Page 1410 - Hematology_ Basic Principles and Practice ( PDFDrive )

1256 Part VII Hematologic Malignancies

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for FCR was observed in Binet stage A and B patients. The OS rate m /day PO) every 28 days for six cycles. Patients were permitted to
at 37.7 months favored FCR over FC (84% vs. 79%; p = .01). FCR receive six additional cycles of chlorambucil if they had evidence of
resulted in more grade 3 and grade 4 neutropenia (34% vs. 21%) and continuing clinical response after six cycles. The median age was 70
leukopenia (24% vs. 12%), but there was no difference in the number years. The OR rate on an intent-to-treat analysis was 82%, with nine
of severe infections or treatment-related deaths between the two arms. patients achieving a CR, 58 patients achieved a partial response (PR),
As with other chemoimmunotherapy trials in CLL, neutropenia was 15 patients achieved a nodular PR (nPR), and 11 patients had stable
more common with FCR than FC. Emerging from this study were disease. The median PFS to date is 23.5 months. The response rate
numerous biologic correlative studies showing the most predictive test in this study was significantly higher than patients receiving chlor-
of long-term PFS and OS was attainment of a minimal residual disease ambucil alone in the CLL4 study, suggesting a benefit of adding
(MRD)–negative state using high-sensitivity flow cytometry. In addi- rituximab. A second Italian phase II study using a similar combina-
tion, patients with unmutated IGHV disease had a shorter PFS and tion of chlorambucil and rituximab together demonstrated a similar
OS with both FCR and FC, although rituximab appeared to benefit favorable response data. Based on these phase II studies, a randomized
both treatment groups. All groups based upon cytogenetic analysis phase III study comparing chlorambucil (Chl) versus chlorambucil
benefited from rituximab with the exception of the del(17p13.1) and with either rituximab (Chl-R) or the human monoclonal antibody
normal karyotype patients, who had similar outcomes to FC or FCR which binds to CD20, obinutuzumab (Chl-O) was conducted by the
treatment. An update of this study demonstrated that IGHV-mutated German CLL Study Group. In this CLL11 trial the Chl-O had higher
CLL have the similar long-term disease free plateau suggestive of ORR (78% vs. 65% vs 31%) and CR rates (20% vs. 7% vs. 0%) in
potential cure after earlier follow up than the MD Anderson series. Chl-O versus Chl-R versus Chl arms respectively. Similarly, PFS was
Thus, even in the age of new targeted therapy, FCR must be strongly also improved significantly with Chl-O (median 26 months vs. 16
considered as a therapeutic option for the younger patient group with months vs. 11 months). Importantly, Chl-O was able to induce a
IGHV-mutated disease given the potential for cure with combined higher proportion of MRD-negative responses when compared with
chemoimmunotherapy. Chl-R. Chl-O was associated with higher incidence of infusion reac-
tions and cytopenias but the incidence of infections was similar in all
Bendamustine and Rituximab three groups. In a similar study, ofatumumab in combination with
Based on promising single agent activity of bendamustine in previ- chlorambucil was compared with chlorambucil alone in previously
ously treated CLL and in vitro studies demonstrating synergy between untreated patients and demonstrated a significantly prolonged
bendamustine and rituximab, the German CLL Study Group exam- median PFS of 22 months versus 13 months. Based on these results
ined the feasibility and safety of this combination in a phase II study both obinutuzumab and the fully human monoclonal antibody for
in 78 relapsed CLL patients. Bendamustine was administered at a CD20, ofatumumab were approved in combination with chloram-
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dose of 70 mg/m days 1 and 2 and rituximab at 375 mg/m on day bucil for the treatment of patients with untreated CLL who would
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0 of cycle 1 and 500 mg/m on day 1 of cycles 2–6. Using an not otherwise be candidates for conventional chemotherapy.
intent-to-treat analysis, the ORR was 59% with a CR of 9%. The
median PFS was 14.7 months. Response was poor (7%) in the
del(17p) patients. Severe infections occurred in 13% of patients. Alemtuzumab
Grade 3 or grade 4 neutropenia, thrombocytopenia, and anemia were
documented in 23%, 28%, and 17% of patients, respectively. Alemtuzumab is a humanized monoclonal antibody against CD52,
A follow-up study (CLL2M) included a total of 117 symptomatic, a cell-surface glycopeptide expressed by virtually all human lympho-
previously untreated CLL patients who were treated with bendamus- cytes, monocytes, and macrophages, a small subset of granulocytes,
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tine (90 mg/m on days 1 and 2) and rituximab (375 mg/m in cycle but not erythrocytes, platelets, or hematopoietic stem cells. CD52 is
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1 and 500 mg/m in cycle 2–6). Treatment was administered every
28 days for up to six cycles. Demographics of the patients included
a median age of 64 years with 48% having Binet C disease. The ORR What Is the Role of Anti-CD20 Antibodies in Chronic Lymphocytic
was 91%, and the CR was 33%. After 18 months, 76% of patients Leukemia?
were still in remission, and median PFS had not been reached at the
time of the report. The treatment was well tolerated with cytopenias Studies of rituximab have demonstrated modest single-agent clinical
and infections being most problematic. Treatment-related mortality activity in both previously untreated CLL patients using the weekly
(TRM) was 2.6%. Patients with all cytogenetic groups based upon dosing schedule and in the relapsed state using more intensive
cytogenetic analyses except for del(17p13.1) responded favorably. dosing regimens. Rituximab does not have activity against CLL with
Based on these encouraging phase II data, the German CLL Study del(17p13.1). For this reason, rituximab monotherapy is generally used
in either of these settings only if more definitive therapy cannot be
Group conducted a phase III study comparing bendamustine/ administered because of other comorbid conditions. Rituximab’s great-
fludarabine (BR) with FCR (CLL10) in previously untreated, physi- est contribution is to combination therapy both in symptomatic, previ-
cally fit CLL patients. FCR therapy demonstrated an improved CR ously untreated CLL patients and relapsed patients receiving the FR or
(39% vs. 30%) and PFS (median 55 months vs. 41%) as compared FCR regimen, particularly in younger patients. Phase III studies have
with BR but OS was similar after an early follow up. FCR was associ- demonstrated the clear benefit of chemoimmunotherapy over traditional
ated with significantly higher risk of neutropenia, thrombocytopenia, chemotherapy alone and have established chemoimmunotherapy as
and infections. However, early data in the favorable IGHV-mutated the standard of care for CLL. Several other studies have combined ritux-
patients has not suggested that a similar disease-free plateau exists imab with other therapies such as bendamustine, chlorambucil, and
with BR as with FCR. Thus, it is our practice in the current era of pentostatin–cyclophosphamide that might be more tolerable to older
patients. Inclusion of rituximab in alternative chemoimmunotherapy
kinase inhibitor therapy to use FCR when considering chemoim- regimens for patients not appropriate for chemotherapy-containing
munotherapy with intent of pursuing extended DFS and potential regimens is reasonable. Multiple other CD20 targeting agents includ-
for patients to be off therapy for an extended period of time. ing especially obinutuzumab, however have been reported to have
demonstrated superiority over rituximab. Although several studies
of maintenance rituximab have been published after completion of
Chlorambucil and Anti-CD20 Antibodies chemoimmunotherapy, the benefit of this is uncertain. These studies
were performed mostly in patients with low-risk disease who would
Based on the success of chemoimmunotherapy and the potential ordinarily be expected to respond well to conventional therapy. Similar
absence of benefit of nucleoside analogs in elderly CLL patients, results have also been reported with ofatumumab suggesting a slight
benefit in patients relapsing after chemoimmunotherapy. At this time,
Hillmen and colleagues initiated a study in 100 elderly, previously maintenance rituximab or other CD20 antibody in CLL cannot be
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untreated CLL patients combining rituximab (day 1; 375 mg/m IV justified and should not be used outside of the context of a clinical trial.
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cycle 1, 500 mg/m cycles 2–6) and chlorambucil (days 1–7; 10 mg/