Follicular lymphoma comprises 20% of all NHL and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[1-3] Most patients with follicular lymphoma are age 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the BCL2 gene is present in more than 90% of patients with follicular lymphoma; overexpression of the BCL2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis.
Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent.[5-7] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment. Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[9,10] An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI]) [11-13] identified five significant risk factors prognostic of overall survival (OS):
Age (≤60 years vs. >60 years).
Serum lactate dehydrogenase (LDH) (normal vs. elevated).
Stage (stage I or stage II vs. stage III or stage IV).
Hemoglobin level (≥120 g/L vs. <120 g/L).
Number of nodal areas (≤4 vs. >4).
Patients with one risk factor or none have an 85% 10-year survival rate, and three or more risk factors confer a 40% 10-year survival rate. In a revised FLIPI-2, an elevated beta-2-microglobulin and lymph node size of more than 6 cm are proposed prognostic factors instead of serum LDH and the number of nodal areas. Although the FLIPI and FLIPI-2 indices can predict progression-free survival (PFS) and OS, the scores cannot be used to establish the need for therapy, nor can they be used to predict response to therapy.[11,14] The primary use of FLIPI or FLIPI-2 is to assure a balance of prognostic factors or to define entry requirements in randomized clinical trials. Individuals with an adverse FLIPI score may well benefit from watchful waiting or may respond well to initial therapy. An alternative prognostic index using only beta-2-microglobulin and initial bone marrow involvement (PRIMA-PI) has the disadvantage of requiring an invasive test not usually required outside the context of a clinical trial.
Two retrospective analyses identified a high-risk group that had a 50% OS rate at 5 years when relapse occurred after induction chemoimmunotherapy at 24 or 30 months; this has not been validated in prospective studies or an independent cohort.[16,17] These higher-risk patients represent a target population for clinical trials.
Follicular, small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.
Because of the often indolent clinical course and the lack of symptoms in some patients with follicular lymphoma, watchful waiting remains a standard of care during the initial encounter and for patients with slow asymptomatic relapsing disease. When therapy is required, numerous therapeutic options may be employed in varying sequences with an OS equivalence at 5 to 10 years.[9,18-20] Rituximab can be given alone or in combination with various chemotherapy options.[20,21] Rituximab can also be combined with the immunomodulating-agent lenalidomide to avoid the short- and long-term toxicities of cytotoxic agents.[22,23] Another anti–CD20 monoclonal antibody, obinutuzumab, can be administered with combination chemotherapy. Inhibitors of phosphatidylinositol 3-kinase (PI3K) are also effective in patients with relapsed or refractory disease.[25-28] Consolidation therapy for relapsed disease after reinduction therapy using autologous stem cell transplant (SCT) or allogeneic SCT can be considered.
Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress and rarely require therapy.[30,31] A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histologic variant are characterized by a lack of BCL2rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.
Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy can be performed, if feasible. Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type. Rapid growth or discordant growth between various disease sites may indicate a histologic conversion. The risk of histologic transformation was 30% by 10 years in a retrospective review of 325 patients from diagnosis between 1972 and 1999. In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, and expectant management (as opposed to treatment being initiated at diagnosis). The 5-year OS rate was more than 50% for patients who had biopsy-proven, aggressive-histology transformation in several multicenter cohort studies employing rituximab plus anthracycline or platinum-based chemotherapy, or similar therapy followed by autologous or allogeneic SCT.[33,36,37]
In a prospective nonrandomized study, at a median follow-up of 6.8 years, 379 (14%) of 2,652 patients subsequently transformed to a more aggressive histology after an initial diagnosis of follicular lymphoma.[Level of evidence: 3iiiDiv] The median OS after subsequent transformation was 5 years; however, among 47 patients with evidence of transformation in conjunction with follicular lymphoma at the time of initial diagnosis, the OS was no worse than that of the other nontransformed patients (5-year OS, 88%; 95% confidence interval [CI], 74%–95%).
Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia). Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Most patients with Waldenström macroglobulinemia carry the MYD88 mutation, which some pathologists consider pathognomonic for the disease. Other lymphomas may also be associated with serum paraproteins. Patients with lymphoplasmacytic lymphoma should be checked for associated hepatitis C virus infection.
Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[9,41,42]
Prognostic factors associated with symptoms requiring therapy include the following:
The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse, small lymphocytic lymphoma/chronic lymphocytic leukemia.[41,43-45] If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and central nervous system [CNS] dysfunction) but can be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, cyclophosphamide, and steroids are often employed. Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
First-line regimens include rituximab and ibrutinib, rituximab alone, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[46-50] In a randomized prospective trial, 150 symptomatic patients (including previously untreated and relapsing patients) received either ibrutinib and rituximab or rituximab and a placebo. With a median follow-up of 2.5 years, the PFS favored the ibrutinib-and-rituximab arm (82%) versus the rituximab-and-placebo arm (28%) (hazard ratio, 0.20; 95% CI, 0.11–0.38; P < .001), and the OS at 30 months was no different in the two arms (OS, 92%–94%).[Level of evidence: 1iDiii] A phase II trial of 30 patients studied single-agent ibrutinib in previously untreated Waldenström macroglobulinemia patients. With a median follow-up of 15 months, the objective response rate was 83%, and the 18-month PFS rate was 92% (95% CI, 73%–98%).[Level of evidence: 3iiiDiv] Rituximab showed 60% to 80% response rates in previously untreated patients, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[46,52,53][Level of evidence: 3iiiDiv] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent, such as cyclophosphamide or the proteosome inhibitor bortezomib.[42,54,55] A combination of bortezomib, dexamethasone, and rituximab has been used with avoidance of an IgM rebound.[56-58] The nucleoside analogs 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[49,59,60][Level of evidence: 3iiiDiv] Single-agent alkylators, bendamustine, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[49,54,61-64][Level of evidence: 3iiiDiv] In the rare case of lymphoplasmacytic lymphoma involving the central nervous system (Bing-Neel syndrome), ibrutinib resulted in an 85% response rate in an anecdotal series of 28 patients.[Level of evidence: 3iiiDiv]
Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[66-69] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia.[46,70] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months, P < .01), no difference was observed in OS.[Level of evidence: 1iiDii]
Marginal Zone Lymphoma
Marginal zone lymphomas were previously included among the diffuse, small lymphocytic lymphomas. When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas, and when they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called mucosa-associated lymphatic tissue (MALT) lymphomas.[72,73] A prognostic index for all of the marginal zone lymphomas has three adverse prognostic factors: age 70 years or older, stage III or stage IV disease, and high LDH level. Fewer than 10% of patients transform to a higher-grade lymphoma; risk factors in one retrospective review included elevated LDH, more than four nodal sites at the time of initial diagnosis of marginal zone lymphoma, and failure to achieve complete response after initial treatment.
Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pyloriinfection may resolve most cases of localized gastric involvement.[76,77] After standard antibiotic regimens, 50% of patients show resolution of gastric MALT by endoscopy after 3 months. Other patients may show resolution after 12 to 18 months of observation. Of the patients who attain complete remission, 30% demonstrate monoclonality by immunoglobulin heavy chain rearrangement on stomach biopsies with a 5-year median follow-up. The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts for poor response to antibiotic therapy, for H. pylori–negative testing, and for poor response to oral alkylator chemotherapy.[79-81] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression. Patients who progress are treated with radiation therapy,[82-85] rituximab, surgery (total gastrectomy or partial gastrectomy plus radiation therapy), chemotherapy, or combined–modality therapy. The use of endoscopic ultrasonography may help clinicians to follow responses in these patients. Four case series (encompassing more than 100 patients with stage IE or IIE diffuse large B-cell lymphoma (DLBCL) with or without associated MALT (but H. pylori-positive) reported durable complete remissions in more than 50% of the patients after treatment of H. pylori.[91-94]
Localized involvement of other sites can be treated with radiation or surgery.[83-85,95-98] Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, with relapses many years and even decades later. Many of these recurrences involve different MALT sites than the original location. When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[101,102] A prospective, randomized trial of 401 patients with nongastric, extranodal MALT compared chlorambucil alone versus rituximab plus chlorambucil versus rituximab alone. With a median follow-up of 7.4 years, the event-free survival was better for the rituximab-plus-chlorambucil arm (68%) than for the rituximab-alone arm (51%) and for the chlorambucil-alone arm (50%) (P = .0009); however, the 5-year OS was 90% in all arms. For patients with ocular adnexal MALT, antibiotic therapy using doxycycline that targeted Chlamydia psittaci resulted in durable remissions for almost half of the patients in a review of the literature that included 131 patients.[Level of evidence: 3iiiDiv] These responses to doxycycline are mainly seen in Italian trials and less often in trials conducted in other geographic sites. Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas. A large, retrospective review of primary ocular adnexal MALT found that after 10 years of follow-up, 4% of stage I patients treated with radiation therapy transformed to DLBCL, and 3% of them developed CNS involvement.
Nodal marginal zone lymphoma
Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with the same paradigm of watchful waiting or therapies as described for follicular lymphoma. Among patients with concomitant HCV infection, the majority attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[Level of evidence: 3iiiDiv]
Mediterranean abdominal lymphoma
The disease variously known as Mediterranean abdominal lymphoma, heavy–chain disease, or immunoproliferative small intestinal disease (IPSID), which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma, which responds to antibiotics in its early stages. Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.
Splenic marginal zone lymphoma
Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[112,113] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[72,114]
Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogs or alkylating agent chemotherapy. Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[112,115,116] Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and infection with HCV, the majority attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[109,117]; [Level of evidence: 3iiiDiv] In contrast, no responses to interferon were seen in six HCV-negative patients.
Primary Cutaneous Anaplastic Large Cell Lymphoma
Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no pre-existing lymphoproliferative disease and no extracutaneous sites of involvement.[119-121] Patients with this type of lymphoma encompass a spectrum ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to a progressive and systemic disease requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder.
Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is applied.[119-121]
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