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Chronic Lymphocytic Leukemia: Current Therapies

 

Chronic Lymphocytic Leukemia: Current TherapiesDespite relatively good long-term survival rates, chronic lymphocytic leukemia  is considered incurable. For many years, first-line therapy was dominated by the oral alkylating agent chlorambucil (GlaxoSmithKline’s Leukeran). The introduction of purine analogues as monotherapy or in combination with alkylating agents into current treatment strategies has vastly improved response rates, although no improvement in overall survival has yet been noted.

Patients with chronic lymphocytic leukemia do not have a wide choice of therapy options. The overall population is elderly and has a low tolerance for toxic chemotherapy regimens. Once patients have failed both chlorambucil and fludarabine (Schering AG and Berlex’s Fludara), the disease becomes extremely difficult to treat. The aim of current drug regimens is to obtain the highest possible rate and duration of remission while balancing the associated toxicity and infection rate in these patients. TABLE. Current Regimens Used for Chronic Lymphocytic Leukemia describes the current regimens used to treat chronic lymphocytic leukemia.

TABLE. Current Regimens Used for Chronic Lymphocytic Leukemia

  Regimen Components Dose  
Regimen Agent Availability   Common Toxicities
Chlorambucil (single agent) Chlorambucil (GlaxoSmith-Kline’s Leukeran) US ,France,  Germany,  Italy, S, UK Chlorambucil: 10 mg/m2/d on days 1 -7. Cycle repeated every 28 days. •  Myelosuppression•  Mild gastrointestinal disturbances

•  Increased risk of secondary malignancy

Fludarabine (single agent) Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Fludarabine (oral): 40 mg/m2/d on days 1-5, (IV) 25 mg/m2/d on days 1 -5. Cycle repeated every 28 days. •  Myelosuppression•  Increased infection

•  Neurotoxicity

•  Malaise/fatigue

•  Nausea/vomiting

•  Anorexia

Fludarabine/ cyclophosphamide (FC) Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Fludarabine (oral): 40 mg/m2/d on days 1-3, (IV) 25 mg/m2/d on days 1 -3. Cycle repeated every 28 days. •  Myelosuppression•  Increased infection

•  Neurotoxicity (fludarabine)

•  Alopecia (more common with cyclophosphamide)

  Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana,Baxter’s

Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin, generics)

US ,France,  Germany,  Italy, Spain,  UK, Japan Cyclophosphamide: 250 mg/m2/d on days 1 -3. Cycle repeated every 28 days. •  Malaise/fatigue•  Nausea/vomiting

•  Anorexia

•  Hemorrhagic cystitis (cyclophosphamide)

•  Neutropenia

Fludarabine/ cyclophosphamide/ mitoxantrone (FCM) Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Fludarabine (oral): 40 mg/m2/d on days 1-3, (IV) 25 mg/m2/d on days 1 -3. Cycle repeated every 28 days. •  Myelosuppression•  Increased infection

•  Neurotoxicity (fludarabine)

•  Alopecia (more common with cyclophosphamide)

  Cyclophosphamide(Bristol-Myers

Squibb’s

Cytoxan/

Endoxan/

Endoxana,

Baxter’s

Endoxan/

Endoxana,

Shionogi’s

Endoxan, Pfizer’s

Cyclostin,

generics) Mitoxantrone

(Serono

Lab/Wyeth/

Takeda’s

Novantrone,

Baxter’s

Onkotrone,

generics)

US ,France,  Germany,  Italy, Spain,  UK, JapanUS ,France,  Germany,  Italy, Spain,  UK, Japan Cyclophosphamide: 200 mg/m2/d on days 1 -3. Cycle repeated every 28 days.Mitoxantrone: 6 mg/m2/d on day 1. Cycle repeated every 28 days. •  Malaise/fatigue•  Nausea/vomiting

•  Anorexia

•  Hemorrhagic cystitis (cyclophosphamide

•  Cardiac toxicity (mitoxantrone)

CHOP Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Cyclophosphamide: 750 mg/m2/d on day 1. Cycle repeated every 28 days. •  Myelosuppression•  Increased infection

•  Alopecia

•  Malaise/fatigue

•  Nausea/vomiting

•  Anorexia

•  Hemorrhagic cystitis (cyclophosphamide)

  Doxorubicin (Pfizer’s Adriamycin/ Adriblastine, Bristol-Myers Squibb’s Rubex, Kyowa’s Adriacin, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Doxorubicin: 50 mg/m2/d on day 1. Cycle repeated every 28 days.  
  Vincristine (Eli Lilly/EG Labo/Lilly-Shionogi’s Oncovin, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Vincristine: 1.4 mg/m2/d on day 1. Cycle repeated every 28 days.  
  Prednisone3 (generics) US ,France,  Germany,  Italy, Spain Prednisone/ Prednisolone: 50 mg/m2 on days 1-5. Cycle repeated every 28 days.  
  Prednisolone (generics) US ,France,  Germany,  Italy, Spain,  UK, Japan    
Cyclophosphamide, Vincristine, Prednisone Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin. generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Cyclophosphamide: 750 mg/m2/d on day. Cycle repeated every 28 days. •  Myelosuppression•  Increased infection

•  Alopecia

•  Malaise/fatigue

•  Nausea/vomiting

•  Anorexia

•  Hemorrhagic cystitis (cyclophosphamide)

  Vincristine (Eli Lilly/EG Labo/Lilly-Shionogi’s Oncovin, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Vincristine: 1 mg/m2/d on day 1. Cycle repeated every 28 days.  
  Prednisone3 (generics) US ,France,  Germany,  Italy,   S Prednisone/ Prednisolone: 50 mg/m2 on days 1-5. Cycle repeated every 28 days.  
  Prednisolone (generics) US ,France,  Germany,  Italy, Spain,  UK, Japan    
Pentostatin/ cyclophosphamide Pentostatin (SuperGen/ Wyeth/Pfizer’s Nipent, Nihonkayaku’s Coforin) US ,France,  Germany,  Italy, Spain,  UK, Japan Pentostatin: 4 mg/m2/d on day 1. Cycle repeated every 28 days. •  Myelosuppression (mild)•  Increased infection

•  Malaise/fatigue

•  Fever

•  Nausea/vomiting

•  Anorexia

•  Hemorrhagic cystitis (cyclophosphamide)

  Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Cyclostin, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Cyclophosphamide: 600 mg/m2/d on day 1. Cycle repeated every 28 days.  
Cladribine (single agent) Cladribine (Ortho-Biotech’s Leustatin, Japananssen-Cilag’s Leustatin/ Leustatine/ Leustat, generics) US ,France,  Germany,  Italy, Spain,  UK, Japan Cladribine: 0.14 mg/kg/d on days 1 -5. •  Myelosuppression•  Increased infection

•  Malaise/fatigue

•  Fever

•  Rash

•  Headache

Alemtuzumab (single agent) Alemtuzumab (Berlex’s Campath, Schering’s Mab Campath) US ,France,  Germany,  Italy, Spain,  UK Alemtuzumab: escalating dose of 3, 10,30 mg/d for week 1, followed by 30 mg/d for 3 days per week. •  Myelosuppression•  Increased infection

•  Anemia

•  Fever

•  Nausea/vomiting

•  Rash

•  Fatigue

•  Urticaria

•  Rigors

• Transient Cytopenia

a. Prednisolone is used where prednisone is not available.

IV = Intravenous; MAB = Monoclonal antibody.

Chlorambucil (Single Agent)

Overview

For the past 40 years, first-line treatment of chronic lymphocytic leukemia has been limited mainly to the alkylating agent chlorambucil (GlaxoSmithKline’s Leukeran). Although newer agents are being used with increasing frequency, chlorambucil still garners a significant patient share in the United States, France, Germany, Italy, Spain, and the United Kingdom. This popularity is the result of its preferable toxicity profile, which is advantageous in chronic lymphocytic leukemia — a disease with an elderly population that is less able to cope with high toxicities.

Mechanism Of Action

Chlorambucil is an alkylating agent. Alkylation of DNA results in breaks in the DNA molecule as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA and ultimately causing cell death.

Clinical Performance

A variety of schedules are in use. Chlorambucil is an agent that can be administered with or without the corticosteroids prednisone or prednisolone (both generic). No evidence from randomized trials exists to prove that adding a corticosteroid enhances the efficacy of chlorambucil or other alkylating agents. However, physicians often include them in cases of bulky disease requiring a rapid response or when chlorambucil produces severe hematologic toxicity.

First-line chlorambucil therapy (plus or minus prednisone) in untreated chronic lymphocytic leukemia patients produces complete response rates of 4-12% and overall response rates of approximately 40-60%. Recent trials have shown that first-line fludarabine therapy (discussed later) provides superior response rates compared with chlorambucil; however, the two compounds’ long-term survival rates are not significantly different.

Chlorambucil does have a less toxic side-effect profile and is therefore the preferred therapy in older patients (65 or older) and those with a poor performance status who are unable to tolerate the severe myelosuppression caused by fludarabine. Another well-established benefit of chlorambucil is its oral formulation, although an oral formulation of fludarabine has become available in some countries.

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