Page 1409 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 77 Chronic Lymphocytic Leukemia 1255

compartment with little improvement in BM disease. In contrast, fludarabine-containing regimens, several trials have also combined
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two trials in which higher doses of rituximab weekly (≤2250 mg/m rituximab with chlorambucil with promising results. Alternative regi-
per dose) or in which rituximab was administered thrice weekly (at mens, including FCR–mitoxantrone (FCR-M) and pentostatin,
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375 mg/m ) to relapsed CLL patients showed improved response rituximab, and cyclophosphamide (PCR), have been published and
rates with response duration approaching that achieved in follicular used in CLL but are unlikely to be building blocks for improvement
B-NHL. These studies established a role for single-agent rituximab in CLL therapy in the future and are therefore not described later.
in patients with relapsed CLL and led to combination therapy with
other agents. Fludarabine and Rituximab
In contrast to studies in relapsed CLL, weekly single-agent ritux- The Cancer and Leukemia Group B (CALGB) 9712 study ran-
imab demonstrated greater clinical efficacy when given to patients domized 104 previously untreated CLL patients to sequential or
with previously untreated SLL/CLL. Forty-four previously untreated concurrent fludarabine and rituximab (FR) therapy. Patients received
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patients with SLL/CLL received 4-weekly doses of rituximab 375 mg/ standard fludarabine 25 mg/m days 1–5 every 4 weeks for six cycles
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m ; the ORR after the first course of rituximab was 51% (CR 4%). with or without concurrent rituximab 375 mg/m on day 1 of each
Twenty-eight patients with stable or responsive disease received addi- cycle with an additional dose on day 4 of cycle 1. Patients in both
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tional 4-week courses of rituximab every 6 months for up to four cycles. arms received rituximab 375 mg/m weekly for four doses begin-
However, there was only a modest increase in ORR (58%) and CR ning 2 months after completion of fludarabine; thus patients in
rates (9%), and the median duration of PFS of 19 months was shorter the concurrent arm received 11 total doses of rituximab compared
than the 36- to 40-month median duration of PFS reported by the with four in the sequential arm. Patients receiving concurrent FR
same investigators using the same regimen in previously untreated therapy enjoyed a superior CR rate (47% vs. 28%) and ORR (90%
patients with follicle center B-NHL. Nonetheless, this response dura- vs. 77%) as compared with patients in the sequential arm. Ret-
tion compared favorably with the response duration achieved with rospective comparison to a fludarabine only–containing treatment
fludarabine in the upfront setting, suggesting that rituximab is active study performed previously by CALGB demonstrated improved PFS
and may have a role in the upfront therapy of SLL/CLL. and OS for patients enrolled in the concurrent arm. Analysis of
Rituximab is selective for the B-cell antigen CD20 and therefore prognostic cytogenetic abnormalities demonstrated that patients with
has a relatively favorable toxicity profile. Toxicity associated with del(11q22.3) and del(17p13.1) have a shorter duration of response
infusion of this agent commonly occurs with the first infusion of to FR. A recent update of this study with a median follow up of 117
rituximab and may be greater in patients with CLL compared with months showed that the median OS was 85 months with 71% of
patients with NHL. These symptoms generally include fever, rigors, patients alive at 5 years. The median PFS was 42 months with 27%
transient hypoxemia, dyspnea, and hypotension, which are partly progression-free at 5 years. Importantly, an estimated 13% of patients
caused by an inflammatory cytokine release syndrome. Although remained free of progression after almost 10 years of follow-up.
poorly understood, CLL patients with platelet counts less than 50 × IGHV-mutated disease status was favorably associated with extended
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10 /L may experience transient, severe thrombocytopenia associated PFS and OS, but not having high-risk cytogenetic abnormality was
with this infusional toxicity and may require platelet transfusions with also associated with a favorable OS. Notably, there were no cases of
the first one or two doses of rituximab. Patients with preexisting tr-MN occurring before relapse contrasting with prior studies with
thrombocytopenia should therefore have a posttherapy platelet count fludarabine- and alkylator-containing regimens.
after the first one or two doses of rituximab. Another uncommon but
potentially severe toxicity is a tumor lysis syndrome, which is generally Fludarabine, Cyclophosphamide, and Rituximab
observed in patients with a high circulating peripheral lymphocyte The most favorable phase II results with chemoimmunotherapy have
count with CLL variants. Such patients should receive prophylactic been reported by the MD Anderson group with a combination FCR
allopurinol, hydration, and careful observation, and inpatient moni- regimen in both previously treated and untreated CLL. A total of 177
toring before administration of rituximab can be considered for the evaluable patients with previously treated CLL received fludarabine
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highest risk patients. Patients who develop tumor lysis syndrome after 25 mg/m and cyclophosphamide 250 mg/m on days 2–4 of cycle
the first dose of rituximab can safely receive subsequent doses, espe- 1 and on days 1–3 of cycles 2–6 in addition to rituximab 375 mg/
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cially after the number of circulating CLL cells is reduced. Other rare m on day 1 of cycle 1 and 500 mg/m on day 1 of cycles 2–6. An
toxicities with rituximab therapy include delayed neutropenia, hepa- ORR of 73% with a 25% CR rate and 16% nodular PR rate was
titis B reactivation, skin toxicity, interstitial pneumonitis, serum reported, and 12 of 37 patients (32%) in CR achieved molecular
sickness, and progressive multifocal encephalopathy. Patients with remission. The same authors administered FCR to 300 previously
prior hepatitis B exposure, as indicated by positive serologies, should untreated CLL patients; the ORR was 95%, with 72% of patients
receive rituximab only if viral load testing indicates no active disease. attaining a CR. Six-year PFS was 51%, and OS was 77%. Features
Such patients should undergo regular viral load monitoring during associated with poor response included high β 2 M levels, del(17p13.1),
and after completion of rituximab therapy, and prophylactic antiviral age older than 70 years, and white blood cell count elevation above
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therapy may be considered to reduce the likelihood of viral reactiva- 150 × 10 /L. Late infectious or other complications were uncommon
tion. Patients who develop profound neutropenia, pulmonary, or skin except for tr-MN, which occurred in 9% of patients. The outcome
toxicity with rituximab should not be challenged with repeated dosing. of patients with tr-MN was poor irrespective of treatment. In a
In general, rituximab is a very well-tolerated therapy, making it ideal multivariate analysis of patients receiving fludarabine-based therapy
for use in combination with other agents in patients with CLL. at MD Anderson, FCR therapy was significantly associated with
improved survival, thereby validating the experience with FR, sug-
Phase II Studies of Rituximab gesting that rituximab therapy was improving OS. Moreover, patients
with mutated IGHV with a low β2M level did not experience any
Chemoimmunotherapy relapse of their disease after 10 years suggesting that a subset of
patients can achieve long-term remissions and potentially cure.
Given its activity and toxicity profile, rituximab has been combined The benefit of adding rituximab to FC was confirmed by the
with cytotoxic chemotherapy in the treatment of CLL, and clinical German CLL study group, which randomized 817 physically fit,
trials have examined several such chemoimmunotherapy regimens. previously untreated CLL patients, ages 30–81 years, to fludarabine
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Studies of chemoimmunotherapy in CLL have focused primarily on 25 mg/m on days 1–3 and cyclophosphamide 250 mg/m IV on days
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fludarabine-based combinations because of the established role of 1–3, with or without rituximab 375 mg/m day 0 of cycle 1 and
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fludarabine therapy in this disease. The approval of bendamustine 500 mg/m day 1 of cycles 2–6 every 28 days for six cycles. A total of
and potentially its unique mechanism of action has led to combina- 761 patients were evaluable for response. FCR induced higher OR
tion therapy with bendamustine and rituximab. Finally, given the (95 vs. 88%) and CR rates (44 vs. 22%) than FC. Median PFS was
recent recognition that elderly patients do not benefit from 32.8 months for FC and 51.8 months for FCR, and the largest benefit