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344 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 345

reagents. Presently, several monoclonal antibodies have received FDA minutes to a maximum rate of 400 mg/h. On subsequent infusion in the
approval for non-Hodgkin lymphoma and CLL, including rituximab absence of reactions, infusions may start at 100 mg/h and increased in
and alemtuzumab. Although several mechanism(s) of action have been 100 mg/h increments every 30 minutes to a maximum rate of 400 mg/h.
described for monoclonal antibodies, including direct induction of Patients with a high degree of circulating tumor cells are at increased
apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and com- risk for tumor lysis syndrome and are given a reduced dose of 50 mg/m
2
plement-dependent cytotoxicity, the clinically important mechanisms on day 1 of treatment in addition to standard tumor lysis prophylaxis.
for most antibodies remain uncertain. 304 The remainder of the dose can then be given on day 3.
Monoclonal antibodies may also be engineered to combine the Resistance to rituximab may occur by down regulation of CD20,
antibody with a toxin (immunotoxin) or a radioactive isotope (radioim- impaired ADCC, decreased complement activation, limited effects on
munoconjugates), or to contain a second specificity (bispecific anti- signaling and induction of apoptosis, and inadequate blood levels. 304,320
bodies). 305–307 For example, it is possible to conjugate an antibody with Studies in relapsed indolent B-cell non-Hodgkin lymphoma have shown
specificity to B-cell lymphomas with an antibody against CD3, which a correlation between higher mean serum rituximab levels and clinical
321
binds to and activates normal T cells, so as to enhance T-cell–mediated responses, suggesting that dose escalation may be a way to overcome
lysis of the lymphoma cell. One such example of a bispecific antibody rituximab resistance. Also polymorphisms in two of the receptors for
blinatumomab contains anti-CD3 and anti-CD19 specificity. Monoclo- the antibody Fc region responsible for complement activation, FcγRIIIa,
nal antibodies raised against the immunoglobulin idiotype on a B-cell and FcγRIIa may predict the clinical response to rituximab monother-
lymphoma represent another therapeutic strategy, which was first apy in patients with follicular lymphoma but not in CLL. 322,323
reported in 1982 by Miller and associates. 308 Rituximab has a several known toxicities including infusional reac-
tions which can be life-threatening. Most are usually mild and include
fever, chills, throat itching, urticaria, and mild hypotension, all of which
NAKED MONOCLONAL ANTIBODIES can respond to decreased infusion rates and antihistamines. There are
Rituximab reports of severe mucocutaneous skin reactions including Stevens-
324
Rituximab, the first monoclonal to receive FDA approval, is a chime- Johnson syndrome. Reactivation of hepatitis B virus also has been
ric antibody containing the human immunoglobulin G and κ constant reported and it is recommended that patients be screened for hepatitis
1
regions with murine variable regions. Rituximab targets the B-cell anti- B prior to initiation of therapy. There also are case reports of progres-
gen CD20 expressed on the surface of normal B cells and on more than sive multifocal leukoencephalopathy caused by the John Cunningham
325
90 percent of B-cell neoplasms, and is present from the pre–B-cell stage virus and resulting in death. Hypogammaglobulinemia and delayed
through terminal differentiation to plasma cells. To date, the biologic neutropenia may occur from 1 to 5 months after administration with
309
functions of CD20 remain uncertain, although incubation of B cells resultant serious infections. 326,327
with anti-CD20 antibody has variable effects on cell-cycle progression,
depending on the monoclonal antibody type. 310,311 Monoclonal antibody Ofatumumab
binding to CD20 generates transmembrane signals that produce a num- Ofatumumab is a fully human immunoglobulin G kappa (IgG κ),
1
1
ber of events including autophosphorylation and activation of serine/ monoclonal antibody which targets a unique epitope on the CD20 anti-
tyrosine protein kinases, and induction of c-myc oncogene expression gen found on the surface of normal and malignant pre-B and mature
and major histocompatibility complex class II molecules. CD20 pro- B cells. Ofatumumab offers many potential advantages over rituximab.
312
328
motes transmembrane Ca conductance through its possible function It has an increased affinity for CD20 compared to rituximab. In vitro
2+
as a Ca channel. These studies demonstrate the importance of CD20 experiments have shown it is superior to rituximab in ability to induce
312
2+
328
in B-cell regulation, but do not in themselves indicate how ligation of cell lysis. Ofatumumab and rituximab both show similar antibody-de-
the receptor produces cell death independent of ADCC or complement- pendent cellular cytotoxicity, but ofatumumab displays increased com-
329
mediated pathways. plement dependent cytotoxicity. In addition, ofatumumab is a fully
Rituximab was initially approved as a single agent for relapsed human monoclonal antibody with a low incidence of human–antihu-
indolent lymphomas, but it has shown activity in a wide variety of clin- man antibody formation. 330
ical settings. It is approved in combination with chemotherapy for the Ofatumumab has been approved for use in patients with CLL
initial treatment of follicular and diffuse large B cell lymphoma. 313,314 refractory to fludarabine and alemtuzumab. In a phase II trial, 138
Rituximab has also been shown to be effective in combination with patients received eight weekly infusions of ofatumumab followed by
chemotherapy for CLL and indolent B-cell non-Hodgkin lymphomas four monthly infusions during a 24-week period (dose 1 = 300 mg;
including mantle cell lymphoma, Waldenström macroglobulinemia, doses 2 to 12 = 2000 mg). The overall response rate was 58 percent with
331
and marginal lymphomas. It is used in combination with salvage che- median progression-free survival of approximately 14 months. No
313
motherapy for many indolent and aggressive B-cell non-Hodgkin lym- dose-limiting effects were observed in the phases I/II studies of ofatu-
phomas even after prior rituximab treatment. The use of maintenance mumab. Most common adverse reactions (>10 percent) were infusion
315
rituximab has gained increased acceptance based the demonstration of reactions, neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia,
delayed time to progression and improved overall survival in the relapse fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract
setting. 316–318 infections. Similar to rituximab above, ofatumumab is being investi-
Rituximab is given by intravenous infusion both as a single agent gated in combination with chemotherapy for both indolent and aggres-
and in combination with chemotherapy at a dose of 375 mg/m . As a sive B cell non-Hodgkin lymphoma.
2
single agent it is given weekly for 4 weeks with maintenance dosing
every 3 to 6 months. It has a half-life of approximately 22 days. Given Obinutuzumab
319
the risk of infusional reactions, pretreatment with antihistamines, acet- Obinutuzumab is a third naked monoclonal antibody that targets the
aminophen, and glucocorticoids have become standard. During the first CD20 antigen. It differs from rituximab in that it is a glycoengineered
administration, the rate must be increased slowly to prevent infusional type 2 antibody that, in preclinical studies, showed improved efficacy
reactions. Infusions are started at 50 mg/h and in the absence of infu- by inducing direct cell death and by enhanced ADCC. Obinutu-
332
sion reactions the rate can be increased in 50 mg/h increments every 30 zumab was recently approved in combination with chlorambucil of

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