Page 1819 - Williams Hematology ( PDFDrive )

1794 Part XI: Malignant Lymphoid Diseases Chapter 109: Macroglobulinemia 1795

vs. fludarabine), time from diagnosis to nucleoside analogue use, nucle- cycle for a total of four cycles. Most patients had been exposed to all
oside analogue treatment as primary or salvage therapy, or treatment active agents for WM and eight patients had received three or more reg-
with an oral alkylator (i.e., chlorambucil)—predicted for the occurrence imens. Six of these patients achieved a partial response which occurred
of transformation or development of myelodysplasia or acute myeloge- at a median of 1 month. The median time to progression in the respond-
nous leukemia in patients treated with a nucleoside analogue. 152 ing patients is expected to exceed 11 months. Peripheral neuropathy
occurred in three patients and one patient developed severe paralytic
CD20-Directed Antibody Therapy ileus in this series. In a prospective study among 27 relapsed or refrac-
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Rituximab is a chimeric monoclonal antibody that targets CD20, a tory patients who received up to eight cycles of bortezomib at 1.3 mg/m
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widely expressed antigen on lymphoplasmacytic cells in WM. Several on days 1, 4, 8, and 11, median serum IgM levels declined significantly
retrospective and prospective studies indicated that rituximab, when from 4.7 g/dL to 2.1 g/dL. The overall response rate was 85 percent,
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used at standard doses (i.e., 4 weekly intravenous infusions of 375 mg/ with 10 and 13 patients achieving a minor (≥25 percent) and major
m ) induced major responses in approximately 30 percent of previously (≥50 percent) decrease in IgM level. Responses occurred at a median of
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treated and untreated patients. 154,155 Even patients who achieved minor 1.4 months. The median time to progression for all responding patients
responses benefited from rituximab by improved hemoglobin and in this study was 7.9 (range: 3.0 to 21.4+) months, and the most com-
platelet counts, and reduction of lymphadenopathy and/or splenomeg- mon grades III/IV toxicities were sensory neuropathies (22.2 percent),
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aly. The median time to treatment failure in these studies was found to leukopenia (18.5 percent), neutropenia (14.8 percent), dizziness (11.1
range from 8 to 27+ months. Patients on an extended rituximab sched- percent), and thrombocytopenia (7.4 percent). Sensory neuropathies
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ule consisting of four weekly courses at 375 mg/m per week, repeated resolved or improved in nearly all patients following cessation of therapy.
3 months later by another 4-week course have demonstrated major Twenty-seven patients with both untreated (44 percent) and previously
response rates of approximately 45 percent, with time to progression treated (56 percent) disease received bortezomib, using the standard
estimates of 16+ to 29+ months. 156,157 schedule until they either demonstrated progressive disease or two cycles
In many WM patients, a transient increase or flare of the serum beyond a complete response or stable disease. The overall response rate
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IgM may occur immediately following initiation of rituximab treat- was 78 percent, with major responses observed in 44 percent of patients.
ment. 156,158,159 Such an increase does not herald treatment failure and Sensory neuropathy occurred in 20 patients following two to four cycles
most patients will return to their baseline serum IgM level by 12 weeks. of therapy. Among the 20 patients developing a neuropathy, 14 showed
Some patients continue to show a prolonged increase in IgM despite an resolution or improvement 2 to 13 months after therapy.
apparent reduction in their marrow tumor cells. However, patients with
baseline serum IgM levels of greater than 50 g/dL or serum viscosity of
greater than 3.5 cp may be particularly at risk for a hyperviscosity-re- Combination Therapies
lated event and plasmapheresis should be considered in these patients Because rituximab is not myelosuppressive, its combination with che-
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in advance of rituximab therapy. Because of the decreased likelihood motherapy has been explored. A regimen of rituximab, cladribine, and
of response in patients with higher IgM levels, as well as the possibility cyclophosphamide used in 17 previously untreated patients resulted in
that serum IgM and blood viscosity levels may abruptly rise, rituximab a partial response in 94 percent of WM patients, including a complete
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monotherapy should not be used as sole therapy for the treatment of response in 18 percent. No patient had relapsed with a median fol-
patients at risk for hyperviscosity signs and symptoms. 128,156,157 lowup of 21 months. The combination of rituximab and fludarabine
Time to response after rituximab is slow and exceeds 3 months on used in 43 patients of whom 32 (75 percent) were previously untreated,
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the average. The time to best response in one study was 18 months. led to an overall response rate of 95.3 percent, with 83 percent of patients
Patients with baseline serum IgM levels of less than 60 g/dL are more achieving a major response (i.e., 50 percent reduction in disease bur-
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likely to respond, regardless of the underlying marrow involvement by den). The median time to progression was 51.2 months in this series,
tumor cells. 156,157 An analysis of 52 patients who were treated with sin- and was longer for those patients who were previously untreated and
gle-agent rituximab found the objective response rate was significantly for those achieving a very good partial remission (i.e., 90 percent reduc-
lower in patients who had either low serum albumin (<35 g/L) or a tion in disease) or better. Hematologic toxicity was common: grade 3
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serum monoclonal protein greater than 40 g/L. The presence of both neutropenia and thrombocytopenia observed in 27 and four patients,
adverse prognostic factors was associated with a short time to progres- respectively. Two deaths occurred in this study from pneumonia. Sec-
sion (3.6 months). Patients who had normal serum albumin and rela- ondary malignancies including transformation to aggressive lymphoma
tively low serum monoclonal protein levels derived a substantial benefit and development of myelodysplasia or acute myelogenous leukemia
from rituximab with a time to progression exceeding 40 months. were observed in six patients in this series. The addition of rituximab
A correlation between polymorphisms at position 158 in the FcγRIIIa to fludarabine and cyclophosphamide has also been explored in previ-
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receptor (CD16), an activating Fc receptor on important effector cells that ously treated patients, of whom four of five patients had a response. In
mediate antibody-dependent cell-mediated cytotoxicity, and rituximab another combination study, rituximab along with pentostatin and cyclo-
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response was observed in WM patients. Individuals may encode either the phosphamide given to 13 patients with untreated and previously treated
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amino acid valine or phenylalanine at position 158 in the FcγRIIIa receptor. WM or LPL resulted in a major response in 77 percent of patients.
WM patients who carried the valine amino acid (either in a homozygous The combination of rituximab, dexamethasone, and cyclophosphamide
or heterozygous pattern) had a fourfold higher major response rate (i.e., 50 was used as primary therapy to treat 72 patients with WM in whom a
percent decline in serum IgM levels) to rituximab versus those patients who major response was observed in 74 percent of patients in this study, and
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expressed phenylalanine in a homozygous pattern. the 2-year progression-free survival was 67 percent. Therapy was well
tolerated, although one patient died of interstitial pneumonia.
Proteasome Inhibitors Two studies examined cyclophosphamide, doxorubicin, vin-
Both bortezomib and carfilzomib have been evaluated in prospective cristine, and prednisone (CHOP) in combination with rituximab
studies in patients with WM, although the latter only in combination (R-CHOP). In a randomized trial involving 69 patients, most of whom
therapy (discussed below). In a retrospective study, 10 patients with had WM, the addition of rituximab to CHOP resulted in a higher
refractory or relapsed WM were treated with bortezomib administered overall response rate (94 percent vs. 67 percent) and median time to
intravenously at a dose of 1.3 mg/m on days 1, 4, 8, and 11 in a 21-day progression (63 vs. 22 months) in comparison to patients treated with
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