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B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

General Information About B-Cell Non-Hodgkin Lymphoma

The non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[1] This summary focuses primarily on B-cell NHL, which accounts for about 85% of NHL cases.[2] For more information about T-cell lymphomas, see Peripheral T-Cell Non-Hodgkin Lymphoma Treatment and Mycosis Fungoides (Including Sézary Syndrome) Treatment.

Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. However, NHL is much less predictable than Hodgkin lymphoma and has a far greater tendency to spread to extranodal sites. The prognosis depends on the histological type, disease stage, and treatment.

Incidence and Mortality

Estimated new cases and deaths from NHL in the United States in 2023:[3]

  • New cases: 80,550.
  • Deaths: 20,180.

B-cell lymphomas make up about 85% of NHL cases.[2]

Anatomy

NHL usually originates in lymphoid tissues.

Lymph system; drawing shows the lymph vessels and lymph organs including the lymph nodes, tonsils, thymus, spleen, and bone marrow. One inset shows the inside structure of a lymph node and the attached lymph vessels with arrows showing how the lymph (clear fluid) moves into and out of the lymph node. Another inset shows a close up of bone marrow with blood cells.
Anatomy of the lymph system.

Prognosis and Survival

NHL can be divided into two prognostic groups: indolent lymphomas and 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.[4] 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 NHL types have 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 5-year overall survival rate is over 60%. More than 50% of patients with aggressive NHL 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.[5]

While indolent NHL is responsive to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. However, patients 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.[6,7]

Late Effects of Treatment of NHL

Late effects of treatment of non-Hodgkin lymphoma (NHL) have been observed. Impaired fertility may occur after exposure to alkylating agents.[8] For as many as three decades after diagnosis, patients are at a significantly elevated risk of developing second primary cancers, especially the following:[9,10,11,12]

  • Lung cancer.
  • Brain cancer.
  • Kidney cancer.
  • Bladder cancer.
  • Melanoma.
  • Hodgkin lymphoma.
  • Acute nonlymphocytic leukemia.

Left ventricular dysfunction was a significant late effect in long-term survivors of high-grade NHL who received more than 200 mg/m² of doxorubicin.[8,13]

Myelodysplastic syndrome and acute myelogenous leukemia are late complications of myeloablative therapy with autologous bone marrow or peripheral blood stem cell support, as well as conventional chemotherapy-containing alkylating agents.[10,14,15,16,17,18,19,20,21] Most of these patients show clonal hematopoiesis even before the transplant, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[16,22,23] A series of 605 patients who received autologous bone marrow transplant (BMT) with cyclophosphamide and total-body radiation therapy (as conditioning) were followed for a median of 10 years. The incidence of a second malignancy was 21%, and 10% of those malignancies were solid tumors.[24]

A study of young women who received autologous BMT reported successful pregnancies with children born free of congenital abnormalities.[25] Late-occurring venous thromboembolism can occur after allogeneic or autologous BMT.[26]

Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.[27]

Long-term impaired immune health was evaluated in a retrospective cohort study of 21,690 survivors of diffuse large B-cell lymphoma from the California Cancer Registry. Elevated incidence rate ratios were found up to 10 years later for pneumonia (10.8-fold), meningitis (5.3-fold), immunoglobulin deficiency (17.6-fold), and autoimmune cytopenias (12-fold).[28] Similarly, there are impaired humoral responses to COVID-19 virus vaccination in patients with lymphoma who receive B-cell–directed therapies.[29,30]

References:

  1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012.
  2. American Cancer Society: Types of B-cell Lymphoma. American Cancer Society, 2019. Available online. Last accessed September 14, 2023.
  3. American Cancer Society: Cancer Facts and Figures 2023. American Cancer Society, 2023. Available online. Last accessed Dec. 15, 2023.
  4. 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.
  5. 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.
  6. 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.
  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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. Major A, Smith DE, Ghosh D, et al.: Risk and subtypes of secondary primary malignancies in diffuse large B-cell lymphoma survivors change over time based on stage at diagnosis. Cancer 126 (1): 189-201, 2020.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. Gangaraju R, Chen Y, Hageman L, et al.: Risk of venous thromboembolism in patients with non-Hodgkin lymphoma surviving blood or marrow transplantation. Cancer 125 (24): 4498-4508, 2019.
  27. 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.
  28. 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.
  29. Ghione P, Gu JJ, Attwood K, et al.: Impaired humoral responses to COVID-19 vaccination in patients with lymphoma receiving B-cell-directed therapies. Blood 138 (9): 811-814, 2021.
  30. Terpos E, Trougakos IP, Gavriatopoulou M, et al.: Low neutralizing antibody responses against SARS-CoV-2 in older patients with myeloma after the first BNT162b2 vaccine dose. Blood 137 (26): 3674-3676, 2021.

Cellular Classification of B-Cell Non-Hodgkin Lymphoma

A pathologist should be consulted before a biopsy because some studies require special preparation of tissue (e.g., frozen tissue). Knowledge of cell surface markers and immunoglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light-chain immunoglobulin may differentiate malignant cells from reactive cells. Because the prognosis and the approach to treatment are influenced by histopathology, outside biopsy specimens should be carefully reviewed by a hematopathologist who is experienced in diagnosing lymphomas. Although lymph node biopsies are recommended whenever possible, sometimes immunophenotypic data are sufficient for diagnosis of lymphoma when fine-needle aspiration cytology or core needle biopsy is preferred.[1,2]

Historical Classification Systems

Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation.[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.

Table 1. Historical Classification Systems for Non-Hodgkin Lymphoma (NHL)
Working Formulation[3] Rappaport Classification
Low grade  
A. Small lymphocytic, consistent with chronic lymphocytic leukemia Diffuse lymphocytic, well-differentiated
B. Follicular, predominantly small-cleaved cell Nodular lymphocytic, poorly differentiated
C. Follicular, mixed small-cleaved, and large cell Nodular mixed, lymphocytic, and histiocytic
Intermediate grade  
D. Follicular, predominantly large cell Nodular histiocytic
E. Diffuse small-cleaved cell Diffuse lymphocytic, poorly differentiated
F. Diffuse mixed, small and large cell Diffuse mixed, lymphocytic, and histiocytic
G. Diffuse, large cell, cleaved, or noncleaved cell Diffuse histiocytic
High grade  
H. Immunoblastic, large cell Diffuse histiocytic
I. Lymphoblastic, convoluted, or nonconvoluted cell Diffuse lymphoblastic
J. Small noncleaved-cell, Burkitt, or non-Burkitt Diffuse undifferentiated Burkitt or non-Burkitt

Current Classification Systems

As the histopathological diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathological entities have been described.[4] In addition, the understanding and treatment of many of the previously described pathological subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. Thus, European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) classification.[5,6,7,8] Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system.[9,10]

Updated REAL/WHO classification

The World Health Organization (WHO) modification of the Revised European American Lymphoma (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]

B-cell neoplasms

  1. Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
  2. Peripheral B-cell neoplasms.
    1. B-cell CLL/small lymphocytic lymphoma.
    2. B-cell prolymphocytic leukemia.
    3. Lymphoplasmacytic lymphoma/immunocytoma.
    4. Mantle cell lymphoma.
    5. Follicular lymphoma.
    6. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type.
    7. Nodal marginal zone B-cell lymphoma (± monocytoid B cells).
    8. Splenic marginal zone lymphoma (± villous lymphocytes).
    9. Hairy cell leukemia.
    10. Plasmacytoma/plasma cell myeloma.
    11. Diffuse large B-cell lymphoma.
    12. Burkitt lymphoma.

T-cell and putative NK-cell neoplasms

  1. Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL. For more information, see Adult Acute Lymphoblastic Leukemia Treatment.
  2. Peripheral T-cell and NK-cell neoplasms.
    1. T-cell CLL/prolymphocytic leukemia.
    2. T-cell granular lymphocytic leukemia.
    3. Mycosis fungoides (including Sézary syndrome).
    4. Peripheral T-cell lymphoma, not otherwise characterized.
    5. Hepatosplenic gamma/delta T-cell lymphoma.
    6. Subcutaneous panniculitis-like T-cell lymphoma.
    7. Angioimmunoblastic T-cell lymphoma.
    8. Extranodal T-/NK-cell lymphoma, nasal type.
    9. Enteropathy-type intestinal T-cell lymphoma.
    10. Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+).
    11. Anaplastic large cell lymphoma, primary systemic type.
    12. Anaplastic large cell lymphoma, primary cutaneous type.
    13. Aggressive NK-cell leukemia.

HL

  1. Nodular lymphocyte-predominant HL.
  2. Classical HL.
    1. Nodular sclerosis HL.
    2. Lymphocyte-rich classical HL.
    3. Mixed-cellularity HL.
    4. Lymphocyte-depleted HL.

The REAL classification encompasses all the lymphoproliferative neoplasms. For more information, see the following PDQ summaries:

  • Adult Acute Lymphoblastic Leukemia Treatment
  • Hodgkin Lymphoma Treatment
  • AIDS-Related Lymphoma Treatment
  • Chronic Lymphocytic Leukemia Treatment
  • Hairy Cell Leukemia Treatment
  • Mycosis Fungoides (Including Sézary Syndrome) Treatment
  • Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment
  • Primary CNS Lymphoma Treatment

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.
  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.
  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.
  4. Pugh WC: Is the working formulation adequate for the classification of the low grade lymphomas? Leuk Lymphoma 10 (Suppl 1): 1-8, 1993.
  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.
  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.
  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.
  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.
  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.
  10. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.

Stage Information for B-Cell Non-Hodgkin Lymphoma

Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomography (CT) scans are usually part of the staging evaluation for all patients with lymphoma. The staging system for NHL is similar to the staging system used for Hodgkin lymphoma (HL).

It is common for patients with NHL to have involvement of the following sites:

  • Noncontiguous lymph nodes.
  • Waldeyer ring.
  • Epitrochlear nodes.
  • Gastrointestinal tract.
  • Extranodal presentations. (A single extranodal site is occasionally the only site of involvement in patients with diffuse lymphoma.)
  • Bone marrow.
  • Liver (especially common in patients with low-grade lymphomas).

Cytological examination of cerebrospinal fluid may be positive in patients with aggressive NHL. Involvement of hilar and mediastinal lymph nodes is less common than in HL. Mediastinal adenopathy, however, is a prominent feature of lymphoblastic lymphoma and primary mediastinal B-cell lymphoma, entities primarily found in young adults.

Most patients with NHL present with advanced (stage III or stage IV) disease often identified by CT scans or biopsies of the bone marrow and other accessible sites of involvement. In a retrospective review of over 32,000 cases of lymphoma in France, up to 40% of diagnoses were made by core needle biopsy, and 60% were made by excisional biopsy.[1] After expert review, core needle biopsy provided a definite diagnosis in 92.3% of cases; excisional biopsy provided a definite diagnosis in 98.1% of cases (P < .0001). Laparoscopic biopsy or laparotomy is not required for staging but rarely may be necessary to establish a diagnosis or histological type.[2]

Positron emission tomography (PET) with fluorine F 18-fludeoxyglucose can be used for initial staging. It can also be used for follow-up after therapy as a supplement to CT scanning.[3] Multiple studies have demonstrated that interim PET scans after two to four cycles of therapy do not provide reliable prognostic information. A large cooperative group trial (ECOG-E344 [NCT00274924]) reported problems with interobserver reproducibility. Two prospective trials and one meta-analysis showed no differences in outcomes between PET-negative and PET-positive/biopsy-negative patients.[4,5,6,7]

In a retrospective study of 130 patients with diffuse large B-cell lymphoma, PET scanning identified all clinically important marrow involvement from lymphoma, and bone marrow biopsy did not upstage any patient's lymphoma.[8] A retrospective study of 580 patients with follicular lymphoma from seven National Cancer Institute–sponsored trials showed no improvement in assessing response to therapy when bone marrow biopsy was added to radiological imaging.[9] The workup of NHL should include bone marrow biopsy when management would change (e.g., determining limited stage vs. advanced stage) or when evaluating cytopenias.

For patients with follicular lymphoma, a positive PET result after therapy has a worse prognosis; however, it is unclear whether a positive PET result is predictive when further or different therapy is implemented.[10]

Staging Subclassification System

Lugano classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[11] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[12] with some modifications 18 years later from the Cotswolds meeting.[13,14]

Table 2. Lugano Classification for Hodgkin and Non-Hodgkin Lymphomaa
Stage Stage Description Illustration
CSF = cerebrospinal fluid; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
a Hodgkin 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.
b Stage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors.
c The 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.
Limited stage
I Involvement of a single lymphatic site (i.e., nodal region, Waldeyer's ring, thymus, or spleen).
Stage I adult lymphoma; drawing shows cancer in one lymph node group and in the spleen. Also shown are the Waldeyer's ring and the thymus. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
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.
Stage II adult lymphoma; drawing shows cancer in two lymph node groups above the diaphragm and below the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
IIE Contiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.
Stage IIE adult lymphoma; drawing shows cancer that has spread from a group of lymph nodes to a nearby area. Also shown is a lung and the diaphragm. An inset shows a lymph node with a lymph vessel, an artery, and a vein. Cancer cells are shown in the lymph node.
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.
Stage III adult lymphoma; drawing shows the right and left sides of the body. The right side of the body shows cancer in a group of lymph nodes above the diaphragm and below the diaphragm. The left side of the body shows cancer in a group of lymph nodes above the diaphragm and cancer in the spleen.
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).
Stage IV adult lymphoma; drawing shows four panels: (a) the top left panel shows cancer in the liver; (b) the top right panel shows cancer in the left lung and in two groups of lymph nodes below the diaphragm; (c) the bottom left panel shows cancer in the left lung and in a group of lymph nodes above the diaphragm and below the diaphragm; and (d) the bottom right panel shows cancer in both lungs, the liver, and the bone marrow (pullout). Also shown is primary cancer in the lymph nodes and a pullout of the brain with cerebrospinal fluid (in blue).
Note: Hodgkin lymphoma uses A or B designation with stage group. A/B is no longer used in NHL.

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 pathological 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
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 pathological stage based on the findings from invasive procedures beyond the initial biopsy.

For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might have involvement of the liver and bone marrow. The precise stage of such a patient would be clinical stage IIA, pathological 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:[15]

  • Age.
    • <40 years: 0.
    • 41–60 years: 1.
    • 61–75 years: 2.
    • >75 years: 3.
  • Stage III/IV: 1.
  • Performance status (PS) 2/3/4: 1.
  • Serum lactate dehydrogenase (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.[16] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biological factors.[17]

The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[18,19] Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[20] 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.[21]

References:

  1. Syrykh C, Chaouat C, Poullot E, et al.: Lymph node excisions provide more precise lymphoma diagnoses than core biopsies: a French Lymphopath network survey. Blood 140 (24): 2573-2583, 2022.
  2. Mann GB, Conlon KC, LaQuaglia M, et al.: Emerging role of laparoscopy in the diagnosis of lymphoma. J Clin Oncol 16 (5): 1909-15, 1998.
  3. Barrington SF, Mikhaeel NG, Kostakoglu L, et al.: Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32 (27): 3048-58, 2014.
  4. Horning SJ, Juweid ME, Schöder H, et al.: Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood 115 (4): 775-7; quiz 918, 2010.
  5. Moskowitz CH, Schöder H, Teruya-Feldstein J, et al.: Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol 28 (11): 1896-903, 2010.
  6. Pregno P, Chiappella A, Bellò M, et al.: Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. Blood 119 (9): 2066-73, 2012.
  7. Sun N, Zhao J, Qiao W, et al.: Predictive value of interim PET/CT in DLBCL treated with R-CHOP: meta-analysis. Biomed Res Int 2015: 648572, 2015.
  8. Khan AB, Barrington SF, Mikhaeel NG, et al.: PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood 122 (1): 61-7, 2013.
  9. Rutherford SC, Yin J, Pederson L, et al.: Relevance of Bone Marrow Biopsies for Response Assessment in US National Cancer Institute National Clinical Trials Network Follicular Lymphoma Clinical Trials. J Clin Oncol 41 (2): 336-342, 2023.
  10. Pyo J, Won Kim K, Jacene HA, et al.: End-therapy positron emission tomography for treatment response assessment in follicular lymphoma: a systematic review and meta-analysis. Clin Cancer Res 19 (23): 6566-77, 2013.
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  16. Møller MB, Christensen BE, Pedersen NT: Prognosis of localized diffuse large B-cell lymphoma in younger patients. Cancer 98 (3): 516-21, 2003.
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  18. Scott DW, King RL, Staiger AM, et al.: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood 131 (18): 2060-2064, 2018.
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Indolent B-Cell Non-Hodgkin Lymphoma

Indolent B-cell non-Hodgkin lymphoma (NHL) includes the following subtypes:

  • Follicular lymphoma (grades 1–3a).
  • Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
  • Marginal zone lymphoma.

Follicular Lymphoma (Grades 1–3a)

Follicular lymphoma makes up 20% of all NHLs and as many as 70% of the indolent lymphomas reported in American and European clinical trials.[1,2,3] Most patients with follicular lymphoma are aged 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]

Prognosis

Follicular lymphoma is designated as indolent because median survival ranges from 8 to 15 years, even in advanced stages.[5,6,7] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[8] Watchful waiting, the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[9,10] An international index for follicular lymphoma (the Follicular Lymphoma International Prognostic Index [FLIPI]) [11,12,13] identified five significant risk factors prognostic of overall survival (OS):

  1. Age (=60 years vs. >60 years).
  2. Serum lactate dehydrogenase (LDH) (normal vs. elevated).
  3. Stage (stage I or stage II vs. stage III or stage IV).
  4. Hemoglobin level (=120 g/L vs. <120 g/L).
  5. Number of nodal areas (=4 vs. >4).

Patients with fewer than two risk factors have an 85% 10-year survival rate, and three or more risk factors confer a 40% 10-year survival rate.[11] In a revised FLIPI-2, an elevated beta-2-microglobulin and lymph node size of more than 6 cm are proposed prognostic factors instead of serum LDH and the number of nodal areas.[14] Although the FLIPI and FLIPI-2 indices can predict progression-free survival (PFS) and OS, the scores cannot be used to establish the need for therapy, nor can they be used to predict response to therapy.[11,14] The primary use of FLIPI or FLIPI-2 is to assure a balance of prognostic factors or to define entry requirements in randomized clinical trials. Individuals with an adverse FLIPI score may well benefit from watchful waiting or may respond well to initial therapy. An alternative prognostic index using only beta-2-microglobulin and initial bone marrow involvement (PRIMA-PI) has the disadvantage of requiring an invasive test not usually required outside the context of a clinical trial.[15] An alternative prognostic index using only noninvasive clinical variables outperformed FLIPI, FLIPI-2, and PRIMA-PI, using data from immunochemotherapy trials.[16]

Three retrospective analyses, including one pooled analysis of 5,225 patients from 13 randomized clinical trials, identified a high-risk group that had a 50% OS rate at 5 years when relapses occurred within 24 months of induction chemoimmunotherapy.[17,18,19] A fourth retrospective analysis of 296 patients who received bendamustine and rituximab found a 2-year OS rate of 38% (95% confidence interval [CI], 20%-55%) among those with progression of disease before 24 months (POD24). Most of these patients (76%) had transformed disease (histological progression to diffuse large B-cell lymphoma [DLBCL]).[20] These patients with higher-risk POD24 disease represent a target population for clinical trials.

Follicular small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.

Therapeutic approaches

Because of the often-indolent clinical course and the lack of symptoms in some patients with follicular lymphoma, watchful waiting remains a standard of care during the initial encounter and for patients with slow asymptomatic relapsing disease. When therapy is required, numerous therapeutic options may be used in varying sequences with an OS equivalence at 5 to 10 years.[9,21,22,23] Rituximab can be given alone or in combination with various chemotherapy options.[23,24] Rituximab can also be combined with the immunomodulating-agent lenalidomide to avoid the short- and long-term toxicities of cytotoxic agents.[25,26,27] Another anti–CD20 monoclonal antibody, obinutuzumab, can be administered with combination chemotherapy.[28] Inhibitors of phosphatidylinositol 3-kinase (PI3K) are also effective in patients with relapsed or refractory disease.[29] CD19-directed chimeric antigen receptor (CAR) T cells may be used In patients who have disease progression after two or more prior lines of therapy.[30] Mosunetuzumab, a bispecific CD20-directed CD3 T-cell engager, may also be used in this setting.[31] Consolidation therapy for relapsed disease after reinduction therapy using autologous stem cell transplant (SCT) or allogeneic SCT can be considered.[32]

Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress or require therapy.[33,34] A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histological variant are characterized by a lack of BCL2 rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.[35]

Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy can be performed, if feasible.[36] If disease conversion to a more aggressive histology is confirmed, therapy must change to a regimen applicable to that histological type.[37] Rapid growth or discordant growth between various disease sites may indicate a histological conversion.[36] In a retrospective review of 325 patients diagnosed between 1972 and 1999, the risk of histological transformation was 30% by 10 years.[38] In this series, high-risk factors for subsequent histological transformation were advanced stage, high-risk FLIPI, and expectant management (as opposed to treatment being initiated at diagnosis). The 5-year OS rate was more than 50% for patients who had biopsy-proven, aggressive-histology transformation in several multicenter cohort studies using rituximab plus anthracycline or platinum-based chemotherapy, or similar therapy followed by autologous or allogeneic SCT.[36,39,40]

In a prospective nonrandomized study, at a median follow-up of 6.8 years, 379 of 2,652 patients (14%) subsequently transformed to a more aggressive histology after an initial diagnosis of follicular lymphoma.[41][Level of evidence C3] The median OS after subsequent transformation was 5 years; however, among 47 patients with evidence of transformation in conjunction with follicular lymphoma at the time of initial diagnosis, the OS was no worse than that of the other nontransformed patients (5-year OS rate, 88%; 95% CI, 74%–95%).

Grade 3b follicular lymphoma is managed similarly to DLBCL. For more information, see the Aggressive B-Cell Non-Hodgkin Lymphoma section.

Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[42] 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 indicative for the disease.[43] 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.[9,44,45]

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.[44]

Therapeutic approaches

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia.[46,47,48] If the serum viscosity relative to water is greater than four, the patient may have symptoms of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms such as retinopathy, congestive heart failure, and central nervous system (CNS) dysfunction but can be combined with chemotherapy for prolonged disease control. Symptomatic patients with a serum viscosity of four or lower are usually treated with chemoimmunotherapy or biologically directed therapies. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, bendamustine, and steroids are often used.[45] Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling. Sutimlimab, an immunoglobulin G4 monoclonal antibody that selectively inhibits the complement pathway at C15, can reduce hemolysis when therapies directed at the lymphoplasmacytic lymphoma are ineffective.[49]

First-line regimens include rituximab and ibrutinib (a Bruton tyrosine kinase [BTK] inhibitor), rituximab alone, the nucleoside analogues, and alkylating agents, either as single agents or as part of combination chemotherapy.[50,51,52,53,54] In a randomized prospective trial, 150 symptomatic patients (including patients with previously untreated and relapsing disease) received either ibrutinib and rituximab or rituximab and a placebo. With a median follow-up of 50 months, the 4.5-year PFS rate favored the ibrutinib-and-rituximab arm (68%; 95% CI, 55%–78%) versus the rituximab-and-placebo arm (25%; 95% CI, 15%–37%) (hazard ratio, 0.25; 95% CI, 0.15–0.42; P < .0001). The OS rate at 30 months was no different in the two arms (92%–94%).[54][Level of evidence B1] Zanubrutinib, another BTK inhibitor, was compared with ibrutinib in a randomized prospective clinical trial of 164 patients with relapsed disease and 38 with previously untreated disease.[55] With a median follow-up of 18 months, the PFS rate was the same in both groups at 84%. The zanubrutinib group had fewer cases of atrial fibrillation (11 vs. 1) and 50% fewer cases of hypertension (statistics not provided).[55][Level of evidence C3] BTK inhibition with ibrutinib allowed all 13 patients with cold-antibody–mediated autoimmune hemolytic anemia and acrocyanosis to attain clinical remission regardless of underlying pathology or MYD88 status.[56][Level of evidence C3]

Previously untreated patients who received rituximab had response rates of 60% to 80%, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[50,57,58][Level of evidence C3] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent, such as cyclophosphamide, or the proteosome inhibitors bortezomib or ixazomib.[45,59,60,61] A combination of bortezomib, dexamethasone, and rituximab has been used without causing IgM rebound.[62,63,64] Previously untreated patients with lymphoplasmacytic lymphoma who received the nucleoside analogues cladribine and fludarabine showed similar response rates.[53,65,66][Level of evidence C3] Patients who received single-agent alkylators, bendamustine, bortezomib, venetoclax, and combination chemotherapy with or without rituximab also showed similar response rates.[53,59,61,67,68,69,70,71][Level of evidence C3] In the rare case of lymphoplasmacytic lymphoma involving the CNS (Bing-Neel syndrome), ibrutinib resulted in an 85% response rate in an anecdotal series of 28 patients.[72][Level of evidence C3]

Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[73,74,75,76] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogues, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia.[50,77] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to receive either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months, P < .01), no difference was observed in OS.[78][Level of evidence B1]

Marginal Zone Lymphoma

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.[79,80] Splenic marginal zone lymphoma is a distinct clinical entity which usually presents with massive splenomegaly. A variant form of MALT lymphoma is known as immunoproliferative small intestinal disease (IPSID).[80] 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.[81] Fewer than 10% of patients transform to a higher-grade lymphoma. In one retrospective review, risk factors for transformation 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.[82]

Gastric MALT

Many patients have a history of autoimmune disease, such as Hashimoto thyroiditis or Sjögren syndrome, or of Helicobacter gastritis. Most patients present with stage I or stage II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pylori infection may resolve most cases of localized gastric involvement.[83,84] After standard antibiotic regimens, 50% of patients show resolution of gastric MALT by endoscopy after 3 months. Other patients may show resolution after 12 to 18 months of observation. Of the patients who attain complete remission, 30% demonstrate monoclonality by immunoglobulin heavy chain rearrangement on stomach biopsies with a 5-year median follow-up.[85] The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts poor response to both antibiotic therapy and oral alkylator therapy, and predicts negative H. pylori testing results.[86,87,88] Patients with stable asymptomatic disease and persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[84] Patients with disease progression are treated with radiation therapy,[89,90,91,92,93] rituximab,[94] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[95] chemotherapy,[96] or combined-modality therapy.[97] Endoscopic ultrasonography may help clinicians monitor responses in these patients.[98] Four case series encompassing more than 100 patients with stage IE or IIE DLBCL with or without associated MALT (but H. pylori -positive) reported durable complete remissions in more than 50% of the patients after treatment of H. pylori.[99,100,101,102]

Extragastric MALT

Localized involvement of other sites can be treated with radiation therapy or surgery.[90,91,92,103,104,105,106] Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, and relapses can happen many years and even decades later.[107] Many of these recurrences involve different MALT sites than the original location.[108] When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[109,110] A prospective randomized trial of 401 patients with nongastric extranodal MALT compared chlorambucil alone versus rituximab plus chlorambucil versus rituximab alone.[111] With a median follow-up of 7.4 years, the event-free survival was 68% in the rituximab-plus-chlorambucil arm, 51% in the rituximab-alone arm, and 50% in the chlorambucil-alone arm (P = .0009). However, the 5-year OS rate was 90% in all arms.[111] For patients with ocular adnexal MALT, antibiotic therapy using doxycycline that targeted Chlamydia psittaci resulted in durable remissions for almost half of the patients in a review of the literature that included 131 patients.[112][Level of evidence C3] These responses to doxycycline are mainly seen in Italian trials and less often in trials conducted in other geographic sites.[113] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[114] A large, retrospective review of primary ocular adnexal MALT found that after 10 years of follow-up, 4% of stage I patients treated with radiation therapy transformed to DLBCL, and 3% of them developed CNS involvement.[115]

Nodal marginal zone lymphoma

Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with watchful waiting or therapies as described for lymphoplasmacytic lymphoma. Rituximab alone or combined with cytotoxic agents (such as bendamustine) can be used. Zanubrutinib is approved for patients with disease relapse after a rituximab-containing regimen. This approval is based on a single-arm phase II study.[116] With a median follow-up of 15.7 months, the overall response rate was 68.2% and the complete response rate was 25.8%. The median duration of response was 93% at 12 months.[116][Level of evidence C3] Ibrutinib also showed similar efficacy in patients with relapsed marginal zone lymphoma.[117][Level of evidence C3] Similar to follicular lymphoma, patients with POD24 who required initiation of therapy had a worse prognosis (53% 3-year OS rate) than did the patients without POD24 (95% 3-year OS rate).[118] Among patients with concomitant hepatitis C virus (HCV) infection, 40% to 60% attained a complete or partial remission after loss of detectable HCV RNA with antiviral treatment.[119,120][Level of evidence C3]

Mediterranean abdominal lymphoma

The disease variously known as Mediterranean abdominal lymphoma, heavy-chain disease, or IPSID, which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma, which responds to antibiotics in its early stages.[121]Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[122]

Splenic marginal zone lymphoma

Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[123,124] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[125,126]

Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogues or alkylating agent chemotherapy.[127] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[123,127,128] Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and HCV infection, most attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[119,129]; [130][Level of evidence C3] In contrast, no responses to interferon were seen in six HCV-negative patients.

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Aggressive B-Cell Non-Hodgkin Lymphoma

Aggressive B-cell non-Hodgkin lymphoma (NHL) includes the following subtypes:

  • Diffuse large B-cell lymphoma.
  • Primary mediastinal large B-cell lymphoma.
  • Intravascular large B-cell lymphoma (intravascular lymphomatosis).
  • Follicular lymphoma (grade 3b).
  • Mantle cell lymphoma.
  • Burkitt lymphoma/diffuse small noncleaved-cell lymphoma.
  • B-cell lymphoblastic lymphoma.
  • Primary effusion lymphoma.
  • Plasmablastic lymphoma.
  • Polymorphic posttransplant lymphoproliferative disorder.
  • Lymphomatoid granulomatosis.

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL and makes up 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). For more information about weight loss, see Nutrition in Cancer Care.

Some cases of large B-cell lymphoma have a prominent background of reactive T cells and often of histiocytes, so-called T-cell/histiocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with DLBCL.[2,3,4] At diagnosis, some patients with DLBCL have a concomitant indolent small B-cell component. While overall survival (OS) appears similar to de novo DLBCL after multidrug chemotherapy, there is a higher risk of indolent relapse.[5]

Prognosis

Most patients with localized disease are curable with combined-modality therapy or combination chemotherapy alone.[6] Among patients with advanced-stage disease, 50% are cured with doxorubicin-based combination chemotherapy and rituximab, typically R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).[7,8,9]

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:[10]

  • Age.
    • <40 years: 0.
    • 41–60 years: 1.
    • 61–75 years: 2.
    • >75 years: 3.
  • Stage III/IV: 1.
  • Performance status (PS) 2/3/4: 1.
  • Serum lactate dehydrogenase (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.[11] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biological factors.[12]

The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYC gene, or both, confer a particularly poor prognosis.[13,14,15] Dose-intensive therapies, infusional therapies, and stem cell transplant (SCT) consolidation are being explored in this high-risk group.[16,17] A retrospective review evaluated 159 patients with previously untreated DLBCL who underwent double-hit genetic testing by fluorescence in situ hybridization (FISH) and achieved complete response.[18] The induction therapy did not alter 3-year relapse-free survival or OS when autologous SCT was used.

In a retrospective review of 117 patients with relapsed or refractory DLBCL who underwent autologous SCT, the 4-year OS rate was 25% for patients with double-hit lymphomas (rearrangement of BCL2 and MYC), 61% for patients with double-expressor lymphomas (no rearrangement, but increased expression of BCL2 and MYC), and 70% for patients without these features.[19] Patients at high risk of relapse consider for clinical trials.[20]

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.[21] For example, true anaplastic lymphoma kinase (ALK)-positive large B-cell lymphomas are extremely rare, and they do not respond well to conventional R-CHOP therapy. Anecdotal responses to ALK inhibitors like lorlatinib or alectinib have been reported.[22][Level of evidence C3] Coexpression of CD20 and CD30 may define a subgroup of patients with DLBCL with a unique molecular signature and a more favorable prognosis. Patients in this subgroup may be treated with an anti-CD30–specific therapy, such as brentuximab vedotin.[23] Patients with DLBCL who are event-free after 2 years have a subsequent OS equivalent to that of the age- and sex-matched general population.[24]

Central nervous system (CNS) prophylaxis

The CNS-IPI tool predicts which patients have a CNS relapse risk exceeding 10%. It was developed by the German Lymphoma Study Group and validated by the British Columbia Cancer Agency database. The presence of four to six of the CNS-IPI risk factors (age >60 years, performance status =2, elevated LDH, stage III or IV disease, >1 extranodal site, or involvement of the kidneys or adrenal glands) was used to define a high-risk group for CNS recurrence (a 12% risk of CNS involvement by 2 years).[25]

CNS prophylaxis (usually with four to six doses of intrathecal methotrexate) is often recommended for patients with testicular involvement.[26,27,28][Level of evidence C3] A retrospective analysis of the German RICOVER studies compared intrathecal methotrexate with no prophylaxis in patients with DLBCL. This study was completed during the R-CHOP treatment era. With the possible exception of patients with testicular involvement, the analysis showed that intrathecal methotrexate did not reduce the risk of CNS disease.[29][Level of evidence C3] Some clinicians use high-dose intravenous (IV) methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[30] A retrospective study evaluated 1,162 patients from 21 U.S. academic centers where 77% received intrathecal methotrexate, 20% received high-dose IV methotrexate, and 3% received both sequentially (because of toxicity).[31] There was no difference in CNS relapse rates between patients who received intrathecal methotrexate or high-dose IV methotrexate (5.4% vs. 6.8%, P = .40). Testicular involvement, nongerminal center subtype, and high extranodal involvement predicted increased CNS relapse regardless of the route of prophylaxis.[31] Two retrospective studies evaluating high-dose methotrexate in patients with high-risk DLBCL also showed no improvement in CNS relapse rate.[32,33][Level of evidence C3] Patients deemed at high risk for CNS relapse (e.g., patients with four to six CNS-IPI risk factors) often receive intrathecal methotrexate or high-dose IV methotrexate, but the lack of confirmatory randomized studies calls this standard into question and shows an urgent need for better therapeutics verified in clinical trials. Patients with testicular involvement are an exception, as they show benefit from intrathecal or high-dose IV methotrexate.[26,27,28][Level of evidence C3]

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses.[29,34][Level of evidence C3] Patients with CNS dissemination at diagnosis or at relapse usually receive rituximab and high doses of methotrexate and/or cytarabine followed by autologous SCT, but this approach has not been assessed in randomized trials.[35,36][Level of evidence C3]

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a subset of DLBCL with molecular characteristics that are most similar to nodular-sclerosing Hodgkin lymphoma (HL).[37] Mediastinal lymphomas with features intermediate between primary mediastinal B-cell lymphoma and nodular-sclerosing HL are called mediastinal gray-zone lymphomas.[38,39] 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 using dose-adjusted R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) or R-CHOP showed high cure rates while avoiding any mediastinal radiation.[39,40,41,42,43,44,45][Level of evidence C1] 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.[40,46,47,48]

A retrospective review of 109 patients with PMBCL showed that 63% had a negative end-of-treatment PET-CT (EOT-PET-CT) (Deauville score 1–3).[49] No radiation therapy was offered and the 5-year time-to-progression rate (similar to disease-free survival, but restricted to lymphoma relapse) was 90%, and the 5-year OS rate was 97%.[49][Level of evidence C3] Patients with a positive EOT-PET-CT received radiation therapy consolidation. It is unclear from this study whether those patients might have done just as well without radiation therapy. Clinicians may monitor patients with Deauville 4 scores on EOT-PET-CT scans for improvement over time, as an alternative to giving radiation therapy. However, this approach has not been studied in a clinical trial.

In situations where mediastinal radiation therapy 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.[50] For more information, see the Superior Vena Cava Syndrome section in Cardiopulmonary Syndromes.

Because PMBCL 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 was 73% (95% CI, 54%-88%).[51][Level of evidence C3] Similarly, phase I and II trials of pembrolizumab in 74 patients with relapsed or refractory disease showed an objective response rate of 45% to 48%. The median duration of response was not reached for the 21 patients with a median follow-up of 29 months or for the 53 patients with a median follow-up of 12.5 months.[52][Level of evidence C3]

Among those who had received two prior lines of therapy, more than half of patients who received CAR T-cell therapy with lisocabtagene maraleucel had disease response.[53][Level of evidence C3]

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.[54,55,56]

Follicular Lymphoma (Grade 3b)

Prognosis

The natural history of follicular large cell lymphoma remains controversial.[57] While there is agreement about the significant number of long-term disease-free survivors with early-stage disease, the potential for cure in patients with advanced disease (stage III or stage IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma).[58] Other investigators report a plateau in freedom from progression at levels expected for an aggressive lymphoma (40% at 10 years).[59,60] This discrepancy may be caused by variations in histological classification between institutions and the rarity of patients with follicular large cell lymphoma. A retrospective review of 252 patients, all treated with anthracycline-containing combination chemotherapy, showed that patients with more than 50% diffuse components on biopsy had a worse OS than other patients with follicular large cell lymphoma.[61]

Therapeutic approaches

Treatment of follicular large cell lymphoma is more similar to treatment of aggressive NHL than it is to the treatment of indolent NHL. In support of this approach, treatment with high-dose chemotherapy and autologous hematopoietic peripheral SCT shows the same curative potential in patients with follicular large cell lymphoma who relapse as it does in patients with diffuse large cell lymphoma who relapse.[62][Level of evidence C1]

Among those who had received two prior lines of therapy, more than half of patients who received CAR T-cell therapy with lisocabtagene maraleucel had disease response.[53][Level of evidence C3]

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[63] MCL is characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein.[63] MCL may be divided into two clinical subtypes. The first is a classical version with lymphadenopathy with high SOX-11 expression that manifests with an aggressive clinical course and a worse prognosis. The second is a leukemic, non-nodal version with low SOX-11 expression and a more indolent course and a better prognosis.[64] A complex karyotype predicts poor response to induction therapy and inferior survival.[65] 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.[66,67]

Like the low-grade lymphomas, MCL 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. This histology is now considered to be an aggressive lymphoma.[68] 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.[67,69] A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[70,71]

Therapeutic approaches

Asymptomatic patients with low-risk scores on the IPI may do well when initial therapy is deferred.[72,73][Level of evidence C3] There is no standard approach to MCL. Several induction chemotherapy regimens may be used for symptomatic progressing disease. These regimens range in intensity from rituximab alone to rituximab plus ibrutinib, rituximab plus bendamustine, R-CHOP, or high-dose intensive regimens such as R-hyper C-VAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine). Some physicians use autologous SCT or allogeneic SCT consolidation next, while others prefer rituximab maintenance, reserving high-dose consolidation for a later time.[74] Ibrutinib, lenalidomide, and bortezomib have shown activity in relapsing patients, and these drugs are being incorporated up front.[75,76,77,78,79,80]

It is unclear which therapeutic approach offers the best long-term survival in this clinicopathological entity.

In a phase II trial of previously untreated patients with MCL older than 64 years, 50 patients received the B-cell receptor-inhibitor ibrutinib plus rituximab. With a median follow-up of 45 months, the overall response rate was 96%, the complete response rate was 71%, the 3-year PFS rate was 87%, and the 3-year OS rate was 94%.[80][Level of evidence C3] In a phase II trial of 131 previously untreated patients with MCL aged 65 years or younger, 1 year of ibrutinib plus 4 weeks of rituximab resulted in a complete response rate of 89% prior to any chemotherapy consolidation.[81][Level of evidence C3] Another phase II trial using ibrutinib plus rituximab included asymptomatic patients with previously untreated MCL; the complete response rate was 87%.[82][Level of evidence C3] Previously treated patients who received ibrutinib had a response rate of 86% (21% complete response rate) and a median PFS of 14 months.[77][Level of evidence C3] In a prospective randomized trial, 280 patients with relapsed or refractory MCL received either ibrutinib or temsirolimus.[83] With a median follow-up of 15 months, the median PFS favored ibrutinib (14.6 months vs. 6.2 months; HR, 0.43; 95% CI, 0.32–0.58, P < .0001).[83][Level of evidence B1] Ibrutinib was combined with another active agent, venetoclax, in a phase II study of 23 patients with relapsed or refractory MCL.[84] An unprecedented 71% of patients had a complete response and 78% of responding patients maintained response at 15 months.[84][Level of evidence C3]

A prospective randomized trial included 523 patients aged 65 years and older with MCL. Patients were randomly assigned to receive either ibrutinib, bendamustine, and rituximab or bendamustine and rituximab alone.[85] With a median follow-up of 84.7 months, the median PFS was 80.6 months for patients who received ibrutinib, and 52.9 months for patients who received bendamustine and rituximab alone (HR, 0.75; 95% CI, 0.59–0.96; P = .01). There was no difference in the 7-year OS rate (55.0% vs. 56.8%; HR, 1.07; 95% CI, 0.81–1.40).[85][Level of evidence B1] It is unclear if patients who received ibrutinib alone could have achieved these same results without receiving conventional chemotherapy. The magnitude of benefit demonstrated by the PFS results contrasted with the insufficient OS benefit after 7 years may cast doubt on the long-term safety of this combination.

In a prospective randomized trial, 560 patients older than 60 years and not eligible for SCT were given either R-CHOP or R-FC (rituximab, fludarabine, cyclophosphamide) for six to eight cycles, followed by maintenance therapy in responders randomly assigned to rituximab or interferon-alpha maintenance therapy.[86] With a median follow-up of 7.6 years, the median OS was significantly shorter after R-FC than after R-CHOP (3.9 years vs. 6.4 years; P = .0054).[86][Level of evidence A1] In the same trial, with a median follow-up of 8 years for the 316 responding patients, rituximab maintenance resulted in improved OS over interferon maintenance (median OS, 9.8 years vs. 7.1 years; P = .009).[86][Level of evidence A1] Patients responsive to R-CHOP benefitted most from rituximab in OS (median, 9.8 years vs. 6.4 years; P = .0026).[86][Level of evidence C1] A randomized trial compared bendamustine plus rituximab (BR) with R-CHOP and showed improved PFS (35 vs. 22 months; HR, 0.49; 95% CI, 0.28–0.79; P = .004) but no difference in OS.[87][Level of evidence B1] However, this trial failed to show any benefit for rituximab maintenance after BR. A prospective randomized trial of 487 patients compared VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) with R-CHOP.[88] With a median follow-up of 82 months, the median OS was longer for VR-CAP (90.7 months) compared with R-CHOP (55.7 months) (HR, 0.66; 95% CI, 0.51-0.85; P = .001).[88][Level of evidence A1]

A prospective randomized trial of 497 patients younger than 65 years compared six cycles of R-CHOP with six cycles of alternating R-CHOP and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), with both groups then receiving autologous SCT.[89,90][Level of evidence B1] With a median follow-up of 10.6 years, the 10-year PFS rate was 73% for patients who received R-DHAP and 57% for patients who received R-CHOP (HR, 0.56; P = .038), but there was no difference in the 10-year OS rates (60% [R-DHAP] vs. 55% [R-CHOP]; HR, 0.80; 95% CI, 0.61–1.06; P = .12).[91][Level of evidence B1] This is the randomized trial referenced by all subsequent articles establishing a role for cytarabine in induction therapy; the ultimate lack of survival advantage casts doubt on this assertion.

Randomized trials have not confirmed an OS benefit in patients who receive consolidation therapy with autologous or allogeneic SCT.[92,93,94,95,96,97]

In a prospective trial (NCT00921414) of 299 patients with previously untreated MCL, 257 responders received four courses of R-DHAP and autologous SCT. The patients were randomly assigned to receive rituximab maintenance therapy for 3 years versus no maintenance therapy. After randomization and a median follow-up of 50.2 months, the 4-year PFS rate was 83% in the rituximab-maintenance arm (95% CI, 73%–88%) and 64% in the no-maintenance arm (95% CI, 55%–73%; P < .001). The 4-year OS rate also favored the rituximab-maintenance arm at 89% (95% CI, 81%–94%) versus the no-maintenance arm at 80% (95% CI, 72%–88%; P = .04).[98][Level of evidence A1]

Lenalidomide with or without rituximab also shows response rates of around 50% in relapsed patients, with even higher response rates for previously untreated patients.[76,79,99,100][Level of evidence C3]

Acalabrutinib (another B-cell receptor inhibitor via the Bruton tyrosine kinase [BTK] pathway) was studied in 124 patients with relapsed or refractory MCL.[101] In a phase II study, there was an 81% overall response rate, 40% complete response rate, and 67% 1-year PFS rate.[101][Level of evidence C3] The BTK inhibitor zanubrutinib was evaluated in a phase II study of 86 patients with relapsed or refractory MCL.[102] After a median follow-up of 35.3 months, the overall response rate was 84%, the complete response rate was 78%, and the median PFS was 33.0 months.[102][Level of evidence C3]

Patients with relapsed or refractory MCL whose disease did not respond to ibrutinib or acalabrutinib were enrolled in a phase II trial using brexucabtagene autoleucel, an anti-CD19 CAR T-cell therapy.[103] With a median follow-up of 36 months, 68 patients had an objective response rate of 91% (95% CI, 82%-97%) and a complete response rate of 68% (95% CI, 55%-78%). Median PFS and OS were 25.8 months (95% CI, 10–48) and 46.6 months (95% CI, 24.9–not estimable), respectively.[103][Level of evidence C3] Grade 3 or higher cytokine release syndrome occurred in 15% of patients, and neurological events occurred in 31% of patients.

In summary, the optimal sequencing of these various therapies is unclear and is the subject of an ongoing Intergroup clinical trial. Rituximab, lenalidomide, ibrutinib, acalabrutinib, venetoclax, and zanubrutinib represent directed biological agents that may lead to chemotherapy-free treatment strategies for patients with MCL.[104]

Routine administration of CNS prophylaxis in high-risk MCL has never been studied in a prospective randomized trial. The use of intrathecal or high-dose methotrexate or the use of systemic therapies with CNS penetration like ibrutinib, high-dose cytarabine, or venetoclax, have not been studied and proven efficacious in this situation.[67]

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.[105] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the MYC gene on chromosome 8.[106] A subgroup of patients with dual translocation of MYC and BCL2 appear to have an extremely poor outcome despite aggressive therapy (median OS, 5 months).[107][Level of evidence C1]

In some patients with larger B cells, there is morphological 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.[108,109,110] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing Epstein-Barr virus (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.

Therapeutic approaches

Treatment of Burkitt lymphoma/diffuse small noncleaved-cell lymphoma involves aggressive multidrug regimens in combination with rituximab, similar to those used for the advanced-stage aggressive lymphomas (diffuse large cell).[111,112,113,114] Aggressive combination chemotherapy, which is modeled after that used in childhood Burkitt lymphoma, has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[115,116,117,118] Adverse prognostic factors include bulky abdominal disease and high serum LDH. Patients with Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. Prophylaxis with intrathecal chemotherapy is required as part of induction therapy.[119] Patients with HIV-associated Burkitt lymphoma also benefit from less-toxic modification of the aggressive multidrug regimens in combination with rituximab.[120][Level of evidence C3] For more information, see Primary CNS Lymphoma Treatment and AIDS-Related Lymphoma Treatment.

B-Cell Lymphoblastic Lymphoma

B-cell lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It is less common than T-cell lymphoblastic lymphoma.

Treatment is usually modeled after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without bone marrow transplant is the standard treatment for this aggressive histological type of NHL.[121,122,123] 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 is confirmed. Careful review of the pathological specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. For more information, see Adult Acute Lymphoblastic Leukemia Treatment.

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.[124] Patients are usually HIV seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.[125]

Prognosis

The prognosis of primary effusion lymphoma is extremely poor.

Therapeutic approaches

Therapy is usually modeled after the treatment of comparably staged diffuse large cell lymphomas.

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.[126] Anecdotal reports suggest using aggressive chemotherapy for Burkitt or lymphoblastic lymphoma, followed by SCT consolidation in responding patients, when feasible.[126,127,128]

Polymorphic Posttransplant Lymphoproliferative Disorder

Patients who undergo transplant of the heart, lung, liver, kidney, or pancreas usually require lifelong immunosuppression. This may result in posttransplant lymphoproliferative disorder (PTLD) in 1% to 3% of recipients, which appears as an aggressive lymphoma.[129] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[130]

Prognosis

Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[131,132]

Therapeutic options

In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[133,134] When this is unsuccessful or not feasible, a course of rituximab may be considered, because it has shown durable remissions in approximately 60% of patients and a favorable toxicity profile.[133,135,136] If these measures fail, doxorubicin-based combination chemotherapy (R-CHOP) is recommended, although some patients can avoid cytotoxic therapy.[136,137] Localized presentations can be controlled with surgery or radiation therapy alone. These localized mass lesions, which may grow over a period of months, are often phenotypically polyclonal and tend to occur within weeks or a few months after transplant.[130] Multifocal, rapidly progressive disease occurs late after transplant (>1 year) and is usually phenotypically monoclonal and associated with EBV.[138] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[138,139,140] Instances of EBV-negative PTLD occur even later (median, 5 years posttransplant) and have a worse prognosis; R-CHOP chemotherapy can be applied directly in this circumstance.[141] A sustained clinical response after failure from chemotherapy was attained using an immunotoxin (anti-CD22 B-cell surface antigen antibody linked with ricin, a plant toxin).[142] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[143]

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[144,145] 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.

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  105. Blum KA, Lozanski G, Byrd JC: Adult Burkitt leukemia and lymphoma. Blood 104 (10): 3009-20, 2004.
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Other Lymphoproliferative and Related Disorders

Castleman Disease

A biopsy of localized or multifocal collections of lymph nodes may lead to a diagnosis of Castleman disease (CD), although it is an uncommon diagnosis. Strictly speaking, this is not a lymphoma, nor is it even a malignancy. Yet, many patients with CD may be seen and treated by hematologists or oncologists.

Localized or unicentric CD is usually asymptomatic and occurs in the mediastinum, which is the most common presentation for CD.[1] Watchful waiting, surgery, or radiation therapy can be used for this indolent form. Multicentric CD (30% of CD patients) presents with lymphadenopathy in multiple sites; symptoms such as fever, night sweats, weight loss, and fatigue; and laboratory abnormalities such as anemia, low albumin, elevated C-reactive protein, and high fibrinogen.[1] Multicentric CD (MCD) is subdivided into human herpes virus-8–associated MCD (usually with HIV or with severe immunocompromise) or idiopathic MCD. Cytopenias and cytokine storm are attributed to interleukin-6 overproduction. MCD is a feature seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities) syndrome [2] and TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) syndrome.[3,4] Therapy with siltuximab (an anti–IL-6 monoclonal antibody), rituximab (an anti-CD20 monoclonal antibody), or chemotherapeutic agents has been presented in anecdotal nonrandomized series.[5,6,7,8]

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.[9,10] Care must be taken with immunophenotypic tests to exclude ALCL or hemophagocytic syndromes caused by viral infections, especially Epstein-Barr virus.

Therapeutic options

Therapy is modeled after the treatment of comparably staged diffuse large cell lymphomas, but the optimal approach remains to be defined.

References:

  1. van Rhee F, Voorhees P, Dispenzieri A, et al.: International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood 132 (20): 2115-2124, 2018.
  2. Dispenzieri A: POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management. Am J Hematol 94 (7): 812-827, 2019.
  3. Zhang Y, Suo SS, Yang HJ, et al.: Clinical features and treatment of 7 Chinese TAFRO syndromes from 96 de novo Castleman diseases: a 10-year retrospective study. J Cancer Res Clin Oncol 146 (2): 357-365, 2020.
  4. Fujimoto S, Sakai T, Kawabata H, et al.: Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease? Am J Hematol 94 (9): 975-983, 2019.
  5. Tonialini L, Bonfichi M, Ferrero S, et al.: Siltuximab in relapsed/refractory multicentric Castleman disease: Experience of the Italian NPP program. Hematol Oncol 36 (4): 689-692, 2018.
  6. Dong Y, Zhang L, Nong L, et al.: Effectiveness of rituximab-containing treatment regimens in idiopathic multicentric Castleman disease. Ann Hematol 97 (9): 1641-1647, 2018.
  7. Zhang L, Zhao AL, Duan MH, et al.: Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease. Blood 133 (16): 1720-1728, 2019.
  8. van Rhee F, Wong RS, Munshi N, et al.: Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 15 (9): 966-74, 2014.
  9. Soslow RA, Davis RE, Warnke RA, et al.: True histiocytic lymphoma following therapy for lymphoblastic neoplasms. Blood 87 (12): 5207-12, 1996.
  10. Kamel OW, Gocke CD, Kell DL, et al.: True histiocytic lymphoma: a study of 12 cases based on current definition. Leuk Lymphoma 18 (1-2): 81-6, 1995.

Treatment Option Overview for B-Cell Non-Hodgkin Lymphoma

Treatment of non-Hodgkin lymphoma (NHL) depends on the histological type and stage. Many of the improvements in survival have been made using clinical trials (experimental therapy) that have attempted to improve on the best available accepted therapy (conventional or standard therapy).

In asymptomatic patients with indolent forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses. When treatment is deferred, the clinical course of patients with indolent NHL varies; frequent and careful observation is required so that effective treatment can be initiated when the clinical course of the disease accelerates. Some patients have a prolonged indolent course, but others have disease that rapidly evolves into more aggressive types of NHL that require immediate treatment.

Radiation techniques differ somewhat from those used in the treatment of Hodgkin lymphoma. The dose of radiation therapy usually varies from 25 Gy to 50 Gy and is dependent on factors that include the histological type of lymphoma, the patient's stage and overall condition, the goal of treatment (curative or palliative), the proximity of sensitive surrounding organs, and whether the patient is being treated with radiation therapy alone or in combination with chemotherapy. Given the patterns of disease presentations and relapse, treatment may need to include unusual sites such as Waldeyer ring, epitrochlear nodes, or mesenteric nodes. The associated morbidity of the treatment must be considered carefully. Most patients who receive radiation are treated on only one side of the diaphragm. Localized presentations of extranodal NHL may be treated with involved-field techniques with significant (>50%) success.

Table 4. Treatment Options for B-Cell Non-Hodgkin Lymphoma (NHL)
Stage Treatment Options
BMT = bone marrow transplant; CAR = chimeric antigen receptor; CNS = central nervous system; IF-XRT = involved-field radiation therapy; PI3K = phosphatidylinositol 3-kinase; R-ACVBP = rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; SCT = stem cell transplant.
Indolent Stage I and Indolent, Contiguous Stage II B-cell NHL Radiation therapy
Rituximab with or without chemotherapy
Watchful waiting
Other therapies as designated for patients with advanced-stage disease
Indolent, Noncontiguous Stage II/III/IV B-cell NHL Watchful waiting for asymptomatic patients
Rituximab alone or in combination with cytotoxic agents used in front-line therapy
Lenalidomide and rituximab
Maintenance rituximab
Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy
PI3K inhibitor
EZH2 inhibitor
Radiolabeled anti-CD20 monoclonal antibodies
Intensive therapy with chemotherapy with or without total-body irradiation or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or peripheral SCT (under clinical evaluation)
Phase III clinical trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine
Extended-field radiation therapy (stage III patients only) (under clinical evaluation)
Ofatumumab (under clinical evaluation)
Short-course low-dose, palliative radiation therapy (2 × 2 Gy) (under clinical evaluation)
Indolent, Recurrent B-cell NHL Rituximab alone or in combination with cytotoxic agents used in front-line therapy
Obinutuzumab alone or in combination with cytotoxic agents used in front-line therapy
Lenalidomide and rituximab
PI3K inhibitor
EZH2 inhibitor
Palliative radiation therapy
Chemotherapy (single agent or combination)
Radiolabeled anti-CD20 monoclonal antibodies
CAR T-cell therapy
Bispecific T-cell engagers
SCT
Aggressive Stage I and Aggressive, Contiguous Stage II B-cell NHL R-CHOP with or without IF-XRT
R-ACVBP (under clinical evaluation)
Aggressive, Noncontiguous Stage II/III/IV B-cell NHL Pola-R-CHP
R-CHOP
Other combination chemotherapy
Radiation therapy consolidation to sites of bulky disease(under clinical evaluation)
Aggressive, Recurrent B-cell NHL CAR T-cell therapy for primary refractory disease or relapse within 1 year
BMT or SCT consolidation
CAR T-cell therapy for relapse after autologous SCT
Tafasitamab plus lenalidomide
Rituximab plus lenalidomide
Polatuzumab vedotin plus rituximab and bendamustine
Loncastuximab tesirine
Bispecific T-cell engagers
Palliative radiation therapy
B-cell Lymphoblastic Lymphoma/Acute Lymphocytic Leukemia Intensive therapy
Radiation therapy
Diffuse Small Noncleaved-Cell/Burkitt Lymphoma Aggressive multidrug regimens
CNS prophylaxis

Even though existing treatments cure a significant fraction of patients with lymphoma, numerous clinical trials that explore treatment improvements are in progress. If possible, patients can be included in these studies. Standardized guidelines for response assessment have been suggested for use in clinical trials.[1]

Several retrospective reviews suggest that routine surveillance scans offer little to no value in patients with diffuse-large B-cell lymphoma (DLBCL) who have attained a clinical complete remission after induction therapy. Prognostic value is also difficult to identify for an interim positron emission tomography-computed tomography scan during induction therapy for DLBCL.[2,3,4,5]

Aggressive lymphomas are increasingly seen in patients with HIV. Treatment of these patients requires special consideration. For more information, see AIDS-Related Lymphoma Treatment

In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C can be assessed before treatment with rituximab and/or chemotherapy.[6,7] Patients with detectable hepatitis B virus (HBV) benefit from prophylaxis with entecavir in the context of rituximab therapy.[8,9] Patients with a resolved HBV infection (defined as hepatitis B surface antigen-negative but hepatitis B core antibody-positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. Prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients.[10] Similarly, prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for Pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually given to patients receiving rituximab with or without combination chemotherapy. Long-term impaired immune health was evaluated in a retrospective cohort study of 21,690 survivors of DLBCL from the California Cancer Registry. Elevated incidence rate ratios were found up to 10 years later for pneumonia (10.8-fold), meningitis (5.3-fold), immunoglobulin deficiency (17.6-fold), and autoimmune cytopenias (12-fold).[11]

Among 2,508 patients in a Danish registry, the incidence of doxorubicin-induced congestive heart failure increased for 115 NHL survivors with a history of cardiac disease (hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.15-6.36) and/or multiple cardiovascular risk factors (HR, 2.86; 95% CI, 1.56-5.23).[12]

Several unusual presentations of lymphoma occur that often require somewhat modified approaches to staging and therapy. The reader is referred to reviews for a more detailed description of extranodal presentations in the gastrointestinal system,[13,14,15,16,17,18,19,20,21] thyroid,[22,23] spleen,[24] testis,[25,26,27] paranasal sinuses,[28,29,30,31] bone,[32,33] orbit,[34,35,36,37,38] and skin.[39,40,41,42,43,44,45,46,47,48]

For more information, see Primary CNS Lymphoma Treatment.

References:

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Treatment of Indolent Stage I and Indolent, Contiguous Stage II B-Cell Non-Hodgkin Lymphoma

Although localized presentations are uncommon in B-cell non-Hodgkin lymphoma (NHL), the goal of treatment is to cure the disease in patients with confirmed localized occurrence after undergoing appropriate staging.

Treatment Options for Indolent Stage I and Indolent, Contiguous Stage II B-Cell NHL

Treatment options for indolent stage I and indolent, contiguous stage II B-cell 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). There was no difference in overall survival (OS) (87% and 95%, P = .40).[1][Level of evidence B1]

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 C2] 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?

Radiation therapy

Long-term disease control within radiation fields can be achieved in a significant number of patients with indolent stage I or stage II NHL by using dosages of radiation that usually range from 25 Gy to 40 Gy to involved sites or to extended fields that cover adjacent nodal sites.[1,4,5,6] Almost half of all patients treated with radiation therapy alone will have out-of-field relapse within 10 years.[1,6,7]

A retrospective review of 512 patients from an international consortium evaluated patients with early-stage follicular lymphoma who received at least 24 Gy of localized radiation therapy at initial presentation. With a median follow-up of 52 months, 29.1% of patients developed recurrent lymphoma at a median of 23 months (range, 1-143 months).[8] With a median follow-up of 33 months after relapse, the 3-year OS rate was 91.4% after patients received subsequent systemic chemotherapy that involved rituximab, usually with chemotherapy.[8]

Very low-dose radiation therapy with 4 Gy (2 Gy × 2 fractions) can result in 50% remission rates for patients who cannot tolerate higher doses.[9] In a multicenter, randomized, prospective trial, 548 patients with follicular or marginal zone lymphoma received radiation therapy, either 4 Gy in 2 fractions or 24 Gy in 12 fractions.[10]

  • At a median follow-up of 73.8 months, the 5-year local complete response rate was 89.9% (85.5%–93.1%) after 24 Gy and 70.4% (64.7%–75.4%) after 4 Gy (hazard ratio [HR], 3.46; 95% CI, 2.25–5.33, P < .0001).[10]
  • Although durable local control was superior for patients who received 24 Gy, the 4 Gy regimen was nearly comparable with less radiation exposure, less time undergoing therapy, and less cost.

In situations in which mediastinal radiation would encompass the left side of the heart or would increase breast cancer risk in young female patients, proton therapy may be considered to reduce the radiation dose to organs at risk.[11]

Rituximab with or without chemotherapy

For symptomatic patients who require therapy, when radiation therapy is contraindicated, or when an alternative treatment is preferred, rituximab with or without chemotherapy can be used (as outlined below for more advanced-stage patients). The value of adjuvant treatment with radiation to decrease relapse, plus rituximab (an anti–CD20 monoclonal antibody) either alone or in combination with chemotherapy, has been extrapolated from trials of patients with advanced-stage disease and has not been confirmed.[12,13]

Watchful waiting

Watchful waiting can be considered for asymptomatic patients.[14] Watchful waiting has never been compared with up-front radiation therapy in a prospective randomized trial. A retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) Program database in patients diagnosed over a span of 30 years showed improved outcomes for up-front radiation therapy.[15]

Other therapies as designated for patients with advanced-stage disease

Patients with disease unable to be encompassed by radiation therapy are treated as outlined for patients with stage III or stage IV low-grade lymphoma.