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1534 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1535

Similarly, other combinations of alkylating agents with nucleoside antiviral and antimicrobial prophylaxis therapy should be initiated in
agents have been tested with varying success. These include cladribine all patients receiving alemtuzumab and should be continued for at least
and prednisone, which combination was shown to be better than chlo- 6 months after completing therapy.
rambucil and prednisone in terms of responses, but without improve- A subsequent large phase III (CAM307) clinical trial was per-
ments in OS and with a higher incidence of infectious complications formed that compared alemtuzumab to chlorambucil as first-line
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in the cladribine-treated arm. 198,199 Similarly, the addition of cyclophos- therapy. Two hundred ninety-seven patients were randomized to
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phamide and prednisone to cladribine resulted in higher responses but chlorambucil 40 mg/m every 4 weeks for 12 cycles or alemtuzumab
more myelosuppression and related complications. 200–202 Pentostatin was 30 mg intravenous infusion three times per week for 12 weeks. Overall
also combined with cyclophosphamide and resulted in ORR of 74 per- response with alemtuzumab was 83 percent, with 24 percent CRs and
cent and CR rates of 17 percent in patients with fludarabine refractory with time to next treatment of 23 months. This was significantly bet-
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disease. Pentostatin in combination with chlorambucil and predni- ter than the results observed with chlorambucil, which resulted in an
sone also resulted in promising responses but was extremely immuno- ORR of 55 percent with 2 percent CRs and time to next treatment of
suppressive and resulted in an unacceptably high incidence of infectious 14 months. Moreover, approximately one-third of patients treated with
complications. 204 alemtuzumab achieved a minimal residual disease (MRD)-negative
Fludarabine was also combined with mitoxantrone without sig- CR that was later shown to correlate with OS. Both agents were well-
nificant improvements in outcome. Although mitoxantrone appeared tolerated but alemtuzumab resulted in a higher incidence of CMV
to improve outcomes when added to cladribine, it came at the cost infections. This trial resulted in the approval of alemtuzumab as initial
of significant toxicity. 205,206 Likewise, the combination of fludarabine, therapy for CLL in 2007.
cyclophosphamide, and mitoxantrone resulted in an ORR of 78 percent Infusion reactions and infectious complications are the major
and CR rates of 50 percent in patients with relapsed disease and an ORR issues observed with the use of alemtuzumab. Infusion reactions can
of 90 percent with a CR rate of 38 percent in patients with previously be diminished with a subcutaneous administration which appears to
untreated disease. The major toxicity was myelosuppression. 206,207 be equally efficacious but with similar toxicity profiles. 214,215 Despite the
encouraging results and approvals by the FDA, alemtuzumab never
gained mass popularity and was not used by practicing physicians very
ANTIBODY THERAPY often. It is no longer being marketed by the company for CLL but (as
The advent of antibodies for the treatment of patients with CLL has of 2015) can be obtained upon written request at no cost. The limited
been a major advance in the management of this disease with the first future prospects of alemtuzumab precludes exhaustive discussion.
true consistent evidence of improving survival. Numerous antibodies Alemtuzumab has been studied in combination with chemotherapy
targeting different receptors have been developed and are at various and as consolidative therapy after chemotherapy and has shown some
stages of development. Four antibodies are currently approved for rou- benefit, but is generally associated with significant serious infectious
tine management. Unfortunately, one of these (alemtuzumab) is no lon- morbidity. 216–219
ger actively marketed for this indication.
CD20 Targeting Antibodies
Alemtuzumab Rituximab Rituximab is a chimeric, murine, CD20-targeting, mono-
Alemtuzumab is a CD52-targeting, humanized, monoclonal antibody clonal antibody that has been extensively used for the treatment of
that mediates its efficacy through direct cytotoxicity, complement- patients with CD20+ lymphoid malignancies. CD20 is a calcium chan-
dependent cytotoxicity (CDC) and antibody-dependent cell-mediated nel that interacts with BCR complex and is ubiquitously expressed on
cytotoxicity (ADCC). CD52 is ubiquitously expressed on lymphocytes B-cell non-Hodgkin lymphomas and has a weak expression on CLL
(including B and T cells) and monocytes and this explains the efficacy cells. Rituximab exerts its efficacy through direct CDC and ADCC. 220–222
and toxicity of the antibody. Alemtuzumab is extremely effective in The dose and schedule of treatment with rituximab was deter-
clearing the blood and marrow of disease and is also active in patients mined empirically and has since been modified repeatedly. Initial trials
with del 17p disease which is generally refractory to conventional che- were performed with four weekly infusions at 375 mg/m and showed
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motherapy. However, alemtuzumab has limited efficacy in patients limited efficacy in patients with CLL. 223,224 Responses were higher when
208
with bulky lymphadenopathy, especially in patients with lymph nodes higher doses (up to 2250 mg/m ) or dose-dense regimens (375 mg/m
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that are greater than 5 cm in diameter. 209–211 Alemtuzumab was ini- three times a week) were used but was primarily limited to the blood
tially approved in 2001 by the FDA for the treatment of patients who and nodal areas. 225,226 Nonetheless, these studies established the efficacy
had failed prior therapy with nucleoside analogues. This was primar- of rituximab and supported combination trials with chemoimmuno-
ily based on small trials that administered alemtuzumab intravenously therapy where their impact has been most impactful.
three times a week for 12 weeks and showed modest response rates Rituximab is generally tolerated very well with the most common
of approximately 30 to 40 percent and CRs in less than 5 percent of toxicity being infusion reactions that are predominantly observed pri-
patients. 209–211 Responses were short-lived in this cohort of patients and marily with the first dose. These are generally mild fevers or chills, but
the median response duration was approximately 9 months. Treatment occasionally may result in serious reactions that mimic severe allergic or
was also complicated by infusion-related toxicities in the vast majority anaphylactic reactions or cytokine release syndrome. The infusion reac-
of patients. To minimize these reactions, alemtuzumab is started at a tions can be minimized with the routine use of prophylactic acetamino-
dose of 3 mg and escalated to 10 mg for the second dose and 30 mg phen, antihistamine, and corticosteroids, glucocorticoid, and by slowing
for the third dose, as tolerated. Another major toxicity was immuno- the infusion rate. Patients may also experience transient, severe throm-
suppression that resulted in multiple recurrent infections especially bocytopenia, the mechanism of which is poorly understood. Therefore,
with opportunistic organisms that are commonly seen in patients with rituximab should be used with caution in patients with a preexisting
chronic immunocompromised states like HIV/AIDS such as CMV, thrombocytopenia. Another important and potentially severe toxicity is
pneumocystis, or varicella zoster. 209–211 Patients also experienced pro- tumor lysis syndrome, which is generally observed in patients with a high
longed cytopenias, especially of natural killer (NK) and T cells, which circulating peripheral lymphocyte count. These patients should be mon-
can persist for more than 9 months following therapy. Consequently, itored closely and should receive prophylactic hydration, allopurinol,
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