Cytomustine

Uses

Chronic Lymphocytic Leukemia (CLL): Cytomustine is used for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

Non-Hodgkin Lymphoma (NHL): Cytomustineis used for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Also used for Multiple myeloma.

Cytomustine is also used to associated treatment for these conditions: Chronic Lymphocytic Leukaemia (CLL), Follicular Non-Hodgkin's Lymphoma Refractory, Refractory Hodgkin Lymphoma, Refractory Mantle Cell Lymphoma, Waldenström's Macroglobulinemia (WM), Recurrent multiple myeloma, Refractory indolent B cell non-hodgkin lymphoma

How Cytomustine works

Cytomustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action is unknown.

Dosage

Cytomustine dosage

Intravenous (Adult):

Chronic lymphocytic leukaemia:100 mg/m2infused over 30-60 min on days 1 and 2 of a 28-day cycle for up to 6 cycles. For severe haematological or non-haematological toxicity: Reduce dose to 50 mg/m2on days 1 and 2 of each cycle. If severe haematological toxicity recurs, further reduce dose to 25 mg/m2on days 1 and 2 of each cycle. May consider dose re-escalation in subsequent cycles.

Multiple myeloma:120-150 mg/m2infused over 30-60 min on days 1 and 2 of a 28-day cycle. IV or oral prednisone may be given at a dose of 60 mg/m2on days 1-4 of the cycle.

Non-Hodgkin's lymphoma:120 mg/m2infused over 30-60 min on days 1 and 2 of a 21-day cycle for up to 8 cycles. For severe haematological or non-haematological toxicity: Reduced to 90 mg/m2on days 1 and 2 of each cycle. If severe toxicity recurs, further reduce dose to 60 mg/m2on days 1 and 2 of each cycle.

Reconstitute powder for inj by adding 5 ml or 20 ml of sterile water for inj to a vial containing 25 mg or 100 mg, respectively to provide a soln containing 5 mg/ml. The lyophilised powder should be dissolved w/in 5 min, shake well to facilitate dissolution. within 30 min of reconstitution, the appropriate volume should be withdrawn from the vial to further dilute in 500 ml of either NaCl 0.9% inj or dextrose 2.5% and NaCl 0.45% inj to a final concentration of 0.2-0.6 mg/ml.

Side Effects

Malignant and pre-malignant disease; pyrexia, nausea, vomiting, cough, headache, fatigue, diarrhoea, constipation, anorexia, wt decrease, rash, stomatitis, lymphopenia, anaemia, thrombocytopenia, leucopenia, neutropenia.

Toxicity

Risk for tumor-lysis syndrome. Discontinue use in the event of severe/progressive skin reactions. Hematologic malignancies of different forms reported. Discontinue use in the case of severe infusion reactions. May cause extravasation. Mild to moderate renal impairment. Mild hepatic impairment. Sepsis (infections) may occur. Avoid use if pregnant. Possibility of anaphylaxis or infusion reactions- severe in rare cases.

Precaution

Mild to moderate hepatic and renal impairment. Pregnancy and lactation.

Interaction

May increase plasma levels with CYP1A2 inhibitors (e.g. ciprofloxacin, fluvoxamine). May reduce plasma levels with CYP1A2 inducers (e.g. omeprazole and tobacco smoking).

Food Interaction

Cytomustine Drug Interaction

Unknown: sulfamethoxazole / trimethoprim, rosuvastatin, dexamethasone, apixaban, arginine, levocarnitine, cysteine, levofloxacin, lithium, pregabalin, acetaminophen, lenalidomide, rituximab, valproic acid, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione, menaquinone

Cytomustine Disease Interaction

Major: hepatic impairment, renal impairmentModerate: infections, myelosuppression

Volume of Distribution

The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20-25 L. Steady-state volume of distribution for total radioactivity was approximately 50 L, indicating that neither bendamustine nor total radioactivity are extensively distributed into the tissues.

Elimination Route

Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.

Half Life

40 minutes

Clearance

700 mL/min

Elimination Route

Mean recovery of total radioactivity in cancer patients following IV infusion of [14C] bendamustine hydrochloride was approximately 76% of the dose. Approximately 50% of the dose was recovered in the urine and approximately 25% of the dose was recovered in the feces. Urinary excretion was confirmed as a relatively minor pathway of elimination of bendamustine, with approximately 3.3% of the dose recovered in the urine as parent. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.

Pregnancy & Breastfeeding use

Pregnancy category D. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Patient with history of hypersensitivity (e.g. anaphylaxis and anaphylactoid reactions); jaundice, severe bone marrow suppression, low leukocyte or platelet count. Severe hepatic impairment. Major surgery <30 days prior to treatment.

Special Warning

Hepatic Impairment: Moderate: Reduce dose by 30%.

Acute Overdose

Symptoms: Cardiotoxicity, thrombocytopenia.

Management: May perform bone marrow transplantation and transfusions to control haematological effects. It is dialysable to a small extent.

Storage Condition

Store below 25° C, prior to reconstitution. Protect from light.

Innovators Monograph

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