Page 1601 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 87 Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma 1427

or salvage therapy, or treatment with an oral alkylator (i.e., chloram- a prospective study including 27 relapsed or refractory patients who
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bucil)—predicted the occurrence of transformation or development received up to 8 cycles of bortezomib at 1.3 mg/m on days 1, 4, 8,
of myelodysplasia or acute myelogenous leukemia in patients treated and 11, median serum IgM levels declined significantly, from 4.7 g/
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with a nucleoside analogue. 152 dL to 2.1 g/dL. The ORR was 85%, with 10 and 13 patients
achieving a minor (<25%) and major (<50%) decrease in IgM level,
CD20-Directed Antibody Therapy. Rituximab is a chimeric respectively. Responses occurred after a median of 1.4 months. The
monoclonal antibody that targets CD20, a widely expressed antigen median time to progression for all responding patients in this study
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on lymphoplasmacytic cells in WM. Several retrospective and was 7.9 (range, 3–21.4+) months, and the most common grade III/
prospective studies have indicated that rituximab, when used at IV toxicities were sensory neuropathies (22.2%), leukopenia (18.5%),
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standard doses (i.e., 4 weekly infusions of 375 mg/m /week) induced neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia
major responses in approximately 30% of previously treated and (7.4%). Sensory neuropathies resolved or improved in nearly all
untreated patients. 154,155 Even patients who achieved minor responses patients following cessation of therapy. Twenty-seven patients with
benefited from rituximab by improved hemoglobin and platelet both untreated (44%) and previously treated (56%) disease received
counts, as well as reduction of lymphadenopathy and/or spleno- bortezomib, using the standard schedule until they either demon-
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megaly. The median time to treatment failure in these studies was strated progressive disease or two cycles beyond a complete response
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found to range from 8 to 27+ months. Patients on an extended or stable disease. The ORR was 78%, with major responses
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rituximab schedule consisting of 4 weekly courses at 375 mg/m per observed in 44% of patients. Sensory neuropathy occurred in 20
week, repeated 3 months later by another 4-week course have dem- patients following two to four cycles of therapy. Among the 20
onstrated major response rates of approximately 45%, with time to patients who developed a neuropathy, 14 showed resolution or
progression estimates of 16+ to 29+ months. 156,157 improvement 2–13 months after therapy.
In many patients with WM, a transient increase or flare of the
serum IgM may occur immediately following initiation of rituximab Combination Therapies. Because rituximab is not myelosuppres-
treatment. 156,158,159 Such an increase does not herald treatment failure, sive, its use in combination with chemotherapy has been explored. A
and most patients will return to their baseline serum IgM level by 12 regimen of rituximab, cladribine, and cyclophosphamide in 17 previ-
weeks. Some patients continue to show a prolonged increase in IgM ously untreated patients resulted in a partial response in 94% of
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despite an apparent reduction in their marrow tumor cells. However, patients with WM, including a complete response in 18%. No
patients with baseline serum IgM levels >50 g/dL or serum viscosity patient had relapsed with a median follow-up of 21 months. The
>3.5 cp may be particularly at risk for a hyperviscosity-related event, combination of rituximab and fludarabine was used in 43 patients,
and plasmapheresis should be considered in these patients in advance of whom 32 (75%) were previously untreated, which led to an ORR
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of rituximab therapy. Because of the decreased likelihood of of 95.3%, with 83% of patients achieving a major response (i.e., 50%
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response in patients with higher IgM levels, as well as the possibility reduction in disease burden). The median time to progression was
that serum IgM and blood viscosity levels may abruptly rise, ritux- 51.2 months in this series, and it was longer for those patients who
imab monotherapy should not be used as sole therapy for the treat- were previously untreated and for those achieving a very good partial
ment of patients at risk for hyperviscosity symptoms. 128,156,157 remission (i.e., 90% reduction in disease) or better. Hematologic
Time to response after rituximab is slow and exceeds 3 months toxicity was common: Grade 3 neutropenia and thrombocytopenia
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on average. The time to best response in one study was 18 months. were observed in 27 and 4 patients, respectively. Two deaths occurred
Patients with baseline serum IgM levels <60 g/dL are more likely to in this study as a result of pneumonia. Secondary malignancies,
respond, regardless of the underlying degree of marrow involvement including transformation to aggressive lymphoma and development
by tumor cells. 156,157 An analysis of 52 patients who were treated with of myelodysplasia or acute myelogenous leukemia, were observed in
single-agent rituximab found the objective response rate was signifi- six patients. The addition of rituximab to fludarabine and cyclophos-
cantly lower in patients who had either low serum albumin (<35 g/L) phamide has also been explored in previously treated patients, and
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or a serum monoclonal protein greater than 40 g/L. The presence four of five patients had a response. In another combination study,
of both adverse prognostic factors was associated with a short time rituximab along with pentostatin and cyclophosphamide given to 13
to progression (3.6 months). Patients who had normal serum albumin patients with untreated and previously treated WM or LPL resulted
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and relatively low serum monoclonal protein levels derived a substan- in a major response in 77% of patients. The combination of
tial benefit from rituximab, with a time to progression exceeding 40 rituximab, dexamethasone, and cyclophosphamide was used as
months. primary therapy to treat 72 patients with WM, among whom a major
A correlation between polymorphisms at position 158 in the response was observed in 74% of patients, and the 2-year progression-
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FcγRIIIa receptor (CD16), an activating Fc receptor on important free survival was 67%. Therapy was well tolerated, although one
effector cells that mediate antibody-dependent, cell-mediated cyto- patient died as a result of interstitial pneumonia.
toxicity, and rituximab response was observed in patients with Two studies have examined cyclophosphamide, doxorubicin,
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WM. Individuals may encode either the amino acid valine or vincristine, and prednisone (CHOP) therapy in combination with
phenylalanine at position 158 in the FcγRIIIa receptor. Patients with rituximab (R-CHOP). In a randomized trial involving 69 patients,
WM who carried the valine amino acid (either in a homozygous or most of whom had WM, the addition of rituximab to CHOP resulted
heterozygous pattern) had a fourfold higher major response rate (i.e., in a higher ORR (94% vs. 67%) and median time to progression (63
50% decline in serum IgM levels) to rituximab versus those patients vs. 22 months) in comparison to patients treated with CHOP
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who expressed phenylalanine in a homozygous pattern. alone. R-CHOP was also used in 13 patients with WM, 10 of
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whom had relapsed or refractory disease. Among 13 evaluable
Proteasome Inhibitors. Both bortezomib and carfilzomib have been patients, 10 patients achieved a major response (77%), including 3
evaluated in prospective studies in patients with WM, though the complete and 7 partial remissions. Two other patients achieved a
latter only in combination therapy (discussed below). In a retrospec- minor response. Patients in a retrospective study of symptomatic WM
tive study, 10 patients with refractory or relapsed WM were treated received either R-CHOP; rituximab, cyclophosphamide, vincristine,
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with bortezomib administered intravenously at a dose of 1.3 mg/m and prednisone (R-CVP); or cyclophosphamide, prednisone, and
on days 1, 4, 8, and 11 in a 21-day cycle for a total of four cycles. rituximab (R-CP). The patients were similar in most pretreatment
Most patients had been exposed to all other active agents for WM, variables, and the ORRs to therapy were comparable among all three
and eight patients had received three or more regimens. Six of these treatment groups—R-CHOP (96%), R-CVP (88%), and R-CP
patients achieved a partial response that occurred after a median of (95%)—although there was a trend for more complete remissions
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1 month. The median time to progression in the responding patients among patients treated with R-CVP and R-CHOP. Adverse events
is expected to exceed 11 months. Peripheral neuropathy occurred in attributed to therapy showed a higher incidence for neutropenic fever
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three patients, and one patient developed severe paralytic ileus. In and treatment-related neuropathy for R-CHOP and R-CVP versus