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342 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 343

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(including nuclear factor [NF]-κB, caspase inhibitors, and Bcl-2 fam- load”), such as immunoglobulins. It is not yet determined, if this con-
ily members). 284–287 The composite outcome of these events is an irre- cept also applies to mantle cell lymphoma.
285
versible commitment of myeloma cells to apoptosis, as well as the The safety profile of both bortezomib and carfilzomib includes
sensitization of myeloma cells to diverse established agents (e.g., alky- thrombocytopenia, possibly reflecting a requirement for constitutive
lator, 287,288 anthracyclines, 287,289 and thalidomide derivatives) or inves- proteasome activity in platelets to degrade the apoptosis regulator,
287
298
tigational agents such as HDAC inhibitors . As a result, bortezomib Bax, and preserve their normal life span. Unlike bortezomib, carfil-
has been a key component of diverse antimyeloma combination regi- zomib does not cause peripheral neuropathy, but cardiopulmonary side
mens. However, patients eventually develop resistance to bortezomib effects (e.g., dyspnea, hypoxemia, pulmonary hypertension) and serum
290
292
or experience sensory peripheral neuropathy, the main dose-limiting creatinine elevations have been reported. These differences may be
291
toxicity for this drug. Carfilzomib and other second-generation protea- explained by reports that bortezomib, but not carfilzomib, also inhibits
some inhibitors were thus developed to circumvent these limitations. In the neuroprotective molecule, Htra2/Omi, and blocks a number of
299
2012, carfilzomib received FDA accelerated approval for the treatment serum proteases, including cathepsin G and cathepsin A, which may
of myeloma patients relapsed and refractory to bortezomib and at least contribute to renal injury. 300–302 ; inhibition of proteases may contribute
one thalidomide derivative. The observation that carfilzomib can be to renal injury. The mechanistic basis for cardiopulmonary adverse
292
303
active in some bortezomib-refractory cases has been attributed to the events with proteasome inhibition remains under investigation.
fact that new proteasomes must be synthesized to fully restore protea- The clinical activity of bortezomib and carfilzomib, as well as the
some capacity in cells treated with this irreversible inhibitor. However, promising early studies with additional second-generation proteasome
the reversible-versus-irreversible nature of a proteasome inhibitor may inhibitors, has validated the notion that pathways for intracellular regu-
not be the only determinant of its clinical activity; for example, another lation of protein homeostasis represent an important therapeutic target
second-generation proteasome inhibitor in clinical trials, MLN2238, for plasma cell dyscrasias, mantle cell lymphoma, and potentially other
and its clinically administered prodrug, ixazomib (MLN9708), exhibit neoplasias.
293
preclinical and clinical activity in bortezomib-resistant cells, despite
reversible binding to β5. 294
Despite the important role of the proteasome for normal cells, THERAPEUTIC MONOCLONAL
the administration of bortezomib and carfilzomib is associated with a ANTIBODIES
clinically meaningful therapeutic window, likely because the clinically
achievable levels of these agents do not completely shut down the chy- Monoclonal antibodies are an important class of agents for the treat-
motrypsin-like activity of the proteasome and also spare its other ment of hematologic malignancies. As a group, lymphoid cells express a
295
296
proteolytic (trypsin-like and caspase-like) activities. Consequently, variety of antigens that are attractive targets for monoclonal-based ther-
there is only modest (<40 percent) decrease in the overall rate of protein apy, as shown in Table 22–6. Development of monoclonal antibodies
degradation in either normal or tumor cells. Although normal cells can against specific targets has been largely accomplished by the empiric
recover from this degree of perturbation, malignant plasma cells may method of immunizing mice against human tumor cells and screening
not, because their available active proteasome particles (“proteasome the hybridomas for antibodies of interest. Because murine antibodies
capacity”) are apparently close to their functional saturation by the have a short half-life and induce a human antimouse antibody immune
increased quantities of unassembled or misfolded proteins (“proteasome response, they are partially or fully humanized when used as therapeutic

TABLE 22–6. Dose and Toxicity of FDA-Approved Monoclonal Antibody-Based Drugs
Drug Mechanism Dose and Schedule Major Toxicity
Rituximab Antibody-dependent cytotox- 375 mg/m infusion weekly × 4 as single agent, Infusion related; late-onset
2
icity, complement activation, 375 mg/m infusion in combination with neutropenia
2
induction of apoptosis chemotherapy
Ofatumumab Antibody-dependent cellular 8 weekly followed by 4 monthly infusions during a Infusion related; late-onset
cytotoxicity, complement- 24-week period (dose 1 = 300 mg; doses 2 to neutropenia
dependent cytotoxicity 12 = 2000 mg
Obinutuzumab Direct cell death and anti- 100 mg infusion on cycle 1 day 1, 900 mg on Infusion reactions,
body-dependent cellular day 2; 1000 mg on days 8 and 15 of cycle 1 and neutropenia
cytotoxicity subsequently 1000 mg on day 1 of cycles
2 through 6 in combination with chlorambucil
Alemtuzumab Complement activation, Escalation 3, 10, 30 mg infusion TIW followed by Infusion-related toxicity with
antibody-dependent 30 mg TIW for 4 to 12 weeks fever, rash, and dyspnea; T-cell
cytotoxicity, possible depletion with increased
induction of apoptosis infections
Brentuximab Antibody drug conjugate 1.8 mg/kg infusion every 3 weeks Peripheral neuropathy,
vedotin comprising an anti-CD 30 neutropenia
monoclonal antibody linked to
mono-methylauristatin E
90 Y-ibritumomab Targeted radiotherapy 0.4 mCi/kg infusion Hematologic toxicity,
tiuxetan myelodysplasia

Kaushansky_chapter 22_p0313-0352.indd 343 9/18/15 10:26 PM