Incidence and Mortality

Estimated new cases and deaths from NHL in the United States in 2021:[2]

• New cases: 81,560.
• Deaths: 20,720.

Anatomy

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.[3] 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, the overall survival rate at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. Most 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.[4]

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 if 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]

Related Summaries

Other PDQ summaries containing information related to non-Hodgkin lymphoma treatment include the following:

• Childhood Non-Hodgkin Lymphoma Treatment

References

1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PubMed: 22835603]
2. American Cancer Society: Cancer Facts and Figures 2021. American Cancer Society, 2021. Available online. Last accessed October 8, 2021.
3. Tan D, Horning SJ, Hoppe RT, et al.: Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 122 (6): 981-7, 2013. [PMC free article: PMC3739040] [PubMed: 23777769]
4. Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 (4): 1024-8, 1992. [PubMed: 1737086]
5. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PubMed: 9193357]
6. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PubMed: 7602362]

References

1. Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006. [PubMed: 16520465]
2. Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993. [PubMed: 8230284]
3. Hemminki K, Lenner P, Sundquist J, et al.: Risk of subsequent solid tumors after non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26 (11): 1850-7, 2008. [PubMed: 18347006]
4. Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16 (6): 2070-9, 1998. [PubMed: 9626206]
5. Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006. [PubMed: 16339404]
6. Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994. [PubMed: 7989926]
7. Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12 (12): 2535-42, 1994. [PubMed: 7989927]
8. Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003. [PubMed: 12610191]
9. André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004. [PubMed: 14576060]
10. Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998. [PubMed: 9720728]
11. Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004. [PubMed: 15611507]
12. McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005. [PMC free article: PMC1895007] [PubMed: 15741224]
13. Morton LM, Curtis RE, Linet MS, et al.: Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (33): 4935-44, 2010. [PMC free article: PMC3020697] [PubMed: 20940199]
14. Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998. [PubMed: 9616144]
15. Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19 (9): 2472-81, 2001. [PubMed: 11331326]
16. Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23 (10): 2208-14, 2005. [PubMed: 15753460]
17. Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997. [PubMed: 9498711]
18. Shree T, Li Q, Glaser SL, et al.: Impaired Immune Health in Survivors of Diffuse Large B-Cell Lymphoma. J Clin Oncol 38 (15): 1664-1675, 2020. [PMC free article: PMC7238489] [PubMed: 32083991]
19. Westin JR, Thompson MA, Cataldo VD, et al.: Zoledronic acid for prevention of bone loss in patients receiving primary therapy for lymphomas: a prospective, randomized controlled phase III trial. Clin Lymphoma Myeloma Leuk 13 (2): 99-105, 2013. [PMC free article: PMC3881262] [PubMed: 23276888]

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.[3] 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.[4] 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.[5-8] 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]

References

1. Zeppa P, Marino G, Troncone G, et al.: Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 102 (1): 55-65, 2004. [PubMed: 14968418]
2. Young NA, Al-Saleem T: Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer 87 (6): 325-45, 1999. [PubMed: 10603186]
3. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PubMed: 6896167]
4. Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leuk Lymphoma 10 (Suppl 1): 1-8, 1993. [PubMed: 8481658]
5. Harris NL, Jaffe ES, Stein H, et al.: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84 (5): 1361-92, 1994. [PubMed: 8068936]
6. Pittaluga S, Bijnens L, Teodorovic I, et al.: Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation. Blood 87 (10): 4358-67, 1996. [PubMed: 8639796]
7. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PubMed: 9704731]
8. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PubMed: 9166827]
9. Pileri SA, Milani M, Fraternali-Orcioni G, et al.: From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol 9 (6): 607-12, 1998. [PubMed: 9681073]
10. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.

Follicular Lymphoma

Follicular lymphoma comprises 20% of all NHL and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[1-3] Most patients with follicular lymphoma are age 50 years and older and present with widespread disease at diagnosis. Nodal involvement is most common and is often accompanied by splenic and bone marrow disease. Rearrangement of the BCL2 gene is present in more than 90% of patients with follicular lymphoma; overexpression of the BCL2 protein is associated with the inability to eradicate the lymphoma by inhibiting apoptosis.[4]

Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[40] 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.[41] 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.[9,42,43]

Prognostic factors associated with symptoms requiring therapy include the following:

• Age 70 years or older.
• Beta-2-microglobulin of 3 mg/dL or more.
• Increased serum LDH.[42]

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.[73,74] 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.[75] 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.[76]

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.[121-123] 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.[121-123]

(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.)

References

1. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PubMed: 9704731]
2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PubMed: 9166827]
3. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.
4. López-Guillermo A, Cabanillas F, McDonnell TI, et al.: Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood 93 (9): 3081-7, 1999. [PubMed: 10216105]
5. Peterson BA, Petroni GR, Frizzera G, et al.: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 21 (1): 5-15, 2003. [PubMed: 12506163]
6. Swenson WT, Wooldridge JE, Lynch CF, et al.: Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23 (22): 5019-26, 2005. [PubMed: 15983392]
7. Liu Q, Fayad L, Cabanillas F, et al.: Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 24 (10): 1582-9, 2006. [PubMed: 16575009]
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9. Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003. [PubMed: 12932382]
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13. Buske C, Hoster E, Dreyling M, et al.: The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108 (5): 1504-8, 2006. [PubMed: 16690968]
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79. Wündisch T, Thiede C, Morgner A, et al.: Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 23 (31): 8018-24, 2005. [PubMed: 16204012]
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82. Nakamura S, Ye H, Bacon CM, et al.: Clinical impact of genetic aberrations in gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence in situ hybridisation. Gut 56 (10): 1358-63, 2007. [PMC free article: PMC2000261] [PubMed: 17525089]
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84. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Stage I and II MALT lymphoma: results of treatment with radiotherapy. Int J Radiat Oncol Biol Phys 50 (5): 1258-64, 2001. [PubMed: 11483337]
85. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21 (22): 4157-64, 2003. [PubMed: 14615444]
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87. Martinelli G, Laszlo D, Ferreri AJ, et al.: Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 23 (9): 1979-83, 2005. [PubMed: 15668468]
88. Cogliatti SB, Schmid U, Schumacher U, et al.: Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 101 (5): 1159-70, 1991. [PubMed: 1936785]
89. Zinzani PL, Magagnoli M, Galieni P, et al.: Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients. J Clin Oncol 17 (4): 1254, 1999. [PubMed: 10561186]
90. Thieblemont C, Bastion Y, Berger F, et al.: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 15 (4): 1624-30, 1997. [PubMed: 9193362]
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92. Morgner A, Miehlke S, Fischbach W, et al.: Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 19 (7): 2041-8, 2001. [PubMed: 11283137]
93. Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PubMed: 11709568]
94. Chen LT, Lin JT, Tai JJ, et al.: Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 97 (18): 1345-53, 2005. [PubMed: 16174856]
95. Kuo SH, Yeh KH, Wu MS, et al.: Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood 119 (21): 4838-44; quiz 5057, 2012. [PubMed: 22403257]
96. Uno T, Isobe K, Shikama N, et al.: Radiotherapy for extranodal, marginal zone, B-cell lymphoma of mucosa-associated lymphoid tissue originating in the ocular adnexa: a multiinstitutional, retrospective review of 50 patients. Cancer 98 (4): 865-71, 2003. [PubMed: 12910532]
97. Bayraktar S, Bayraktar UD, Stefanovic A, et al.: Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients. Br J Haematol 152 (1): 72-80, 2011. [PMC free article: PMC3076069] [PubMed: 21083656]
98. Stefanovic A, Lossos IS: Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114 (3): 501-10, 2009. [PMC free article: PMC2713468] [PubMed: 19372259]
99. Vazquez A, Khan MN, Sanghvi S, et al.: Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the salivary glands: a population-based study from 1994 to 2009. Head Neck 37 (1): 18-22, 2015. [PubMed: 24733777]
100. Raderer M, Streubel B, Woehrer S, et al.: High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res 11 (9): 3349-52, 2005. [PubMed: 15867234]
101. Sretenovic M, Colovic M, Jankovic G, et al.: More than a third of non-gastric malt lymphomas are disseminated at diagnosis: a single center survey. Eur J Haematol 82 (5): 373-80, 2009. [PubMed: 19141118]
102. Nathwani BN, Drachenberg MR, Hernandez AM, et al.: Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Semin Hematol 36 (2): 128-38, 1999. [PubMed: 10319381]
103. Raderer M, Wöhrer S, Streubel B, et al.: Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol 24 (19): 3136-41, 2006. [PubMed: 16769982]
104. Zucca E, Conconi A, Martinelli G, et al.: Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. J Clin Oncol 35 (17): 1905-1912, 2017. [PubMed: 28355112]
105. Kiesewetter B, Raderer M: Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature. Blood 122 (8): 1350-7, 2013. [PubMed: 23770778]
106. Grünberger B, Hauff W, Lukas J, et al.: 'Blind' antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa. Ann Oncol 17 (3): 484-7, 2006. [PubMed: 16500916]
107. Kuo SH, Chen LT, Yeh KH, et al.: Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J Clin Oncol 22 (17): 3491-7, 2004. [PubMed: 15337797]
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109. Thieblemont C, Molina T, Davi F: Optimizing therapy for nodal marginal zone lymphoma. Blood 127 (17): 2064-71, 2016. [PubMed: 26989202]
110. Luminari S, Merli M, Rattotti S, et al.: Early progression as a predictor of survival in marginal zone lymphomas: an analysis from the FIL-NF10 study. Blood 134 (10): 798-801, 2019. [PubMed: 31292118]
111. Vallisa D, Bernuzzi P, Arcaini L, et al.: Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol 23 (3): 468-73, 2005. [PubMed: 15659492]
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117. Arcaini L, Lazzarino M, Colombo N, et al.: Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood 107 (12): 4643-9, 2006. [PubMed: 16493005]
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123. Kempf W, Pfaltz K, Vermeer MH, et al.: EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 118 (15): 4024-35, 2011. [PMC free article: PMC3204726] [PubMed: 21841159]

Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL and comprises 30% of newly diagnosed cases.[1] 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.[2-4] 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.[5]

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.[35,36] 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 are 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 show high cure rates while avoiding any mediastinal radiation.[36-40][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.[37,41-43] 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.[44] (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%).[45][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.[46][Level of evidence: 3iiiDiv]

Follicular Large Cell Lymphoma

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.[53]

The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin-anaplastic lymphoma kinase (ALK).[53,54]

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.[55,56]

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.[57] 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).[57][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),[58-61] romidepsin,[62] and pralatrexate.[63][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.[61][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.[64][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.[65] 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.[66-69]

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.[70] 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.[71] 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.[72-79]

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,[80] while high-risk patients fared best with a strategy of radiation therapy combined with chemotherapy.[78,81,82]

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.[83][Level of evidence: 3iiiDiv]

Higher doses of radiation therapy administered at more than 50 Gy are associated with improved outcomes according to anecdotal reports.[78] 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.[79,84-88] L-asparaginase-containing regimens have shown anecdotal response rates greater than 50% for relapsing, refractory, or newly diagnosed patients.[79,89-91] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[92] A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy can be distinguished from NK-/T-cell lymphoma.[93]

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[94,95] 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.[96-99] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia.[71] (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.[100]

Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is recommended as it is for other aggressive lymphomas.[96,99] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[57][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.[101] Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[87,102-104] Anecdotal responses have been reported for cyclosporine,[105] pralatrexate,[106] bendamustine,[107] the histone deacetylase inhibitor romidepsin, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[62,108][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.[109] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[71,110] This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells.

Enteropathy-type Intestinal T-cell Lymphoma

Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[71,133-135] 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.[134-136] 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.[87,134,137][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.[138-140]

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.[141] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the MYC gene on chromosome 8.[142] A subgroup of patients with dual translocation of MYC and BCL2 appear to have an extremely poor outcome despite aggressive therapy (5-month OS).[143][Level of evidence: 3iiiA]

In some patients with larger B cells, there is morphologic overlap with DLBCL. These Burkitt-like large cell lymphomas show MYC deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[144-146] 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.

Lymphoblastic Lymphoma

Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often, but not exclusively, occurs in young patients.[157] 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.[158-160] 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.[161,162] ATL has been divided into four clinical subtypes:[163,164]

• Acute (aggressive course with leukemia, with or without extranodal or nodal involvement).
• Lymphoma (aggressive course with lymphadenopathy and no leukemia).
• Chronic (indolent course with leukemia and lymphadenopathy).
• Smoldering (indolent course with only leukemia).

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.[165-167] Using combination chemotherapy, less than 10% of 807 patients were alive after 4 years.[167] Anecdotal durable remissions have been reported after allogeneic SCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[168][Level of evidence: 3iiiDiv] Among 815 patients who underwent allogeneic SCT in two retrospective reviews, the 3-year OS rates were 36% and 26%.[169,170][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.[171-175] In a multicenter phase II study of 26 relapsed patients, 42% responded to lenalidomide (including four CR).[176][Level of evidence: 3iiiDiv] Symptomatic local progression of all subtypes responds well to palliative radiation therapy.[177] In the relapsed setting, an ORR above 50% is seen using mogamulizumab, a humanized monoclonal antibody against the C-C chemokine receptor 4 (CCR4).[178][Level of evidence: 3iiiDiv] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[57][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).[179] 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.[179] 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.[180] A complex karyotype predicts poor response to induction therapy and inferior survival.[181] 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.[182]

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.[183] 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.[184] A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[185,186]

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.[213] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[214]

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.[228,229] Care must be taken with immunophenotypic tests to exclude ALCL or hemophagocytic syndromes caused by viral infections, especially EBV.

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.[230] Patients are usually HIV seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.[231]

Plasmablastic Lymphoma

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.[232] Anecdotal reports suggest using aggressive chemotherapy for Burkitt or lymphoblastic lymphoma, followed by SCT consolidation in responding patients, when feasible.[232-234]

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208. Dreyling M, Jurczak W, Jerkeman M, et al.: Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 387 (10020): 770-8, 2016. [PubMed: 26673811]
209. Tam CS, Anderson MA, Pott C, et al.: Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med 378 (13): 1211-1223, 2018. [PubMed: 29590547]
210. Wang M, Rule S, Zinzani PL, et al.: Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet 391 (10121): 659-667, 2018. [PMC free article: PMC7864374] [PubMed: 29241979]
211. Martin P, Ruan J, Leonard JP: The potential for chemotherapy-free strategies in mantle cell lymphoma. Blood 130 (17): 1881-1888, 2017. [PubMed: 28899853]
212. Wang M, Munoz J, Goy A, et al.: KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med 382 (14): 1331-1342, 2020. [PMC free article: PMC7731441] [PubMed: 32242358]
213. Morrison VA, Dunn DL, Manivel JC, et al.: Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med 97 (1): 14-24, 1994. [PubMed: 8030652]
214. Knowles DM, Cesarman E, Chadburn A, et al.: Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85 (2): 552-65, 1995. [PubMed: 7812011]
215. Leblond V, Dhedin N, Mamzer Bruneel MF, et al.: Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 19 (3): 772-8, 2001. [PubMed: 11157030]
216. Ghobrial IM, Habermann TM, Maurer MJ, et al.: Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol 23 (30): 7574-82, 2005. [PubMed: 16186599]
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Staging Subclassification System

Lugano Classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[9] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[10] with some modifications 18 years later from the Cotswolds meeting.[11 ,12]

Table 2. Lugano Classification for Hodgkin and Non-Hodgkin Lymphoma^a

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Stage	Stage Description	Illustration
Limited stage
I	Involvement of a single lymphatic site (i.e., nodal region, Waldeyer’s ring, thymus, or spleen).
IE	Single extralymphatic site in the absence of nodal involvement (rare in Hodgkin lymphoma).
II	Involvement of two or more lymph node regions on the same side of the diaphragm.
IIE	Contiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.
II bulkyb	Stage II with disease bulk.c
Advanced stage
III	Involvement of lymph node regions on both sides of the diaphragm; nodes above the diaphragm with spleen involvement.
IV	Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or noncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease; or any extralymphatic organ involvement in nodal stage III disease. Stage IV includes any involvement of the CSF, bone marrow, liver, or multiple lung lesions (other than by direct extension in stage IIE disease).
Note: Hodgkin lymphoma uses A or B designation with stage group. A/B is no longer used in NHL.

CSF = cerebrospinal fluid; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.

^aHodgkin and Non-Hodgkin Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 937–58.

^bStage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors.

^cThe definition of disease bulk varies according to lymphoma histology. In the Lugano classification, bulk ln Hodgkin lymphoma is defined as a mass greater than one-third of the thoracic diameter on CT of the chest or a mass >10 cm. For NHL, the recommended definitions of bulk vary by lymphoma histology. In follicular lymphoma, 6 cm has been suggested based on the Follicular Lymphoma International Prognostic Index-2 and its validation. In DLBCL, cutoffs ranging from 5 cm to 10 cm have been used, although 10 cm is recommended.

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.

Table 3. Notation to Identify Specific Sites

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N = nodes	H = liver	L = lung	M = bone marrow
S = spleen	P = pleura	O = bone	D = skin

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+).

Several 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:

• Age.
• Performance status (PS).
• Tumor size.
• Lactate dehydrogenase (LDH) values.
• The number of extranodal sites.

The National Comprehensive Cancer Network International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies the following five significant risk factors prognostic of overall survival (OS) and their associated risk scores:[13]

• Age.

  -

  <40 years: 0.

  -

  41–60 years: 1.

  -

  61–75 years: 2.

  -

  >75 years: 3.

• Stage III/IV: 1.
• PS 2/3/4: 1.
• Serum LDH.

  -

  Normalized: 0.

  -

  >1x–3x: 1.

  -

  >3x: 2.

• Number of extranodal sites ≥2: 1.

Risk scores:

• Low (0 or 1): 5-year OS rate, 96%; progression-free survival (PFS) rate, 91%.
• Low intermediate (2 or 3): 5-year OS rate, 82%; PFS rate, 74%.
• High intermediate (4 or 5): 5-year OS rate, 64%; PFS rate, 51%.
• High (>6): 5-year OS rate, 33%; PFS rate, 30%.

Age-adjusted and stage-adjusted modifications of this IPI are used for younger patients with localized disease.[14] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biological factors.[15]

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.[18] 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.[19]

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17. Horn H, Ziepert M, Becher C, et al.: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121 (12): 2253-63, 2013. [PubMed: 23335369]
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19. Sha C, Barrans S, Cucco F, et al.: Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy. J Clin Oncol 37 (3): 202-212, 2019. [PMC free article: PMC6338391] [PubMed: 30523719]

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.

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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:

1. Radiation therapy.
2. Rituximab with or without chemotherapy.
3. Watchful waiting.
4. Other therapies as designated for patients with advanced-stage disease.

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).[1][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.[2] 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%.[2][Level of evidence: 3iiiD] Clinical trials are required to answer questions such as the following:[3]

• If the PET-CT scan is clear after excisional biopsy, is watchful waiting or radiation therapy preferred?
• Should rituximab be added to radiation therapy for stage I follicular lymphoma?
• Is there any role for R-chemotherapy plus radiation therapy?

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.

References

1. MacManus M, Fisher R, Roos D, et al.: Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. J Clin Oncol 36 (29): 2918-2925, 2018. [PubMed: 29975623]
2. Friedberg JW, Byrtek M, Link BK, et al.: Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 30 (27): 3368-75, 2012. [PMC free article: PMC3675665] [PubMed: 22915662]
3. Montoto S: Management of localized-stage follicular lymphoma: changing the paradigm? J Clin Oncol 30 (27): 3328-9, 2012. [PubMed: 22915654]
4. Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PubMed: 12829665]
5. Guckenberger M, Alexandrow N, Flentje M: Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation. Radiat Oncol 7: 103, 2012. [PMC free article: PMC3432005] [PubMed: 22726938]
6. Brady JL, Binkley MS, Hajj C, et al.: Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG. Blood 133 (3): 237-245, 2019. [PubMed: 30446493]
7. Guadagnolo BA, Li S, Neuberg D, et al.: Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 64 (3): 928-34, 2006. [PubMed: 16243446]
8. Binkley MS, Brady JL, Hajj C, et al.: Salvage Treatment and Survival for Relapsed Follicular Lymphoma Following Primary Radiation Therapy: A Collaborative Study on Behalf of ILROG. Int J Radiat Oncol Biol Phys 104 (3): 522-529, 2019. [PMC free article: PMC8162056] [PubMed: 30858143]
9. Hoskin PJ, Kirkwood AA, Popova B, et al.: 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 15 (4): 457-63, 2014. [PubMed: 24572077]
10. Hoskin P, Popova B, Schofield O, et al.: 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol 22 (3): 332-340, 2021. [PubMed: 33539729]
11. Dabaja BS, Hoppe BS, Plastaras JP, et al.: Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 132 (16): 1635-1646, 2018. [PMC free article: PMC6212652] [PubMed: 30108066]
12. Kelsey SM, Newland AC, Hudson GV, et al.: A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol 11 (1): 19-25, 1994. [PubMed: 7921924]
13. Seymour JF, Pro B, Fuller LM, et al.: Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 21 (11): 2115-22, 2003. [PubMed: 12775737]
14. Advani R, Rosenberg SA, Horning SJ: Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 22 (8): 1454-9, 2004. [PubMed: 15024027]
15. Pugh TJ, Ballonoff A, Newman F, et al.: Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 116 (16): 3843-51, 2010. [PubMed: 20564102]

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:

1. Watchful waiting for asymptomatic patients.
2. Rituximab (alone or in combination with cytotoxic agents used in front-line therapy).
3. Lenalidomide and rituximab.
4. Maintenance rituximab.
5. Obinutuzumab (alone or in combination with cytotoxic agents used in front-line therapy).
6. Phosphatidylinositol 3-kinase (PI3K) inhibitors.

   • Copanlisib.
   • Idelalisib.
   • Umbralisib.
7. EZH2 inhibitor.

   • Tazemetostat.
8. Radiolabeled anti-CD20 monoclonal antibodies.

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.

1. Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or peripheral SCT is under clinical evaluation.[62-71]
2. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[72-74]
3. Extended-field radiation therapy (stage III patients only).[75]
4. Ofatumumab—human anti–CD20 monoclonal antibody.[76]
5. Short-course low-dose, palliative radiation therapy (2 × 2 Gy).[77,78]

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.

References

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77. Chan EK, Fung S, Gospodarowicz M, et al.: Palliation by low-dose local radiation therapy for indolent non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 81 (5): e781-6, 2011. [PubMed: 21167657]
78. Rossier C, Schick U, Miralbell R, et al.: Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys 81 (3): e1-6, 2011. [PubMed: 21398049]

Standard Treatment Options for Indolent, Recurrent Adult NHL

Standard treatment options for indolent, recurrent adult non-Hodgkin lymphoma (NHL) include the following:

1. Rituximab (alone or in combination with cytotoxic agents used in front-line therapy).
2. Obinutuzumab (alone or in combination with cytotoxic agents used in front-line therapy).
3. Lenalidomide and rituximab.
4. Phosphatidylinositol 3-kinase (PI3K) inhibitors.

   • Copanlisib.
   • Idelalisib.
   • Umbralisib.
5. EZH2 inhibitor.

   • Tazemetostat.
6. Palliative radiation therapy.
7. Chemotherapy (single agent or combination).
8. Radiolabeled anti-CD20 monoclonal antibodies.

Treatment Options Under Clinical Evaluation for Indolent, Recurrent Adult NHL

Treatment options under clinical evaluation include the following:

• Stem cell transplant. In many institutions, autologous or allogeneic stem cell transplantations (SCT) are being used for patients whose disease has relapsed. Such an approach is still under evaluation but can be considered in the context of a clinical trial.[36-40]

Evidence (stem cell transplant):

• The German Low-Grade Lymphoma Study Group treated 307 patients with follicular lymphoma with two cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like induction chemotherapy and then randomly assigned them to autologous SCT versus interferon maintenance.[41] With a median follow-up of 4.2 years, the 5-year PFS was 65% for transplantation versus 33% for interferon (P < .001), but with no difference in OS.[41][Level of evidence: 1iiDiii]

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.

References

1. Casulo C, Byrtek M, Dawson KL, et al.: Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol 33 (23): 2516-22, 2015. [PMC free article: PMC4879714] [PubMed: 26124482]
2. Weisdorf DJ, Andersen JW, Glick JH, et al.: Survival after relapse of low-grade non-Hodgkin's lymphoma: implications for marrow transplantation. J Clin Oncol 10 (6): 942-7, 1992. [PubMed: 1588373]
3. Peterson BA: Current treatment of follicular low-grade lymphomas. Semin Oncol 26 (5 Suppl 14): 2-11, 1999. [PubMed: 10561012]
4. Haas RL, Poortmans P, de Jong D, et al.: High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 21 (13): 2474-80, 2003. [PubMed: 12829665]
5. Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PubMed: 16710033]
6. Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25 (17): 2426-33, 2007. [PubMed: 17485708]
7. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PubMed: 7602362]
8. Link BK, Maurer MJ, Nowakowski GS, et al.: Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 31 (26): 3272-8, 2013. [PMC free article: PMC3757293] [PubMed: 23897955]
9. Davis TA, White CA, Grillo-López AJ, et al.: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol 17 (6): 1851-7, 1999. [PubMed: 10561225]
10. Piro LD, White CA, Grillo-López AJ, et al.: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 10 (6): 655-61, 1999. [PubMed: 10442187]
11. Davis TA, Grillo-López AJ, White CA, et al.: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 18 (17): 3135-43, 2000. [PubMed: 10963642]
12. Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005. [PubMed: 15657401]
13. Lockmer S, Østenstad B, Hagberg H, et al.: Chemotherapy-Free Initial Treatment of Advanced Indolent Lymphoma Has Durable Effect With Low Toxicity: Results From Two Nordic Lymphoma Group Trials With More Than 10 Years of Follow-Up. J Clin Oncol : JCO1800262, 2018. [PubMed: 30285560]
14. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004. [PubMed: 15284112]
15. Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PubMed: 9164176]
16. van Oers MH, Van Glabbeke M, Giurgea L, et al.: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 28 (17): 2853-8, 2010. [PMC free article: PMC2903319] [PubMed: 20439641]
17. van Oers MH, Klasa R, Marcus RE, et al.: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 108 (10): 3295-301, 2006. [PubMed: 16873669]
18. Martinelli G, Schmitz SF, Utiger U, et al.: Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 28 (29): 4480-4, 2010. [PubMed: 20697092]
19. Sehn LH, Chua N, Mayer J, et al.: Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 17 (8): 1081-93, 2016. [PubMed: 27345636]
20. Cheson BD, Chua N, Mayer J, et al.: Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study. J Clin Oncol 36 (22): 2259-2266, 2018. [PubMed: 29584548]
21. Witzig TE, Wiernik PH, Moore T, et al.: Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol 27 (32): 5404-9, 2009. [PubMed: 19805688]
22. Leonard JP, Jung SH, Johnson J, et al.: Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol 33 (31): 3635-40, 2015. [PMC free article: PMC4622102] [PubMed: 26304886]
23. Matasar MJ, Capra M, Özcan M, et al.: Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 22 (5): 678-689, 2021. [PubMed: 33848462]
24. Dreyling M, Santoro A, Mollica L, et al.: Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 35 (35): 3898-3905, 2017. [PubMed: 28976790]
25. Gopal AK, Kahl BS, de Vos S, et al.: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370 (11): 1008-18, 2014. [PMC free article: PMC4039496] [PubMed: 24450858]
26. Gopal AK, Kahl BS, Flowers CR, et al.: Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy. Blood 129 (22): 3037-3039, 2017. [PubMed: 28325864]
27. Fowler NH, Samaniego F, Jurczak W, et al.: Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 39 (15): 1609-1618, 2021. [PMC free article: PMC8148421] [PubMed: 33683917]
28. Morschhauser F, Tilly H, Chaidos A, et al.: Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 21 (11): 1433-1442, 2020. [PMC free article: PMC8427481] [PubMed: 33035457]
29. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PubMed: 16039113]
30. Hoskin PJ, Kirkwood AA, Popova B, et al.: 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 15 (4): 457-63, 2014. [PubMed: 24572077]
31. Fisher RI, Kaminski MS, Wahl RL, et al.: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 23 (30): 7565-73, 2005. [PubMed: 16186600]
32. Leahy MF, Seymour JF, Hicks RJ, et al.: Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 24 (27): 4418-25, 2006. [PubMed: 16940276]
33. Shadman M, Li H, Rimsza L, et al.: Continued Excellent Outcomes in Previously Untreated Patients With Follicular Lymphoma After Treatment With CHOP Plus Rituximab or CHOP Plus 131I-Tositumomab: Long-Term Follow-Up of Phase III Randomized Study SWOG-S0016. J Clin Oncol 36 (7): 697-703, 2018. [PMC free article: PMC6553811] [PubMed: 29356608]
34. Morschhauser F, Radford J, Van Hoof A, et al.: 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol 31 (16): 1977-83, 2013. [PubMed: 23547079]
35. Kusumoto S, Arcaini L, Hong X, et al.: Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy. Blood 133 (2): 137-146, 2019. [PMC free article: PMC6337873] [PubMed: 30341058]
36. Freedman A, Friedberg JW, Gribben J: High-dose therapy for follicular lymphoma. Oncology (Huntingt) 14 (3): 321-6, 329; discussion 330-2, 338, 2000. [PubMed: 10742961]
37. Brice P, Simon D, Bouabdallah R, et al.: High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol. Ann Oncol 11 (12): 1585-90, 2000. [PubMed: 11205467]
38. Khouri IF, McLaughlin P, Saliba RM, et al.: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111 (12): 5530-6, 2008. [PMC free article: PMC4624452] [PubMed: 18411419]
39. Sebban C, Brice P, Delarue R, et al.: Impact of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma: a GELA study. J Clin Oncol 26 (21): 3614-20, 2008. [PubMed: 18559872]
40. Thomson KJ, Morris EC, Milligan D, et al.: T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 28 (23): 3695-700, 2010. [PubMed: 20606089]
41. Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004. [PubMed: 15238420]

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:

1. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without IF-XRT.

Treatment Options Under Clinical Evaluation for Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHL

Treatment options under clinical evaluation include the following:

• R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone).[4,5]

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.

References

1. Persky DO, Unger JM, Spier CM, et al.: Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol 26 (14): 2258-63, 2008. [PubMed: 18413640]
2. Lamy T, Damaj G, Soubeyran P, et al.: R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood 131 (2): 174-181, 2018. [PMC free article: PMC5757680] [PubMed: 29061568]
3. Poeschel V, Held G, Ziepert M, et al.: Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet 394 (10216): 2271-2281, 2019. [PubMed: 31868632]
4. Reyes F, Lepage E, Ganem G, et al.: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 352 (12): 1197-205, 2005. [PubMed: 15788496]
5. Ketterer N, Coiffier B, Thieblemont C, et al.: Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol 24 (4): 1032-7, 2013. [PubMed: 23235801]

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:

1. R-CHOP.
2. Other combination chemotherapy.

Treatment Options Under Clinical Evaluation for Aggressive, Noncontiguous Stage II/III/IV Adult NHL

Treatment options under clinical evaluation include the following:

1. Bone marrow transplant (BMT) or SCT.
   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.[41-48]; [49-51][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.[42,48] 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.[52]
2. Radiation therapy consolidation to sites of bulky disease.
   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.[53-55] Increased risks, such as long-term toxicities (e.g., second malignancies), must be considered.

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.

References

1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PubMed: 22835603]
2. Coiffier B: State-of-the-art therapeutics: diffuse large B-cell lymphoma. J Clin Oncol 23 (26): 6387-93, 2005. [PubMed: 16155024]
3. Cunningham D, Hawkes EA, Jack A, et al.: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381 (9880): 1817-26, 2013. [PubMed: 23615461]
4. Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002. [PubMed: 11807147]
5. Coiffier B, Thieblemont C, Van Den Neste E, et al.: Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116 (12): 2040-5, 2010. [PMC free article: PMC2951853] [PubMed: 20548096]
6. Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006. [PubMed: 16648042]
7. Pfreundschuh M, Kuhnt E, Trümper L, et al.: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12 (11): 1013-22, 2011. [PubMed: 21940214]
8. Récher C, Coiffier B, Haioun C, et al.: Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378 (9806): 1858-67, 2011. [PubMed: 22118442]
9. Casasnovas RO, Ysebaert L, Thieblemont C, et al.: FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study. Blood 130 (11): 1315-1326, 2017. [PubMed: 28701367]
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11. Gobba S, Moccia AA, Gulden-Sala W, et al.: Outcome of patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) treated with "standard" immunochemotherapy: A large retrospective study from 4 institutions. Hematol Oncol 36 (1): 84-92, 2018. [PubMed: 28621491]
12. Wang Y, Link BK, Witzig TE, et al.: Impact of concurrent indolent lymphoma on the clinical outcome of newly diagnosed diffuse large B-cell lymphoma. Blood 134 (16): 1289-1297, 2019. [PMC free article: PMC6888139] [PubMed: 31350266]
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15. Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PubMed: 11709568]
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20. Maurer MJ, Ghesquières H, Link BK, et al.: Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials. J Clin Oncol 36 (16): 1603-1610, 2018. [PMC free article: PMC5978469] [PubMed: 29672223]
21. Cuccuini W, Briere J, Mounier N, et al.: MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. Blood 119 (20): 4619-24, 2012. [PMC free article: PMC3815438] [PubMed: 22408263]
22. Johnson NA, Slack GW, Savage KJ, et al.: Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30 (28): 3452-9, 2012. [PMC free article: PMC3454768] [PubMed: 22851565]
23. Green TM, Young KH, Visco C, et al.: Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30 (28): 3460-7, 2012. [PubMed: 22665537]
24. Horn H, Ziepert M, Becher C, et al.: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121 (12): 2253-63, 2013. [PubMed: 23335369]
25. Canellos GP: CHOP may have been part of the beginning but certainly not the end: issues in risk-related therapy of large-cell lymphoma. J Clin Oncol 15 (5): 1713-6, 1997. [PubMed: 9164176]
26. Sha C, Barrans S, Cucco F, et al.: Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy. J Clin Oncol 37 (3): 202-212, 2019. [PMC free article: PMC6338391] [PubMed: 30523719]
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28. Cortes J, Moore JO, Maziarz RT, et al.: Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol 28 (27): 4207-13, 2010. [PMC free article: PMC4979236] [PubMed: 20713865]
29. Schmitz N, Zeynalova S, Nickelsen M, et al.: CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP. J Clin Oncol 34 (26): 3150-6, 2016. [PubMed: 27382100]
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31. Vitolo U, Chiappella A, Ferreri AJ, et al.: First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 29 (20): 2766-72, 2011. [PubMed: 21646602]
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33. Boehme V, Schmitz N, Zeynalova S, et al.: CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood 113 (17): 3896-902, 2009. [PubMed: 19144985]
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35. Puckrin R, El Darsa H, Ghosh S, et al.: Ineffectiveness of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma. Am J Hematol 96 (7): 764-771, 2021. [PubMed: 33811794]
36. Jeong H, Cho H, Kim H, et al.: Efficacy and safety of prophylactic high-dose MTX in high-risk DLBCL: a treatment intent-based analysis. Blood Adv 5 (8): 2142-2152, 2021. [PMC free article: PMC8095148] [PubMed: 33881464]
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38. Ferreri AJ, Donadoni G, Cabras MG, et al.: High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial. J Clin Oncol 33 (33): 3903-10, 2015. [PubMed: 26282634]
39. Schmitz N, Wu HS: Advances in the Treatment of Secondary CNS Lymphoma. J Clin Oncol 33 (33): 3851-3, 2015. [PubMed: 26282665]
40. Kusumoto S, Arcaini L, Hong X, et al.: Risk of HBV reactivation in patients with B-cell lymphomas receiving obinutuzumab or rituximab immunochemotherapy. Blood 133 (2): 137-146, 2019. [PMC free article: PMC6337873] [PubMed: 30341058]
41. Haioun C, Lepage E, Gisselbrecht C, et al.: Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 18 (16): 3025-30, 2000. [PubMed: 10944137]
42. Haioun C, Lepage E, Gisselbrecht C, et al.: Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1131-7, 1997. [PubMed: 9060555]
43. Santini G, Salvagno L, Leoni P, et al.: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16 (8): 2796-802, 1998. [PubMed: 9704732]
44. Gianni AM, Bregni M, Siena S, et al.: High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 336 (18): 1290-7, 1997. [PubMed: 9113932]
45. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al.: Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 93 (1): 22-30, 2001. [PubMed: 11136838]
46. Gisselbrecht C, Lepage E, Molina T, et al.: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20 (10): 2472-9, 2002. [PubMed: 12011124]
47. Martelli M, Gherlinzoni F, De Renzo A, et al.: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 21 (7): 1255-62, 2003. [PubMed: 12663712]
48. Milpied N, Deconinck E, Gaillard F, et al.: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350 (13): 1287-95, 2004. [PubMed: 15044639]
49. Betticher DC, Martinelli G, Radford JA, et al.: Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 17 (10): 1546-52, 2006. [PubMed: 16888080]
50. Stiff PJ, Unger JM, Cook JR, et al.: Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med 369 (18): 1681-90, 2013. [PMC free article: PMC3985418] [PubMed: 24171516]
51. Chiappella A, Martelli M, Angelucci E, et al.: Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol 18 (8): 1076-1088, 2017. [PubMed: 28668386]
52. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PubMed: 10076716]
53. Held G, Murawski N, Ziepert M, et al.: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 32 (11): 1112-8, 2014. [PubMed: 24493716]
54. Kahl BS: Bulky aggressive B-cell lymphoma: to radiate or not to radiate--that is the question. J Clin Oncol 32 (11): 1097-8, 2014. [PubMed: 24550422]
55. Phan J, Mazloom A, Medeiros LJ, et al.: Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 28 (27): 4170-6, 2010. [PubMed: 20713859]

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).[1] 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:

1. Bone marrow transplantation or stem cell transplantation.
2. Re-treatment with standard agents.
3. Palliative radiation therapy.

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.

References

1. Crump M, Neelapu SS, Farooq U, et al.: Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 130 (16): 1800-1808, 2017. [PMC free article: PMC5649550] [PubMed: 28774879]
2. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PubMed: 10076716]
3. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PubMed: 2332768]
4. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990. [PubMed: 2302456]
5. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992. [PubMed: 1403052]
6. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84 (4): 1050-5, 1994. [PubMed: 8049425]
7. Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995. [PubMed: 7884420]
8. Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333 (23): 1540-5, 1995. [PubMed: 7477169]
9. Vellenga E, van Putten WL, van 't Veer MB, et al.: Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 111 (2): 537-43, 2008. [PubMed: 17971487]
10. Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998. [PubMed: 9779700]
11. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993. [PubMed: 8105034]
12. Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994. [PubMed: 7911318]
13. Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001. [PubMed: 11208832]
14. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011. [PubMed: 21321299]
15. Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004. [PubMed: 15280203]
16. Rezvani AR, Norasetthada L, Gooley T, et al.: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol 143 (3): 395-403, 2008. [PMC free article: PMC2654416] [PubMed: 18759762]
17. Ghosh N, Ahmed S, Ahn KW, et al.: Association of Reduced-Intensity Conditioning Regimens With Overall Survival Among Patients With Non-Hodgkin Lymphoma Undergoing Allogeneic Transplant. JAMA Oncol 6 (7): 1011-1018, 2020. [PMC free article: PMC7273311] [PubMed: 32496525]
18. Gisselbrecht C, Glass B, Mounier N, et al.: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28 (27): 4184-90, 2010. [PMC free article: PMC3664033] [PubMed: 20660832]
19. Crump M, Kuruvilla J, Couban S, et al.: Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32 (31): 3490-6, 2014. [PubMed: 25267740]
20. Neelapu SS, Locke FL, Bartlett NL, et al.: Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 377 (26): 2531-2544, 2017. [PMC free article: PMC5882485] [PubMed: 29226797]
21. Schuster SJ, Bishop MR, Tam CS, et al.: Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med 380 (1): 45-56, 2019. [PubMed: 30501490]
22. Locke FL, Ghobadi A, Jacobson CA, et al.: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20 (1): 31-42, 2019. [PMC free article: PMC6733402] [PubMed: 30518502]
23. Abramson JS, Palomba ML, Gordon LI, et al.: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396 (10254): 839-852, 2020. [PubMed: 32888407]
24. Lin JK, Muffly LS, Spinner MA, et al.: Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma. J Clin Oncol 37 (24): 2105-2119, 2019. [PubMed: 31157579]
25. Jacobson CA, Hunter BD, Redd R, et al.: Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity. J Clin Oncol 38 (27): 3095-3106, 2020. [PMC free article: PMC7499617] [PubMed: 32667831]
26. Nastoupil LJ, Jain MD, Feng L, et al.: Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. J Clin Oncol 38 (27): 3119-3128, 2020. [PMC free article: PMC7499611] [PubMed: 32401634]
27. Salles G, Duell J, González Barca E, et al.: Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol 21 (7): 978-988, 2020. [PubMed: 32511983]
28. Zinzani PL, Pellegrini C, Gandolfi L, et al.: Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11 (6): 462-6, 2011. [PubMed: 21859554]
29. Wiernik PH, Lossos IS, Tuscano JM, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 26 (30): 4952-7, 2008. [PubMed: 18606983]
30. Sehn LH, Herrera AF, Flowers CR, et al.: Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol 38 (2): 155-165, 2020. [PMC free article: PMC7032881] [PubMed: 31693429]
31. Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997. [PubMed: 9164181]
32. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PubMed: 16039113]

Standard Treatment Options for LBL/ALL

Standard treatment options for LBL include the following:

1. Intensive therapy.
2. Radiation therapy.

(Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

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.)

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.

Standard Treatment Options for Diffuse, Small Noncleaved-Cell/Burkitt Lymphoma

Standard treatment options for diffuse, small, noncleaved-cell/Burkitt lymphoma include the following:

1. Aggressive multidrug regimens.
2. CNS prophylaxis.

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.

References

1. Blum KA, Lozanski G, Byrd JC: Adult Burkitt leukemia and lymphoma. Blood 104 (10): 3009-20, 2004. [PubMed: 15265787]
2. Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006. [PubMed: 16502413]
3. Hoelzer D, Walewski J, Döhner H, et al.: Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood 124 (26): 3870-9, 2014. [PMC free article: PMC4271177] [PubMed: 25359988]
4. Dunleavy K, Pittaluga S, Shovlin M, et al.: Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med 369 (20): 1915-25, 2013. [PMC free article: PMC3901044] [PubMed: 24224624]
5. Magrath I, Adde M, Shad A, et al.: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14 (3): 925-34, 1996. [PubMed: 8622041]
6. Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996. [PubMed: 8555471]
7. Mead GM, Sydes MR, Walewski J, et al.: An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol 13 (8): 1264-74, 2002. [PubMed: 12181251]
8. Rizzieri DA, Johnson JL, Niedzwiecki D, et al.: Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer 100 (7): 1438-48, 2004. [PubMed: 15042678]
9. Magrath IT, Haddy TB, Adde MA: Treatment of patients with high grade non-Hodgkin's lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 21 (1-2): 99-105, 1996. [PubMed: 8907276]

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.[1]

Stage Information for NHL During Pregnancy

To avoid exposure to ionizing radiation, magnetic resonance imaging is the preferred tool for staging evaluation.[2] (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

References

1. Ward FT, Weiss RB: Lymphoma and pregnancy. Semin Oncol 16 (5): 397-409, 1989. [PubMed: 2678489]
2. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27 (6): 623-32, 2000. [PubMed: 11130469]
3. Steiner-Salz D, Yahalom J, Samuelov A, et al.: Non-Hodgkin's lymphoma associated with pregnancy. A report of six cases, with a review of the literature. Cancer 56 (8): 2087-91, 1985. [PubMed: 4027936]
4. Spitzer M, Citron M, Ilardi CF, et al.: Non-Hodgkin's lymphoma during pregnancy. Gynecol Oncol 43 (3): 309-12, 1991. [PubMed: 1752504]
5. Gelb AB, van de Rijn M, Warnke RA, et al.: Pregnancy-associated lymphomas. A clinicopathologic study. Cancer 78 (2): 304-10, 1996. [PubMed: 8674008]
6. Horowitz NA, Benyamini N, Wohlfart K, et al.: Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review. Lancet Oncol 14 (7): e275-82, 2013. [PubMed: 23725710]
7. Evens AM, Advani R, Press OW, et al.: Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis. J Clin Oncol 31 (32): 4132-9, 2013. [PubMed: 24043736]
8. Avilés A, Díaz-Maqueo JC, Torras V, et al.: Non-Hodgkin's lymphomas and pregnancy: presentation of 16 cases. Gynecol Oncol 37 (3): 335-7, 1990. [PubMed: 2351317]
9. Moore DT, Taslimi MM: Multi-agent chemotherapy in a case of non-Hodgkin's lymphoma in second trimester of pregnancy. J Tenn Med Assoc 84 (9): 435-6, 1991. [PubMed: 1921384]
10. Nantel S, Parboosingh J, Poon MC: Treatment of an aggressive non-Hodgkin's lymphoma during pregnancy with MACOP-B chemotherapy. Med Pediatr Oncol 18 (2): 143-5, 1990. [PubMed: 1689451]
11. Mandal PK, Dolai TK, Bagchi B, et al.: B cell suppression in newborn following treatment of pregnant diffuse large B-cell lymphoma patient with rituximab containing regimen. Indian J Pediatr 81 (10): 1092-4, 2014. [PubMed: 24562617]

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 in the care of their 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:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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:

• Eric J. Seifter, MD (Johns Hopkins University)

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.

Disclaimer

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.

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