Page 1436 - Hematology_ Basic Principles and Practice ( PDFDrive )

1282 Part VII Hematologic Malignancies

treatment of early disease is directed at bacterial eradication. Historic Alkylating Agents
rates of remission vary between 30% and 70%, depending on the
study. Maximal responses may take more than 5 months of therapy, Single-agent alkylators have also been used in this setting. A study of
and relapses occur in a fraction of patients. 24 patients with gastric ENMZL (stages IE or IV) treated with daily
oral chlorambucil or cyclophosphamide for 12–24 months showed a
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CR rate of 75%, with the remaining patients achieving PR. Remis-
Other Extranodal Marginal Zone Lymphoma sions were durable in approximately half of the patients after a median
follow-up time of 45 months. Another study of 21 patients (stages I
Early-stage ENMZL in other primary sites is managed in a similar to IV) treated with continuous alkylating drugs documented a CR
way to ocular adnexal or cutaneous forms. When feasible, surgery can rate of 42% and 89% in t(11;18)–positive and t(11;18)–negative
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be potentially curative and often may be done with primary diagnostic disease, respectively. After a median follow up of 7.5 years, CR was
intent. If full resection is achieved, these patients may be observed. sustained in all patients with translocation-negative disease, but in
Otherwise, for sites not amenable to surgery or if there is residual only one patient otherwise.
disease after surgical excision (i.e., positive margins), radiation therapy The combination of rituximab and chlorambucil has produced an
is the usual preferred approach. If radiation is contraindicated and impressive 100% CR rate in 13 patients with t(11;18)–positive
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the patient is asymptomatic, observation is an option. Otherwise, gastric ENMZL (stages I to IV). No relapses were observed after a
systemic therapy as for advanced stage, preferably one with minimal median follow-up of 24 months in this report but long-term data
toxicity, is appropriate. 9,140 were not available.
This combination has been studied in a randomized controlled
trial versus each single agent in 393 patients not responding or not
Therapy for Advanced-Stage (III/IV) Disease suitable for local therapy. 146,147 CR rate, and 5-year event-free and
progression-free survival were better with the combination, but 5-year
The data regarding management of advanced-stage disease are also overall survival was 90% in the whole population, without significant
limited, because most large treatment series with long-term follow-up differences between the three arms.
aggregate all indolent lymphomas and include only a small fraction
of patients with MZL among other more frequent histologies. Thus
most treatment approaches have been modeled after those for FL (see Purine Analogues
Chapter 80), and indeed the most common recommendation is that
9
advanced ENMZL be managed as advanced FL. In any case, there The purine analogue cladribine has also been used as single-agent
is some suggestion that responses may be better, possibly because of a therapy in a series of 25 patients (stages I to IV), and CR was obtained
usually lower burden of disease. Eligible patients should be included in 84% of them. After a median follow-up time of 80 months, seven
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whenever possible in clinical trials. patients experienced disease relapse. Of note, one of the patients
As in other indolent lymphomas, extensive disease is likely incur- treated developed a myelodysplastic syndrome immediately after the
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able with current approaches, which together with a generally slow third infusion of the drug. Another purine analogue, fludarabine,
pace of progression means that systemic treatment is not always has been used in combination with rituximab to treat a series of 22
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indicated. Because no benefit in survival has been demonstrated with patients (stages I to IV). At the end of treatment (three cycles,
early systemic treatment of asymptomatic disease, unless a treatable with some patients requiring six), 90% of patients achieved CR. The
etiology has been identified, initial management of asymptomatic progression-free survival rate at 2 years in patients with gastric and
patients with expectant observation is acceptable. While on this extragastric ENMZL was 100% and 89%, respectively. Both purine
watch-and-wait approach, patients should be reassessed approximately analogues seem to have activity in t(11;18)–positive gastric ENMZL.
every 3 months with history, physical examination, complete blood
counts, basic chemistry, and LDH. Any new symptoms or findings
suggestive of transformation should be investigated with a repeat Other Single Agents
biopsy to rule it out. Routine repeat imaging studies are controversial
but often used. Other single chemotherapeutic agents whose use has been reported
Indications for initiating systemic treatment include symptomatic in ENMZL include oxaliplatin, bendamustine, bortezomib, and
disease caused by mass effect or effusion, risk for local compressive vorinostat. In a study of 16 patients (stages I to IV) treated with
disease, bulky lymphadenopathy, symptomatic splenomegaly, B oxaliplatin, a CR rate of 56% with a median time to response of 4
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symptoms, cytopenias arising from bone marrow involvement, or months was observed. Responses to bendamustine (with or without
rapid disease progression. Although unlikely to contribute to regres- rituximab) have been documented in patients with relapsed/refractory
sion of established advanced disease, treatment of an underlying indolent lymphomas, a small fraction of which were ENMZL 152,153 ;
infection associated with the lymphoma (such as H. pylori for primary a retrospective series of 14 ENMZL patients reported 10 CR and
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gastric ENMZL and C. jejuni for IPSID) is advisable to remove any three PR with the combination of bendamustine and rituximab.
inciting factor. Otherwise, as already mentioned, the same treatment Other studies of patients with relapsed, multiply treated indolent
approaches used for FL (see Chapter 80) are usually followed for lymphomas report encouraging responses to bortezomib (two cases
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ENMZL. Nonetheless, a few studies specifically addressing MZL are with PR out of two patients) and vorinostat (one CR and one PR
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worth reviewing here. out of nine patients). Long-term follow up is not available; there-
fore, the role of these agents as first-line therapy has not been
established.
Rituximab
Given its low toxicity, single-agent immunotherapy with rituximab Combination Chemotherapy
has generated a lot of interest in the management of advanced disease.
Two series of approximately 30 patients each, pooling early- and Combination chemotherapy regimens reported in ENMZL patients
advanced-stage ENMZL, have reported overall response rates of include CVP (cyclophosphamide, vincristine, and prednisone) fol-
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around 75%, 141,142 with up to 48% CR in patients without previous lowed by radiation therapy, FM (fludarabine and mitoxantrone),
therapy. In one of the series, median time to treatment failure was CHOP (cyclophosphamide, hydroxydaunomycin, vincristine
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22 versus 12 months in chemotherapy-naive versus non-naive [Oncovin], and prednisone) followed by CVP, MCP (mitoxan-
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patients, respectively. Rituximab has activity in t(11;18)–positive trone, chlorambucil, and prednisone), R-CHOP (rituximab,
disease. 142 cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and