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346 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 347

TABLE 22–7. Monoclonal Antibodies in Myeloma impressive overall response rate of 75 percent and a complete remission
rate of 34 percent with 96 percent of patients having some improvement
Target mAb Stage of Development in their disease. The median progression-free survival for all patients
346
Surface molecules was 5.6 months but notably the median duration of response for those
CS1/SLAMF7 Elotuzumab Phase 2/3 achieving a complete remission was 20.5 months. In refractory anaplas-
CD38 Daratumumab Phase 1/2/3 tic large cell lymphoma, a similarly impressive overall response rate of
SAR650984 Phase 1/2 86 percent was seen with 57 percent of patients achieving a complete
remission and 97 percent of patients having a reduction in tumor vol-
MOR202 Phase 1/2 ume. The overall duration of response was 12.6 months and those in a
307
CD74 Milatuzumab Phase 1/2 complete remission experiencing a duration of response of 13.2 months.
CD40 Dacetuzumab Phase 1 Dosing is at 1.8 mg/kg as an intravenous infusion every 3 weeks. Dose
CD56 Lorvotuzumab Phase 1 reductions to 1.2 mg/kg are recommended for patients with hepatic or
mertansine severe renal impairment. The main toxicity is cumulative peripheral
CD138 BT062 Phase 1 neuropathy reported in up to 54 percent of the patients in the above
trials. Patients experiencing new or worsening peripheral neuropathy
Signaling molecules may require a delay, dose reduction, or discontinuation of brentuximab
IL-6 Siltuximab Phase 3 vedotin. Other common toxicities include neutropenia, thrombocy-
RANKL Denosumab Phase 3 topenia, fatigue, and nausea.
B cell activating Tabalumab Phase 2/3
factor (BAFF)
VEGF Bevacizumab Phase 2 RADIOIMMUNOCONJUGATES
DKK1 BHQ880 Phase 2 Radioimmunoconjugates provide monoclonal antibody targeted deliv-
ery of radioactive particles to tumor cells. 306,347 Iodine-131 is a commonly
Data from Richardson et al. et al. IMW 2013 (Abstract P-214), poster used radioisotope because it is readily available, relatively inexpensive,
presentation. and easily conjugated to a monoclonal antibody. The β-emitter Y has
90
Plesner et al. ASH 2013 (Abstract 1987), poster presentation. emerged as an attractive alternative to I, based on its higher energy
131
Martin et al. ASH 2013 (Abstract 284), oral presentation. and longer path length, which may be more effective in tumors with
http://www.clinicaltrials.gov/ct2/show/NCT00421525 larger diameters. It also has a short half-life and remains conjugated,
http://www.clinicaltrials.gov/ct2/show/NCT00079716 even after endocytosis, providing a safer profile for outpatient use. Clin-
http://www.clinicaltrials.gov/ct2/show/NCT00346255 ically, radioimmunoconjugates were developed with murine monoclo-
nal antibodies against CD20 conjugated with I (tositumomab) or Y
131
90
http://www.clinicaltrials.gov/ct2/show/NCT01001442 (ibritumomab tiuxetan). Response rates in relapsed lymphoma of 65 to
Wong et al. ASH 2013 (Abstract 505), oral presentation. 80 percent were achieved. 306,347,348 Both drugs were well tolerated with
Hageman et al. Ann Pharmacother 2013;47:1069-74. most toxicity attributable to marrow suppression; however, there have
been worrisome reports of secondary leukemias. Collaboration between
treating physicians and nuclear medicine departments is required for
administration. I tositumomab is no longer available, but Y ibritu-
131
90
internalize once bound to its receptor, together with the potency of the momab tiuxetan remains in clinical use and is being investigated as a
toxin molecule. Two agents, denileukin diftitox (which combines IL-2 consolidation therapy and as conditioning prior to hematopoietic cell
and the catalytically active fragment of diphtheria toxin) with activity transplant.
in non-Hodgkin lymphoma and gemtuzumab ozogamicin (composed
of an antibody that recognizes CD33 linked to a potent chemical toxin,
calicheamicin) with activity in AML, show a proof of principle but have REFERENCES
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