Page 1003 - Hematology_ Basic Principles and Practice ( PDFDrive )

886 Part VII Hematologic Malignancies

most commonly used in preparatory regimens for bone marrow cancer. In hematologic malignancies, its major indication is in the
transplantation. It is also used in solid tumors and as an immunosup- treatment of refractory lymphomas.
pressant in nonmalignant conditions such as glomerulonephritis and
systemic lupus erythematosus. Melphalan (Melphalan)

Ifosfamide (Ifex) Chemistry: Melphalan is synthesized from nitrogen mustard and
phenylalanine. It is a bifunctional chloroethylating agent that forms
Chemistry: Ifosfamide is an oxazaphosphine nitrogen mustard that DNA cross-links.
differs from cyclophosphamide by the placement of chloroethyl
groups. Absorption, Fate, and Excretion: The oral bioavailability of
melphalan is quite variable, 20%–50% of the drug being excreted in
Absorption, Fate, and Excretion: As in the case of cyclophos- the stool. Some patients show virtually no oral absorption. This fact
phamide, the parent compound is inactive and is metabolized by the is particularly pertinent in the treatment of patients with myeloma,
CYP system in the liver. The metabolism of ifosfamide is influenced in whom a lack of response to melphalan may simply be caused by
by the dose and schedule of administration. When administered as a poor oral absorption. Melphalan has a half-life of approximately
single bolus, 60% is eliminated into the urine, 53% as unchanged 90 minutes. It is extensively metabolized, with only approximately
inactive drug. When administered daily for 5 consecutive days, 56% 10%–15% of an administered dose excreted unchanged in the
is excreted into the urine, 15% as the inactive parent compound. The urine.
half-life is 7 hours when administered daily for 5 consecutive days
and 15 hours when given as a single bolus dose. There is poor penetra- Preparation and Administration: Melphalan is commercially
tion across the blood–brain barrier. Its longer half-life and slower available in 2-mg tablets and in IV formulation for high-dose therapy.
metabolic activation allow higher doses to be given.
Toxic Effects: The dose-limiting toxicity is myelosuppression,
Preparation and Administration: The drug is provided in 1-g manifested by leukopenia and thrombocytopenia, and generally
vials and should be reconstituted in sterile water or bacteriostatic occurring 2–3 weeks after therapy. Recovery may take 6 weeks,
water to a final concentration of 50 mg/mL. Ifosfamide can be however, in patients who have been heavily pretreated with chemo-
diluted further in 5% dextrose, normal saline, or Ringer solution for therapy drugs, radiotherapy, or both. Nausea, vomiting, and alopecia
injection to achieve concentrations of between 0.6 and 20 mg/mL. are uncommon side effects and are usually mild. Occasionally,
The solution should be infused over 30 minutes. To prevent hemor- amenorrhea and azoospermia, pulmonary fibrosis, dermatitis, and
rhagic cystitis, patients must receive Mesna disulfide for protection secondary malignancies (e.g., leukemia) occur, especially in patients
against urotoxicity and must be kept well hydrated (2 L/day). Mesna receiving the drug over the long term. At cumulative doses of less
is a thiol compound that is rapidly oxidized to dimesna in vivo. than 600 mg, the incidence of second hematologic malignancy is
Mesna and dimesna are filtered by the glomeruli, reabsorbed in the probably less than 2% but may be greater than 15% at higher doses.
proximal tubule, and finally secreted back into the tubular lumen of Higher doses used in transplant patients result in gastrointestinal
the kidney. In the tubules, approximately one-third of the filtered toxicity that is dose limiting. At these doses, the syndrome of inap-
dimesna is readily converted back to Mesna. The free sulfhydryl propriate secretion of antidiuretic hormone, pneumonitis, and
group of this compound reacts with the urotoxic metabolite acrolein hepatic venoocclusive disease have been observed.
produced by both ifosfamide and cyclophosphamide (see Fig. 57.7).
This reaction creates a nontoxic acrolein–Mesna thioether that is Potential Drug Interactions: Administration of high-dose IV
safely eliminated in the urine. Mesna has also been shown to inhibit melphalan with cyclosporine increases the risk of cyclosporine
the degradation of ifosfamide or cyclophosphamide to acrolein. nephrotoxicity.
Mesna has been given in combination with ifosfamide in different
doses and schedules. One recommended schedule uses IV bolus Therapeutic Indications: The major use of melphalan is for the
injection in a dosage equal to 20% of the ifosfamide dose (on a treatment of multiple myeloma (MM), either as a single agent or in
milligram-to-milligram basis) at the time of ifosfamide administra- combination with other alkylating agents and prednisone (e.g., the
tion and 4 and 8 hours after each dose of ifosfamide. Mesna has also MP and VMCP regimens). The IV formulation has been approved
been given by continuous infusion with excellent results. The two for isolated limb perfusion in melanoma. It is used in high-dose
2
agents may be mixed together in the same IV solution; however, protocols for myeloma and solid tumors at doses of 140–200 mg/m .
Mesna is not compatible with cisplatin.
Chlorambucil
Toxic Effects: With the use of Mesna to protect against urotoxic-
ity, myelosuppression—especially leukopenia and, to a lesser extent, Chemistry: Chlorambucil is an aromatic derivative of
thrombocytopenia—is the dose-limiting side effect. Renal tubular mechlorethamine.
acidosis can occur. CNS effects, observed in approximately 10% of
patients treated, include somnolence, confusion, depressive psychosis, Absorption, Fate, and Excretion: Chlorambucil is well absorbed
and hallucinations. Less commonly, dizziness, disorientation, and after oral administration. It is extensively metabolized in the liver to
cranial nerve dysfunction occur. Nausea and vomiting are common. its major metabolite, phenylacetic acid mustard (PAAM), which also
Low serum albumin and elevated serum creatinine may enhance CNS has bifunctional alkylating activity. The half-lives of chlorambucil
toxicity. As with cyclophosphamide, such side effects as alopecia, and PAAM are 1.5 and 2.5 hours, respectively; less than 1% of either
leukemogenesis, and infertility also occur. Cardiac toxicity is rare. chlorambucil or PAAM is excreted in the urine.

Potential Drug Interactions: Because ifosfamide is also metabo- Preparation and Administration: Chlorambucil is commercially
lized by the P450 system, physicians should remain alert for the same available as 2-mg tablets.
type of potential drug interactions that have been reported with
cyclophosphamide. A recent report advises close monitoring of Toxic Effects: Treatment is usually well tolerated, with myelosup-
warfarin anticoagulant control in patients receiving ifosfamide/ pression the dose-limiting toxic effect. Patients on a daily oral
Mesna. schedule should have biweekly complete blood counts. Nausea and
vomiting are uncommon, but mild alopecia and skin rashes occasion-
Therapeutic Indications in Hematology: Ifosfamide was ally occur. As with the other alkylating agents, azoospermia (especially
recently approved for treatment of patients with refractory testicular above a cumulative dose of 400 mg), amenorrhea, and secondary