Bendamustine Hydrochloride for Chronic Lymphocytic Leukemia

Overview:

Bendamustine hydrochloride is a cancer-treating drug (chemotherapeutic drug) used mainly to treat neoplastic conditions like chronic lymphocytic leukemia and non-Hodgkin lymphoma. This drug belongs to the alkylating group of drugs and is known to treat cancer by inhibiting protein synthesis. It was initially authorized in the United States in December 2008 to treat chronic lymphocytic leukemia. However, Bendamustine hydrochloride was expanded to treat conditions like indolent non-Hodgkin lymphoma, secondary to treatment with Rituximab.

Dosage and Route of Administration:

Bendamustine hydrochloride is generally administered through a vein (intravenous administration) over 10 minutes. The dosage depends on the purpose of administration.

• For chronic lymphocytic leukemia, the dosage required is 100 mg/sq.m (milligram per meter square) on the first and second day of a 28-day cycle in a chemotherapeutic schedule. This is continued for six cycles. If the number of blood and progenitor cells in the bone marrow goes very low even after treatment, dose modifications become imperative based on the grading.

• For indolent B-cell non-Hodgkin lymphoma, the dosage is 120 mg/sq.m on the first two days in a 21-day cycle and will be continued till eight cycles of the chemotherapy schedule.

For Patients:

What Is Chronic Lymphocytic Leukemia?

As the name says, chronic lymphocytic leukemia is a kind of blood cancer with excessive production of a type of blood cell called lymphocytes. There are various types of lymphocytes of which B-lymphocyte production becomes excessive in this condition. The abnormal and excessive production of B-lymphocytes and non-destruction leads to the accumulation of lymphocytes in the circulating blood, bone marrow, and lymph nodes.

What Are the Symptoms of Chronic Lymphocytic Leukemia?

In the disease's initial stages, no symptoms will be noticed by the affected people. After a few days, the patients may experience symptoms like:

• Enlarged lymph nodes, often painless, in areas like the neck, armpits, or groin.

• Fatigue or weakness due to anemia (low red blood cell count).

• Frequent infections, as CLL compromise the immune system.

• Bruising and bleeding (as a result of thrombocytopenia).

• Unintentional weight loss.

• Night sweats.

• Abdominal discomfort or fullness caused by an enlarged spleen or liver.

• Shortness of breath during physical activity.

• Tightness in the regions of the abdomen.

• Bloated feeling.

• If the lymph nodes become infected, patients may complain of swelling with pain.

Why Is Bendamustine Hydrochloride Prescribed for Chronic Lymphocytic Leukemia?

Bendamustine hydrochloride is an antineoplastic drug that stops DNA (deoxyribonucleic acid) and protein formation by the neoplastic cells. In chronic lymphocytic leukemia, abnormally formed lymphocytes are seen in the blood, bone marrow, and lymph nodes. Bendamustine targets and kills such excessively produced lymphocytes. This disrupts the growth of neoplastic (cancer) cells and also reduces the process of replication by the cells. Thus, the progression of chronic lymphocytic leukemia is halted. Bendamustine hydrochloride is generally used with other anticancer drugs for improved efficiency in treating the condition. Since Bendamustine hydrochloride is an alkylating agent, it is effective against cancer cells in all stages of cell growth and replication. This proves that the drug's efficacy against chronic lymphocytic leukemia is high.

What Are the Side Effects of Taking Bendamustine Hydrochloride?

Two kinds of side effects are observed after taking Bendamustine hydrochloride. One set of symptoms is non-hematologic (not pertaining to blood), and the others are of hematologic origin.

Non-hematologic side effects noted are:

• Tachycardia (Elevated heart rate to more than 100 beats per minute).

• Hypotension.

• Nausea.

• Vomiting.

• Diarrhea.

• Constipation.

• Stomatitis.

• Fatigue.

• Pain in the abdomen.

• Dyspepsia (Discomfort in the stomach due to indigestion).

• Dry mouth.

• Bloating.

• Pyrexia.

• Chills.

• Peripheral edema.

• Pharyngitis.

• Chest pain.

• Infusion site reactions.

• Hair loss.

• Anorexia.

• Reduced appetite.

• Dehydration.

• Pain in the back and extremities.

• Joint pain.

• Dizziness.

• Headache.

• Anxiety.

• Depression.

• Insomnia.

• Difficulty breathing.

• Wheezing.

Hematologic side effects noticed are:

• Reduced platelet count causes easy bruising and excessive bleeding on low-impact trauma.

• Reduced white blood cell counts increased the incidence of infections in the individuals. Some common infections noticed are Herpes zoster, candidiasis, infection of the respiratory tract, gastrointestinal tract, urinary tract, genital area, and also pneumonia.

• Reduced erythrocytes (red blood cells) can lead to side effects like anemia that manifests as pale and dry skin, nails that become brittle, and loss of interest and energy to perform everyday activities.

The most severe side effects are febrile neutropenia (fever that develops due to reduced circulating neutrophils), renal and cardiac failure, tumor lysis syndrome, and myelodysplastic syndrome (reduced progenitor cells to form the blood cells).

What Are the Precautionary Measures to Be Followed While Taking Bendamustine Hydrochloride?

• Regular blood tests should be taken to look for any increase or decrease in the blood cell count and modify the treatment regimen accordingly.

• Bendamustine hydrochloride can put the individual at risk of developing infections due to reduced immune response. So, patients must avoid contact with sick people and always follow stringent hygiene protocols. To reduce the likelihood of transmitting infections, people who want to visit patients should also be asked to follow safety and hygiene protocols, like washing hands before the visit.

• Medications will be given before the parenteral administration of Bendamustine hydrochloride. Such medicines should be taken to prevent the incidence of nausea and vomiting.

• Avoid receiving live vaccines during Bendamustine treatment, as the weakened immune system may not respond adequately to these vaccines.

For Doctors:

Indications:

• Chronic lymphocytic leukemia.

• Indolent B-cell non-Hodgkin lymphoma.

Bendamustine is advocated along with other chemotherapeutic agents for better efficacy.

Contraindications:

• People who are allergic to the ingredients of Bendamustine hydrochloride.

• Individuals with meager blood count or bone marrow suppression.

• Patients with impaired liver function are also contraindicated for treatment with Bendamustine hydrochloride.

Half-Life:

The half-life of Bendamustine hydrochloride is approximately 40 minutes to 4 hours. The active metabolites of Bendamustine formed upon its administration have longer half-lives, ranging from 3 to 30 hours.

Drug Ingredients:

Active Ingredients: Bendamustine hydrochloride.

Inactive Ingredients: Mannitol, sodium chloride, polyethylene glycol, and water may be used to stabilize the drug.

Clinical Pharmacology:

Bendamustine hydrochloride, an alkylating agent with a unique chemical structure, demonstrates a dual mechanism of action as an anti-cancer medication. Upon administration, it undergoes rapid hydrolysis in plasma to form active metabolites. These metabolites act by inducing DNA damage in cancer cells through alkylation and subsequent cross-linking of DNA strands, ultimately leading to cell death. Unlike other chemotherapy agents, Bendamustine exhibits cell-cycle phase specificity, acting in both the resting and dividing phases of the cell cycle, and a unique resistance profile that may provide efficacy in cases resistant to other treatments. So, the destruction of cancer cells occurs in both the quiescent and dividing stages.

Pharmacokinetics:

Absorption:

Bendamustine hydrochloride is primarily administered intravenously and is rapidly hydrolyzed to active metabolites upon infusion. The intravenous route allows for direct entry into the systemic circulation, bypassing the gastrointestinal system and achieving therapeutic concentrations necessary for its anti-cancer effects. The rapid hydrolysis of Bendamustine in plasma leads to the formation of active metabolites, such as gamma-hydroxy Bendamustine and N-desmethyl-Bendamustine, which contribute to its pharmacological activity against cancer cells.

Metabolism:

The metabolites of Bendamustine are formed by the action of enzymes esterases and cytochrome P450 enzymes, primarily CYP1A2 and CYP2C19, in the liver. They undergo glucuronidation and sulfation subsequently to form inactive metabolites.

Distribution:

Bendamustine is known to be distributed into various body tissues, including the blood, plasma, liver, kidneys, and bone marrow, where it exerts its cytotoxic effects on cancer cells, particularly lymphocytes. The drug also crosses the blood-brain barrier, allowing it to reach the central nervous system, which can be relevant in certain hematologic malignancies involving the central nervous system. Protein binding of Bendamustine and its active metabolites is moderate, primarily to plasma proteins like albumin and alpha-1 acid glycoprotein.

Excretion:

Bendamustine hydrochloride and its metabolites are primarily eliminated from the body via the renal route.

Pharmacodynamics:

Bendamustine exerts the anti-neoplastic action by damaging DNA. This is achieved by binding to DNA to form covalent bonds. This forms crosslinks within the strands and among various strands of the DNA structure. This action interferes with DNA replication and transcription, ultimately causing DNA damage and triggering programmed cell death (apoptosis) in cancer cells. This apoptosis process occurs in the resting and dividing phases (G0 and S phase). The entire process of alkylation and apoptosis is responsible for killing the cancer cells effectively.

How Is Bendamustine Hydrochloride Administered for Patients?

Since this drug has cytotoxic properties, it is important to handle the medication with caution and follow the prescribed protocol.

This is an intravenously administered drug, and the dosage to be given to a patient depends on their body surface area. For chronic lymphocytic leukemia, it is necessary to administer 100 mg/sq.m for adequate action.

• The required volume should be removed from the vial containing Bendamustine hydrochloride for intravenous administration.

• The drug volume should then be diluted with 0.9 percent sodium chloride, 2.5 percent dextrose, 2.5 percent sodium chloride, or 5 percent dextrose.

• The entire diluted drug should be transferred to an infusion bag to administer the drug intravenously for 30 to 40 minutes.

Glasses and gloves should be used during the entire procedure. In case Bendamustine hydrochloride contacts the skin or mucosa, the area should be washed and flushed thoroughly with water and soap.

Clinical Toxicity:

• Hematological toxicity can result in reduced cell count and volume. This results in anemia, leukopenia, and thrombocytopenia. This can make the patient susceptible to developing any kind of infection or hemorrhage on minor trauma.

• Mucous membrane inflammation (mucositis) has been reported.

• The immune system will lose its capacity to fight against any antigens.

• Bendamustine and its metabolites are excreted through the kidneys, and in rare cases, it may cause renal impairment or renal failure.

• Peripheral neuropathy has been seen in certain populations.

Drug Interactions:

• Since it is an immunosuppressant drug, any other drug with similar potential should not be prescribed together.

• Any kind of vaccine, especially live vaccines, should not be given.

• Drugs that trigger or reduce the action of liver enzymes CYP1A2 and CYP2C19 should be avoided. Some drugs with that action include Fluvoxamine and Rifampicin.

• Concurrent use of Allopurinol, a medication used to treat gout, may increase the risk of skin reactions when used concomitantly with Bendamustine.

• Medications that affect or alter the QT interval, like macrolides, antidepressants, and antiarrhythmic drugs, should be avoided as they predispose the individual to develop arrhythmias.

Guidelines for Specific Population:

• Pregnant and Lactating People: Bendamustine hydrochloride is contraindicated for such people as it may hinder the development of the baby. Also, women should be instructed not to get pregnant throughout the course and until three months of treatment with Bendamustine hydrochloride. Men should also be advised to use proper ways of contraception during the treatment period with Bendamustine hydrochloride.

• Pediatric Population: Bendamustine hydrochloride is generally not indicated for children under 18 years.

• Geriatric Population: Regarding geriatric use, caution is often exercised when using Bendamustine in elderly patients due to age-related changes in organ function and other comorbidities. Dose adjustments or closer monitoring may be considered based on the individual's overall health status, organ function, and tolerance to the medication.

• For any person under the treatment of Bendamustine hydrochloride, regularly conducting hematological investigations that measure the counts of erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets) becomes essential to identify and diagnose myelosuppression.

Overall, Bendamustine hydrochloride, an alkylating chemotherapy agent, is a valuable treatment option for Chronic Lymphocytic Leukemia (CLL) when other therapies have proven ineffective. Administered intravenously, Bendamustine disrupts cancer cell growth by inducing DNA damage, thereby impeding cell replication and triggering cell death. Its unique dual mechanism of action, affecting both resting and dividing cells, contributes to its efficacy against CLL. Bendamustine has effectively slowed disease progression and improved symptoms in CLL patients. However, its use may be associated with various side effects, including hematologic toxicity, gastrointestinal disturbances, and immunosuppression. As with any chemotherapy, careful monitoring, dosage adjustments, and supportive care are essential elements in managing CLL patients undergoing Bendamustine therapy.