Page 1600 - Hematology_ Basic Principles and Practice ( PDFDrive )

1426 Part VII Hematologic Malignancies

TREATMENT male sex, hemoglobin less than 10 g/dL, leukocytes less than 4 ×
9
9
10 /L, and platelets less than 150 × 10 /L. Organomegaly, signs of
Initiating Treatment hyperviscosity, renal failure, monoclonal IgM level, blood lymphocy-
tosis, and percentage of marrow lymphoid cells were not significantly
133
As part of the Second International Workshop on Waldenström’s correlated with survival. Additional factors to be taken into account
Macroglobulinemia, a consensus panel was organized to recommend in considering alkylating agent therapy for patients with WM include
127
criteria for the initiation of therapy in patients with WM. The necessity for more rapid disease control, given the slow response, as
panel recommended that initiation of therapy should not be based well as consideration for preserving stem cells in patients who are
on the IgM level per se, because this may not correlate with the clini- candidates for autologous SCT. A large randomized study showed an
cal manifestations of WM. The consensus panel did, however, agree inferior response rate and time to progression in patients with WM
that initiation of therapy is appropriate for patients with constitu- receiving chlorambucil versus fludarabine, as well as a higher inci-
tional symptoms, such as recurrent fever, night sweats, fatigue as a dence of secondary malignancies in the former. Neutropenia was
consequence of anemia, or weight loss. Progressive symptomatic more pronounced, however, in those patients on fludarabine. 134
lymphadenopathy and/or splenomegaly provide additional reasons to
begin therapy. Anemia with a hemoglobin value ≤10 g/dL or a Nucleoside Analogue Therapy. Cladribine administered as a single
9
platelet count ≤100 × 10 /L owing to marrow infiltration also justifies agent by continuous intravenous infusion, by 2-hour daily infusion,
treatment. Certain complications, such as hyperviscosity syndrome, or by subcutaneous bolus injections for 5–7 days has resulted in
symptomatic sensorimotor peripheral neuropathy, systemic amyloi- major responses in 40% to 90% of patients who received primary
dosis, renal insufficiency, or symptomatic cryoglobulinemia, may also therapy, whereas in the previously treated patients, responses have
be indications for therapy. 16,127 ranged from 38% to 54%. 135–141 Median time to achievement of
response in responding patients following cladribine ranged from 1.2
to 5 months. The ORR with daily infusion of fludarabine, adminis-
Initial Therapy tered mainly on 5-day schedules, in previously untreated and treated
patients ranged from 38% to 100% and from 30% to 40%, respec-
The International Workshops on Waldenström’s Macroglobulinemia tively, 142–147 similar to the responses to cladribine. Median time to
have also formulated consensus recommendations for both initial achievement of response for fludarabine (3–6 months) was also
therapy and therapy for refractory disease based on the best available similar to cladribine. In general, response rates and durations of
evidence. The most recent recommendations emerged from the responses have been greater for patients receiving nucleoside ana-
Seventh International Workshop on Waldenström’s Macroglobulin- logues as initial therapy, although no difference in the ORR was
128
emia. Individual patient considerations, including the presence of reported in several studies in which both untreated and previously
cytopenias, need for more rapid disease control, age, and candidacy treated patients were enrolled.
for autologous transplant therapy, should be taken into account in Myelosuppression commonly occurs following prolonged expo-
making the choice of the drugs to use. For patients who are candidates sure to either of the nucleoside analogues. A sustained decrease in
+
+
for autologous stem cell transplant (SCT), which typically is reserved both CD4 and CD8 T lymphocytes, measured 1 year following
for those patients younger than 70 years of age, the panel recom- initiation of therapy, is notable. 135–137 Treatment-related mortality as
mended that exposure to alkylating agents or nucleoside analogues a consequence of myelosuppression and/or opportunistic infections
should be limited. The use of nucleoside analogues should be attributable to immunosuppression occurred in up to 5% of all
approached cautiously in patients with WM because there appears to treated patients in some series with nucleoside analogues.
be an increased risk for the development of disease transformation as Factors predicting a better response to nucleoside analogues
well as myelodysplasia and acute myelogenous leukemia. include younger age at start of treatment (<70 years), higher pretreat-
9
ment hemoglobin (>95 g/L), higher platelet count (>75 × 10 /L),
Oral Alkylating Agents. Oral alkylating drugs, alone and in com- disease relapsing off-therapy, and a long interval between firstline
bination therapy with glucocorticoids, have been evaluated extensively therapy and initiation of a nucleoside analogue in relapsing
in the treatment of WM. Chlorambucil has been administered on patients. 135,140,146 There are limited data on the use of an alternate
both a continuous (i.e., daily dose schedule) and an intermittent nucleoside analogue in previously treated patients in whom disease
schedule. Patients receiving chlorambucil on a continuous schedule relapsed or who had resistance when not on cladribine or fludarabine
typically receive 0.1 mg/kg per day, whereas on the intermittent therapy. 148,149 Three (75%) of 4 patients responded to cladribine after
schedule patients typically receive 0.3 mg/kg for 7 days, every 6 progression following an unmaintained remission with fludarabine,
weeks. In a prospective, randomized study, no significant difference whereas only 1 (10%) of 10 with disease resistant to fludarabine
148
in the overall response rate (ORR) between these schedules was responded to cladribine. A response to fludarabine has been
129
observed, although the median response duration was greater for reported in two (33%) of six patients and disease stabilization in the
patients receiving intermittent- versus continuous-dose chlorambucil remaining patients, in spite of an inadequate response or progressive
(46 vs. 26 months). Despite the favorable median response duration disease, following cladribine therapy. 149
in this study for use of the intermittent schedule, no difference in the Harvesting autologous blood stem cells succeeded on the first
median overall survival was observed. Moreover, an increased inci- attempt in 14 of 15 patients who did not receive nucleoside analogue
dence for development of myelodysplasia and acute myelogenous therapy, as compared with 2 of 6 patients who received a nucleoside
150
leukemia with the intermittent (3 of 22 patients) versus the continu- analogue. A sevenfold increase in patients transforming to an
ous (0 of 24 patients) chlorambucil schedule prompted the preference aggressive lymphoma and a threefold increase in the development of
for use of continuous chlorambucil dosing. The use of glucocorticoids myelodysplasia or acute myelogenous leukemia were observed among
in combination with alkylating agent therapy has also been explored. patients who received a nucleoside analogue versus other therapies
151
2
2
Chlorambucil (8 mg/m ) plus prednisone (40 mg/m ) given orally for their WM. A meta-analysis of several trials in which patients
for 10 days, every 6 weeks, resulted in a major response (i.e., reduc- with WM were treated with nucleoside analogues included patients
130
tion of IgM by more than 50%) in 72% of patients. Alkylating who had previously received an alkylating agent, and the results
agent regimens employing melphalan and cyclophosphamide in showed a crude incidence of approximately 8% of developing a
combination with glucocorticoids have also been examined. 131,132 disease transformation event and approximately 5% for developing
152
This approach produced slightly higher ORRs and response dura- myelodysplasia or acute myelogenous leukemia. None of the risk
tions, although the benefit of these more complex regimens over factors—that is, sex, age, family history of WM, or B-cell malignan-
chlorambucil remains to be demonstrated. Pretreatment factors cies, typical markers of tumor burden and prognosis, type of nucleo-
associated with shorter survival in the entire population of patients side analogue therapy (cladribine vs. fludarabine), time from diagnosis
receiving single-agent chlorambucil were older than 60 years of age, to nucleoside analogue use, nucleoside analogue treatment as primary