a strong correlation wasseen between antibody serum levelsand clinical response (as determinedby flow cytometry for minimal diseasein the bone marrow). This impliesthat serum levels of alemtuzumab mayprovide a useful predictive clinicaltest and warrants further investigation.Upgrading Response LevelThe results presented by Dr. Haleand colleagues were supported by asmall clinical study presented by Mar-co Montillo, MD, of Niguarda Ca'Granda Hospital in Milan Italy (ASHabstract 3175).[5] Twelve patients(nine male, three female) with CLLwho responded to fludarabine (Fludara)treatment received sequentialSC alemtuzumab three times per weekfor 6 weeks in escalating doses up to10 mg. All patients had monoclonalrearrangement of the gene for immunoglobulinH before receiving alemtuzumab.All patients also receivedprophylactic acyclovir (Zovirax), cotrimoxazole,and bone marrow stimulantsprior to peripheral blood stemcell harvest.After fludarabine treatment, twopatients achieved a complete response,six experienced a nodular partial response,and four experienced a partialresponse. After alemtuzumab, allfour patients who previously had apartial response experienced a completeresponse and two also achievedmolecular remission. Among the sixpatients with a previous nodular partialresponse, five experienced a completeresponse, with polyclonal rearrangementof the gene forimmunoglobulin H in 1 patient. Finally,of the two patients who had acomplete response before alemtuzumabtreatment, one converted to amolecular complete response.Overall, after sequential administrationof fludarabine and SC alemtuzumab,11 of 12 patients achieved acomplete response, including 3 whoachieved molecular remission.All 12 patients were evaluable fortoxicity. No infectious episodes werereported. Five patients experiencedcytomegalovirus reactivation, andfour were successfully treated withoral ganciclovir (Cytovene) withoutpneumonia. A skin reaction (grade 1to 2 by World Health Organizationstandards) was observed in 50% ofthe patients at the injection site.Preliminary ResultsIndicate EfficacyTaken together, these resultspresent exciting new preliminary evidencethat SC administration of alemtuzumabmay provide efficacy similarto that of IV administration whiledecreasing the incidence of severecomplications associated with IV administration.It will be important toconfirm that SC alemtuzumab remainsas effective as IV alemtuzumabin a large, multicenter, randomizedclinical trial.

References:

1.

Campath® (alemtuzumab)[finalpackage insert]: Cambridge, Mass;Millennium and ILEX Partners, LP;2001.

2.

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.

3.

Hale G, Rebello P, Kimby E, etal: Blood levels of alemtuzumab duringtreatment of patients with chroniclymphocytic leukemia. Comparisonof intravenous and subcutaneousroutes of administration (abstract777). Blood 100:207a, 2002.

4.

Hale G, Rebello P, Kennedy B, etal: Antiglobulin responses to alemtuzumabduring treatment of patientswith chronic lymphocytic leukemia.Comparison of intravenous and subcutaneousroutes of administration(abstract 5011). Blood 100:363b, 2002.

5.

Montillo M, Tedeschi A, CafroAM, et al: Sequential subcutaneousadministration of CAMPATH-1H astreatment of minimal residual diseasein CLL patients responding to fludarabine(FAMP) (abstract 3175).Blood 100:804a, 2002.