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Chapter 77 Chronic Lymphocytic Leukemia 1253

TABLE Modified Indications for Treatment of Chronic the novel type II monoclonal anti-CD20 antibody obinutuzumab.
77.5 Lymphocytic Leukemia (Both obinutuzumab and ofatumumab are discussed later in this
chapter.)
• Grade 2 or greater fatigue limiting life activities
• B symptoms persisting for ≥2 weeks
• Lymph nodes >10 cm or progressively enlarging lymph nodes Bendamustine
causing symptoms
• Spleen or liver with progressive enlargement or causing symptoms Although typically classified as a bifunctional alkylator, bendamustine
• Anemia (hemoglobin <11 g/dL) referable to CLL has an uncertain mechanism of action. Although the drug predomi-
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• Thrombocytopenia (platelets <100 × 10 /L) referable to CLL or ITP nantly promotes cytotoxicity by inducing DNA damage and the
poorly responsive to traditional therapy generation of reactive oxygen species, bendamustine displays a distinct
• Severe paraneoplastic (e.g., insect hypersensitivity, vasculitis, pattern of activity unrelated to other DNA-alkylating agents but
myositis) process related to CLL not responsive to traditional closest to melphalan. Unlike other alkylating agents, bendamustine
therapies activates a base excision DNA repair pathway rather than an alkyl-
CLL, chronic lymphocytic leukemia; ITP, idiopathic thrombocytopenic purpura. transferase DNA repair mechanism. Studies of bendamustine in a
variety of solid tumors, non-Hodgkin lymphoma (NHL), multiple
myeloma, Hodgkin disease, and CLL have shown single agent activ-
selecting the initial treatment for CLL. In addition, several studies ity. Bendamustine has been widely used in East Germany and several
have shown that CLL patients older than 70 years of age or who have European countries for decades and was approved by the U.S. Food
multiple comorbid illnesses do not benefit from fludarabine- and Drug Administration (FDA) for treatment of CLL in 2008. This
containing regimens, which should be factored into treatment algo- was based on a well-controlled, randomized phase III study compar-
2
rithms. Below, we summarize the findings of clinical studies of ing bendamustine 100 mg/m intravenous (IV) on days 1 and 2 with
different treatments for CLL; where such data exist, we integrate chlorambucil 0.8 mg/kg PO on days 1 and 15 every 4 weeks for six
genomic biomarkers as well as clinical features, including age and cycles. A total of 319 patients were enrolled with an overall response
comorbid illnesses. Different therapies are outlined below with atten- rate (ORR) of 68% and 31% CR with bendamustine versus 31%
tion to details related to their initial use in previously untreated CLL. ORR and 2% CR with chlorambucil treatment (p < .0001). The
Because many of these regimens were also developed in relapsed CLL median PFS was significantly better (p < .0001) with bendamustine
patients, these data will be reviewed and later referred to in the section (21.6 vs. 8.3 months) than chlorambucil. Grade 3/4 hematologic
Treatment of Patients With Relapsed Chronic Lymphocytic toxicity and severe infections (grades 3–4) occurred more commonly
Leukemia. with bendamustine. Overall, this study and others that have followed
showed that bendamustine is well tolerated in young and old CLL
Cytotoxic Chemotherapy patients. This agent has been effectively combined with rituximab
and will be discussed later in this chapter.
Alkylating Agents
Combination Chemotherapy With Alkylating Agents
Chlorambucil and other alkylating agents have served as first-line
therapy for CLL for many decades, and chlorambucil is still given as A variety of trials combining alkylating agents and other cytotoxic
first-line therapy for some patients, particularly older patients and agents have been performed. A phase III Eastern Cooperative Oncol-
patients who cannot tolerate purine analog therapy. Chlorambucil is ogy Group (ECOG) study of chlorambucil and prednisone (CP) with
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generally administered as a single pulse dose 40 mg/m orally (PO) or without vincristine (CVP) demonstrated no benefit in PFS for the
every 28 days with or without concomitant steroid therapy, although CVP arm. The French CLL group showed that a modified cyclophos-
alternative dosing schedules are used, particularly in Europe. Chlor- phamide, Adriamycin, vincristine, prednisone (CHOP) regimen was
ambucil is typically given without steroid therapy because the addi- superior to CVP and achieved similar results as fludarabine mono-
tion of steroids to alkylating agent therapy has not been shown to therapy. A metaanalysis compared alkylating agent-based combina-
improve survival. Although a high-dose continuous dosing schedule tion regimens with a single-agent regimen based on an alkylating
of 15 mg/day PO has been evaluated in several large European studies agent and demonstrated no survival benefit. Given that alkylating
and led to results superior to those of pulse therapy, high-dose therapy agent–based combination regimens are associated with more toxicity
is associated with greater myelosuppression and frequently requires and show no benefit over fludarabine-based therapy, there is a limited
dose reduction, particularly in older or more fragile patients in whom role for combination alkylator-based therapy in the routine manage-
chlorambucil is typically considered. Although high-dose therapy ment of patients with CLL. In the relapse setting, although salvage
may be more effective if maximal cytoreduction is desired, the less lymphoma regimens such as CHOP-R; rituximab, ifosfamide, carbo-
intensive pulse dosing schedule should generally be used outside the platin, and etoposide (R-ICE); and etoposide, methylprednisolone,
setting of a clinical trial. Because most studies of alkylating agent cytarabine, cisplatin, and rituximab (ESHAP-R) are used to treat
therapy predated widespread use of cytogenetic and biologic risk CLL, clinical studies of these regimens in CLL are lacking, and the
factors, data on the effect of biomarkers on predicting response to utility of these regimens is undefined.
chlorambucil are limited. However, the existing data indicate that
patients with del(11q22.3) or del(17p13.1) have a lower response rate
and a shorter duration of remission to chlorambucil compared with Purine Analogs
patients without these abnormalities. The primary advantages of
chlorambucil are its well-established toxicity profile and its low cost; The introduction of purine analogs in the 1980s by Grever and later
its primary disadvantages are its low CR rate, even in previously Keating revolutionized CLL therapy, and fludarabine has demon-
untreated patients, and the small possibility of developing myelodys- strated significant clinical efficacy in both relapsed and previously
plasia with extended therapy. Although not typically given as a single untreated CLL. Pentostatin was the first nucleoside analog that
agent to younger patients, its use should be considered in older demonstrated clinical activity in CLL and related B-cell lymphopro-
patients and other patients who may not tolerate more intensive liferative disorders; however, subsequent phase II studies showed
chemotherapy based regimens. Given the benefit of the chimeric modest activity, limiting further trials of this agent. Given its more
monoclonal anti-CD20 antibody rituximab as part of chemoimmu- favorable myelosuppression profile compared with other nucleoside
notherapy regimens with fludarabine, several studies have been per- analogs, pentostatin has been combined with other agents and shown
formed combining chlorambucil with rituximab, ofatumumab and favorable clinical activity and toxicity in selected populations. Two