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Fludarabine Phosphate 50 mg Powder for Solution for Injection or Infusion

Fludarabine phosphate

1. WHAT FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECCTION OR INFUSION IS AND WHAT IT IS USED FOR

Fludarabine phosphate is an anti-cancer medicine. Fludarabine phosphate is used in the treatment of B-cell chronic lymphocytic leukaemia (B-CLL) in patients who have a sufficient amount of healthy blood cells in their bone marrow.

First treatment for chronic lymphocytic leukaemia with fludarabine phosphate should only be started in patients with advanced disease having disease related symptoms or evidence of disease progression.

Fludarabine phosphate works by stopping the growth of new cancer cells. All cells of the body produce new cells like themselves by dividing. For this purpose, the cells’ genetic material (DNA) must be copied and reproduced. Fludarabine phosphate is taken up by the cancer cells and works by hindering the production of new DNA.

In cancers of the white blood cells (as chronic lymphocytic leukaemia), the body produces many abnormal white blood cells (lymphocytes) and lymph nodes start to grow in various parts of the body. The abnormal white blood cells cannot carry out the normal disease fighting functions. If there are too many abnormal white blood cells, they push aside healthy blood cells – which can result in infections, decrease in number of red blood cells (anaemia), bruising, unusually severe bleeding or even organ failure.

2. BEFORE YOU USE FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECTION OR INFUSION

Do not use Fludarabine Phosphate Powder for Solution for Injection or Infusion if you are allergic (hypersensitive) to fludarabine phosphate or any of the other ingredients of Fludarabine Phosphate Powder for Solution for Injection or Infusion

• if your kidney function is severely reduced
• if you have a low number of red blood cells because of a cetain type of anaemia (decompensated haemolytic anaemia)

Your doctor will have told you if you have this condition.

if you are pregnant or breast-feeding (see section Pregnancy and Breast-feeding)

It is important that you tell your doctor if you have problems even if those are on the above list or not.

Take special care with Fludarabine Phosphate Powder for Solution for Injection or Infusion

-  because the active substance of Fludarabine Phosphate Powder for Solution for Injection or Infusion, fludarabine phosphate, is a very strong active substance. Therefore, the side effects can be very serious and toxic (poisonous).

For these reasons, your doctor will watch you closely if he/she prescribed you fludarabine phosphate. Therefore, it is very important that you report to your doctor all side effects which occur during the use of fludarabine phosphate. This concerns mainly the following adverse events: You are not feeling well.

This is especially important to report if your bone marrow is not working properly, if your immune system is not working well or if you are susceptible to infections.

After injury you notice unusual bruising or excessive bleeding. This can point to a reduction in healthy blood cells. Changes of your skin, such as rash or blisters. This is especially important if you have or have had skin cancer. Your doctor may decide not to give you fludarabine phosphate, or to give you this medicine with special precautions, if you experience one of the above mentioned side effects. You will have regular blood checks during treatment

if you are catching a lot of infections (if you have a poorly functioning or depressed immune system or a history of serious infections). Your immune system may attack different parts of your body (called ‘autoimmune phenomenon’), and this may also be directed against your red blood cells (called ‘autoimmune hemolysis’). This condition can be life threatening and even lead to death. If you experience this condition you may receive further medication such as transfusion of blood (irradiated, see below) and adrenocorticoids.

-  when you receive a high dose. When fludarabine phosphate is used in patients with acute leukaemia at very high doses (up to four times greater than the

recommended dose for CLL) a third of patients experienced severe central nervous system effects (including blindness, coma and death). In patients receiving the recommended dose for CLL, coma, seizures or agitation are rare events. Confusion occasionally occurs. You should mention to your doctor any unusual symptoms you experience.

-  when you use fludarabine for a lengthy period. The effect of long-term use of fludarabine phosphate on the central nervous system is unknown. However, some people have endured the recommended dose for up to 26 courses of therapy.

-  if you need a blood transfusion and you are being (or have been) treated with fludarabine phosphate, you should mention this to your doctor. Your doctor will ensure that you receive blood only, which has gone through a special treatment (irradiation). There have been severe complications and even death reported when non-irradiated blood has been given.

-  if you need to have stem cells collected and you are being (or have been) treated with fludarabine phosphate, tell your doctor that you have received fludarabine phosphate.

-  when you need a vaccination, consult your doctor, because live virus vaccines should be avoided during and after treatment with fludarabine phosphate.

-  if you have very severe chronic lymphocytic leukaemia, your body may not be able to get rid of all the waste products from the cells destroyed by fludarabine phosphate. This may cause dehydration, reduced kidney function and heart problems. Your doctor will be aware of this and may give you other drugs to deal with this problem.

-  if you have skin cancer, the damaged areas of your skin may become worse when you use this medicine. Tell your doctor if you notice any changes to your skin either while you are receiving this medicine or even after you have finished taking this medicine.

-  with children. No data are available concerning the use of fludarabine phosphate in children.

-  with men and women who may still be fertile, see Section “Pregnancy and breast-feeding”.

-  if your liver does not work properly; your doctor may decide not to give you this medicine, or may give you this medicine with caution.

-  if you have any form of kidney disease or if you are over 70 years old, your kidney function should be checked regularly. If your kidneys are found not to work properly you may be given fludarabine phosphate at a reduced dose. If your kidneys work at only a very low level you will not be given this medicine at all.

-  if you are over 75 years old, fludarabine phosphate will be given with caution.

Consult your doctor if one of the above mentioned warnings is applicable to you, or has been in the past.

Taking or Using other medicines

Attention: the following remarks can also apply to the use of medicines in the past or in the near future.

The medicines mentioned in this section may be known to you under a different name, often the brand name. In this section only the name of the active ingredient or group of active ingredients of the medicine is mentioned and not the brand name! Therefore, check on the package or insert what the active ingredient is of the medicine you are using.

An interaction means that medicines, when used at the same time, can influence each other’s action and/or side effects. An interaction can occur with this medicine when used together with:

pentostatin (=deoxycoformycin) (another medicine that inhibits the growth of cancer); you may not be treated with fludarabine phosphate some blood thinning medicines, such as dipyridamole; they reduce the effectiveness of fludarabine phosphate

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

• Pregnancy and Breast-feeding

You should not be given fludarabine phosphate if you are pregnant, because animal studies and limited experience in humans have shown a possible risk of abnormalities in the developing foetus. If you are a woman who may still be fertile, you must avoid becoming pregnant. However, if you do become pregnant inform your doctor immediately, (see also Section “Do not use Fludarabine Phosphate Powder for Solution for Injection or Infusion”).

Men and women who may still be fertile must use a reliable form of contraception during and for at least 6 months after stopping treatment.

It is not known if fludarabine appears in the breast milk of women treated with this medicine. However, in animal studies fludarabine has been found in breast milk. Therefore you should not breast feed during your treatment with this medicine. Ask your doctor for advice before taking any medicine.

• Driving and using machines

The effects of treatment with this medicine on the patient’s ability to drive or to operate machinery has not been evaluated. Consult your doctor if you doubt whether fludarabine phosphate negatively effects your ability to drive or react.

3. HOW TO USE FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECTION OR INFUSION

Carefully follow the advice of your doctor when using fludarabine phosphate. Your doctor will decide when and how long fludarabine phosphate will be given to you. Consult your doctor if you have the feeling that fludarabine phosphate is acting too strongly or not strongly enough.

The administered amount of fludarabine phosphate (the dose) depends on the size of your body. Technically this is measured in square metres (m²), but actually is calculated from your height and weight.

Fludarabine phosphate should be used under the supervision of a qualified doctor experienced in the use of anticancer therapy.

General guidance

The usual dose is 25 mg/m² body surface per day. This will be given either as an injection or as an infusion for 5 consecutive days. This five day course of treatment will be repeated every 28 days until your doctor has decided that the best possible effect has been achieved. In general this is after 6 cycles, in other words after approximately 6 months. The dosage may be decreased or the repeat course delayed if side effects are a problem.

If you have kidney problems you will receive a reduced dose and you will have regular blood tests.

If you take more Fludarabine Phosphate Powder for Solution for Injection or Infusion than you should

As this medicine is given in a hospital, it is unlikely that you will be given too little or too much, however tell your doctor if you have any concerns.

There is no specific antidote for fludarabine phosphate overdosage. If you received too much fludarabine phosphate the doctor will stop the therapy and treat the symptoms.

High doses of fludarabine phosphate have been associated with irreversible central nervous system side effects characterised by delayed blindness, coma, and death. High doses are also associated with severe reduction in the number of certain types of blood cells (severe thrombocytopenia (decreased number of platelets attended with bruises and bleeding) and neutropenia (decreased number of white blood cells attended with increased infection risk)) due to decreased activity of the bone marrow (bone marrow suppression).

If administration of Fludarabine Phosphate Powder for Solution for Injection or Infusion is forgotten.

Your doctor will set the times at which you are to receive this medicine. If you think you may have missed a dose, contact your doctor as soon as possible.

4. POSSIBLE SIDE EFFECTS

Like all medicines, fludarabine phosphate can cause side effects, although not everybody gets them.

Very common side effects: occurs in more than 1 out of 10 patients

Common side effects: occurs in more than 1 out of 100 patients, but in less than 1 out of 10 patients

Uncommon side effects: occurs in more than 1 out of 1,000 patients, but less than 1 out of 100 patients

Rare side effects: occurs in more than 1 out of 10,000 patients, but less than 1 out of 1,000 patients

Very rare side effects: occurs in less than 1 out of 10,000 patients

One or more of the following side effects can occur:

Immune system

Serious infections have occurred in patients treated with fludarabine phosphate. In some cases this has resulted in death.

Blood

A common side effect is the reduced production of blood cells by the bone marrow, which can lead to anaemia, abnormal bleeding or bruising.

A reduction in the number of blood cells has been reported in most patients treated with fludarabine phosphate. In rare cases, the production of blood cells was severely reduced (myelodysplastic syndrome), but most of these patients received other cancer treatments during or prior to treatment with fludarabine phosphate. Because of the way in which this medicine works, you are more susceptible to infections. Sometimes, during or after use of fludarabine phosphate, your body’s own immune system might attack different parts of your body. This can cause a number of conditions all related to the function or production of red blood cells. These are:

-   anaemia as a consequence of a severe breakdown of the blood (autoimmune haemolytic anaemia)

-  blood disorders (low platelet count) accompanied with easy bruising and bleeding(autoimmune thrombocytopenia)

-  bruising, nosebleeds and bleeding gums caused by blood disorders (thrombocytopenic purpura)

-   skin disease characterised by blistering, affecting the entire body (pemphigus)

-  “Evan’s syndrome”, a disease characterised by fatigue, pale skin, shortness of breath, anaemia, bleeding tendencies and bruising.

Although these conditions are rare, they can sometimes be fatal.

Tell your doctor immediately:

• if you feel unusually tired or breathless
• if you notice any unusual bruising or excessive bleeding after injury
• if you seem to be catching a lot of infections
• if you have a rash or any blisters on your skin. (See section ‘Take special care with Fludarabine Phosphate Powder for Solution for Injection or Infusion’).

Nervous system

Numb or weak limbs (peripheral neuropathy) are commonly observed. Confusion occasionally occurs. Coma, excitement and restlessness (agitation) and seizures (fits, epileptic attacks) are rarely observed.

Eyes

Problems with sight are commonly reported. In rare cases, inflammation of the optic nerve, damage of the optic nerve and blindness have occurred.

Heart

In rare cases, heart failure and an abnormal heart rate have been reported. If you experience any difficulty in breathing, have chest pains or suddenly become aware of your heart beat (palpitations), tell your doctor immediately.

Respiratory system

Infection of the lung (pneumonia) commonly occurs in association with fludarabine phosphate treatment. Other allergic type reactions (pulmonary hypersensitivity) have been uncommonly observed. If you experience any difficulty in breathing, have a cough or have chest pains tell your doctor immediately.

Gastrointestinal tract

Gastrointestinal side effects such as nausea (feeling sick), vomiting (being sick), diarrhoea, inflammation of the lining of the mouth (stomatitis) and loss of appetite are common. Gastrointestinal bleeding occurs occasionally. There may also be changes in the proteins (enzymes) found in the pancreas.

Liver or bile

Changes in the proteins (enzymes) found in the liver are uncommon.

Skin

Skin rash has been commonly reported. In rare cases the skin may redden, peel (blister forming) or get inflamed (Stevens-Johnson syndrome or toxic epidermal necrolysis).

Kidneys and urinary tract

In rare cases inflammation of the bladder with blood in the urine (haemorrhagic cystitis) has been reported.

Other

A condition called tumour lysis syndrome may occur where the body is unable to cope with all the waste products of the cells killed by fludarabine phosphate. Although uncommon, it may lead to abnormal levels of waste products in your blood and possibly to kidney failure. If you notice a pain in your side or blood in your urine, tell your doctor immediately.

Inflammations (infections), fever, feeling of tiredness, weakness, general feeling of illness, oedema and chills have been commonly reported.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECTION OR INFUSION

Keep out of the reach and sight of children. As packaged for sale: Store below 25°C.

For storage conditions after reconstitution and dilution: please refer to section ‘Information for medical and healthcare professionals’

Do not use Fludarabine Phosphate Powder for Solution for Injection or Infusion after the expiry date which is stated on the carton and vial after EXP. The expiry date refers to the last day of that month.

Any vials which are damaged in anyway should be discarded.

The reconstituted solution is clear and colourless, only clear, colourless and particle free solutions should be used.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

• What Fludarabine Phosphate Powder for Solution for Injection or Infusion contains

The active substance is fludarabine phosphate. Each vial contains 50 mg fludarabine phosphate

The other ingredients are mannitol and sodium hydroxide used as a pH adjuster 1 ml of reconstituted solution contains 25 mg of fludarabine phosphate.

• What Fludarabine Phosphate Powder for Solution for Injection or Infusion looks like and contents of the pack

Fludarabine Phosphate Powder for Solution for Injection or Infusion is a sterile white to off-white powder for solution for injection or infusion in a 10 ml clear, colourless vial sealed with a rubber closure and a flip-off cap. The powder is reconstituted with Water for Injection and further diluted.

The reconstituted solution is clear and colourless.

Fludarabine Phosphate Powder for Solution for Injection or Infusion is available in packs containing 5 vials.

The following information is intended for medical or healthcare professionals only:

Fludarabine Phosphate Powder for Solution for Injection or Infusion as other potiential cytotoxic medicines should be prepared by qualified personnel in a designated area. Consideration should be given to handling and disposal according to guidelines used for cytotoxic drugs

For intravenous use only

Incompatibilities

Must not be mixed with other drugs.

Instructions for use and handling Reconstitution

Fludarabine Phosphate Powder for Solution for Injection or Infusion should be prepared for use by aseptically adding sterile Water for Injections. When reconstituted with 2 ml of sterile Water for Injections, the powder should fully dissolve in 15 seconds or less. Each ml of the resulting solution will contain 25 mg of fludarabine phosphate. The solution should be inspected visually. The reconstituted solution should be clear, colorless and without particles.

• Dilution

The reconstituted solution draws up into a syringe. For intravenous bolus injection this dose is further diluted into 10 ml 0.9 % sodium chloride. For intravenous infusion

the solution is diluted into 100 ml 0.9 % sodium chloride and infused over 30 minutes. In clinical studies, the product has been diluted in 100 ml or 125 ml of 5 % dextrose (for injection) or 0.9 % sodium chloride solution.

• Storage

Shelf-life after reconstitution: After reconstitution with sterile Water for Injections to concentration of 25 mg/ml, should the product be stored in 2°C-8°C protected against light or in 25°C in normal light up to 8 hours. Reconstituted solution with sodium chloride 0.9 % or glucose 5 % is chemically stable stored in infusion bag in 2°C-8°C protected against light or in 25°C in normal light up to 8 hours.

From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. In-use storage times and conditions prior to use and would normally not be longer than 8 hours at 2-8°C or 8 hours at room temperature.

• If any fludarabine phosphate solution is accidentally spilt:

If any of the fludarabine phosphate solution comes into contact with your skin or the lining of your nose or mouth, wash the area thoroughly with soap and water. If the solution gets into your eyes, rinse them thoroughly with plenty of tap water. Avoid any exposure by inhalation.

 

Overview

Although conventional cytotoxic drugs are the mainstay of therapy for most cancers, immunotherapies (and more recently, the protein tyrosine kinase inhibitor imatinib) have played a more prominent role in chronic myelogenous leukemia. Accordingly, few antineoplastic agents are in active development for chronic myelogenous leukemia. We discuss only ChemGenex’s version of homoharringtonine (Ceflatonin) in this section. The Chinese Academy of Medical Science has also launched a version of homoharringtonine.

Mechanism Of Action

Conventional cytotoxic agents interrupt the DNA replication and repair processes required for functional cell division. They act in several ways, including alkylating DNA, resulting in strand breakage; inhibiting crucial enzymes required for DNA strand formation; and interfering with spindle formation. Homoharringtonine inhibits the initiation of protein, DNA, and RNA biosynthesis.

Homoharringtonine

Homoharringtonine (ChemGenex’s Ceflatonin, formerly CGX-653) is an intravenous formulation of a natural product derived from the cephalotaxus evergreen tree. Homoharringtonine affects several cellular pathways, including the regulation of genes associated with apoptosis and angiogenesis. In the several years prior to the launch of imatinib, homoharringtonine was extensively investigated for chronic-phase chronic myelogenous leukemia, in first- and second-line therapy, alone, and in combination with interferon-a and/or cytarabine (Pfizer’s Cytosar-U, generics). ChemGenex has initiated a combination Phase II trial of homoharringtonine and imatinib in chronic myelogenous leukemia patients who are developing resistance to imatinib. Phase II trials are ongoing in the acute myelogenous leukemia setting.

A preclinical study in four paired imatinib-sensitive/resistant cell lines investigated the potency of homoharringtonine, cytarabine, daunorubicin, and hydroxyurea, alone or in combination with imatinib. Primary blasts from advanced-stage, imatinib-refractory chronic myelogenous leukemia patients were studied using semi-solid media clonogenic assays to test the sensitivity of the tumor cells to homoharringtonine. Investigators found that homoharringtonine achieved major inhibition of chronic myelogenous leukemia cell-line proliferation.

In a clinical trial, homoharringtonine, combined with interferon-a in the first-line setting, achieved a CHR in 85% of patients, a cytogenetic response in 21% of patients, and an major cytogenetic response in 49% of patients. Combined with low-dose cytarabine as a second-line treatment, homoharringtonine induced a CHR among 72% of patients, major cytogenetic response in 15% of patients, and cytogenetic response in 5% of patients. In a triple-therapy study among patients with early chronic-phase chronic myelogenous leukemia, 90 patients received treatment with interferon-a, cytarabine, and homoharringtonine. Patients received 5 million units (MU)/m² interferon-a and cytarabine 10 mg, both subcutaneously daily, and homoharringtonine 2.5 mg/m² by continuous infusion over 24 hours daily on days 1-5 every 28 days. After a median duration of 16.5 months of therapy, 78 patients switched to imatinib 400 mg orally daily.

With the triple regimen, 94% of patients achieved a CHR and 74% achieved a cytogenetic response. The cytogenetic response was complete (Ph-positive cells 0%) in 22% of treated patients and major in 46% of treated patients. Significant myelosuppression occurred, resulting in major dose reductions. After 12 months of therapy, the median interferon-a dosage was 1.6 MU/m² daily, the median cytarabine dosage was 1.85 mg daily, and the median number of homoharringtonine-treated days was two every month. Only three patients developed blastic-phase disease while receiving the triple regimen. After switching to imatinib, and after a median follow-up of 46 months from the start of triple therapy, 63% of patients achieved a cytogenetic response and a further 13% achieved an major cytogenetic response. Nine percent of patients had entered the blastic phase. Investigators estimate that five-year survival will stand at 88%.

In a small Phase I/II trial, nine patients with Ph-positive accelerated-phase chronic myelogenous leukemia previously treated with imatinib received treatment with a semi-synthetic formulation of homoharringtonine by daily subcutaneous injection for seven days, every 28 days. With a median follow-up of 12 months, 80% of patients had achieved a second chronic phase, and 67% of patients had achieved a complete hematologic response. No patient achieved a cytogenetic response. According to investigators, homoharringtonine was well tolerated with minimal nonhematologic toxicity. Grade IV neutropenia was observed in three patients, and grade IV thrombocytopenia requiring platelet support occurred in two patients. All patients were monitored for mutations in the ABL kinase domain, and, in one patient, a kinase domain mutation detected at the start of treatment was no longer detectable after six months of treatment.

One problem facing older drugs in clinical trials for chronic myelogenous leukemia, such as homoharringtonine and arsenic trioxide, is that physicians would rather place patients in clinical trials testing the new tyrosine kinase inhibitors and use these older agents only as last resorts. However, the primary limitations of homoharringtonine are its hematologic toxicity and its relatively low incidence of CCRs. The hematologic toxicity has restricted the dose of homoharringtonine in clinical trials, and most patients ultimately received only two days, rather than the planned five days, of treatment per month. Homoharringtonine’s hematologic toxicity profile will probably preclude a role in combination with imatinib in the first-line setting.

Overview

Hypermethylation of DNA in the regulatory area of selected genes has been shown to be common in neoplasia and is associated with tumor resistance or progression.

Both 5-azacytidine (Pfizer’s Vidaza/Mylosar) and decitabine (Supergen and MGI Pharma’s Dacogen) are potent DNA methylation inhibitors and have shown significant antileukemic activity in myeloid malignancies, including acute myelogenous leukemia and myelodysplastic syndrome. In chronic myelogenous leukemia, these agents have been used mostly in the accelerated and blastic phases.

Mechanism Of Action

The Pa promoter of abl and several other genes that are central to the development of chronic myelogenous leukemia are hypermethylated in a significant proportion of patients, and methylation increases with disease progression. The p15 gene is hypermethylated with chronic myelogenous leukemia progression, and different patterns of hypermethylation for myeloid and lymphoid blastic phases have been reported. Therefore, hypomethylating agents may play a role in treating chronic myelogenous leukemia. Decitabine

Decitabine is a DNA methyltransferase inhibitor under development by Supergen and MGI Pharma for the potential treatment of a range of hematologic malignancies, solid tumors, and sickle cell disease. Decitabine has shown activity in accelerated-phase and blastic-phase chronic myelogenous leukemia as a single agent and is now being investigated in combination with other chemotherapeutic agents and imatinib. The agent is in Phase II trials for the treatment of chronic myelogenous leukemia.

Decitabine is a cytidine analogue that exerts potent DNA hypomethylating effects through its covalent binding to DNA methyltransferase. Decitabine is cytotoxic at high doses, hypomethylating at low doses, and has clinical activity in myeloid malignancies that appears to be optimal at low doses.

In a Phase II study, the activity of decitabine mono therapy (at 15 mg/m² intravenously [IV] over one hour daily, five days a week for two weeks) in patients who were either imatinib-intolerant or had chronic myelogenous leukemia that was refractory to imatinib was evaluated. Thirty-five patients were enrolled (12 in the chronic phase, 17 in the accelerated phase, and 6 in the blastic phase). CHRs were seen in 12 patients (34%), partial hematologic responses were seen in 7 patients (20%), and hematologic improvement was seen in 4 patients (11%); there was an overall hematologic response rate of 65% (83% in the chronic phase, 59% in the accelerated phase, and 50% in the blastic phase). MCRs were observed in 7 patients (20%), and minor cytogenetic responses were seen in 9 patients (26%), with an overall cytogenetic response rate of 46%. Median response duration was three months. The only common grade 3 or 4 toxicities observed were related to myelosuppression. There were two deaths in the study, both related to thrombocytopenia and hemorrhage.

Another study showed synergy between imatinib and decitabine. Ten patients who presented with untreated accelerated or blastic-phase chronic myelogenous leukemia were treated with a combination of decitabine (15 mg/m², IV, for 10 days) and imatinib (600 mg po daily). Of the ten patients enrolled, six were evaluable; two patients achieved CHR, and one patient achieved a minor cytogenetic response.

If approved for the treatment of chronic myelogenous leukemia, decitabine will likely be used in accelerated-phase and blastic-phase disease that is unresponsive to imatinib therapy. The agent is unlikely to be used alone and will be used in combination with imatinib and other therapies.

Overview

Chronic myelogenous leukemia is among the malignancies most susceptible to immune recognition and eradication. The strongest evidence for this immune response is the graft-versus-leukemia effect, which is most clearly seen in chronic myelogenous leukemia after allogeneic stem-cell transplantation (allo-Stem-cell transplantation) and donor lymphocyte infusion (DLI). The cancer vaccines being developed are designed to induce antigen-specific antitumor immune responses against the specific cancer cells present in the patient.

Problems with production, storage, and administration could deter the acceptance and use of vaccines in the clinic, especially because of the availability of an effective oral drug, imatinib. Among patients treated with imatinib, though, only 39% achieve an major molecular response (defined as a reduction in BCR-ABL transcript levels of at least 3 log). Therefore, vaccines might instead be used to control and reduce minimal residual disease levels (the BCR-ABL transcript level) in patients being treated with drug therapy.

Mechanism Of Action

Some vaccines contain antigens or parts of antigens purified from cancer cells obtained from the patient or from another individual. DNA vaccines are being tested that contain the DNA encoding the specific antigen. In some approaches, cells are isolated in the laboratory and start making antibodies after the cancer antigen is inserted. In each case, the vaccines’ method of action is to render the cancer cells susceptible to immune attack by cytotoxic T lymphocytes (CTLs) by heightening the recognition of markers within cancer cells. The goal is to encourage the patient’s immune system to inhibit the growth of cancer cells.

AG-858

Antigenics’ AG-858 (HSPPC-70-C) is a personalized HSP70 cancer vaccine. A Phase II trial of the agent in combination with imatinib is underway.

AG-858 is a vaccine comprising HSP70-peptide complexes that have been isolated from individual patients’ cancer cells. Patients undergo a blood-filtering process called leukopheresis, during which white blood cells (WBCs) are collected. The WBCs are then sent to Antigenics for production of the personalized vaccines.

HSPs are a family of chaperone proteins that participate in the degradation process of intracellular proteins. Because it associates with multiple potentially anti-genic peptides and cannot interact with antigen-presenting cells (APCs), HSP70 was proposed as an approach to develop tumor-specific vaccines. When the patient is vaccinated, the HSP70-peptide complexes interact with the immune system’s APCs at the site of injection. The HSP complexes bind to the CD91 receptor on APCs, and are taken into the cells. The APCs then travel to the lymph nodes where they re-present the antigenic peptides on their surfaces. This process triggers a response by cytotoxic T-lymphocytes against antigens expressed in cells from which the HSP70 was derived.

A Phase II study is evaluating the safety and efficacy of AG-858 in combination with imatinib in up to 120 patients in the United Kingdom and the United States with chronic chronic myelogenous leukemia who are receiving imatinib but have not achieved complete cytogenetic response (cytogenetic response).

In a pilot trial, 11 chronic myelogenous leukemia patients who had failed to achieve an major cytogenetic response after six months of imatinib therapy were treated with AG-858 and imatinib. HSP was successfully purified from all patients and, after vaccination, a cytogenetic response was achieved in all five patients who had completed the eight planned injections; two patients had a complete molecular response (complete molecular response).

Overview

Chemotherapy uses anticancer or “cytotoxic” drugs to destroy cancer cells by disrupting their growth. Cytarabine is commonly used in combination with interferon-a and in chemotherapy regimens to treat blastic-phase chronic myelogenous leukemia. The cytotoxic agents hydroxyurea and busulfan were the treatments of choice until interferon-a was introduced into the chronic myelogenous leukemia market twenty years ago. The older agents are less costly than interferon-a or imatinib and are orally administered.

Once chronic myelogenous leukemia enters the blastic phase, no treatment is particularly effective for controlling the disease. Clinicians use a wide variety of multidrug regimens that are based on the treatments for acute myelogenous leukemia and acute lym-phocytic leukemia. Commonly used cytotoxic agents are idarubicin (Pfizer’s Zavedos/Idamycin), daunorubicin (Sanofi-Aventis’s Cerubidin, Bedford’s Cerubidine, generics), and vincristine (Eli Lilly’s Oncovorin, generics).

Mechanism Of Action

Chemotherapeutic drugs work by damaging cancer cells as they undergo division, or mitosis, and preventing their further reproduction. Cells that are at rest (e.g., most normal cells) are much less vulnerable to chemotherapeutic damage. The cell cycle is composed of four distinct phases, G1, S, G2, and Go, during which the cell prepares for and undergoes mitosis. Combination chemotherapy includes drugs that damage cells at different stages in the process of cell division. Using more than one drug increases the chance of killing a greater number of cells. Chemotherapy also affects healthy body tissues that grow constantly (e.g., skin, hair, digestive system), a factor that explains the side effects, such as hair loss, suffered by patients.

Cytarabine

In the treatment of chronic-phase chronic myelogenous leukemia, cytarabine (Pfizer’s Cytosar-U, generics) is generally used in conjunction with interferon-a. The addition of cytarabine to interferon-a increases the toxicity of the treatment; whether the combination of the two therapies increases response rates is controversial.

Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA via multiple mechanisms including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and, most importantly, incorporation into DNA. Cytotoxicity is highly specific for the S phase of the cell cycle.

One study analyzed the efficacy of daily treatment with interferon-a (5 MU/m²) combined with LDAC (10 mg) (IFN+LDAC) in 140 patients with Ph-positive early chronic chronic myelogenous leukemia. Results were compared with those in patients receiving interferon-a with or without intermittent LDAC (seven days per month). CHRs were observed in 92% of patients treated with IFN+LDAC, and cytogenetic responses were observed in 74% (major in 50%, complete in 31%). The estimated four-year survival rate was 70%. The incidence of CHR was higher with IFN+LDAC than with intermittent or no LDAC (92% versus 84% versus 80%, respectively); similar results were noted for cytogenetic response (74% versus 73% versus 58%, respectively). Also, the time to achievement of a major cytogenetic response was significantly shorter than was obtained with previous interferon-a regimens.

Another study randomized 721 patients with Ph-positive, early chronic-phase chronic myelogenous leukemia to receive treatment with either hydroxyurea (50 mg/kg) and interferon-a (5 MU/m²/d) or hydroxyurea, interferon-a, and monthly courses of LDAC (20 mg/m² for 10 days/month). The rate of CHR was 66% in the IFN+LDAC group versus 55% in the interferon-a/hydroxyurea group. The cytogenetic response rate was 66% in patients treated with LDAC (major in 41%, complete in 15%), which was significantly higher than the 52% response rate (major in 24%, complete in 9%) among patients treated with interferon-a/hydroxyurea. Patients in the IFN+LDAC group had a significantly better survival rate than patients in the interferon-a/hydroxyurea group: three-year survival rates were 86% versus 79%.

Cytarabine is generally administered as an intravenous preparation. An oral form of cytarabine is available in Japan.

Hydroxyured

Hydroxyurea (also known as hydroxycarbamide) (Bristol-Myers Squibb’s Hydrea, generics) effectively produces rapid hematologic responses and controls overall tumor burden in chronic myelogenous leukemia, as assessed by white blood cell count and spleen size. Although up to 80% of patients achieve hematologic remissions with hydroxyurea, cytogenetic responses are rare, and when they occur, are normally transient. Hydroxyurea is superior to busulfan, but inferior to interferon-a therapy, in terms of both survival rates (median survival 56 months with hydroxyurea and 44 months with busulfan) and toxicity. Hydroxyurea is also used to treat acute myeloid leukemia, head and neck cancers (before radiotherapy treatment), and ovarian cancer.

Hydroxyurea acts primarily as an inhibitor of ribonucleotide reductase. Inhibition of this protein leads to the depletion of essential DNA precursors. Another proposed mechanism of cytotoxicity involves direct chemical damage to DNA by hydroxyurea or a metabolite. Hydroxyurea also inhibits repair of DNA damaged by chemotherapy or radiation, offering potential synergy between hydroxyurea and radiation or alkylating agents. Laboratory studies suggest that hydroxyurea acts selectively against the episomes responsible for drug resistance. Hydroxyurea is specific for the S-phase of the cell cycle.

Because of its rapid onset of action, hydroxyurea can be used to reduce the leukemic burden in newly diagnosed patients before initiating interferon-a or progenitor stem-cell transplantation. Hydroxyurea is also used in patients with refractory disease or those who are intolerant of first-line therapy.

Common side effects associated with hydroxyurea are threefold. They include a temporary drop in bone marrow function, causing a fall in white blood cell count that increases the risk of severe infection; a drop in red cell count (anemia), causing fatigue and shortness of breath; and a drop in platelet numbers in the blood, causing bleeding or bruising.

Busulfan

Low-dose therapy with busulfan (GlaxoSmithKline’s Myleran) was once the mainstay of treatment for chronic myelogenous leukemia. The superior survival rates produced by imatinib, interferon-a, and hydroxyurea have reduced busulfan’s role to that of myeloablative therapy prior to allo-Stem-cell transplantation. This medication is also used to treat other disorders of the blood or bone marrow (e.g., myeloproliferative disorder, thrombocytosis, myelofibrosis).

Busulfan is a bifunctional alkylating agent that has been in clinical use since 1959. Carbonium ions rapidly form after systemic absorption of busulfan, leading to alkylation of DNA. This alkylation 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. The antitumor activity of busulfan is cell cycle phase-nonspecific. Selective effects on granulocytopoesis are not well understood.

In the treatment of chronic myelogenous leukemia, busulfan is most commonly used in high doses as a myeloablative agent in patients receiving progenitor stem-cell transplantation. The dose of busulfan in this setting depends on the protocol, ranging from 8 to 16 mg/kg given over four days. The major dose-limiting effects of busulfan are myelotoxicity and pancytopenia. Myelotoxicity may be increased in patients who are recovering from the effects of prior chemotherapy or those who have received radioactive phosphorus or radiation to marrow-bearing bones.

Busulfan can lower the body’s ability to fight an infection, as well as prevent normal blood clotting. Other side effects associated with busulfan include hyperpigmentation, pulmonary toxicity, abnormal gonadal function, seizures, and veno-occlusive disease.

Overview

Cladribine (Ortho Biotech’s Leustatin, Japananssen-Cilag’s Leustatin/ Leustatine/Leustat, generics; also known as chlorodeoxyadenosine and 2-CDA)  is primarily used to treat hairy-cell leukemia. Cladribine is used much less frequently than fludarabine for chronic lymphocytic leukemia because many more, and larger, randomized trials have evaluated the latter agent. It has now been approved.

Mechanism Of Action

Cladribine is a purine analogue that closely resembles fludarabine; it inhibits DNA synthesis by interfering with DNA polymerases, thereby preventing the elongation of DNA strands.

Clinical Performance

A multicenter, randomized prospective study analyzed the efficacy and toxicity of cladribine plus prednisone versus chlorambucil plus prednisone in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia. As with other study designs, patients were randomized to receive either therapy; evaluated after a certain number of courses (in this case, three); and switched to the alternate therapy arm if they had not responded. As mentioned previously, this method obscures the interpretation of long-term survival data. However, in the initial evaluation following three courses of therapy, 59/126 (47%) patients receiving cladribine plus prednisone achieved a CR and 50/126 (40%) achieved a PR, giving a total response rate of 87%. In the chlorambucil plus prednisone arm, 12/103 (12%) patients achieved a CRs and 46/103 (45%) of patients achieved a PR, giving an overall response rate of 57%. In addition, early relapses occurred more frequently in the chlorambucil arm than in the cladribine arm.

Patients who did not respond to first-line treatment with either regimen were switched to the alternate arm of the study. Second-line treatment with cladribine plus prednisone was found to be more effective (10/43 CR, 19/43 PR) than chlorambucil plus prednisone (0/26 CR and 7/26PR).

Response rates in the cladribine arm were comparable to responses obtained in patients receiving fludarabine. Although both the overall response rates and progression-free survival improved in the cladribine arm, this improvement did not translate into a significant difference in terms of overall survival rates. This effect may be associated with the switching of patients from one arm to another early on in the study.

Analysis of the drug-induced toxicity confirmed cladribine’s myelosuppressive effects, which resulted in a high incidence of neutropenia and infections compared with patients in the chlorambucil arm. Thrombocytopenia occurred with equal frequency in both arms.

Several Phase II studies have examined the efficacy of cladribine in combination chemotherapy in regimens such as cladribine/cyclophosphamide and cladribine/cyclophosphamide/mitoxantrone. In untreated patients, the former regimen produced overall response rates of 88%, with a CR of 29%. Large-scale, randomized trial data are lacking for this drug.

Overview

Pentostatin (SuperGen{/Wyefh/Pfizer}’s Nipent) was first administered to patients with acute leukemia in the 1970s, but it was associated with severe extramedullary toxicity, and enthusiasm for its use declined. However, patients with hairy-cell leukemia and chronic lymphocytic leukemia have shown responses at lower doses, so pentostatin is being investigated again as part of a combination regimen. This agent will garner an increasing, but modest, off-label share of sales throughout the study period owing to current investigation into its use in chronic lymphocytic leukemia by investigators at the Mayo Clinic College of Medicine and the Memorial Sloan-Kettering Cancer Center.

Mechanism of Action

•  Pentostatin, a purine analogue, is a potent, irreversible inhibitor of adenosine deaminase produced by Streptomyces ontibioticus. adenosine deaminase is a vital enzyme in the purine salvage pathway, and its inhibition results in the accumulation of adenosine and deoxyadenosine metabolites, which inhibit ribonucleotide reductase. The depletion of the nucleotide pool leads to the inhibition of DNA synthesis and subsequent toxicity to the cell. adenosine deaminase is a ubiquitous enzyme but is found in higher concentrations in lymphoid tissue.

•  Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.

Clinical Performance

Pentostatin is thought to be the least myelosuppressive of the purine analogues in use to treat chronic lymphocytic leukemia. Its usage, though, is not widespread and few trial data are available.

A study published in 2003 describes the combination of pentostatin with cyclophosphamide in 21 patients with intermediate- or high-risk chronic lymphocytic leukemia and 2 patients with small-cell lymphoma who had received substantial prior therapy (median of three regimens) including fludarabine (87% of patients), chlorambucil (78%), and rituximab (26%). Responses were seen in 17 patients and included 4 CRs (17%), 1 nPR (4%), and 12 PRs (57%). When analyzing the responses in comparison with patients’ responses to previous therapies, where sufficient data were available, investigators in this trial determined that seven patients achieved their best response on this regimen. In addition, 13 patients who had previously failed fludarabine-based treatment responded, including 1 CR. (This latter group of patients is particularly difficult to treat and is left with few therapy options.) The median response duration of all 17 responders was 7 months (13 months for those in CR and 6 months for those in PR). As expected, median survival was longer for responders versus nonresponders (17 versus 8.5 months).

Mild, asymptomatic tumor lysis syndrome (the release of cellular breakdown products into the blood) was detected in 39% of patients, demonstrating the rapid cytotoxic effects of this combination, which resulted in a sharp decline in white blood cell count following the first cycle of chemotherapy. Pentostatin’s different mechanism of action may be clinically relevant in fludarabine-treated patients. The incidence of response was similar among both sensitive and refractory patients, although a higher rate of CR occurred in fludarabine-sensitive patients (30% versus 8%, respectively).

One of the major reasons for using pentostatin versus fludarabine is the potential for reducing myelosuppression. Grade 3/4 thrombocytopenia, neutropenia, and serious infections were observed in 30%, 35%, and 9% of patients in this study. The rates of thrombocytopenia and neutropenia are higher and lower, respectively, than those observed in a study of fludarabine/cyclophosphamide

(19% and 75%), and the rate of infection is lower. However, it is difficult to compare these trials because of different variables, including the use of G-CSF support in the pentostatin/cyclophosphamide study.

Ongoing studies are attempting to determine the efficacy of pentostatin combinations in chronic lymphocytic leukemia patients, particularly combination therapy with monoclonal antibodies.

Overview

Cyclophosphamide, Vincristine, Prednisone incorporates cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, Pfizer’s Neosar/Cyclostin, generics), vincristine (Eli Lilly’s Oncovin), and prednisone (generics). As with CHOP, this older regimen is losing favor to fludarabine-based regimens.

Mechanism of Action

•  Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication

•  Vincristine is a vinca alkaloid. Vinca alkaloids interact with tubulin and disrupt microtubular function in the mitotic spindle. This action leads to metaphase arrest, resulting in mitotic arrest and cell death.

• Prednisone is a corticosteroid and reduces inflammatory responses and suppresses the immune system.

Clinical Performance

The majority of randomized trials comparing Cyclophosphamide, Vincristine, Prednisone (also known as COP) treatment with chlorambucil as first-line therapy report equivalent response rates with the two treatment strategies. An Eastern Cooperative Oncology Group (ECOG) study randomized patients with advanced chronic lymphocytic leukemia to receive either chlorambucil and prednisone or Cyclophosphamide, Vincristine, Prednisone. A median follow-up of seven years determined that chlorambucil/prednisone and Cyclophosphamide, Vincristine, Prednisone invoked no significant differences in survival (4.8 versus 3.9 years), CR rate (25% versus 23%), and duration of response (2.0 versus 1.9 years). These results were also comparable to those obtained using the CHOP regimen.

The French Cooperative Group on chronic lymphocytic leukemia obtained similar results in an analysis of 291 Binet stage B patients, randomized to receive either chlorambucil or Cyclophosphamide, Vincristine, Prednisone (French Cooperative Group on chronic lymphocytic leukemia, 1990). No significant differences were observed either in the three- and five-year survival rates (69% and 44% in the chlorambucil group and 73% and 43% in the Cyclophosphamide, Vincristine, Prednisone group, respectively) or in median survival times (58 months versus 57 months, respectively).

A large-scale meta-analysis of 2,022 chronic lymphocytic leukemia patients in ten trials confirmed that the combination chemotherapy regimens Cyclophosphamide, Vincristine, Prednisone and CHOP offer no benefit in long-term survival when compared with chlorambucil and were significantly more toxic (chronic lymphocytic leukemia Trialists’ Collaborative Group, 1999).

Overview

The CHOP regimen incorporates cyclophosphamide (Bristol-Myers Squibb’s Cytoxan, Baxter’s Endoxan/Endoxana, Pfizer’s Neosar/Cyclostin, generics), doxorubicin (Pfizer’s Adriamycin/Adriblastine, Bristol-Myers Squibb’s Rubex, Kyowa’s Adriacin, generics), vincristine (Eli Lilly’s Oncovin), and prednisone (generics). This combination is frequently used in non-Hodgkin’s lymphoma; its use is becoming less widespread in chronic lymphocytic leukemia.

Mechanism of Action

•  Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.

•  Doxorubicin is an anthracycline. Anthracyclines interact with several different cellular targets, most importantly topoisomerase II. By inhibiting this DNA regulation enzyme, anthracyclines exert their cyto-toxic effect. Another mechanism leading to cell death, known as DNA intercalation, involves insertion of the anthracycline molecule between base pairs. This phenomenon causes single- and double-stranded breaks in DNA that inhibit cell proliferation. The free radicals generated by the reductive metabolism of anthracyclines may also damage cellular structures.

•  Vincristine is a vinca alkaloid. Vinca alkaloids interact with tubulin and disrupt microtubular function in the mitotic spindle. This action leads to metaphase arrest, resulting in mitotic arrest and cell death.

•  Prednisone is a corticosteroid and reduces inflammatory responses and suppresses the immune system.

Clinical Performance

The dosage of cyclophosphamide and doxorubicin in CHOP regimens can vary (300-750 mg/m² cyclophosphamide and 25-50 mg/m² doxorubicin). When lower doses of these drugs are used, it may be referred to as mini-CHOP.

A randomized clinical trial was designed to compare the anthracycline-containing regimens CHOP (incorporating the lower doses of cyclophosphamide and doxorubicin) and CAP (cyclophosphamide, doxorubicin, prednisone) with fludarabine in 938 previously untreated Binet stage B and C chronic lymphocytic leukemia patients. Patients were randomly assigned to receive six monthly courses of CHOP, CAP, or fludarabine. Those patients who received fludarabine or CAP and had stable or progressive disease after three cycles were switched to either CAP or fludarabine, respectively. The CHOP regimen used in this study consisted of lower doxorubicin doses, so responses were assessed after six courses of treatment and patients with stable or progressive disease were switched to fludarabine.

The response rates obtained following six courses of therapy (or at switch during the six courses) showed that both fludarabine and CHOP were clearly superior to CAP. CR rates of 29.6%, 15.2%, and 40.1% and PR rates of 41.9%, 43%, and 31% were achieved in patients receiving CHOP, CAP, and fludarabine, respectively, regardless of stage. Accrual to the CAP arm was prematurely closed

when results of the first interim analysis showed significantly reduced response rates compared with CHOP and fludarabine.

The median follow-up in this study was 70 months and median survival was 67 months, 70 months, and 69 months in the CHOP, CAP, and fludarabine arms, respectively, with five-year survival rates of 57.3%, 59.8%, and 58.4%, respectively. Although distinct differences in remission rates were observed, they did not translate into differences in survival. This effect was generated by the fact that patients who did not respond to their initial therapy were switched to another arm of the study, and the majority of patients received subsequent therapy over the course of their disease, thus obscuring the interpretation of survival data. Similar conclusions have been outlined in other large, prospective multicenter trials.

A higher frequency and severity of nausea, vomiting, and hair loss in patients receiving anthracycline-containing regimens were observed, whereas myelosuppression predominated in the fludarabine group. However, the increased rate of infection associated with myelosuppression in fludarabine-treated patients reported in previous trials was not observed in this study. The authors suggested that this absence may be explained by the fact that this patient group was previously untreated.

Additional studies have shown that standard doses of CHOP did not result in any advantage in terms of response duration or survival when compared with chlorambucil plus prednisone. A meta-analysis of 2,022 chronic lymphocytic leukemia patients in ten trials of combination chemotherapy (CHOP or COP [cyclophosphamide, oncovin, prednisone]) versus chlorambucil plus or minus corticosteroids was carried out to compare overall long-term survival rates (chronic lymphocytic leukemia Trialists’ Collaborative Group, 1999). No benefit was seen for combination chemotherapy over single-agent chlorambucil in terms of five-year survival rates.

The combination of the toxicity associated with CHOP and the response rates gained with other agents have convinced physicians that CHOP should be reserved for those patients who fail chlorambucil or fludarabine therapy.

Overview

The fludarabine, cyclophosphamide, and mitoxantrone (Serono/Wyeth/Takeda’s Novantrone, Baxter’s Onkotrone, generics) regimen is under investigation in clinical trials and is used as the standard of care in some hospitals in Germany and Spain.

Mechanism of Action.

•  Fludarabine is a purine analogue and is metabolized rapidly to F-Ara-ATP, which inhibits DNA synthesis by inhibition of DNA polymerases and prevents elongation of DNA strands through direct incorporation into the DNA molecule.

•  Cyclophosphamide is an alkylating agent. These agents alkylate DNA bases, thereby producing “cross-links” that covalently link the two DNA strands and prevent cell replication.

•  Mitoxantrone is a synthetic antineoplastic anthracenedione. It is a DNA-reactive agent that intercalates with DNA by hydrogen bonding,causing cross-links and strand breaks. It also reacts with RNA and is a potent inhibitor of topoisomerase II.

Clinical Performance

In vitro studies have demonstrated fludarabine’s synergistic effect with both cyclophosphamide and mitoxantrone. On the basis of these results, a clinical trial was designed to test the efficacy of these agents in previously treated chronic lymphocytic leukemia patients. Of the 60 patients treated with FCM, 34 had received one prior therapy, 18 had received two, and 8 had received three or more. Previous therapies included chlorambucil with or without prednisone (70%), cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (32%), and fludarabine monotherapy (8%). FCM was administered following relapse in 25 cases (42%) and following development of resistance to prior therapy in 35 (58%) patients.

Thirty patients (50%) achieved a CR and 17 patients (28%) achieved a PR. Of the 30 patients in CR, 10 were found to be negative for minimal residual disease by flow cytometry and polymerase chain reaction (PCR; so-called molecular remission). The CR and PR rate was significantly higher among patients who had relapsed (32% and 40%, respectively) compared with those who were resistant to prior treatment (6% and 28%, respectively). None of the five patients previously treated with fludarabine achieved a CR, although they did respond to FCM therapy. The median duration of response was 19 months in patients who achieved a CR, similar to that achieved with other fludarabine combinations, and was not significantly different if patients were minimal residual disease-negative (17 versus 21 months) or between relapsed and resistant cases.

Hematologic toxicities and infections were the most significant side effects, as reported in other fludarabine-based regimens. Sixty-three percent of patients suffered from grade 3 or 4 neutropenia, and this toxicity was greater in patients who had prior chlorambucil treatment (81% versus 47%). Grade 3/4 thrombocytopenia and anemia were observed in 16% and 17% of cases, respectively, and grade 3/4 infections/fever occurred in 23% of patients.

Although no large-scale trials describing the use of FCM in first-line therapy of chronic lymphocytic leukemia have been performed, the regimen is being used in this setting in some European countries.