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

the treatment of patients with previously untreated CLL. This approval have received purine analogues. 336,337 Patients should receive antibiotic
was based on a phase III, 781-person trial with three arms comparing prophylaxis against Pneumocystis carinii and herpes virus during treat-
single-agent chlorambucil versus chlorambucil plus rituximab versus ment. Serious infections with cytomegalovirus are seen and monitoring
chlorambucil plus obinutuzumab. A main feature of this trial was is recommended. Alemtuzumab in combination with chemotherapy
333
that it enrolled mainly older patients (median age: 73 years) with mul- has been explored in the treatment of T-cell lymphomas but trials were
tiple medical comorbidities representative of the majority of patients limited by significant infectious complications. 338
diagnosed with CLL. The median progression-free survival was greatly
improved in obinutuzumab plus chlorambucil arm at 26.7 months ver- Elotuzumab, Daratumumab, and Others
sus 11.1 months with chlorambucil alone and 16.3 months with rituxi- A number of naked antibodies have been developed for the therapeutic
mab plus chlorambucil. Obinutuzumab is similar to other monoclonal targeting of myeloma. Mechanistically, this approach depends on the
antibodies associated with infusion reactions. The first dose was split recruitment of ADCC, complement-dependent cytotoxicity, and apopto-
over 2 days with the patient receiving 100 mg intravenously on cycle sis, as well as growth arrest via the selected targeting of signaling path-
1 day 1 and 900 mg on day 2. Patients then received 1000 mg on days ways (Fig. 22–9). Targets include surface molecules as well as signaling
339
8 and 15 of cycle 1 and subsequently 1000 mg on days 1 of cycles 2 molecules (Table 22–7). Of these antibodies, one of the most promising
339
through 6. Patients concurrently received chlorambucil orally at a dose is elotuzumab, which specifically targets CS1 (also known as SLAMF7)
of 0.5 mg/kg on days 1 and 15 of each cycle. This combination was, through which its mechanism of action includes the enhancement of NK-
in general, well tolerated. There was a slightly increased risk of grade cell activation directly via SLAMF7 and indirectly by CD16, as well as
3 neutropenia (33 vs. 28 percent) compared to the rituximab control the targeted killing of SLAMF7-expressing myeloma cells by ADCC. 340, 341
group, but no increased risk of infection (12 vs. 14 percent). Other com- Combinatorial strategies for this particular approach have been especially
mon toxicities included infusion reactions, anemia, thrombocytopenia, promising, including regimens with lenalidomide and dexamethasone
and leukopenia. where high qualities of response and impressive progression-free survival
have been seen. 341
Alemtuzumab Separately, daratumumab as a first-in-class monoclonal anti-
Alemtuzumab is a humanized monoclonal antibody targeted against body that effectively targets CD38 has shown particularly encouraging
the CD52 antigen present on the surface of normal neutrophils and activity as both a monotherapy and in combination. Similarly, the
342
lymphocytes as well as most B- and T-cell lymphomas. CD52 is CD38-targeting monoclonal antibody SAR650984 has shown impres-
334
expressed at reasonable levels and does not modulate with antibody sive activity, validating this as an appropriate target as well as further
binding, making it a good target for unconjugated monoclonal antibod- supporting the therapeutic potential of this class of antibodies. 339,340
ies. Mechanistically, alemtuzumab can induce tumor cell death through Combination studies are ongoing and the outlook for the rational devel-
ADCC and complement dependent cytotoxicity. Clinical activity opment of several monoclonal antibody combinations in myeloma now
335
has been demonstrated in CLL, including in patients with purine ana- looks very promising. 341,342
logue refractory disease. 336,337 In refractory CLL, overall response rates
are approximately 38 percent with complete responses of 6 percent
in multiple series. Response rates in patients with untreated CLL are IMMUNOTOXINS
higher (overall response rates of 83 percent and complete responses Immunotoxins combine immune proteins such as antibodies, anti-
336
of 24 percent). The most concerning side effects are acute infusion body Fab fragments, or interleukins and toxins such as ricin A chain or
reactions and depletion of normal neutrophils and T cells. Opportu- Pseudomonas exotoxin. These molecules have the advantage of the high
nistic infections are a serious consequence, particularly in patients who specificity of the protein for its receptor or antigen, and its ability to

Figure 22–9. Monoclonal-based therapeutic
MAb-Based Therapeutic Targeting of Myeloma targeting of myeloma. MAb, monoclonal antibody.
(Adapted with permission from Tai YT, Anderson KC:
Apoptosis/growth Antibody-based therapies in multiple myeloma, Bone
Antibody-dependent arrest Marrow Res 2011.)
cellular cytotoxicity Complement-dependent via targeting
(ADCC) cytotoxicity (CDC) signaling pathways

C1q
Effector cells: CDC C1q
MM
MM
ADCC FcR
• huN901-DM1 (CD56)
• Daratumumab • nBT062-maytansionoid
• SAR650984 (CD138)
(CD38) • Siltuximab (1339) (IL-6)
MM
• BHQ880 (DKK1)
• RAP-011 (activin A)
• Lucatumumab or Dacetuzumab (CD40) • Daratumumab, SAR650984
• Elotuzumab (CS1; SLAMF7) (CD38)
• Daratumumab, SAR650984 (CD38)

• XmAb 5592 (HM1.24)

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