CLL-001 (10 Mg Vs

CHRONIC LYMPHOCYTIC LEUKEMIA

® ALEMTUZUMAB (CAMPATH ) - INTRAVENOUS Alemtuzumab‡ Dose titration IV* Weeks 1 – 2 Alemtuzumab‡ 30 mg TIW IV* Weeks 2 – 14

‡Routine premedications administered; *Administer over 2 hours. Initial dosage titration should start at 3 mg daily, when this dose is tolerated, increase the dose to 10 mg daily, when this is tolerated increase to 30 mg. Once at the maximum single dose (30 mg), administer it 3 times a week i.e., Monday, Wednesday, and Friday. If there is greater than 7 days between doses the patient should be re-tolerized, ie increase the dose from 3 mg, to 10 mg to 30 mg as if starting again.

NOTE: Due to the potent immunosuppressive effects of alemtuzumab, please prescribe prophylaxis against PCP and herpes viruses (if patient positive). Prophylaxis should continue for 2 months after the completion of alemtuzumab therapy, or until the CD 4+ count is 200 cells/microliter or greater whichever is later.

Reference: Package insert, Berlex Laboratories.

® ALEMTUZUMAB (CAMPATH ) - SUBCUTANEOUS Alemtuzumab‡ 30 mg TIW* SQ Up to a maximum of 18 weeks

‡Routine premedication administered; *Dosing was initiated at 3 mg on Day 1, 10 mg on Day 3, and 30 mg on Day 5 if tolerated. The 30 mg dose was split into 2 separate injections in 1.5 mL each site.

NOTE: If treatment was interrupted by 7 days or more, then reinitiate dosing at the 3 mg or 10 mg dosing level and titrate up again to 30 mg. Patients received allopurinol for the first 4 weeks of therapy. Anti-infective prophylaxis with valacyclovir 500 mg PO BID, fluconazole 50 mg PO QD, and cotrimoxazole PO BID 3 times per week was given during, and for 8 weeks following completion of alemtuzumab dosing.

Continue dosing three times weekly for a maximum of 18 weeks.

Reference: Lundin J, et al. Blood 2002:100:768 – 73.

Last Updated on September 24, 2007

ALEMTUZUMAB – FLUDARABINE – CYCLOPHOSPHAMIDE – RITUXIMAB (CFAR) Alemtuzumabǂ 30 mg IV Days 1, 3 and 5 Fludarabine 25 mg/m2/day IV Days 3 – 5 Cyclophosphamide 250 mg/m2/day IV Days 3 – 5 Rituximabǂ 375 – 500 mg/m2 IV Day 2

ǂPremedication administered as follows: Methylprednisolone 125 mg IV Day 1, and hydrocortisone 50 mg IV on Days 2, 3 and 5.

NOTE: Tumor lysis precautions for the first cycle include allopurinol 300 mg PO daily for 7 days (adjust doses according to renal dysfunction). Prophylactic antibacterial agents administered including: trimethoprim/sulfamethoxazole twice daily for 2 – 3 days per week; herpes simplex virus prophylaxis. Patients should be screened weekly for CMV reactivation (in CMV seropositive patients) and pre-emptive treatment initiated for any positive result or if the patient is clinically symptomatic. Patients can receive filgrastim or pegfilgrastim for neutropenia prophylaxis.

Repeat cycle every 28 days to a maximum of 6 cycles.

Reference: Wierda WG, et al. Blood 2006;108. [Abstract 31].

CHLORAMBUCIL "CONTINUOUS" DOSING Chlorambucil 0.1 mg/kg/day PO Daily

Continue therapy for up to 3 years.

Reference: Dighiero G, et al. N Engl J Med 1998;338:1506 – 14.

CHLORAMBUCIL "PULSE" DOSING Chlorambucil 40 mg/m2 PO Day 1

NOTE: Patients received allopurinol 300 mg PO QD for 9 days, starting the day prior to chemotherapy through Day 8 during the first 3 cycles.

Repeat cycle every 28 days for up to 12 cycles.

Reference: Rai KR, et al. N Engl J Med 2000;343:1750 – 7.

Last Updated on September 24, 2007

CLADRIBINE Cladribine 0.1 mg/kg/day CIVI Days 1 - 5

Repeat cycle every 28 days to a maximum of 6 cycles.

Reference: Tallman MS, et al. J Clin Oncol 1995;13:983 – 8.

CLADRIBINE Cladribine 0.12 mg/kg/day IV* Days 1 - 5

*Administer over 2 hours.

Repeat cycle every 28 days to a maximum of 6 cycles.

Reference: Robak T, et al. Blood 2006; 108:473 - 9.

CLADRIBINE - PREDNISONE Cladribine 0.12 mg/kg/day IV* Days 1 – 5 Prednisone 30 mg/m2/day PO Days 1 – 5

*Administer over 2 hours.

Repeat cycle every 28 days for 3 cycles.

Reference: Robak T, et al. Blood 2000;96:2723 – 9.

CVP (CYCLOPHOSPHAMIDE – VINCRISTINE - PREDNISONE) Cyclophosphamide 300 mg/m2/day PO Days 1 – 5 Vincristine 1.4 mg/m2* IV Day 1 Prednisone 100 mg/m2/day PO Days 1 – 5

*Maximum dose 2 mg.

Repeat cycle every 21 days for up to 9 months.

Reference: Raphael B, et al. J Clin Oncol 1991;9:770 – 6.

Last Updated on September 24, 2007

FCR "INITIAL THERAPY" (FLUDARABINE - CYCLOPHOSPHAMIDE - RITUXIMAB) CYCLE 1* Rituximab‡ 375 mg/m2 IV Day 1 Fludarabine 25 mg/m2/day IV** Days 2 - 4 Cyclophosphamide 250 mg/m2/day IV*** Days 2 - 4

‡Routine premedication administered; *All patients received allopurinol 300 mg PO QD for 7 days on first cycle; **Administer over 30 minutes; ***Administer over 1 hour.

CYCLE 2 - 6 Rituximab‡ 500 mg/m2 IV Day 1 Fludarabine 25 mg/m2/day IV* Days 1 - 3 Cyclophosphamide 250 mg/m2/day IV** Days 1 - 3

‡Routine premedication administered; *Administer over 30 minutes; **Administer over 1 hour.

DOSE REDUCTIONS: The first cohort of patients enrolled in this trial received fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day. Due to significant tumor lysis the doses of these agents were reduced to 25 mg/m2 and 250 mg/m2 respectively. Doses of fludarabine and cyclophosphamide were reduced if blood counts did not recover (i.e., platelets < 80 x 109/L and ANC < 1 x 109/L) within 5 weeks of the last course of therapy or if major infections occurred. Both fludarabine and cyclophosphamide were reduced by one dose level (20 and 200 mg/m2, respectively) or two dose levels (15 and 150 mg/m2, respectively). No dosage adjustments were made for rituximab.

NOTE: Oral sulfamethoxazole-trimethoprim was administered as Pneumocystis carinii pneumonia prophylaxis twice weekly (50% cohort); Oral valacyclovir 500 mg PO QD was administered as viral prophylaxis to 68% patients.

Repeat cycle every 28 days for a total of 6 cycles.

Reference: Keating MJ, et al. J Clin Oncol 2005;23:4079 - 88.

FLUDARABINE – CYCLOPHOSPHAMIDE (FC) Fludarabine 25 mg/m2/day IV Days 1 – 3 Cyclophosphamide 250 mg/m2/day IV Days 1 – 3

NOTE: Prophylaxis with trimethoprim/sulfamethoxazole recommended while on treatment and for at least 6 months following treatment discontinuation. Antiviral prophylaxis was recommended for lymphopenic patients with a history of herpes zoster. Allopurinol was recommended for 7 days for the first two to three cycles. G-CSF was used according to local neutropenia guidelines, but the authors recommend more liberal use/threshold as prophylaxis given toxicity data.

Repeat cycle every 28 days to a maximum of 6 cycles.

Reference: Catovsky D, et al. Lancet 2007;370:230 – 9.

Last Updated on September 24, 2007

FCR "RELAPSED - REFRACTORY" (FLUDARABINE - CYCLOPHOSPHAMIDE - RITUXIMAB) CYCLE 1 Rituximab‡ 375 mg/m2 IV Day 1 Fludarabine 25 mg/m2/day IV Days 2 - 4 Cyclophosphamide 250 mg/m2/day IV Days 2 - 4

‡Routine premedication administered.

CYCLE 2 - 6 Rituximab‡ 500 mg/m2 IV Day 1 Fludarabine 25 mg/m2/day IV Days 1 - 3 Cyclophosphamide 250 mg/m2/day IV Days 1 - 3

‡Routine premedication administered.

DOSE REDUCTIONS: Nonhematologic toxicity (Grade 3/4) required dose reductions to level -1 or -2 respectively. Dose level -1 was fludarabine 25 mg/m2 daily for 3 days and cyclophosphamide 200 mg/m2 daily for 3 days; and dose level -2 was fludarabine 20 mg/m2 and cyclophosphamide 200 mg/m2 daily for 3 days. No dosage adjustments were made for rituximab.

NOTE: Oral sulfamethoxazole-trimethoprim was administered twice weekly as Pneumocystis carinii pneumonia prophylaxis at the discretion of the physician. Oral valacyclovir 500 mg PO QD was administered as viral prophylaxis at the physician's discretion.

Repeat cycle every 28 days for a total of 6 cycles.

Reference: Wierda W, et al. J Clin Oncol 2005;23:4070 - 8.

FLUDARABINE Fludarabine 25 mg/m2/day IV* Days 1 - 5

*Administer over 10 - 30 minutes.

NOTE: Patients received allopurinol 300 mg PO QD for 9 days, starting the day prior to chemotherapy through Day 8 during the first 3 cycles.

Repeat cycle every 28 days to a maximum of 12 cycles.

Reference: Rai KR, et al. N Engl J Med 2000;343:1750 – 7.

Last Updated on September 24, 2007

FR (FLUDARABINE - RITUXIMAB) φ CYCLE 1 Fludarabine 25 mg/m2/day IV* Days 1 – 5 Rituximab‡ 50 mg/m2 IV** Day 1

Followed by

Rituximab‡ 325 mg/m2 IV*** Day 3

Followed by

Rituximab‡ 375 mg/m2 IV*** Day 5

φ Allopurinol 300 mg PO QD was administered to all patients for the first 14 days on cycle 1 only; ‡Routine premedications administered; *Administer over 20 - 30 minutes; **Administer over 4 hours; ***Administer at a rate of 50 mg/hour, with the infusion rate increased in 50 mg/hour increments to a maximum of 400 mg/hour as tolerated. Day 5 and all other subsequent infusions administered at 100 mg/hour for the first 15 minutes, and then increased to infuse the remainder of the entire dose over the next 45 minutes.

CYCLE 2 - 6 Fludarabine 25 mg/m2/day IV* Days 1 – 5 Rituximab‡ 375 mg/m2 IV** Day 1

‡Routine premedications administered; *Administer over 20 - 30 minutes; ** Administer at a rate of 100 mg/hour for the first 15 minutes, and then increased to infuse the remainder of the entire dose over the next 45 minutes.

Repeat cycle every 28 days to a maximum of 6 cycles.

MAINTENANCE THERAPY (in patients with stable disease or better only 2 months after completing cycle 6) Rituximab‡ 375 mg/m2 IV** Q week for 4 doses

References: Byrd JC, et al. Blood 2003;101:6 – 14; Byrd JC, et al. Blood 2005;105:49 - 53.

Last Updated on September 24, 2007

® LENALIDOMIDE (REVLIMID ) Lenalidomide 25 mg/day* PO Days 1 – 21

Repeat cycle every 28 days.

*Treatment protocol revised to allow slow dose escalation. Lenalidomide started at 5 mg/day and increased by 5 mg every 1-2 weeks to 25 mg/day maximum.

NOTE 1: Allopurinol 300 mg daily (dose adjust according to renal function) was initiated 2 to 3 days before treatment and continued for up to 14 days for the prevention of tumor lysis syndrome (cycle 1). Tumor flare does occur with this regimen, and clinically presents with sudden onset of tender enlargement of the lymph nodes and/or spleen with low-grade fever and/or rash. The flare reaction was treated with NSAIDs. Treatment was not stopped nor was the dose of lenalidomide reduced for the flare reaction. In the initial cohort no prophylaxis against a flare reaction was used, however in the last cohort of patients prednisone 20 mg PO QD for 7 days followed by prednisone 10 mg PO QD for 7 days was administered as prophylaxis.

NOTE 2: The CLL-001 (10 mg vs. 25 mg QD) clinical trial sponsored by Celgene is currently on hold due to a number of unexpected deaths. Lenalidomide should be used with caution in patients with CLL until such time as the appropriate dose is defined.

DOSE MODIFICATIONS: Recommended for neutropenia and thrombocytopenia. Refer to the lenalidomide monograph in the Pharmacology Section.

Lenalidomide available as 5 mg and 10 mg capsules.

Reference: Chanan-Khan A, et al. J Clin Oncol 2006;24: 5343 – 9.

PC (PENTOSTATIN – CYCLOPHOSPHAMIDE) Cyclophosphamide 600 mg/m2 IV* Day 1

Followed by

Pentostatin 4 mg/m2 IV* Day 1

*Administer at least 1500 mL hydration with the pentostatin/cyclophosphamide.

NOTE: In the original study filgrastim (300 micrograms for patients 70 kg and below or 480 micrograms for patients weighing more than 70 kg) was prescribed from Day 2 until the ANC was greater than 5 x 109/L x 1 or greater than 1.5 x 109/L for 2 consecutive days. Prophylactic antibiotics were administered and included: sulfamethoxazole/trimethoprim 1 DS PO BID 3 times per week and acyclovir 800 mg PO BID for HSV prophylaxis.

DOSE MODIFICATION: Chemotherapy was withheld if the serum creatinine was greater than 2 mg/dL or greater than 20% above baseline for the patient. Therapy was withheld until the renal function had improved to these levels or to a CrCL of 50 mL/minute or greater.

Repeat cycle every 21 days to a maximum of 6 cycles.

Reference: Weiss MA, et al. J Clin Oncol 2003;21:1278 – 84.

Last Updated on September 24, 2007

PCR (PENTOSTATIN – CYCLOPHOSPHAMIDE – RITUXIMAB) CYCLE 1: Cyclophosphamide 600 mg/m2 IV Day 1

Followed by

Pentostatin 4 mg/m2 IV* Day 1 Filgrastim See below for dose SQ Day 3 until ANC greater than 5 x 109/L for 1 day or greater than 1.5 x 109/L for 2 consecutive days.

CYCLES 2 - 6: Cyclophosphamide 600 mg/m2 IV Day 1

Followed by

Pentostatin 4 mg/m2 IV* Day 1

Followed by

Rituximab‡ 375 mg/m2 IV** Day 1 Filgrastim See below for dose SQ Day 3 until ANC greater than 5 x 109/L for 1 day or greater than 1.5 x 109/L for 2 consecutive days.

*Prehydration of 1500 mL NS administered prior to each pentostatin dose; ‡Routine premedication administered; **Rituximab was NOT prescribed for cycle 1, rather was started on cycle 2.

NOTE: Prophylaxis against Pneumocystis carinii pneumonia and herpes virus (those HSV positive) was administered to all recipients. Filgrastim was administered to all patients as follows: 300 micrograms for patients less than or equal to 70 kg and 480 micrograms for patients greater than 70 kg. Chemotherapy to be withheld if the serum creatinine is greater than 2 mg/dL or if there is a 20% increase in serum creatinine from baseline.

Repeat cycle every 21 days to a maximum of 6 cycles.

Reference: Lamanna N, et al. J Clin Oncol 2006;24:1575 – 81.

Last Updated on September 24, 2007

PCR (PENTOSTATIN – CYCLOPHOSPHAMIDE – RITUXIMAB) CYCLE 1: Pentostatin 2 mg/m2 IV* Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Rituximab‡ 100 mg/m2 IV** Day 1 Rituximab‡ 375 mg/m2 IV** Days 3 and 5

CYCLES 2 - 6: Pentostatin 2 mg/m2 IV* Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Rituximab‡ 375 mg/m2 IV** Day 1

‡Routine premedication administered; *Prehydration prior to each pentostatin dose; **Rituximab dose titration occurred in cycle 1 as described above.

NOTE: Prophylaxis against Pneumocystis carinii pneumonia and herpes virus (those HSV positive) was administered to all recipients for 1 year starting with cycle 1. All patients received filgrastim on days 3 – 13 of each cycle or until the ANC was greater than 1 x 109/L for 2 consecutive days.

Repeat cycle every 21 days to a maximum of 6 cycles.

References: Kay NE, et al. Blood 2007;109:405 – 11; Shanafelt TD, et al. Cancer 2007;109:2291 - 8.

RITUXIMAB Rituximab‡ 375 mg/m2 IV* Once a week for 4 weeks

‡Routine premedications administered; *Rituximab dose was titrated gradually during first week of administration. On Day 1 a dose of 50 mg was administered over 4 hours, followed by 150 mg on day 2, and the remainder of a 375 mg/m2 dose infused on Day 3.

Repeated every 6 months for four total courses pending disease response and tolerance.1

References: Huhn D, et al. Blood 2001;98:1326 - 31; 1Hainsworth JD, et al. J Clin Oncol 2003;21:1746 – 51.

Last Updated on September 24, 2007