Page 1818 - Williams Hematology ( PDFDrive )

1792 Part XI: Malignant Lymphoid Diseases Chapter 109: Macroglobulinemia 1793

The consensus panel did, however, agree that initiation of therapy is agent therapy for patients with WM include necessity for more rapid
appropriate for patients with constitutional symptoms, such as recur- disease control given the slow response, as well as consideration for pre-
rent fever, night sweats, fatigue as a consequence of anemia, or weight serving stem cells in patients who are candidates for autologous stem
loss. Progressive symptomatic lymphadenopathy and/or splenomegaly cell transplantation therapy. A large randomized study showed an infe-
provide additional reasons to begin therapy. Anemia with a hemoglobin rior response rate and time to progression in WM patients receiving
value of 10 g/dL or less or a platelet count of 100 × 10 /L or less owing chlorambucil versus fludarabine, as well as a higher incidence of sec-
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to marrow infiltration, also justifies treatment. Certain complications, ondary malignancies in the former. Neutropenia was, however, more
such as hyperviscosity syndrome, symptomatic sensorimotor periph- pronounced in those patients on fludarabine. 134
eral neuropathy, systemic amyloidosis, renal insufficiency, or symptom-
atic cryoglobulinemia, may also be indications for therapy. 16,127 Nucleoside Analogue Therapy
Cladribine administered as a single agent by continuous intravenous
INITIAL THERAPY infusion, by 2-hour daily infusion, or by subcutaneous bolus injections
The International Workshops on Waldenström Macroglobulinemia have for 5 to 7 days has resulted in major responses in 40 to 90 percent of
also formulated consensus recommendations for both initial therapy and patients who received primary therapy, whereas in the previously
therapy for refractory disease based on the best available evidence. The treated patients, responses have ranged from 38 to 54 percent. 135–141
most recent recommendations emerged from the Seventh International Median time to achievement of response in responding patients follow-
Workshop on Waldenström Macroglobulinemia. Individual patient ing cladribine ranged from 1.2 to 5 months. The overall response rate
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considerations, including the presence of cytopenias, need for more with daily infusion of fludarabine, administered mainly on 5-day sched-
rapid disease control, age, and candidacy for autologous transplant ther- ules, in previously untreated and treated patients, ranged from 38 to
apy, should be taken into account in making the choice of the drugs to 100 percent and 30 to 40 percent, respectively, 142–147 similar to the
use. For patients who are candidates for autologous stem cell transplanta- responses to cladribine. Median time to achievement of response for
tion, which typically is reserved for those patients younger than 70 years fludarabine (3 to 6 months) was also similar to cladribine. In general,
of age, the panel recommended that exposure to alkylating agents or response rates and durations of responses have been greater for patients
nucleoside analogues should be limited. The use of nucleoside analogues receiving nucleoside analogues as initial therapy, although in several
should be approached cautiously in patients with WM as there appears studies in which both untreated and previously treated patients were
to be an increased risk for the development of disease transformation, as enrolled, no difference in the overall response rate was reported.
well as myelodysplasia and acute myelogenous leukemia. Myelosuppression commonly occurs following prolonged expo-
sure to either of the nucleoside analogues. A sustained decrease in both
Oral Alkylating Agents CD4+ and CD8+ T lymphocytes, measured 1 year following initiation
Oral alkylating drugs, alone and in combination therapy with gluco- of therapy, is notable. 135–137 Treatment-related mortality as a conse-
corticoids, have been extensively evaluated in the treatment of WM. quence of myelosuppression and/or opportunistic infections attribut-
Chlorambucil has been administered on both a continuous (i.e., daily able to immunosuppression occurred in up to 5 percent of all treated
dose schedule) and an intermittent schedule. Patients receiving chlo- patients in some series with nucleoside analogues.
rambucil on a continuous schedule typically receive 0.1 mg/kg per day, Factors predicting for a better response to nucleoside analogues
whereas on the intermittent schedule patients typically receive 0.3 mg/ include younger age at start of treatment (<70 years), higher pretreat-
kg for 7 days, every 6 weeks. In a prospective randomized study, no sig- ment hemoglobin (>95 g/L), higher platelet count (>75 × 10 /L), disease
9
nificant difference in the overall response rate between these schedules relapsing off therapy, and a long interval between first-line therapy and
was observed, although the median response duration was greater for initiation of a nucleoside analogue in relapsing patients. 135,140,146 There are
129
patients receiving intermittent-dose versus continuous-dose chloram- limited data on the use of an alternate nucleoside analogue in previously
bucil (46 vs. 26 months). Despite the favorable median response dura- treated patients among whom disease relapsed or who had resistance
tion in this study for use of the intermittent schedule, no difference in when not on cladribine or fludarabine therapy. 148,149 Three of four (75
the median overall survival was observed. Moreover, an increased inci- percent) patients responded to cladribine after progression following an
dence for development of myelodysplasia and acute myelogenous leu- unmaintained remission to fludarabine, whereas only one of 10 (10 per-
kemia with the intermittent (three of 22 patients) versus the continuous cent) with disease resistant to fludarabine responded to cladribine. A
148
(zero of 24 patients) chlorambucil schedule prompted the preference response in two of six patients (33 percent) and disease stabilization in
for use of continuous chlorambucil dosing. The use of glucocorticoids the remaining patients to fludarabine, in spite of an inadequate response
in combination with alkylating agent therapy has also been explored. or progressive disease, following cladribine therapy has been reported. 149
Chlorambucil (8 mg/m ) plus prednisone (40 mg/m ) given orally for Harvesting autologous blood stem cells succeeded on the first
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2
10 days, every 6 weeks, resulted in a major response (i.e., reduction attempt in 14 of 15 patients who did not receive nucleoside analogue
of IgM by more than 50 percent) in 72 percent of patients. Alkylat- therapy as compared to two of six patients who received a nucleoside
130
ing agent regimens employing melphalan and cyclophosphamide in analogue. A sevenfold increase in transformation to an aggressive
150
combination with glucocorticoids also have been examined. 131,132 This lymphoma and a threefold increase in the development of myelodyspla-
approach produced slightly higher overall response rates and response sia or acute myelogenous leukemia were observed among patients who
durations, although the benefit of these more complex regimens over received a nucleoside analogue versus other therapies for their WM.
151
chlorambucil remains to be demonstrated. Pretreatment factors associ- A meta-analysis of several trials in which patients were treated with
ated with shorter survival in the entire population of patients receiving nucleoside analogues in WM patients, included patients who had pre-
single-agent chlorambucil were age older than age 60 years, male sex, viously received an alkylating agent, and showed a crude incidence of
hemoglobin less than 10 g/dL, leukocytes less than 4 × 10 /L, and plate- approximately 8 percent for development of disease transformation and
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lets less than 150 × 10 /L. Organomegaly, signs of hyperviscosity, renal of approximately 5 percent for development of myelodysplasia or acute
9
failure, monoclonal IgM level, blood lymphocytosis, and percentage of myelogenous leukemia. None of the risk factors—that is, gender, age,
152
marrow lymphoid cells were not significantly correlated with survival. family history of WM, or B-cell malignancies, typical markers of tumor
133
Additional factors to be taken into account in considering alkylating burden and prognosis, type of nucleoside analogue therapy (cladribine

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