Chlorambucil

L01A - Alkylating agents ATC L01AA02 Small molecule approved 1957 Oral Natural product Black-box warning

JFDA label: Leukeran Tablets

⚠ Black-Box Warning

Bone marrow suppression:
Fertility effects:

Mechanism of Action

Inhibitor of DNA — DNA inhibitor

Target	Action	Gene / class
DNA efficacy	INHIBITOR

Indications

Approved

Chronic lymphocytic leukemia
Lymphomas

Off-label

Nephrotic syndrome, steroid sensitive (pediatrics)
Waldenström macroglobulinemia

Class profile

mechanismClass	Alkylating agent (nitrogen mustard)
targetMolecule	DNA (cross-linking)
targetPathway	DNA damage response
generation	Classic
primaryTumors	CLL,Lymphoma,Ovarian
resistanceMechanisms	Reduced drug uptake,Enhanced DNA repair,p53 mutations,BCL-2 overexpression
source	NCCN/OncoKB/Goodman&Gilman13ed

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Use within 4 weeks of a full course of radiation or chemotherapy Absolute
Hypersensitivity to chlorambucil or any component of the formulation Absolute
hypersensitivity to other alkylating agents (may have cross-hypersensitivity) Absolute
prior (demonstrated) resistance to chlorambucil Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Not Known Drug fever · peripheral neuropathy

Hepatobiliary disorders (2)

Not Known Hepatotoxicity · jaundice

Renal and urinary disorders (3)

Not Known Azoospermia · cystitis (sterile) · infertility

Blood and lymphatic system disorders (10)

Not Known Anemia · bone marrow depression · bone marrow failure (irreversible) · leukemia (secondary) · leukopenia · lymphocytopenia · malignant neoplasm (secondary) · neutropenia (onset: 3 weeks; recovery: 10 days after last dose) · pancytopenia · thrombocytopenia

Immune system disorders (2)

Not Known Angioedema · hypersensitivity reaction

Metabolism and nutrition disorders (1)

Not Known Amenorrhea

Gastrointestinal disorders (4)

Not Known Diarrhea (infrequent) · nausea (infrequent) · oral mucosa ulcer (infrequent) · vomiting (infrequent)

Skin and subcutaneous tissue disorders (3)

Not Known Allergic skin reaction · skin rash · urticaria

General disorders and administration site conditions (1)

Not Known Fever

Respiratory, thoracic and mediastinal disorders (2)

Not Known Interstitial pneumonitis · pulmonary fibrosis

Other (13)

Not Known Agitation · ataxia · confusion · erythema multiforme · flaccid paralysis · hallucination · muscle twitching · myoclonus · seizure (focal/generalized) · SIADH (syndrome of inappropriate antidiuretic hormone secretion) · Stevens-Johnson syndrome · toxic epidermal necrolysis · tremor

Dosing

Source: Lexicomp

Note: Reduce initial dose if full-dose radiation or myelotoxic drugs have been administered within the last month. With bone marrow lymphocytic infiltration involvement (in CLL, Hodgkin lymphoma, or NHL), the maximum dose is 0.1 mg/kg/day. While short treatment courses are preferred, if maintenance therapy is required, the maximum dose is 0.1 mg/kg/day. Chronic lymphocytic leukemia (CLL): Oral: 0.1 mg/kg/day for 3 to 6 weeks or 0.4 mg/kg pulsed doses administered intermittently, biweekly, or monthly (increased by 0.1 mg/kg/dose until response/toxicity observed) CLL (off-label dosing): 0.4 mg/kg day 1 every 2 weeks; if tolerated may increase by 0.1 mg/kg with each treatment course to a maximum dose of 0.8 mg/kg and maximum of 24 cycles (Eichhorst 2009) or 30 mg/m2 day 1 every 2 weeks (in combination with prednisone) (Raphael 1991) or 40 mg/m2 day 1 every 4 weeks until disease progression or complete remission or response plateau for up to a maximum of 12 cycles (Rai 2000) CLL in previously untreated patients (off-label combinations): Oral: In combination with obinutuzumab: 0.5 mg/kg on days 1 and 15 every 28 days for 6 cycles (Goede 2014) In combination with ofatumumab: 10 mg/m2 once daily for 7 days (days 1 to 7) every 28 days for a minimum of 3 cycles and up to 12 cycles or best response (clinical response that did not improve after 3 additional cycles); if necessary, reduce dose to 7.5 mg/m2/day and then to 5 mg/m2/day for hematologic toxicity (Hillmen 2015) Hodgkin lymphoma: Oral: 0.2 mg/kg/day for 3 to 6 weeks Non-Hodgkin lymphomas (NHL): Oral: 0.1 mg/kg/day for 3 to 6 weeks Waldenström macroglobulinemia (off-label use): Oral: 0.1 mg/kg/day (continuously) for at least 6 months or 0.3 mg/kg/day for 7 days every 6 weeks for at least 6 months (Kyle 2000)

(For additional information see "Chlorambucil: Pediatric drug information") Nephrotic syndrome, steroid sensitive (off-label use): Oral: 0.2 mg/kg once daily for ~8 weeks (Hodson 2010)

Refer to adult dosing. Begin at the lower end of dosing range(s)

There are no dosage adjustments provided in the manufacturer's labeling; however, renal elimination of unchanged chlorambucil and active metabolite (phenylacetic acid mustard) is minimal and renal impairment is not likely to affect elimination. The following adjustments have been recommended: Adults: Aronoff 2007: CrCl >50 mL/minute: No adjustment necessary. CrCl 10 to 50 mL/minute: Administer 75% of dose. CrCl Peritoneal dialysis (PD): Administer 50% of dose. Kintzel 1995: Based on the pharmacokinetics, dosage adjustment is not indicated

Chlorambucil undergoes extensive hepatic metabolism. Although dosage reduction should be considered in patients with hepatic impairment, there are no dosage adjustments provided in the manufacturer's labeling (data is insufficient).

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

[U.S. Boxed Warning]: May cause severe bone marrow suppression; neutropenia may be severe. Reduce initial dosage if patient has received myelosuppressive or radiation therapy within the previous 4 weeks, or has a depressed baseline leukocyte or platelet count. Irreversible bone marrow damage may occur with total doses approaching 6.5 mg/kg. Progressive lymphopenia may develop (recovery is generally rapid after discontinuation).

Fertility effects

[U.S. Boxed Warning]: Affects human fertility; probably mutagenic and teratogenic as well; chromosomal damage has been documented. Reversible and irreversible sterility (when administered to prepubertal and pubertal males), azoospermia (in adult males) and amenorrhea (in females) have been observed.

Secondary malignancy

[U.S. Boxed Warning]: Carcinogenic; acute myelocytic leukemia and secondary malignancies may be associated with chronic therapy. Duration of treatment and higher cumulative doses are associated with a higher risk for development of leukemia.

Seizures

Have been observed with use; patients with a history of nephrotic syndrome and high pulse doses are at higher risk of seizures. Use with caution in patients with a history of seizure disorder or head trauma.

Skin reactions

Rare instances of severe skin reactions (eg, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported; discontinue promptly if skin reaction occurs. Disease-related concerns:

Hepatic impairment

Chlorambucil is primarily metabolized in the liver. Dosage reductions should be considered in patients with hepatic impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Vaccines

Avoid administration of live vaccines to immunocompromised patients.

Pregnancy & Lactation

Pregnancy

FDA category D Teratogenic

Animal reproduction studies have demonstrated teratogenicity. Chlorambucil crosses the human placenta. Following exposure during the first trimester, case reports have noted adverse renal effects (unilateral agenesis). Women of childbearing potential should avoid becoming pregnant while receiving treatment. [U.S. Boxed Warning]: Affects human fertility; probably mutagenic and teratogenic as well; chromosomal damage has been documented. Reversible and irreversible sterility (when administered to prepubertal and pubertal males), azoospermia (in adult males) and amenorrhea (in females) have been observed. Fibrosis, vasculitis and depletion of primordial follicles have been noted on autopsy of the ovaries.

Lactation

It is not known if chlorambucil is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the decision to discontinue chlorambucil or to discontinue breast-feeding should take into account the benefits of treatment to the mother.

Monitoring

Efficacy	Tumour response (RECIST criteria, tumour markers, imaging); progression-free survival; performance status (ECOG/Karnofsky)
Toxicity	CBC with differential (nadir timing depends on agent); LFTs; renal function; ECG (QT for relevant agents); echocardiogram for cardiotoxic agents (anthracyclines, trastuzumab); cumulative dose tracking for dose-limited toxicities
Clinical pearl	Treatment response is assessed after 2–3 cycles. Grade 3–4 toxicities typically require dose reduction or interruption per protocol-defined criteria.
Counseling	Attend all scheduled blood tests and imaging appointments. Report fever > 38°C (risk of neutropaenic sepsis — medical emergency), unusual bleeding, or new pain immediately.

Chemistry & Properties

Formula	C14H19Cl2NO2
Molecular weight	304.22 g/mol
IUPAC name	4-[4-[bis(2-chloroethyl)amino]phenyl]butanoic acid
CAS	305-03-3
PubChem CID	2708
InChIKey	`JCKYGMPEJWAADB-UHFFFAOYSA-N`
logP	3.38 (XLogP 1.7)
Polar surface area	40.54 Å²
H-bond acceptors / donors	2 / 1
Drug-likeness (QED)	0.71
Lipinski violations	0

SMILES

O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No (logBB -1.7)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C9	Substrate	—
CYP2D6	Inhibitor	IC₅₀ 65.09999999999997 µM

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)OATP1A2 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Measles virus vaccine live attenuated	major
Mumps virus strain B level jeryl lynn live antigen	major
Nalidixic acid	major
Natalizumab	major
Ozanimod	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Thalidomide	major
Thiotepa	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Aldesleukin	moderate
Alefacept	moderate
Alemtuzumab	moderate
Amphotericin B	moderate
Amphotericin B (cholesteryl sulfate)	moderate
Amphotericin B (lipid complex)	moderate
Amphotericin B (liposomal)	moderate
Anakinra	moderate
Anthrax vaccine	moderate

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Leukeran Tablets	Tablet 2 mg	25 tab	Suleiman Tannous & Sons Co. Ltd	18.460