1. FARMACOCINÉTICA DE ALEMTUZUMAB Javier Bautista Paloma Hospital U Virgen del Rocío

2. What is Alemtuzumab? Unconjugated, nonmodulating, humanised IgG1 kappa monoclonal antibody which targets the CD52 antigen Recombinant DNA derived

3. Mechanism of Action CD52 21-28 kD cell surface glycoprotein Expressed on more than 95% of malignant and normal T and B cells (lymphocytes, monocytes, macrophages, eosinophils) Function is unknown Alemtuzumab binds to CD52 bearing cells Causes cell death through host-effector mechanisms (complement-mediated lysis, antibody dependent cellular cytotoxicity

6. 67% de los pacientes habían recibido >= 3 líneas de tratamiento Eficacia mayor en pacientes respondedores a ttos previos (37,5% vs 28,9%) Tiempo hasta la progresión (mediana): 9 meses Supervivencia (mediana): 16 meses

7. Seguridad Incidencia de efectos adversos graves: 49% Muertes durante el tratamiento ó inmediatamente después: 10% (más de la mitad directamente relacionadas con Alemtuzumab: infecciones) Muertes durante el seguimiento: 5% (posible relación con el tratamiento)

8. CAM 307 Preliminary phase III efficacy and safety of alemtuzumab vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphociytic leukemia (BCLL) 1er ensayo clínico de Alemtuzumab en 1ª línea de LLC-B 297 pacientes: Alemtuzumab vs Clorambucilo Respuesta Completa: 24% vs 2% (p < 0.0001) Efectos adversos graves: 34.7% vs 19.7% EAG directamente relacionados con el fármaco: 21.1% 4.1%

9. Pharmacokinetic properties The pharmacokinetics profile of MabCampath administered as a 30 mg intravenous infusion 3 times per week was evaluated in chronic lymphocytic leukaemia patients who were treated for a maximum of 12 weeks. Peak and trough levels of MabCampath rose during the first few weeks of treatment and then approached steady state by approximately week 6. The rise in serum concentration corresponded with a marked reduction in lymphocytosis: Patients with peripheral lymphocyte counts of >30 000/microL at baseline had significantly lower peak and trough levels of MabCampath during the first 4 to 5 weeks of treatment compared to those with lymphocyte counts <30 000/microL. This suggests that lymphocytosis represents a compartment in the blood in which MabCampath is concentrated.

10. Volumen de Distribución (SS): 0.15 L/Kg (0.1 – 0.4) El aclaramiento sistémico disminuye con las dosis repetidas (saturación de los receptores) Vida media de eliminación inicial: 8 h (2 – 32) Vida media de eliminación final (SS): 6 días (1 – 14) NO se observó diferencias por sexos NO se observó diferencias según la edad

11. Vía de administración I.V. Incidencia elevada de reacciones agudas relacionadas con la liberación de citoquinas Fiebre Rigidez Náuseas y vómitos Erupción cutanea, urticaria, prurito, disneabroncoespasmo Cefalea Diarrea Aparecen habitualmente durante la 1ª semana de tto Se reducen sustancialmente en semanas sucesivas Raramente: shock anafiláctico, IAM, muerte Debe utilizarse premedicación antihistamínica y antitérmica-analgésica

12. Vía de administración Subcutanea Intento de disminuir los problemas de la administración IV Disminuye la incidencia de reacciones agudas Biodisponibilidad: 50% ó inferior Dosis acumulada necesaria para obtener los mismos niveles plasmáticos: 6 veces superior Se eleva mucho el coste Mayor producción de anticuerpos frente a Alemtuzumab Diarrea Se está llevando a cabo actualmente un EC aleatorizado y cruzado para comparar las características PK y PD de Alemtuzumab administrado por vía IV y SC

13. BCCA Protocol Summary BCCA Protocol Summary for the Treatment of Fludarabine-Refractory B-Chronic Lymphocytic Leukemia (B-CLL) with Alemtuzumab www.bccancer.bc.ca

14. Eligibility Criteria Patients with B-CLL and 18 years or older Have not responded to or had early documented relapse after Fludarabine Have received at least one alkylating agent- containing regimen Life expectancy of at least 12 weeks Rai Stage II, III or IV with symptomatic splenomegaly, lymphadenopathy, or cytopenias related to marrow infiltration or sequestration. WHO performance status 0-2

15. Exclusion Criteria Hypersensitivity reactions to other monoclonal antibody therapies HIV seropositivity Pregnant or lactating New York Heart Association grade III or IV congestive heart failure Active systemic infection Bulky (>5 cm) adenopathy at any site Pre-existing autoimmune cytopenias

16. Dosage Dosing three times each week, usually MWF, for maximum of 12 weeks All doses flat dose in mg, not mg/m 2 Week 1: 3 mg 10 mg 30 mg Week 2+: 30 mg 30 mg 30 mg

17. Dosage (2) Escalate to 10 mg, then 30 mg only if toxicities grade I or II, and improving. If grade III or IV reactions occur, lower dose to maximum tolerated dose (3 or 10 mg) until well tolerated for one week, then resume escalation to maximum of 30 mg/dose. Maximum total weekly dose is 90 mg. If treatment is interrupted for more than 7 days for any reason, re-initiate treatment at 3 mg, and escalate as above

18. SC (thigh) (Note: divide 30 mg dose into two injection sites) OR IV in 100 mL NS over 2 hours NOTE: Due to ampoule format, draw up dose with a 5 micron filter needle. Discard all unused portions of the ampoule Administration

19. Sample Pre-Printed Order Have Available in Treatment Room: Diphenhydramine 50 mg for IV injection (if required) Epinephrine 1:1000 1 mL for IV injection (if required, dilute in 10 mL) Methylprednisolone 125 mg for IV injection (if required) Salbutamol Nebules plus nebulizer (if required, for inhalation use)

20. Adverse Effects Infusion-Related Events (2) Premedication Diphenhydramine 50 mg PO prior to Alemtuzumab Acetaminophen 650 mg PO prior to Alemtuzumab Prednisone 10 mg PO 15-30 minutes prior to Alemtuzumab for the first two weeks

22. CONCLUSIONES Son necesarios más estudios para establecer el papel de Alemtuzumab Se necesitan EECC aleatorizados, comparativos frente a otras alternativas Los datos sobre características Farmacocinéticas son escasos Se necesitan estudios farmacocinéticos en poblaciones especiales (IR, IH, ancianos, etc.) Se precisa más investigación sobre vías alternativas de administración que mejoren la seguridad

23. Gracias!