Alemtuzumab

1. Alemtuzumab Lynne Nakashima, BSc(Pharm), Pharm.D Nov. 29, 2003

2. Outline • What is Alemtuzumab? • Mechanism of action • Indication for Use • BCCA Protocol Summary • Dosage and Administration • Sample Pre-printed Order • Adverse Effects • Health Canada’s Special Access Program • Summary of Data from the BCCA

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

4. Mechanism of ActionCD52 • 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

5. Mechanism of Action (2) • Alemtuzumab binds to CD52 bearing cells • Causes cell death through host-effector mechanisms (complement-mediated lysis, antibody dependent cellular cytotoxicity)

6. Indication for Use B-Chronic Lymphocytic Leukemia (CLL) • Most common adult leukemia in western hemisphere (20-30%) • Median age at diagnosis is 64 years • 95% of patients express CD52 • Treatment options: chlorambucil, fludarabine

7. Indication for Use (2) T-Prolymphocytic Leukemia (T-PLL) • Rare aggressive post thymic malignancy • Treatment options: cladribine, chlorambucil, fludarabine

8. Clinical Efficacy • To date, all studies in B-CLL and T-PLL have been non-comparative, phase I/II trials

9. Clinical Efficacy (2) Blood 2002;99(10):3554-61 • Phase II, 93 patients relapsed/refractory B-CLL • OR = 33% (CR 2%, PR 31%) • Median duration of response = 8.7 mo • At median follow-up of 29 mo, median survival = 16 mo (historical control 8 mo)

10. Clinical Efficacy (3) T-PLL: • 4 non-comparative trials (n=12-76) • OR rates = 24-76% JCO 2002;20(1):205-13 • 76 compassionate treated patients • OR = 50% (CR 37.5%, PR 12.5%) • Median duration of CR = 8.7 mo

11. BCCA Protocol SummaryULYALEM BCCA Protocol Summary for theTreatment of Fludarabine-Refractory B-Chronic Lymphocytic Leukemia (B-CLL) and T-Prolymphocytic Leukemia (T-PLL) with Alemtuzumab www.bccancer.bc.ca

12. Eligibility Criteria Patients with B-CLL or T-PLL 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

13. 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

14. Dosage • Dosing three times each week, usually MWF, for maximum of 12 weeks • All doses flat dose in mg, not mg/m2 Week 1: 3 mg 10 mg 30 mg Week 2+: 30 mg 30 mg 30 mg

15. 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

16. Dosage (3) Peak Plasma Concentration: 26.4 ug/mL Elimination Half-Life: 12 days

17. Administration • 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

18. 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)

19. Sample Pre-Printed Order (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.

20. Sample Pre-Printed Order (3) IV Alemtuzumab • Alemtuzumab 3 mg OR 10 mg OR 30 mg (circle desired dose) IV in 100 mL NS over 2 hours on day 1, 3, 5 SC Alemtuzumab • Alemtuzumab 3 mg OR 10 mg OR 30 mg (circle desired dose) SC three times weekly (M, W, F)

21. Adverse EffectsInfusion-Related Events • Rigor, fever, nausea, vomiting, skin rash, dyspnea, hypotension • “flu-like” syndrome • Usually occur during first alemtuzumab infusion • Decrease in intensity and/or frequency during subsequent infusions

22. Adverse EffectsInfusion-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

23. Adverse EffectsInfusion-Related Events (3) • Flu-like symptoms may be reduced in severity in patients receiving SC injections • SC injection results in transient injection-site skin reactions during week 1-2; may result in slower dose escalation

24. Adverse EffectsInfectious Complications • Note: in most phase I/II studies, patients had failed fludarabine • Alemtuzumab causes lymphopenia • Immunosuppression can last several months • Increased risk of infections

25. Adverse EffectsInfectious Complications (2) • Prophylactic Antibiotics (start at week 1 and continue until 2 months after completion of treatment)Cotrimoxazole 1 DS tab PO 3 times each weekValacyclovir 500 mg PO BIDORAcyclovir 400 mg PO BID

26. Adverse EffectsInfectious Complications (3) • 55% experience one or more infections • 25% have severe or life-threatening infections • 15% diagnosed with septicemia • 11% diagnosed with opportunistic infections • Retrospective analysis of 1538 patients, overall incidence CMV = 3.6%

27. Adverse EffectsHematological • Grade III/IV neutropenia = 70% • Grade III/IV thrombocytopenia = 52% • Grade III/IV anemia = 47% • Median duration: 26 days • However, growth factors generally not used in the clinical trials to date

28. Adverse EffectsHematologic (2) • CBC, diff weekly • Hold dose if ANC < 0.25 x 109/L or platelets < 25 x 109/L • Resume when ANC > 0.5 x 109/L and platelets > 50 x 109/L • If therapy interrupted for more than 7 days, re-institute with gradual dose escalation

29. Adverse EffectsOther • Immunizations with live vaccines are not permitted, due to immunosuppression • No formal drug interaction studies have been completed

30. Special Access Program • Not commercially available • Manufacturer: Berlex Canada • Approval from Health Canada SAP program required • Supplied in 30 mg/3 mL ampoules • $650 per ampoule • 12 week course = $23,400

31. BCCA Data • Undesignated request required • Between July 2002 and Oct. 2003, a total of 21 patients have received approval for 23 courses • 20 CLL, 1 T-PLL • Average time between approvals for repeat treatments = 9.5 mo

32. BCCA Data (2) Hospitals Requesting Approval: - BCCA - LGH - Royal Columbian - Kamloops - St. Paul’s

33. Conclusions • Alemtuzumab is a novel medication for the treatment of B-CLL and T-PLL • Future research focusing on combination therapy with chemotherapy