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Home > Fitness & Health > Health Library > Adult Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
The non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.
Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.
Incidence and Mortality
Estimated new cases and deaths from NHL in the United States in 2021:
NHL usually originates in lymphoid tissues.
Anatomy of the lymph system.
Prognosis and Survival
NHL can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas.
Indolent NHL types have a relatively good prognosis with a median survival as long as 20 years, but they usually are not curable in advanced clinical stages. Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology.
The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.
In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.
While indolent NHL is responsive to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. Patients, however, can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support.[5,6]
Other PDQ summaries containing information related to non-Hodgkin lymphoma treatment include the following:
Late effects of treatment for non-Hodgkin lymphoma (NHL) have been observed. Pelvic radiation therapy and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility. For as many as three decades after diagnosis, patients are at a significantly elevated risk of developing second primary cancers, especially the following:[1,2,3]
Left ventricular dysfunction was a significant late effect in long-term survivors of high-grade NHL who received more than 200 mg/m² of doxorubicin.[4,5]
Myelodysplastic syndrome and acute myelogenous leukemia are late complications of myeloablative therapy with autologous bone marrow or peripheral blood stem cell support, as well as conventional chemotherapy-containing alkylating agents.[1,6,7,8,9,10,11,12,13] Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[8,14,15] With a median 10-year follow-up after autologous bone marrow transplantation (BMT) with conditioning using cyclophosphamide and total-body radiation therapy, in a series of 605 patients, the incidence of a second malignancy was 21%, and 10% of those were solid tumors.
Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT.
Long-term impaired immune health was evaluated in a retrospective cohort study of 21,690 survivors of diffuse large B-cell lymphoma from the California Cancer Registry. Elevated incidence rate ratios were found up to 10 years later for pneumonia (10.8-fold), meningitis (5.3-fold), immunoglobulin deficiency (17.6-fold), and autoimmune cytopenias (12-fold).
Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.
A pathologist should be considered for consultation before a biopsy because some studies require special preparation of tissue (e.g., frozen tissue). Knowledge of cell surface markers and immunoglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light-chain immunoglobulin may differentiate malignant from reactive cells. Since the prognosis and the approach to treatment are influenced by histopathology, outside biopsy specimens should be carefully reviewed by a hematopathologist who is experienced in diagnosing lymphomas. Although lymph node biopsies are recommended whenever possible, sometimes immunophenotypic data are sufficient to allow diagnosis of lymphoma when fine-needle aspiration cytology is preferred.[1,2]
Historical Classification Systems
Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation. The Working Formulation combined results from six major classification systems into one classification. This allowed comparison of studies from different institutions and countries. The Rappaport classification, which also follows, is no longer in common use.
Current Classification Systems
As the understanding of NHL has improved and as the histopathologic diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathologic entities have been described. In addition, the understanding and treatment of many of the previously described pathologic subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. Thus, European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) classification.[5,6,7,8] Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system.[9,10]
The WHO modification of the REAL classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma (HL). Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For example, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma are simply different manifestations of the same neoplasm, as are lymphoblastic lymphomas and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.[9,10]
Updated REAL/WHO classification
T-cell and putative NK-cell neoplasms
The REAL classification encompasses all the lymphoproliferative neoplasms. Refer to the following PDQ summaries for more information:
PDQ modification of REAL classification of lymphoproliferative diseases
Indolent non-Hodgkin lymphoma (NHL) includes the following subtypes:
Follicular lymphoma comprises 20% of all NHL and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[1,2,3] 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.[5,6,7] 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]) [11,12,13] identified five significant risk factors prognostic of overall survival (OS):
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] A third retrospective analysis of 296 patients who received bendamustine-rituximab found a 2-year OS rate of 38% (95% confidence interval [CI], 20%−55%) after progression of disease at 24 months (POD24). Most of these patients (76%) had transformed disease (histologic progression to diffuse large B-cell lymphoma). These higher-risk POD24 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.[9,19,20,21] Rituximab can be given alone or in combination with various chemotherapy options.[21,22] Rituximab can also be combined with the immunomodulating-agent lenalidomide to avoid the short- and long-term toxicities of cytotoxic agents.[23,24,25] 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.[27,28,29,30] 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.[32,33] 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 BCL2 rearrangement 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.[35,38,39]
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 rate, 88%; 95% CI, 74%–95%).
Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)
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.[9,43,44]
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.[45,46] 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 (a Bruton tyrosine kinase inhibitor), rituximab alone, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[47,48,49,50,51] 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 rate 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 rate at 30 months was no different in the two arms (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] Zanubrutinib, another Bruton tyrosine kinase inhibitor, was compared with ibrutinib in a randomized prospective clinical trial of 164 patients with relapsed disease and 38 previously untreated patients. With a median follow-up of 18 months, the PFS rate was the same in both groups at 84%. The zanubrutinib group had fewer cases of atrial fibrillation (11 cases vs. 1 case) and 50% fewer cases of hypertension (statistics not provided).[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.[47,54,55][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.[44,56,57] A combination of bortezomib, dexamethasone, and rituximab has been used with avoidance of an IgM rebound.[58,59,60] The nucleoside analogs 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[50,61,62][Level of evidence: 3iiiDiv] Single-agent alkylators, bendamustine, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[50,56,63,64,65,66][Level of evidence: 3iiiDiv] In the rare case of lymphoplasmacytic lymphoma involving the CNS (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.[68,69,70,71] 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.[47,72] 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.[74,75] 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 pylori infection may resolve most cases of localized gastric involvement.[78,79] 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.[81,82,83] 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,[84,85,86,87] 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.[93,94,95,96]
Localized involvement of other sites can be treated with radiation or surgery.[85,86,87,97,98,99,100] 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.[103,104] 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 rate 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. Similar to follicular lymphoma, patients with POD24 who required initiation of therapy had a worse prognosis (53% 3-year OS rate) than did the patients without POD24 (95% 3-year OS rate). 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.[115,116] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[74,117]
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.[115,118,119] 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.[112,120]; [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.[122,123,124] 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.[122,123,124]
(Refer to the PDQ summaries on Chronic Lymphocytic Leukemia Treatment; Mycosis Fungoides [Including Sézary Syndrome] Treatment; Hairy Cell Leukemia Treatment; and Adult Hodgkin Lymphoma Treatment for more information.)
Aggressive non-Hodgkin lymphoma (NHL) includes the following subtypes:
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common NHL and comprises 30% of newly diagnosed cases. Most patients present with rapidly enlarging masses, often with both local and systemic symptoms (designated B symptoms with fever, recurrent night sweats, or weight loss). (Refer to the PDQ summary on Nutrition in Cancer Care for more information on weight loss.)
Some cases of large B-cell lymphoma have a prominent background of reactive T cells and often of histiocytes, so-called T-cell/histiocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with DLBCL.[2,3,4] Some patients with DLBCL at diagnosis have a concomitant indolent small B-cell component; while overall survival (OS) appears similar after multidrug chemotherapy, there is a higher risk of indolent relapse.
The vast majority of patients with localized disease are curable with combined–modality therapy or combination chemotherapy alone. For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[7,8,9]
The National Comprehensive Cancer Network International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:
Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease. Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biologic factors.
The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[13,14,15] Dose-intensive therapies, infusional therapies, and stem cell transplantation consolidation are being explored in this high-risk group.[16,17] A retrospective review evaluated 159 patients with previously untreated DLBCL who underwent double-hit genetic testing by fluorescence in situ hybridization (FISH) and achieved complete response (CR). The induction therapy did not alter 3-year relapse-free survival or OS when autologous stem cell transplantation (SCT) was employed.
In a retrospective review of 117 patients with relapsed or refractory DLBCL who underwent autologous SCT, the 4-year OS rate was 25% for double-hit lymphomas (rearrangement of BCL2 and MYC), 61% for double-expressor lymphomas (no rearrangement, but increased expression of BCL2 and MYC), and 70% for patients without these features. Patients at high risk of relapse may be considered for clinical trials.
Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy. Patients who have DLBCL with coexpression of CD20 and CD30 may define a subgroup with a unique molecular signature, a more favorable prognosis, and possible therapeutic implication for the use of anti-CD30–specific therapy, such as brentuximab vedotin. Patients with DLBCL who are event-free after 2 years have a subsequent OS equivalent to that of the age- and sex-matched general population.
Central nervous system (CNS) prophylaxis
CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased. CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[25,26]
A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% confidence interval [CI], 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[Level of evidence: 3iiiDiii]
The CNS-IPI is a tool used to predict which patients have a risk of CNS relapse above 10%. It was developed by the German Lymphoma Study Group and validated by the British Columbia Cancer Agency database. Four to six of the IPI risk factors (refer to the Prognosis section of this summary for more information) and involvement of the kidneys or adrenal glands were used to define the high-risk group that might benefit from CNS prophylaxis.
The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses.[29,30] Patients with CNS dissemination at diagnosis or at relapse usually receive rituximab and high doses of methotrexate and/or cytarabine followed by autologous SCT, but this approach has not been assessed in randomized trials.[31,32][Level of evidence: 3iiiDiv]
Primary Mediastinal Large B-cell Lymphoma
Primary mediastinal (thymic) large B-cell lymphoma is a subset of DLBCL with molecular characteristics that are most similar to nodular-sclerosing Hodgkin lymphoma (HL). Mediastinal lymphomas with features intermediate between primary mediastinal B-cell lymphoma and nodular-sclerosing HL are called mediastinal gray-zone lymphomas.[33,34] Patients are usually female and young (median age, 30–40 years). Patients present with a locally invasive anterior mediastinal mass that may cause respiratory symptoms or superior vena cava syndrome.
Prognosis and therapy is the same as for other comparably staged patients with DLBCL. Uncontrolled, phase II studies employing dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) show high cure rates while avoiding any mediastinal radiation.[34,35,36,37,38][Level of evidence: 3iiiA] These results suggest that patients who receive R-CHOP–based regimens may avoid the serious long-term complications of radiation therapy when given with chemotherapy. Posttreatment fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET-CT) scans are controversial; it remains unclear if PET scans can reliably identify patients who can take or omit radiation therapy consolidation.[35,39,40,41] The only randomized trial showing an OS advantage for combined modality therapy was retracted. In situations where mediastinal radiation would encompass the left side of the heart or would increase breast cancer risk in young female patients, proton therapy may be considered to reduce radiation dose to organs at risk. (Refer to the Superior Vena Cava Syndrome section in the PDQ summary on Cardiopulmonary Syndromes for more information.)
Because primary mediastinal large B-cell lymphoma is characterized by high expression of programmed death-ligand 1 (PD-L1) and variable expression of CD30, a phase II study evaluated nivolumab plus brentuximab vedotin in 30 patients with relapsed disease. With a median follow-up of 11.1 months, the objective response rate (ORR) was 73% (95% CI, 54%−88%).[Level of evidence: 3iiiDiv] Similarly, phase I and II trials of pembrolizumab in 74 patients with relapsed or refractory disease showed an ORR of 45% to 48%. The median duration of response was not reached for the 21 patients with a median follow-up of 29 months or for the 53 patients with a median follow-up of 12.5 months.[Level of evidence: 3iiiDiv]
Follicular Large Cell Lymphoma
The natural history of follicular large cell lymphoma remains controversial. While there is agreement about the significant number of long-term disease-free survivors with early-stage disease, the curability of patients with advanced disease (stage III or stage IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma). Other investigators report a plateau in freedom from progression at levels expected for an aggressive lymphoma (40% at 10 years).[47,48] This discrepancy may be caused by variations in histologic classification between institutions and the rarity of patients with follicular large cell lymphoma. A retrospective review of 252 patients, all treated with anthracycline-containing combination chemotherapy, showed that patients with more than 50% diffuse components on biopsy had a worse OS than other patients with follicular large cell lymphoma.
Treatment of follicular large cell lymphoma is more similar to treatment of aggressive NHL than it is to the treatment of indolent NHL. In support of this approach, treatment with high-dose chemotherapy and autologous hematopoietic peripheral SCT shows the same curative potential in patients with follicular large cell lymphoma who relapse as it does in patients with diffuse large cell lymphoma who relapse.[Level of evidence: 3iiiA]
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphomas (ALCL) may be confused with carcinomas and are associated with the Ki-1 (CD30) antigen. These lymphomas are usually of T-cell origin, often present with extranodal disease, and are found especially in the skin.
The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin-anaplastic lymphoma kinase (ALK).[51,52]
Patients whose lymphomas express ALK (immunohistochemistry) are usually younger and may have systemic symptoms, extranodal disease, and advanced-stage disease; however, they have a more favorable survival rate than that of ALK-negative patients.[53,54]
In a prospective randomized trial of 452 patients with CD30-positive T-cell lymphoma, 70% of whom had ALCL (22% ALK-positive and 48% ALK-negative patients), the previously used standard regimen, CHOP, was compared with brentuximab vedotin (an anti-CD30 monoclonal antibody conjugated to a cytotoxic agent) combined with cyclophosphamide, doxorubicin, and prednisone. With a median follow-up of 35 months, the brentuximab combination (3-year OS rate, 77%) showed an OS advantage over CHOP (3-year OS rate, 68%); (hazard ratio [HR], 0.66; 95% CI, 0.46–0.95; P = .02).[Level of evidence: 1iiA] This established brentuximab plus cyclophosphamide, doxorubicin, and prednisone as a new option for patients with ALCL and other CD30-positive T-cell lymphomas, such as angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. For patients with relapsed disease, anecdotal responses have been reported for brentuximab vedotin (anti-tubulin agent attached to a CD30-specific monoclonal antibody),[56,57,58,59] romidepsin, and pralatrexate.[Level of evidence: 3iiiDiv] In a phase II study (NCT00866047), 66% of 58 patients attained a CR with brentuximab vedotin. At a median follow-up of 58 months, the 5-year PFS rate was 57% (95% CI, 41%–74%), and the 5-year OS rate was 79% (95% CI, 65%–92%) with 42% of these patients undergoing hematopoietic SCT.[Level of evidence: 3iiiDiv] For patients with relapsed disease, autologous or allogeneic SCT showed a 50% 3-year PFS for 39 patients in a retrospective review.[Level of evidence: 3iiiDiii]
ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy. Patients with breast implant–associated ALCL may do well without chemotherapy after capsulectomy and implant removal if the disease is confined to the fibrous capsule, and no associated mass or lymphadenopathy is present.[64,65,66,67]
Extranodal Natural Killer (NK)-/T-cell Lymphoma
Extranodal natural killer (NK)-/T-cell lymphoma (nasal type) is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region. Other extranodal sites include the palate, trachea, skin, and gastrointestinal tract. Hemophagocytic syndrome may occur; historically, these tumors were considered part of lethal midline granuloma. In most cases, Epstein-Barr virus (EBV) genomes are detectable in the tumor cells and immunophenotyping shows CD56 positivity. Cases with blood and marrow involvement are considered NK-cell leukemia.
The increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, concurrently, before the start of chemotherapy or between cycle two and three of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.[70,71,72,73,74,75,76,77]
A retrospective review of 1,273 early-stage patients stratified them into a low-risk group and high-risk group using stage, age, LDH, performance status, and primary tumor invasion. Low-risk patients fared best with radiation therapy alone, while high-risk patients fared best with a strategy of radiation therapy combined with chemotherapy.[76,79,80]
In a retrospective review of 303 previously untreated patients from an international consortium who received nonanthracycline chemotherapy, the OS rates were identical for early-stage patients (72%−74% at 5 years) who received either concurrent chemotherapy and radiation therapy or chemotherapy followed by radiation therapy.[Level of evidence: 3iiiDiv]
Higher doses of radiation therapy administered at more than 50 Gy are associated with improved outcomes according to anecdotal reports. The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced-stage disease or extranasal presentation, has led some investigators to recommend autologous or allogeneic peripheral SCT consolidation.[77,82,83,84,85,86] L-asparaginase-containing regimens have shown anecdotal response rates greater than 50% for relapsing, refractory, or newly diagnosed patients.[77,87,88,89] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56. A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy can be distinguished from NK-/T-cell lymphoma.
Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[92,93] The histology shows association with angioinvasion and vasculitis, usually manifesting as pulmonary lesions or paranasal sinus involvement.
Patients are managed like others with diffuse large cell lymphoma and require doxorubicin-based combination chemotherapy.
Angioimmunoblastic T-cell Lymphoma
Angioimmunoblastic T-cell lymphoma (AITL or ATCL) was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma.[94,95,96,97] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia. (Refer to the information on weight loss in the PDQ summary on Nutrition in Cancer Care and the information on skin rash in the PDQ summary on Pruritus.) Opportunistic infections are frequent because of an underlying immune deficiency. B-cell EBV genomes are detected in most affected patients.
Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is recommended as it is for other aggressive lymphomas.[94,97] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[Level of evidence: 1iiD] (Refer to the Anaplastic Large Cell Lymphoma section of this summary for more information.) The International Peripheral T-Cell Lymphoma Project involving 22 international centers identified 243 patients with AITL or ATCL; the 5-year OS and failure-free survival rates were 33% and 18%, respectively. Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[85,100,101,102] Anecdotal responses have been reported for cyclosporine, pralatrexate, bendamustine, the histone deacetylase inhibitor romidepsin, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[60,106][Level of evidence: 3iiiDiv] Occasional spontaneous remissions and protracted responses to steroids only have been reported.
Peripheral T-cell Lymphoma
Patients with peripheral T-cell lymphoma have diffuse large cell or diffuse mixed lymphoma that expresses a cell surface phenotype of a postthymic (or peripheral) T-cell expressing CD4 or CD8 but not both together. Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[69,108] This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells.
Most investigators report worse response and survival rates for patients with peripheral T-cell lymphomas than for patients with comparably staged B-cell aggressive lymphomas.[108,109] Most patients present with multiple adverse prognostic factors (i.e., older age, stage IV, multiple extranodal sites, and elevated LDH), and these patients have a low (<20%) failure-free survival and OS at 5 years.[108,109] As with other lymphomas (e.g., DLBCL or follicular lymphoma), event-free survival at 24 months predicts a 5-year OS of 78%.
Therapy involves doxorubicin-based combination chemotherapy (such as CHOP or CHOPE [CHOP plus etoposide]), which is also used for DLBCL. For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[Level of evidence: 1iiD] (Refer to the Anaplastic Large Cell Lymphoma section of this summary for more information.) For patients with early-stage disease, anecdotal retrospective series disagree on the value of consolidative radiation therapy after combination chemotherapy.[Level of evidence: 3iiiDiv] Consolidation using high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell support has been applied to patients with advanced-stage peripheral T-cell lymphoma after induction therapy with CHOP-based regimens and after response to reinduction therapy at first relapse. Evidence for this approach is anecdotal.[85,100,102,113,114,115] For relapsing patients, pralatrexate has shown a 30% response rate and a median 10-month duration of response for 109 evaluable patients in a prospective trial.[60,116][Level of evidence: 3iiiDiv] Also for relapsing patients, similar response rates were seen for romidepsin for 130 evaluable patients in a prospective trial.[Level of evidence: 3iiiDiv] Anecdotal responses have been seen with a combination of pralatrexate and romidepsin, single-agent bendamustine, belinostat, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[Level of evidence: 3iiiDiv] Incorporation of these new agents with CHOP chemotherapy is under clinical evaluation.[55,108] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, after relapse from previous chemotherapy. The median PFS after first relapse was less than 6 months in one series of 163 patients with peripheral T-cell lymphoma.
An unusual type of peripheral T-cell lymphoma occurring mostly in young men, hepatosplenic T-cell lymphoma, appears to be localized to the hepatic and splenic sinusoids, with cell surface expression of the T-cell receptor gamma/delta.[120,121,122] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[123,124,125,126] These patients have cells that express alpha-beta phenotype. Those with gamma-delta phenotype have a more aggressive clinical course and are classified as cutaneous gamma-delta T-cell lymphoma.[127,128,129] These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa. These entities have extremely poor prognoses with an extremely aggressive clinical course and are treated within the same paradigm as the highest-risk groups with DLBCL.[85,122] An indolent T-cell lymphoproliferative disease of the gastrointestinal tract must be distinguished from peripheral T-cell lymphoma because no therapy may be indicated.
Enteropathy-type Intestinal T-cell Lymphoma
Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[69,131,132,133] Because a gluten-free diet prevents the development of lymphoma, patients diagnosed with celiac sprue in childhood rarely develop lymphoma. The diagnosis of celiac disease is usually made by finding villous atrophy in the resected intestine. Surgery is often required for diagnosis and to avoid perforation during therapy.
Therapy is with doxorubicin-based combination chemotherapy, but relapse rates appear higher than for comparably staged diffuse large cell lymphoma.[132,133,134] Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. (Refer to the PDQ summary on Nutrition in Cancer Care for more information on parenteral nutrition.) Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. High-dose therapy with hematopoietic stem cell rescue has been applied in first remission or at relapse.[85,132,135][Level of evidence: 3iiiDiii] Evidence for this approach is anecdotal.
Intravascular Large B-cell Lymphoma (Intravascular Lymphomatosis)
Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen. The brain, kidneys, lungs, and skin are the organs most likely affected by intravascular lymphomatosis.
With the use of aggressive R-CHOP–based combination chemotherapy, as is used in DLBCL, the prognosis is similar to that of conventional stage IV DLBCL.[136,137,138]
Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma
Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric NHL. These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-Myc gene on chromosome 8. A subgroup of patients with dual translocation of C-Myc and BCL2 appear to have an extremely poor outcome despite aggressive therapy (5-month OS).[Level of evidence: 3iiiA]
In some patients with larger B cells, there is morphologic overlap with DLBCL. These Burkitt-like large cell lymphomas show C-Myc deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[142,143,144] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing EBV genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high LDH but are potentially curable with intensive doxorubicin-based combination chemotherapy.
Treatment of Burkitt lymphoma/diffuse small noncleaved-cell lymphoma involves aggressive multidrug regimens in combination with rituximab, similar to those used for the advanced-stage aggressive lymphomas (diffuse large cell).[145,146,147,148] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[149,150,151,152] Adverse prognostic factors include bulky abdominal disease and high serum LDH. Patients with Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. Prophylaxis with intrathecal chemotherapy is required as part of induction therapy. Patients with HIV-associated Burkitt lymphoma also benefit from less-toxic modification of the aggressive multidrug regimens in combination with rituximab.[Level of evidence: 3iiiDiv] (Refer to the PDQ summaries on Primary CNS Lymphoma Treatment and AIDS-Related Lymphoma Treatment for more information.)
Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often, but not exclusively, occurs in young patients. It is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the CNS.
Treatment is usually patterned after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without bone marrow transplantation is the standard treatment for this aggressive histologic type of NHL.[156,157,158] Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Adult T-cell Leukemia/Lymphoma
Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus human T-lymphotrophic virus 1 and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to combination chemotherapy.[159,160] ATL has been divided into four clinical subtypes:[161,162]
The acute and lymphoma types of ATL have done poorly with strategies of combination chemotherapy and allogeneic SCT with a median OS under 1 year.[163,164,165] Using combination chemotherapy, less than 10% of 807 patients were alive after 4 years. Anecdotal durable remissions have been reported after allogeneic SCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[Level of evidence: 3iiiDiv] Among 815 patients who underwent allogeneic SCT in two retrospective reviews, the 3-year OS rates were 36% and 26%.[167,168][Level of evidence: 3iiiA]
The combination of zidovudine and interferon-alpha has activity against ATL, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in the majority of presenting patients with this combination but are not seen in patients with the lymphoma subtype of ATL.[169,170,171,172,173] In a multicenter phase II study of 26 relapsed patients, 42% responded to lenalidomide (including four CR).[Level of evidence: 3iiiDiv] Symptomatic local progression of all subtypes responds well to palliative radiation therapy. In the relapsed setting, an ORR above 50% is seen using mogamulizumab, a humanized monoclonal antibody against the C-C chemokine receptor 4 (CCR4).[Level of evidence: 3iiiDiv] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[Level of evidence: 1iiD] (Refer to the Anaplastic Large Cell Lymphoma section of this summary for more information.)
Mantle Cell Lymphoma
Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). Mantle cell lymphoma is characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein. Mantle cell lymphoma may be divided into two clinical subtypes: a classical version with lymphadenopathy with high SOX-11 expression that manifests with an aggressive clinical course and a worse prognosis versus a leukemic, non-nodal version with low SOX-11 expression and a more indolent course and a better prognosis. A complex karyotype predicts poor response to induction therapy and inferior survival. There is frequent overlap on presentation with these subtypes, and the therapeutic implication remains unclear. However, both of these versions can converge later in their course into a blastoid phenotype or treatment-resistant phenotype due to genomic instability and selection.
Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemotherapy and occurs in older patients with generally asymptomatic advanced-stage disease. The median survival, however, is significantly shorter (5–7 years) than that of other lymphomas, and this histology is now considered to be an aggressive lymphoma. A diffuse pattern and the blastoid variant have an aggressive course with shorter survival, while the mantle zone type may have a more indolent course. A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[183,184]
Asymptomatic patients with low-risk scores on the IPI may do well when initial therapy is deferred.[185,186][Level of evidence: 3iiiDiv] There is no standard approach to mantle cell lymphoma. Several induction chemotherapy regimens may be employed for symptomatic progressing disease. These regimens range in intensity from rituximab alone to rituximab plus bendamustine, to R-CHOP, to high-dose intensive regimens such as R-hyper C-VAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine). Some physicians use autologous SCT or allogeneic SCT consolidation next, while others prefer rituximab maintenance, reserving high-dose consolidation for a later time. Ibrutinib, lenalidomide, and bortezomib have shown activity in relapsing patients, and these drugs are being incorporated upfront.[188,189,190,191,192]
It is unclear which therapeutic approach offers the best long-term survival in this clinicopathologic entity. In a prospective randomized trial, 560 patients older than 60 years and not eligible for SCT were given either R-CHOP or R-FC (rituximab, fludarabine, cyclophosphamide) for six to eight cycles, followed by maintenance therapy in responders randomly assigned to rituximab or interferon-alpha maintenance therapy. With a median follow-up of 7.6 years, the median OS was significantly shorter after R-FC than after R-CHOP (3.9 years versus 6.4 years; P = .0054).[Level of evidence: 1iiA] In the same trial, with a median follow-up of 8 years for the 316 responding patients, rituximab maintenance resulted in improved OS over interferon maintenance (median OS, 9.8 years vs. 7.1 years; P = .009).[Level of evidence: 1iiA] Patients responsive to R-CHOP benefitted most from rituximab in OS (median 9.8 years vs. 6.4 years; P = .0026).[Level of evidence: 3iiA] A randomized trial compared bendamustine plus rituximab (BR) with R-CHOP and showed improved PFS (35 vs. 22 months; HR, 0.49; 95% CI, 0.28–0.79; P = .004) but no difference in OS.[Level of evidence: 1iiDiii] However, this trial failed to show any benefit for rituximab maintenance after BR. A prospective, randomized trial of 487 patients compared VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) with R-CHOP. With a median follow-up of 82 months, the median OS was longer for VR-CAP (90.7 months) compared with R-CHOP (55.7 months) (HR, 0.66; 95% CI, 0.51−0.85; P = .001).[Level of evidence: 1iiA]
A prospective randomized trial of 497 patients younger than 65 years compared six cycles of R-CHOP to six cycles of alternating R-CHOP and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), with both groups then receiving autologous SCT.[Level of evidence: 1iiDiii] With a median follow-up of 6.1 years, the time to treatment failure (TTF) was longer in the cytarabine group, with a median TTF follow-up of 9.1 years (95% CI, 6.3 years to not reached) compared with 3.9 years (95% CI, 3.2‒4.4 years) (HR, 0.56; corrected P = .038) for the control group. Despite this surprising difference in TTF, the OS was not different.
Many investigators are exploring high-dose chemoradiation immunotherapy with stem cell/bone marrow support or nonmyeloablative allogeneic SCT.[197,198,199,200,201,202] Thus far, randomized trials have not confirmed OS benefits from these newer approaches.
In a prospective trial (NCT00921414) of 299 patients who were previously untreated for mantle cell lymphoma, 257 responders received four courses of R-DHAP and autologous SCT. The patients were randomly assigned to receive rituximab maintenance therapy for 3 years versus no maintenance therapy. After randomization, a median follow-up at 50.2 months showed the rate of PFS at 4-years favored the rituximab-maintenance arm at 83% (95% CI, 73%–88%) versus the no-maintenance arm at 64% (95% CI, 55%–73%; P < .001). The 4-year OS rate also favored the rituximab-maintenance arm at 89% (95% CI, 81%–94%) versus the no-maintenance arm at 80% (95% CI, 72%–88%; P = .04).[Level of evidence: 1iiA]
Lenalidomide with or without rituximab also shows response rates of around 50% in relapsed patients, with even higher response rates for previously untreated patients.[189,192,204,205][Level of evidence: 3iiDiv]
The B-cell receptor-inhibitor, ibrutinib, showed a response rate of 86% (21% CR rate) in previously treated patients with a median PFS time of 14 months.[Level of evidence: 3iiiDiv] In a prospective randomized trial of 280 patients with relapsed/refractory mantle cell lymphoma, patients received either ibrutinib or temsirolimus. With a median follow-up of 15 months, the median PFS favored ibrutinib (14.6 months vs. 6.2 months; HR, 0.43; 95% CI, 0.32–0.58, P < .0001).[Level of evidence: 1iiDiii] Ibrutinib has been combined with another active agent, venetoclax, in a phase II study of 23 patients with relapsed or refractory mantle cell lymphoma. An unprecedented 71% of patients had CR and 78% of responding patients maintained response at 15 months.[Level of evidence: 3iiiDiv]
Acalabrutinib (another B-cell receptor inhibitor via the Bruton tyrosine kinase pathway) was studied in 124 patients with relapsed/refractory mantle cell lymphoma. In a phase II study, there was an 81% ORR, 40% CR rate, and the 1-year PFS rate was 67%.[Level of evidence: 3iiiDiv] Rituximab, lenalidomide, ibrutinib, acalabrutinib, and venetoclax represent directed biologic agents that may lead the way to chemotherapy-free strategies for patients with mantle cell lymphoma.
Patients with relapsed or refractory mantle cell lymphoma whose disease did not respond to ibrutinib or acalabrutinib were enrolled in a phase II trial using KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. With a median follow-up of 12 months, 60 patients had an overall response rate of 93% (95% CI, 84%−98%) and a 67% CR (95% CI, 53%−78%).[Level of evidence: 3iiiDiv] Grade 3 or higher cytokine release syndrome occurred in 15% of patients, and neurologic events occurred in 31% of patients.
Posttransplantation Lymphoproliferative Disorder
Patients who undergo transplantation of the heart, lung, liver, kidney, or pancreas usually require lifelong immunosuppression. This may result in posttransplantation lymphoproliferative disorder (PTLD) in 1% to 3% of recipients, which appears as an aggressive lymphoma. Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.
Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[213,214]
In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[215,216] When this is unsuccessful or not feasible, a course of rituximab may be considered, because it has shown durable remissions in approximately 60% of patients and a favorable toxicity profile.[215,217,218] If these measures fail, doxorubicin-based combination chemotherapy (R-CHOP) is recommended, although some patients can avoid cytotoxic therapy.[218,219] Localized presentations can be controlled with surgery or radiation therapy alone. These localized mass lesions, which may grow over a period of months, are often phenotypically polyclonal and tend to occur within weeks or a few months after transplantation. Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV. These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[220,221,222] Instances of EBV-negative PTLD occur even later (median, 5 years posttransplant) and have a worse prognosis; R-CHOP chemotherapy can be applied directly in this circumstance. A sustained clinical response after failure from chemotherapy was attained using an immunotoxin (anti-CD22 B-cell surface antigen antibody linked with ricin, a plant toxin). An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.
True Histiocytic Lymphoma
True histiocytic lymphomas are very rare tumors that show histiocytic differentiation and express histiocytic markers in the absence of B-cell or T-cell lineage-specific immunologic markers.[226,227] Care must be taken with immunophenotypic tests to exclude ALCL or hemophagocytic syndromes caused by viral infections, especially EBV.
Therapy is modeled after the treatment of comparably staged diffuse large cell lymphomas, but the optimal approach remains to be defined.
Primary Effusion Lymphoma
Primary effusion lymphoma presents exclusively or mainly in the pleural, pericardial, or abdominal cavities in the absence of an identifiable tumor mass. Patients are usually HIV seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.
The prognosis of primary effusion lymphoma is extremely poor.
Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas.
Plasmablastic lymphoma is most often seen in patients with HIV infection and is characterized by CD20-negative large B cells with plasmacytic features. This type of lymphoma has a very aggressive clinical course, including poor responses and short remissions with standard chemotherapy. Anecdotal reports suggest using aggressive chemotherapy for Burkitt or lymphoblastic lymphoma, followed by SCT consolidation in responding patients, when feasible.[230,231,232]
Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomography (CT) scans are usually part of the staging evaluation for all lymphoma patients. The staging system is similar to the staging system used for Hodgkin lymphoma (HL).
Common among patients with NHL is involvement of the following:
Cytologic examination of cerebrospinal fluid may be positive in patients with aggressive NHL. Involvement of hilar and mediastinal lymph nodes is less common than in HL. Mediastinal adenopathy, however, is a prominent feature of lymphoblastic lymphoma and primary mediastinal B-cell lymphoma, entities primarily found in young adults.
The majority of patients with NHL present with advanced (stage III or stage IV) disease that can often be identified with limited staging procedures such as CT scanning and biopsies of the bone marrow and other accessible sites of involvement. Laparoscopic biopsy or laparotomy is not required for staging but may be necessary to establish a diagnosis or histologic type. Positron emission tomography (PET) with fluorine F 18-fludeoxyglucose can be used for initial staging and for follow-up after therapy as a supplement to CT scanning. Interim PET scans after two to four cycles of therapy did not provide reliable prognostic information because of problems of interobserver reproducibility in a large cooperative group trial (ECOG-E344 [NCT00274924]) and lack of difference in outcome between PET-negative and PET-positive/biopsy-negative patients in two prospective trials [3,4,5] and in a meta-analysis. For patients with follicular lymphoma, a positive PET result after therapy has a worse prognosis; however, it is unclear whether a positive PET result is predictive when further or different therapy is implemented.
In a retrospective study of 130 patients with diffuse large B-cell lymphoma, PET scanning identified all clinically important marrow involvement from lymphoma, and bone marrow biopsy did not upstage any patient. Bone marrow biopsies are required for some clinical trials and when the identification of marrow involvement would change the therapeutic plan.
Staging Subclassification System
The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma. The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference, with some modifications 18 years later from the Cotswolds meeting.[11,12]
Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.
The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.
Current practice assigns a clinical stage based on the findings of the clinical evaluation and a pathologic stage based on the findings made as a result of invasive procedures beyond the initial biopsy.
For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be clinical stage IIA, pathologic stage IVA(H+)(M+).
A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:
The National Comprehensive Cancer Network International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of overall survival (OS):
Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease. Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biologic factors.
The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[16,17] Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation. Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.
Treatment of non-Hodgkin lymphoma (NHL) depends on the histologic type and stage. Many of the improvements in survival have been made using clinical trials (experimental therapy) that have attempted to improve on the best available accepted therapy (conventional or standard therapy).
In asymptomatic patients with indolent forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses. When treatment is deferred, the clinical course of patients with indolent NHL varies; frequent and careful observation is required so that effective treatment can be initiated when the clinical course of the disease accelerates. Some patients have a prolonged indolent course, but others have disease that rapidly evolves into more aggressive types of NHL that require immediate treatment.
Radiation techniques differ somewhat from those used in the treatment of Hodgkin lymphoma. The dose of radiation therapy usually varies from 25 Gy to 50 Gy and is dependent on factors that include the histologic type of lymphoma, the patient's stage and overall condition, the goal of treatment (curative or palliative), the proximity of sensitive surrounding organs, and whether the patient is being treated with radiation therapy alone or in combination with chemotherapy. Given the patterns of disease presentations and relapse, treatment may need to include unusual sites such as Waldeyer ring, epitrochlear nodes, or mesenteric nodes. The associated morbidity of the treatment must be considered carefully. The majority of patients who receive radiation are usually treated on only one side of the diaphragm. Localized presentations of extranodal NHL may be treated with involved-field techniques with significant (>50%) success.
Even though standard treatment in patients with lymphomas can cure a significant fraction, numerous clinical trials that explore improvements in treatment are in progress. If possible, patients can be included in these studies. Standardized guidelines for response assessment have been suggested for use in clinical trials.
Several retrospective reviews suggest routine surveillance scans after attaining clinical complete remission after induction therapy for diffuse large B-cell lymphoma (DLBCL) offer little to no value. Prognostic value is also difficult to identify for an interim positron emission tomography-computed tomography scan during induction therapy for DLBCL.[2,3,4,5]
Aggressive lymphomas are increasingly seen in HIV-positive patients; treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C can be assessed before treatment with rituximab and/or chemotherapy.[6,7] Patients with detectable hepatitis B viral loads benefit from prophylaxis with entecavir in the context of rituximab therapy.[8,9] Patients with a resolved hepatitis B virus (HBV) infection (HBsAg negative + HBcAb positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. Prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients. Similarly, prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually applied with rituximab with or without combination chemotherapy. Long-term impaired immune health was evaluated in a retrospective cohort study of 21,690 survivors of DLBCL from the California Cancer Registry. Elevated incidence rate ratios were found up to 10 years later for pneumonia (10.8-fold), meningitis (5.3-fold), immunoglobulin deficiency (17.6-fold), and autoimmune cytopenias (12-fold).
Among 2,508 patients in a Danish registry, the incidence of doxorubicin-induced congestive heart failure increased for 115 NHL survivors with a history of cardiac disease (hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.15−6.36) and/or multiple cardiovascular risk factors (HR, 2.86; 95% CI, 1.56−5.23).
Several unusual presentations of lymphoma occur that often require somewhat modified approaches to staging and therapy. The reader is referred to reviews for a more detailed description of extranodal presentations in the gastrointestinal system,[13,14,15,16,17,18,19,20,21] thyroid,[22,23] spleen, testis,[25,26,27] paranasal sinuses,[28,29,30,31] bone,[32,33] orbit,[34,35,36,37,38] and skin.[39,40,41,42,43,44,45,46,47,48]
(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Although localized presentations are uncommon in non-Hodgkin lymphoma (NHL), the goal of treatment is to cure the disease in patients who are shown to have truly localized occurrence after undergoing appropriate staging procedures.
Standard Treatment Options for Indolent Stage I and Indolent, Contiguous Stage II Adult NHL
Standard treatment options for indolent stage I and indolent, contiguous stage II adult NHL include the following:
In a prospective randomized trial, 150 patients with stage I or stage II follicular lymphoma were randomly assigned to 30 Gy of involved-field radiation therapy alone or radiation therapy plus six cycles of R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone). With a median follow-up of 9.6 years, the 10-year progression-free survival (PFS) rate favored combined-modality therapy, at 59% (95% confidence interval (CI), 46%–74%) versus 41% for radiation therapy alone (95% CI, 30%–57%) (P = .033), but with no difference in overall survival (OS) (87% and 95%, P = .40).[Level of evidence: 1iiDiii]
The National Lymphocare Study identified 471 patients with stage I follicular lymphoma. Of those patients, 206 were rigorously staged with a bone marrow aspirate and biopsy, and computed tomography (CT) scans or positron emission tomography (PET)-CT scans. Nonrandomized treatments included radiation therapy (27%), rituximab-chemotherapy (R-chemotherapy) (28%), watchful waiting (17%), R-chemotherapy plus radiation therapy (13%), and rituximab alone (12%), although more than one-third of the patients started with expectant therapy. With a median follow-up of 57 months, PFS favored R-chemotherapy or R-chemotherapy plus radiation therapy, but OS was nearly identical, all over 90%.[Level of evidence: 3iiiD] Clinical trials are required to answer questions such as the following:
Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using dosages of radiation that usually range from 25 Gy to 40 Gy to involved sites or to extended fields that cover adjacent nodal sites.[1,4,5,6] Almost half of all patients treated with radiation therapy alone will relapse out-of-field within 10 years.[1,6,7]
A retrospective review of 512 patients from an international consortium evaluated patients with early-stage follicular lymphoma who received at least 24 Gy of localized radiation therapy at initial presentation. With a median follow-up of 52 months, 29.1% of patients developed recurrent lymphoma at a median of 23 months (range, 1−143 months). With a median follow-up of 33 months after relapse, the 3-year OS rate was 91.4% after patients received subsequent systemic chemotherapy that involved rituximab, usually with chemotherapy.
Very low-dose radiation therapy with 4 Gy (2 Gy × 2 fractions) can result in 50% remission rates for patients who cannot tolerate higher doses. In situations in which mediastinal radiation would encompass the left side of the heart or would increase breast cancer risk in young female patients, proton therapy may be considered to reduce the radiation dose to organs at risk.
Rituximab with or without chemotherapy
For symptomatic patients who require therapy, when radiation therapy is contraindicated or when an alternative treatment is preferred, rituximab with or without chemotherapy can be employed (as outlined below for more advanced-stage patients). The value of adjuvant treatment with radiation to decrease relapse, plus rituximab (an anti–CD20 monoclonal antibody) either alone or in combination with chemotherapy, has been extrapolated from trials of patients with advanced-stage disease and has not been confirmed.[11,12]
Watchful waiting can be considered for asymptomatic patients. Watchful waiting has never been compared with upfront radiation therapy in a prospective randomized trial; a retrospective analysis of the Surveillance, Epidemiology and End Results Program (SEER) database over 30 years showed improved outcomes for upfront radiation therapy.
Other therapies as designated for patients with advanced-stage disease
Patients with involvement that is not able to be encompassed by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma.
Optimal treatment of advanced stages of low-grade non-Hodgkin lymphoma (NHL) is controversial because of low cure rates with the current therapeutic options. Numerous clinical trials are in progress to settle treatment issues, and patients are urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete response to treatment. Indeed, relapse may occur many years after treatment. Currently, no randomized trials provide guidance to clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.; [Level of evidence: 1iiDiii]
For patients with indolent, noncontiguous stage II and stage III NHL, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[3,4]
Standard Treatment Options for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Standard treatment options for indolent, noncontiguous stage II/III/IV adult NHL include the following:
Watchful waiting for asymptomatic patients
The rate of relapse is fairly constant over time, even in patients who have achieved complete responses (CR) to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) can be considered.[2,5,6,7] The Follicular Lymphoma International Prognostic Index (FLIPI) and the revised FLIPI-2 can predict progression-free survival (PFS) and overall survival (OS), but the scores cannot be used to establish the need for therapy in asymptomatic patients.[8,9]
Evidence (watchful waiting):
Standard therapy includes rituximab, an anti–CD20 monoclonal antibody, either alone, as was shown in the ECOG-E4402 (NCT00075946) trial,[13,14,15,16,17] or in combination with purine nucleoside analogs, such as fludarabine or 2-chlorodeoxyadenosine, alkylating agents (with or without steroids), or combination chemotherapy. Rituximab may be considered as first-line therapy, either alone or in combination with other agents. Rituximab may be given intravenously or subcutaneously, and biosimilar versions, such as CT-P10 and GP2013, have shown equivalent efficacy and safety.[18,19,20] Combinations include the following:
Evidence (rituximab with or without chemotherapy):
Lenalidomide and rituximab
The combination of the immunomodulating agent lenalidomide with rituximab (the so-called R2 regimen) has been proposed as an alternative regimen to combinations involving cytotoxic agents and their subsequent short- and long-term toxicities.
Evidence (lenalidomide and rituximab):
This trial established that the R2 regimen is equally efficacious to rituximab plus cytotoxic chemotherapy options; analysis of long-term toxicities must await longer follow-up.
After induction therapy with rituximab only or with rituximab plus chemotherapy, rituximab can be used once every 2 to 3 months. Several studies have evaluated this approach.
Evidence (maintenance rituximab for previously untreated patients):
These three randomized trials in previously untreated patients show no advantage for the use of rituximab maintenance versus observation and reinduction of therapy at the time of relapse. The trials suggest a benefit for maintenance rituximab after reinduction for relapsed disease. Many questions remain about rituximab maintenance, particularly about truncating therapy at 2 years and long-term safety and efficacy. A trial extending rituximab maintenance to 5 years showed similar EFS or OS versus 1 year of maintenance after induction therapy with rituximab in previously untreated patients.[Level of evidence: 1iiA]
For previously untreated patients, all of the studies showed improvement of PFS, with no change in OS.
Evidence (maintenance rituximab for previously treated patients):
For previously treated patients, there is more evidence to suggest an OS advantage with the use of rituximab maintenance.
Obinutuzumab is a glycoengineered type II anti–CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity than rituximab.
Several issues have been raised about this study:
In summary, in the absence of any change in OS, switching from rituximab to obinutuzumab in combination with chemotherapy for previously untreated follicular lymphoma is a difficult choice. The PFS differences may be attributable to the imbalance in monoclonal antibody dosing, and the increased side effects and costs are mitigating factors. In this trial, bendamustine combined with either antibody led to unacceptable rates of toxic death.
Phosphatidylinositol 3-kinase (PI3K) inhibitors
The PI3K inhibitors have significant adverse effects, including pneumonitis, colitis, transaminitis, hypertension, hyperglycemia, rash, and increased risk of infections. These adverse events have affected the use of these agents until confirmatory trials can establish their efficacy in combinations. They are currently approved for treatment of relapsed and refractory follicular lymphoma after two previously received lines of therapy.
Tazemetostat is an inhibitor of EZH2, a histone methyltransferase essential to formation of lymph node germinal centers, especially with activating mutations of EZH2.
Radiolabeled anti-CD20 monoclonal antibodies
Yttrium Y 90 (90Y)-ibritumomab tiuxetan (Zevalin) is available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma (iodine I 131 [131I]-tositumomab [Bexxar] is no longer available because of commercial disengagement).[57,58]
Evidence (radiolabeled anti-CD20 monoclonal antibodies):
131I-tositumomab became commercially unavailable in 2013.
Durable responses to radiolabeled monoclonal antibodies, such as 90Y-ibritumomab tiuxetan (commercially available) and iodine I 131-tositumomab (commercially unavailable), have also been reported before and after cytotoxic chemotherapy.[59,61,62][Level of evidence: 1iiDiii] However, the cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia is higher (4% vs. 1%; P = .02) in one of the randomized trials versus nonradiolabeled antibody with chemotherapy.
Treatment Options Under Clinical Evaluation for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Because none of the standard therapies listed above are curative for advanced-stage disease, innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation (SCT), and the use of idiotype vaccines and radiolabeled monoclonal antibodies.
In general, treatment with standard agents rarely produces a cure in patients whose disease has relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse will usually ensue. Favorable survival after relapse has been associated with an age younger than 60 years, complete remission rather than partial remission, and duration of response longer than 2 years. Even the most favorable subset, however, has a tenfold greater mortality compared with age-adjusted U.S. population rates.
Patients who experience a relapse with indolent lymphoma can often have their disease controlled with single agent or combination chemotherapy, rituximab (an anti–CD20 monoclonal antibody), lenalidomide, radiolabeled anti–CD20 monoclonal antibodies, or palliative radiation therapy.[3,4] Long-term freedom from second relapse, however, is uncommon and multiple relapses will usually occur. 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. Documentation of conversion to a more aggressive histology requires an appropriate change to therapy applicable to that histologic type. Rapid growth or discordant growth between various disease sites may indicate a histologic conversion.
In a retrospective review of 325 patients between 1972 and 1999, the risk of histologic transformation was 30% by 10 years from diagnosis. In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk Follicular Lymphoma International Prognostic Index, and expectant management. The median survival after transformation was 1 to 2 years, with 25% of patients alive at 5 years and with approximately 10% to 20% of patients alive 10 years after re-treatment.
A prospective trial of 631 patients with follicular lymphoma and with a median follow-up of 60 months in the rituximab era (2002–2009) found a 5-year transformation rate (11%) to a higher-grade histology. The median overall survival (OS) after transformation was 50 months, and the 5-year OS rate was 66%, if the transformation occurred more than 18 months after a diagnosis of follicular lymphoma. This series describes a better prognosis for patients with transformation than was experienced by patients in the prerituximab era.
(Refer to the Treatment for Aggressive, Recurrent Adult NHL section of this summary for descriptions of the regimens used to treat histologic conversions.) The durability of the second remission may be short, and clinical trials can be considered.
Standard Treatment Options for Indolent, Recurrent Adult NHL
Standard treatment options for indolent, recurrent adult non-Hodgkin lymphoma (NHL) include the following:
Rituximab results in a 40% to 50% response rate in patients who relapse with indolent B-cell lymphomas.[9,10,11,12,13] Rituximab can also be combined with combination chemotherapy.[14,15]
Obinutuzumab is a CD20-binding monoclonal antibody with alternative epitope binding.
Responses of 20% to 56% have been reported for lenalidomide, especially in patients with follicular lymphoma and small lymphocytic lymphoma, with even higher responses noted for the combination of lenalidomide and rituximab.[21,22][Level of evidence: 3iiiDiv]
Palliative radiation therapy
Palliation may be achieved with very low-dose (4 Gy) involved-field radiation therapy in two fractions for patients with indolent and aggressive relapsed disease. In a prospective randomized trial, treatment with 4 Gy was inferior to treatment with 24 Gy in 12 fractions in PFS (77% vs. 92%, P < .0001).[Level of evidence: 1iiDiii]
Chemotherapy (single agent or combination)
Patients may respond to the original induction regimen again, especially if the duration of remission exceeds 1 year. For relapsing patients, rituximab alone or in combination with agents not previously used may induce remissions.
Durable responses to radiolabeled monoclonal antibodies, such as yttrium Y 90 (90Y)-ibritumomab tiuxetan (commercially available) and iodine I 131-tositumomab (commercially unavailable), have also been reported before and after cytotoxic chemotherapy.[31,32,33][Level of evidence: 1iiDiii] However, the cumulative incidence of death resulting from myelodysplastic syndrome or acute myeloid leukemia is higher (4% vs. 1%; P = .02) in one of the randomized trials versus nonradiolabeled antibody with chemotherapy.
Patients with a resolved hepatitis B virus (HBV) infection (HBsAg negative + HBcAb positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. Prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients.
Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL
Treatment options under clinical evaluation include the following:
Evidence (stem cell transplant):
Patients with aggressive stage I or aggressive, contiguous stage II diffuse large B-cell lymphoma (DLBCL) are candidates for combination chemotherapy with or without involved-field radiation therapy (IF-XRT).
Standard Treatment Options for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL
Standard treatment options for aggressive stage I and aggressive, contiguous stage II adult non-Hodgkin lymphoma (NHL) include the following:
R-CHOP with or without IF-XRT
The confirmation of efficacy for rituximab in advanced-stage disease has suggested the use of R-CHOP with or without radiation therapy but its use is only supported by retrospective comparisons.[Level of evidence: 3iiiDiii]
Evidence (R-CHOP with or without IF-XRT):
Similar to the results of randomized studies of radiation therapy in the prerituximab era, radiation therapy can be deferred in nonbulky early-stage patients. For patients unable to tolerate prolonged-course chemotherapy, three cycles of R-CHOP plus radiation therapy has produced equivalent results based on single-arm retrospective trials.
Conclusion: For patients with favorable prognosis nonbulky (<7 cm) stage I or stage II DLBCL, four cycles of R-CHOP is sufficient. For patients with unfavorable prognosis, six cycles of R-CHOP or three cycles of R-CHOP and 40 Gy of radiation therapy can be utilized. Early-stage patients with bulky disease (>7.5 cm) have not been studied in randomized trials; combined modality therapy with R-CHOP for four to six cycles plus radiation therapy is usually chosen.
Treatment Options Under Clinical Evaluation for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL
The treatment of choice for patients with advanced stages of aggressive non-Hodgkin lymphoma (NHL) is combination chemotherapy, either alone or supplemented by local-field radiation therapy.
The following drug combinations are referred to in this section:
Standard Treatment Options for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
Standard treatment options for aggressive, noncontiguous stage II/III/IV adult NHL include the following:
The following studies established R-CHOP as the standard regimen for newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). Dose intensification of R-CHOP by a 14-day versus a 21-day cycle did not result in improved outcomes.
Clinical trials continue to explore modifications of R-CHOP. There is no validated trial for interim positron emission tomography–based treatment intensification. R-CHOP has curative potential even in patients older than 80 years who are frail and require reduced dosage of R-CHOP components. In a retrospective review of 239 patients, the 5-year cause-specific survival rate was 48% (95% CI, 41%−55%).[Level of evidence: 3iiiDiv]
Less than 10% of patients with DLBCL present with a concurrent indolent lymphoma at diagnosis, and these are predominantly of germinal center B-cell phenotype. A retrospective review of 1,324 patients showed similar EFS (HR, 1.19) and OS (HR, 1.09).[Level of evidence: 3iiiDiv] For 847 patients who were treated with R-CHOP and free of disease 24 months after therapy, the rate of indolent lymphoma relapse by 5 years was higher with a concurrent diagnosis of follicular lymphoma (7.4% vs. 2.1% at 5 years, P < .01) and with a germinal center B-cell phenotype (3.9% vs. 0.0% at 5 years, P = .02).
Stage IE or IIE gastric DLBCL
Four case series involving more than 100 patients with stage IE or IIE disease (with or without associated mucosa-associated lymphatic tissue) and with positive Helicobacter pylori infection reported that more than 50% of patients attained a durable complete remission after appropriate antibiotic therapy to eradicate H. pylori.[14,15,16,17][Level of evidence: 3iiiDiv]
The National Comprehensive Cancer Network IPI for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:
Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease. Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biologic factors.
The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[21,22,23,24] Patients at high risk of relapse may be considered for clinical trials. Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.
Treatment of tumor lysis syndrome
Patients with bulky and extensive lymphadenopathy and elevations of serum uric acid and LDH are at increased risk of tumor lysis syndrome resulting in metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and subsequent acute renal failure. Treatment options include: alkaline hydration, allopurinol, and rasburicase, a recombinant urate oxidase.
Central nervous system (CNS) prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with paranasal sinus or testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased. CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, and others do not.[30,31]
Evidence (CNS prophylaxis):
Patients with diffuse, small, noncleaved-cell/Burkitt's lymphoma or lymphoblastic lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis is recommended for these histologies.
Patients with a resolved hepatitis B virus (HBV) infection (HBsAg negative + HBcAb positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. Prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients.
Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL
Several randomized, prospective trials evaluated the role of autologous BMT or SCT consolidation versus chemotherapy alone in patients in first remission with diffuse large cell lymphoma.[34,35,36,37,38,39,40,41]; [42,43,44][Level of evidence: 1iiA] Although some of these trials demonstrated significant increases in EFS (by 10% to 20%) among patients who received high-dose therapy, significant differences in OS could not be demonstrated prospectively in any of the series.
Retrospective analyses of high-intermediate (two risk factors) or high-risk (more than three risk factors) patients as defined by IPI suggest improved survival with BMT in two of the trials.[35,41] These studies do not establish that high-dose consolidation is of value to patients with aggressive lymphoma who are truly at high risk of relapse, and they also demonstrate that EFS may be a poor surrogate for OS for these patients.
After R-CHOP induction chemotherapy (or similar regimens), the addition of involved-field radiation therapy to sites of initial bulky disease (≥5–10 cm) or to extralymphatic sites remains controversial.[46,47,48] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.
Standard Treatment Options for Aggressive, Recurrent Adult NHL
In a retrospective review of multiple international trials, 636 patients were identified as having refractory diffuse large B-cell lymphoma (DLBCL), which was defined as progression or stable disease during or just at completion of full-course chemotherapy or relapse within 1 year after autologous stem cell transplantation (SCT). With subsequent therapy the objective response rate was 26%, complete response (CR) rate was 7%, median overall survival (OS) was 6.3 months, and only 20% of patients were alive at 2 years.
Standard treatment options for aggressive, recurrent adult non-Hodgkin lymphoma (NHL) include the following:
Bone marrow or stem cell transplantation
Bone marrow transplantation (BMT) is the treatment of choice for patients whose lymphoma has relapsed. Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.[3,4,5,6,7]
In general, patients who responded to initial therapy and who responded to conventional therapy for relapse before the BMT have had the best results.
Peripheral SCT has yielded results equivalent to standard autologous SCT.[11,12] Even patients who never experienced complete remission with conventional chemotherapy may have prolonged progression-free survival (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[Level of evidence: 3iiiDiii] Some patients who relapse after a previous autologous SCT can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.[14,15]; [Level of evidence: 3iiiDiv]
Evidence (peripheral SCT):
Tafasitamab plus lenalidomide
Evidence (tafasitamab plus lenalidomide):
This combination was approved by the U.S. Food and Drug Administration (FDA) for patients with relapsed or refractory DLBCL.[Level of evidence: 3iiiDiv]
CAR T-cell therapy
Multiple trials describe patients with refractory large B-cell lymphoma who underwent an infusion of T cells that were engineered to express a chimeric antigen receptor (CAR) to target the CD19 antigen expressed on the malignant B cells using three different constructs: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel.[20,21,22,23,24] Each study reported a 50% to 60% CR, but the long-term durability of response is yet to be determined.[Level of evidence: 3iiiDiv] This represents a therapeutic option for patients with otherwise refractory or resistant disease. Patients who respond adequately may receive an autologous SCT or allogeneic SCT consolidation.
Lenalidomide plus rituximab
Evidence (lenalidomide plus rituximab):
Polatuzumab vedotin plus rituximab and bendamustine
Evidence (polatuzumab vedotin plus rituximab and bendamustine):
The polatuzumab vedotin combination with BR was approved by the U.S. FDA for patients with relapsed or refractory DLBCL.
In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy. Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.
LBL is a very aggressive form of non-Hodgkin lymphoma (NHL), which often occurs in young patients but not exclusively. LBL is the lymphomatous manifestation of ALL. The treatment paradigms are based on trials for ALL because LBL and ALL are considered different manifestations of the same biologic disease. LBL is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the central nervous system (CNS). (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.) Intensive combination chemotherapy with CNS prophylaxis is the standard treatment of this aggressive histologic type of NHL. Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed.
The most important aspects of the pretreatment staging workup include careful review of the following pathological specimens:
Standard Treatment Options for LBL/ALL
Standard treatment options for LBL include the following:
(Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Standard treatment is intensive combination chemotherapy with CNS prophylaxis.
Radiation therapy is sometimes given to areas of bulky tumor masses.
Treatment Options Under Clinical Evaluation for LBL/ALL
New treatment approaches are being developed by the national cooperative groups. Other approaches include the use of bone marrow transplantation for consolidation. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
Diffuse, small, noncleaved-cell/Burkitt lymphoma typically involves younger patients and represents the most common type of pediatric NHL.
Standard Treatment Options for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma
Standard treatment options for diffuse, small, noncleaved-cell/Burkitt lymphoma include the following:
Aggressive multidrug regimens
Standard treatment for diffuse, small, noncleaved-cell/Burkitt lymphoma is usually with aggressive multidrug regimens similar to those used for the advanced-stage aggressive lymphomas (such as diffuse large cell).[2,3,4] Adverse prognostic factors include bulky abdominal disease and high serum lactate dehydrogenase.
Evidence (aggressive multidrug regimens):
Patients with diffuse, small, noncleaved-cell/Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. CNS prophylaxis with methotrexate is recommended for all patients, usually given as four to six intrathecal injections. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information).
General Information About NHL During Pregnancy
Non-Hodgkin lymphomas (NHL) occur more frequently than Hodgkin lymphoma in an older population. This age difference may account for fewer reports of NHL in pregnant patients.
Stage Information for NHL During Pregnancy
To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation. (Refer to the Stage Information for Adult NHL section of this summary for more information.)
Treatment Option Overview for NHL During Pregnancy
Indolent NHL During Pregnancy
Treatment may be delayed for those women with an indolent NHL.
Aggressive NHL During Pregnancy
According to anecdotal case series, most NHL in pregnant patients are aggressive, and delay of therapy until after delivery appears to have poor outcomes.[1,3,4,5] Consequently, some investigators favor immediate therapy, even during pregnancy. In a review of 121 patient case reports from 74 papers, one-half of the patients had very aggressive lymphomas, such as Burkitt lymphoma, and one-half of the patients had involvement of the breast, ovaries, uterus, or placenta. One-half of the patients received therapy antepartum, and the 6-month survival was reported at 53%, with a live-birth rate of 83%.[Level of evidence: 3iiiDiv]
A multicenter retrospective analysis of 50 patients described pregnancy termination in 3 patients, deferral of therapy to postpartum in 15 patients (median 30 weeks gestation), and antenatal therapy applied to the remaining 32 patients (median 21 weeks gestation, all done after the first trimester). With a median follow-up of 41 months, the 3-year progression-free survival was 53%, and overall survival was 82%, using R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or modifications of this regimen.[Level of evidence: 3iiiDiv]
Early delivery when feasible
For some women, early delivery, when feasible, may minimize or avoid exposure to chemotherapy or radiation therapy.
Termination of pregnancy
Termination of pregnancy in the first trimester may be an option that allows immediate therapy for women with aggressive NHL.
Evidence (treatment effect on children exposed in utero):
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Indolent Non-Hodgkin Lymphoma (NHL)
Added text to state that zanubrutinib was compared with ibrutinib in a randomized prospective clinical trial of 164 patients with relapsed lymphoplasmacytic lymphoma and 38 previously untreated patients. With a median follow-up of 18 months, the progression-free survival rate was the same in both groups at 84%, but the zanubrutinib group had fewer cases of atrial fibrillation and 50% fewer cases of hypertension (cited Tam et al. as reference 53 and level of evidence 3iiiDiv).
Added text about the results of phase I and II trials of pembrolizumab in 74 patients with relapsed or refractory lymphoma that showed an objective response rate of 45% to 48%. The median duration of response was not reached for the 21 patients with a median follow-up of 29 months or for the 53 patients with a median follow-up of 12.5 months (cited Armand et al. as reference 44 and level of evidence 3iiiDiv).
Added Pro et al. as reference 122.
Revised text to state that with the use of aggressive R-CHOP–based combination chemotherapy, as in diffuse large B-cell lymphoma (DLBCL), the prognosis is similar to conventional stage IV DLBCL (cited Shimada et al. as reference 138).
Treatment for Indolent, Noncontiguous Stage II/III/IV Adult NHL
Revised the list of standard treatment options for indolent, noncontiguous stage II/III/IV adult NHL.
Added Umbralisib as a new subsection.
Added Tazemetostat as a new subsection.
Treatment for Indolent, Recurrent Adult NHL
Revised the list of standard treatment options for indolent, recurrent adult NHL.
Added Phosphatidylinositol 3-kinase inhibitors as a new subsection.
Treatment for Aggressive, Recurrent Adult NHL
Added Abramson et al. and Lin et al. as references 23 and 24, respectively.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Adult Non-Hodgkin Lymphoma Treatment is:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Adult Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389492]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2021-05-18
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