Kimberly Middleton, PharmD
PGY2 Oncology Pharmacy Resident
UMHM/SCCC
Drug Forum #1 – Alkylating Agents
Alkylating agents:
• Nitrogen mustards (bendamustine, chlorambucil, cyclophosphamide, ifosfamide, melphalan)
• Nitrosoureas (carmustine, lomustine)
• Alkyl sulfonate (busulfan)
• Ethylenimines (thiotepa)
• Lurbinectidin, trabectedin
Mechanism of action:
• Binds alkyl groups to DNA which allows cross linking of base pairs leading to DNA damage and cell cycle arrest
• Bendamustine has a benzimidazole ring (purine analog) which demonstrates only partial cross-resistance with other alkylating agents
Class effects:
• Infertility and risk of secondary malignancies
Agent
Indications
Dosing
Dose Adjustments
Bendamustine
(Bendeka,
Belrapzo, Treanda)
CLL, NHL, R/R HL,
MM (salvage),
waldenstrom
macroglobulinemia
70-120 mg/m2
Renal: CrCl <30 mL/min
not recommended
CLL, HL, NHL,
iIdiopathic
membranous
nephropathy,
necrobiotic
xanthogranuloma,
Waldenstrom
macroglobulinemia
• 0.1-0.5 mg/kg
(increase to
max of 0.8
mg/kg)
• 6-10 mg/m2
Chlorambucil
(Leukeran)
Hepatic: AST or ALT
≥2.5x ULN or total
bilirubin ≥1.5 not
recommended
Renal:
• CrCl ≤50 mL/min: 75%
of dose
• CrCl <10 mL/min: 50%
of dose
Toxicities: hematologic
and skin reactions
Caution with concurrent
chemotherapy/radiation
within 4 weeks
Dosage Forms /
Administration
IV
• Bendeka: Over
10 minutes
regardless of
indication
• Belrapzo,
Treanda: Over
30 mins for CLL,
over 60 mins for
NHL
• Concentrations,
storage,
preparation,
and
administration
vary between
formulations
Oral tablet
• May be
administered as
a single daily
dose
• A 2 mg/mL oral
suspension may
be prepared
with tablets
PK/PD
Emetic Risk
Adverse Events
Interactions
Comments/Notes
• Hepatic
metabolism via
CYP1A2 to
active
metabolites
(M3, M4), and
via hydrolysis to
low cytotoxic
metabolites
(HP1, HP2)
• Half-life:
Bendamustine:
~40 mins, M3:
~3 hrs, M4: ~30
mins
Moderate
• Myelosuppression
(nadir in 3rd week)
• Dermatologic toxicity
(rashes including SJS)
• Hepatotoxicity (usually
within first 3 months)
• TLS
• Progressive multifocal
leukoencephalopathy
(PML)
• Infusion reactions
• Peripheral edema,
weight loss,
constipation or
diarrhea, N/V
Mod/strong
CYP1A2 inhibitors –
consider
modification
(ciprofloxacin,
smoking,
omeprazole)
• Belrapzo and
Bendeka are CI in
patients with
hypersensitivity to
polyethylene
glycol 400,
propylene glycol,
or
monothioglycerol
• PJP prophylaxis
• Consider
premedication
(antihistamines,
antipyretics,
steroids) for
previous grade 1-2
reactions
• Complete
absorption from
GI tract (>70%);
reduced with
food
• Extensive
hepatic
metabolism
primarily to
active
metabolite
Minimal to
low
• Myelosuppression
(BBW)
• Fertility effects (BBW)
– probably
mutagenic/teratogenic
and infertility
• Secondary
malignancies (BBW)
• Seizures: with
nephrotic syndrome
and high pulse doses
• Skin reactions
No significant
interactions
Kimberly Middleton, PharmD
PGY2 Oncology Pharmacy Resident
UMHM/SCCC
Cyclophosphamide
(Cytoxan)
ALL, AML, BC, CLL,
CML, HL, mycosis
fungoides, MM,
neuroblastoma,
NHL, ovarian,
retinoblastoma,
sarcomas, GVHD,
HSCT,
lymphodepleting
therapy prior to
CAR T-cell therapy,
Merkel cell
carcinoma,
ovarian, germ cell
tumors, PCNSL,
SCLC
• IV: 75 mg/m2
to 2,000
mg/m2
• Oral: 1 mg/kg
to 100 mg/kg
• Lower doses in
benign
conditions and
higher doses in
transplant
Renal (depends on
indication):
• CrCl 10-29 mL/min:
75-100% of normal
dose
• CrCl <10 mL/min: 50100% of normal dose
Hepatic:
• Bilirubin 3.5-5 mg/dL
or AST/ALT >3x ULN:
administer 75% of the
dose
• Bilirubin >5 mg/dL:
avoid use
Toxicities:
• Hematologic,
cardiotoxicity,
hemorrhagic cystitis
Ifosfamide (Ifex)
Testicular cancer,
bladder, cervical,
sarcomas, NHL, HL,
thymomas and
thymic cancers,
ovarian
1000-5000
mg/m2
Renal:
• Consider if CrCl ≤ 60
mL/min
Hepatic:
• Bilirubin >3 mg/dL:
25% of dose
Toxicity: hematologic
and encephalopathy
IV/PO
• Protocol
specific infusion
rate
• Administer oral
in the AM
• Ensure patients
drink adequate
fluids (~2-3 L)
with frequent
urination during
infusion and for
1 to 2 days after
• High dose
(SCT):
hyperhydration
and mesna
administration
IV
• Administer
over at least 30
minutes
(infusion times
vary)
• Given with
hydration and
mesna to
prevent bladder
toxicity
(phenylacetic
acid mustard)
• Half-life: ~1.5
hours; active
metabolite ~1.8
hours
• Metabolized
hepatically to
active
metabolites
(acrolein)
• Half-life: 3-12
hours
• Metabolism:
Hepatic to
active
metabolites
(including
acrolein)
• Half-life: 7-15
hours (dose
dependent)
• Excretion: urine
• Peripheral neuropathy
Moderate
to high
(>1500
mg/m2 IV)
Moderate
to high (≥2
g/m2/dose)
• Myelosuppression
(nadir at weeks 1 and 2
and recovery after ~20
days)
• Hemorrhagic cystitis
• Cardiotoxicity (high
doses – DLT in SCT)
• SIADH- (typically with
high doses (>2 g/m2)
• Pulmonary toxicities
• Hepatotoxicity/VOD
(age <3 years old at
increased risk)
• Wound healing
impairment
• Major substrate
of CYP2B6
• Minor substrate
of CYP2A6,
CYP2C19, CYP2C9,
CYP3A4
• Hemorrhagic cystitis DLT (BBW)
• Neurotoxicity (BBW):
onset within a few
hours-days and
generally resolves
within 2-3 days after
discontinuation; higher
risk in
hypoalbuminemia,
renal dysfunction, and
high-dose antiemetic
therapy
• Myelosuppression
(BBW)
• Nephrotoxicity
(BBW)/Fanconi-like
syndrome
• Hepatotoxicity (SOS)
• Major substrate:
CYP3A4
• Minor substrates:
CYP2B6, CYP2C19,
CYP2C8, CYP2C9
• Monitor therapy
with moderate
and strong
CYP3A4 inhibitors
and inducers
Hydration for
urotoxicity
prevention
• Starting ≥ 4 hours
prior to treatment
and continued for
at least 24 hours
after
Mesna
• Activated in
kidneys and binds
to acrolein
• Dose (as % of
cyclophosphamide
dose) may vary
• Administered as
24-hour infusion
starting with
treatment and
continued for at
least 24 hours
after
• May also be given
in divided doses
every 4 hours
• CNS toxicity /
encephalopathy –
treat with
methylene blue
Kimberly Middleton, PharmD
PGY2 Oncology Pharmacy Resident
UMHM/SCCC
Melphalan
(Alkeran,
Evomela)
MM, high dose
conditioning
treatment prior to
HCT, ovarian
cancer,
amyloidosis, HSCT,
HL, regional
perfusion in solid
tumors
• IV: 30-200
mg/m2
• PO: 4-9
mg/m2; 0.150.25 mg/kg; 10
mg (for 4 to 10
days)
• Based on
actual body
weight
Carmustine
(BiCNU)
Brain tumors, HL,
MM, NHL, mycosis
fungoides,
conditioning
regimens for
autologous SCT
20-600 mg/m2
(higher doses
300-600 mg/m2
in SCT)
Brain tumors
75 – 130 mg/m2
Lomustine
(Gleostine)
Busulfan
(Busulfex,
Myleran)
CML conditioning
regimen prior to
allogeneic HCT,
HSCT conditioning
regimens,
polycythemia vera,
essential
thrombocythemia
Glioblastoma: 8
wafers (7.7 mg
each) implanted
intracranially
Conditioning
regimens:
• 130-160
mg/m2 once
daily
• 0.8 mg/kg
every 6 hours
or 3.2 mg/kg
daily (total
dose 3.2 to
12.8 mg/kg)
Renal:
• No clear consensus,
different general
recommendations
based on
route/indication
• For conditioning
regimens can consider
140 mg/m2 for SCr >2,
CrCl < 30, frail, old age
• SCT at SCCC/UMHC:
140 mg/m2 if SCr >2
and CrCl <30
Toxicity: hematologic
Renal:
• CrCl 46-60 mL/min:
80% of the usual dose
• CrCl 31-45 mL/min:
75% of the usual dose
• CrCl ≤30 mL/min:
Consider use of
alternative drug
Renal:
• CrCl 46-60 mL/min:
75% of normal dose
• CrCl 31 to 45 mL/min:
70% of normal dose
• CrCl ≤30 mL/min:
Avoid use
Toxicity: hematologic
(leukocytes/plt)
N/A
IV/PO
• Alkeran (60
mins stability)
infuse over 15
to 20 mins
• Evomela infuse
over 30 mins
(SCT)
• Administer oral
on empty
stomach
• Hepatic
metabolism
primarily via
hydrolysis
• Oral
bioavailability
reduced with
high fat meal
• Half-life: IV:
~75 mins, oral:
1.5 hours
Moderate
to high
(≥140
mg/m2)
IV, wafer
implant, topical
• Hydrolysis,
renal
elimination
Moderate
to high
(>250
mg/m2)
• Achieves high
CNS
concentrations
• Metabolized
hepatically
• Hepatic
metabolism enzymatic
conjugation
with glutathione
• Crosses BBB
and achieves
high CSF
concentrations
• Infuse over a
least 2 hours
• High dose
(>150 mg/m2)
can cause
hypotension,
headache, or
flushing during
infusion due to
ethanol content
• Oral capsules
• Administer on
empty stomach
to reduce N/V
• Only administer
enough
capsules for one
dose
IV, oral tablet
• IV preferred
IV: Over 2-3
hours via a
central line
• Once daily
dosing should
be run over
exactly 3 hours
to get PK labs
• Pulmonary toxicity
• Myelosuppression
(BBW): myeloablation
with high doses (≥ 140
mg/m2)
• GI toxicity: N/V,
diarrhea, mucositis
(DLT in SCT-especially
GI)
• Pulmonary toxicity
• Hepatotoxicity (usually
transient)
No significant
interactions
• Cryotherapy to
prevent mucositis
• Give with
hydration to
prevent
accumulation and
renal precipitation
• Myelosuppression
(BBW)
• Pulmonary toxicity
(BBW) – usually
delayed onset
• Hepatotoxicity
(increases in LFTs)
• Renal toxicity
• Infusion reactions
• Wafer implants:
seizures, meningitis,
intracranial HTN
No significant
interactions
Pulmonary toxicity
risk factors:
• Prior bleomycin,
smoking, chest
radiation,
concomitant
cyclophosphamide
Moderate
to high
• Myelosuppression
(BBW)
• Hepatotoxicity
• Pulmonary toxicity
(may be delayed ≥6
months or longer)
• Renal toxicity
Minor substrate of
CYP2D6
Moderate
• Myelosuppression
(BBW)
• Hepatotoxicity (SOS)
• GI toxicity
• Mucositis
• Pulmonary toxicity
(avg onset 4 years; 4
months-10 years)
• Skin discoloration
• Seizures (Keppra for
prophylaxis
recommended)
• Acetaminophen (hold 72 hours
and at least 24
hours after,
SCCC/UMHC
policy is hold 72
hours pre & post)
• Metronidazole
• Azoles
(voriconazole,
Posaconazole,
itraconazole)
• More effect on
myeloid cells than
lymphoid cells
• PK dosing to a
target AUC based
on TDM
recommended
Low dose: 2 to 6
mg orally daily
Thiotepa
(Tepadina)
HSCT for CNS
malignancy,
leptomeningeal
metastases
(intrathecal)
HSCT:
• 150-250
mg/m2/day for
3 days starting
9 days prior to
transplant
• 50
mg/m2/dose
every 12 hours
for 6 doses
N/A
Oral (HSCT only):
• Multiple tablets
may be placed
into an empty
gelatin capsule
for high doses
IV
• Infusion times
vary by protocol
or dose
Kimberly Middleton, PharmD
PGY2 Oncology Pharmacy Resident
UMHM/SCCC
• Phenytoin
• Extensive
hepatic
metabolism to
the major active
metabolite
TEPA
• Good CSF
penetration
• Excreted via
urine and sweat
Low
• Mucositis
• CNS toxicity
(headache, confusion,
drowsiness,
somnolence,
hallucinations, coma,
seizures)
• Dermatologic: skin
discoloration, pruritus,
blistering,
desquamation, and
peeling
• Myelosuppression
• Hepatic SOS
• Major substrate
of CYP3A4 – avoid
with strong
inhibitors and
inducers
• Inhibits CYP2B6 –
administer
cyclophosphamide
prior to thiotepa
• Myelosuppression
• GI toxicity (N/V,
constipation, diarrhea)
• Hepatotoxicity
(increased LFTs)
• Decreased serum
albumin, magnesium,
sodium, glucose
• Peripheral neuropathy
• Myelosuppression
• Capillary leak
syndrome
• Cardiovascular effects
(including HF)
• Hepatotoxicity
• Rhabdomyolysis
(monitor CPK levels
prior to each dose)
• Minor substrate
of CYP3A4 – avoid
with strong
inhibitors and
inducers
Leptomeningeal:
10 mg
Lurbinectidin
(Zepzelca)
Metastatic SCLC
3.2 mg/m2 once
every 21 days
Toxicities:
• Hepatotoxicity during
treatment (withhold
and resume at the
same dose or reduced
depending on grade
severity)
• Hematologic
IV
• Infuse over 60
minutes
• Metabolized
hepatically by
CYP3A4
• Half-life: 51
hours
Moderate
Trabectidin
(Yondelis)
Soft tissue
sarcoma, ovarian
cancer (platinum
sensitive)
Sarcoma:
• 1.5 mg/m2
once every 3
weeks
Ovarian:
• 1.1 mg/m2
every 3 weeks
Hepatic:
• Reduce dose for
moderate to severe
impairment
IV
• 24-hour
continuous
infusion for soft
tissue sarcoma
• Administer
doxorubicin
liposomal first in
ovarian cancer;
infuse over 3
hours
• Metabolized
hepatically by
CYP3A4
• Half-life: ~175
hours
Moderate
Toxicities:
• Hepatotoxicity,
hematologic, capillary
leak syndrome,
cardiotoxicity, elevated
CPK
• Major CYP3A4
substrate, minor
P-gp substrate –
avoid with strong
CYP3A4 inhibitors
and inducers;
monitor therapy
with moderate
• Excretion in
sweat → skin care
protocol