DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1748 from the site targeted by rituximab. Binding of the drug
results in B-cell lysis (both CDC and ADCC).
Ofatumumab is approved for treating patients with CLL
after failure of fludarabine and alemtuzumab.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
A complex dosing scheme is used, beginning with small (300
mg) doses on day 1, followed by higher doses (up to 2 g/week) for
7 weeks, followed by 2 g every 4 weeks for four additional doses.
Slow rates of infusion are recommended for the initial dose and for
the first 2 hours of subsequent infusions.
Ofatumumab’s primary toxicities consist of immunosuppression
and opportunistic infection, hypersensitivity reactions during antibody
infusion, and myelosuppression, which may be prolonged. Blood
counts should be monitored during treatment. Rarely, patients may
develop reactivation of viral infections, leading to progressive multifocal
leukoencephalopathy or hepatitis B progression. The drug should
not be administered to patients with active hepatitis B infection; liver
function should be monitored closely in hepatitis B carriers.
Alemtuzumab. Alemtuzumab (CAMPATH) is a humanized
IgG-κ monoclonal antibody, composed of a rat
antigen–binding region within human constant regions
and variable framework. The drug binds to CD52 antigen
present on the surface of a subset of normal neutrophils
and on all B and T lymphocytes, on testicular
elements and sperm, and on most B- and T-cell lymphomas
(Kumar et al., 2003). Consistently high levels
of CD52 expression on lymphoid tumor cells and the
lack of CD52 modulation with antibody binding make
this antigen a favorable target for unconjugated monoclonal
antibodies. Alemtuzumab can induce tumor cell
death through ADCC and CDC.
Pharmacokinetics and Dosing. Alemtuzumab is administered intravenously
in dosages of 30 mg/day three times per week.
Premedication with diphenhydramine (50 mg) and acetaminophen
(650 mg) should precede drug infusion. Because of hypersensitivity,
dosing begins with a 3-mg infusion, followed by a 10-mg dose 2 days
later and, if well tolerated, a 30-mg dose 2 days later. The drug has
an initial mean t 1/2
of 1 hour, but after multiple doses, the t 1/2
extends
to 12 days, and steady-state plasma levels are reached at approximately
week 6 of treatment, presumably through saturation of CD52-
binding sites. Clinical activity has been demonstrated in both B- and
T-cell low-grade lymphomas and CLL, including patients with disease
refractory to purine analogs (Hillmen et al., 2007). In
chemotherapy-refractory CLL, overall response rates are ~40%, with
complete responses of 6% in multiple series. Response rates in
patients with untreated CLL are higher (overall response rates of
83% and complete responses of 24%).
Toxicity. The most concerning toxicities include acute infusion reactions
and depletion of normal neutrophils and T cells (Table 62–2).
Serious myelosuppression, with depletion of all blood lineages,
occurs in the majority of patients and may represent either direct
marrow toxicity or auto-immune responses. Immunosuppression by
the antibody leads to a significant risk of fungal, viral, and other
opportunistic infections (Listeria), particularly in patients who have
previously received purine analogs (Keating et al., 2002; Hillmen
et al., 2007). Patients should receive antibiotic prophylaxis against
Pneumocystis carinii and herpes virus during treatment and for at
least 2 months following therapy with alemtuzumab. Because reactivation
of cytomegalovirus (CMV) infections may follow antibody
use, patients should be monitored for symptoms and signs of
viremia, hepatitis, and pneumonia. CD4 + T-cell counts may remain
profoundly depleted (<200 cells/μL) for 1 year. Alemtuzumab does
not combine well with chemotherapy in standard regimens because
of significant infectious complications (Gallamini et al., 2007).
Monoclonal Antibody–Cytotoxic
Conjugates
Gemtuzumab Ozogamicin. Gemtuzumab ozogamicin
(MYLOTARG) consists of a humanized monoclonal antibody
against CD33 covalently linked to a semisynthetic
derivative of calicheamicin, a potent enediyne antitumor
antibiotic (Bernstein, 2000). The CD33 antigen is
present on most hematopoietic cells, on >80% of
AMLs, and on most myeloid cells in patients with
myelodysplasias. However, other normal cell types lack
CD33 expression, making this antigen attractive for targeted
therapy. CD33 has no known biological function,
although monoclonal antibody cross-linking inhibits
normal and myeloid leukemia cell proliferation.
Following its binding to CD33, gemtuzumab ozogamicin
undergoes endocytosis, and cleavage of calicheamicin
from the antibody takes place within the lysosome.
The potent toxin then enters the nucleus, binds in the
minor groove of DNA, and causes double-strand DNA
breaks and cell death (Zein et al., 1988).
Clinical Pharmacology. The antibody conjugate produces a 30%
complete response rate in relapsed AML, when administered at a
dose of 9 mg/m 2 for up to 3 doses at 2-week intervals (Sievers et al.,
2001). Pharmacokinetics of gemtuzumab ozogamicin at the standard
9-mg/m 2 dose are described by a t 1/2
of total and unconjugated
calicheamicin of 41 and 143 hours, respectively (Dowell et al.,
2001). Following a second dose, the t 1/2
of drug-antibody conjugate
increases to 64 hours and the AUC increases to twice that of the initial
dose. Most patients require two to three doses to achieve remission.
The drug currently is approved in patients >60 years of age
with AML in first relapse.
The primary toxicities of gemtuzumab ozogamicin include
myelosuppression in all patients treated and hepatocellular damage
in 30-40% of patients, manifested by hyperbilirubinemia and
enzyme elevations. It also causes a syndrome that resembles hepatic
veno-occlusive disease (tender, enlarged liver and rising serum
bilirubin) when patients subsequently undergo myeloablative therapy
or when gemtuzumab ozogamicin follows high-dose chemotherapy
(Wadleigh et al., 2003). This syndrome reflects injury to hepatic
sinusoids rather than venules. Defibrotide, an orphan drug, may prevent
severe or fatal hepatic injury in patients who develop signs of
hepatic failure while receiving a stem cell transplant following gemtuzumab
ozogamicin (Versluys et al., 2004). Prolonged myelosuppression,
particularly delayed recovery of platelet counts, may