jueves, 7 de marzo de 2019

Adult Non-Hodgkin Lymphoma Treatment (PDQ®) 1/3 —Health Professional Version - National Cancer Institute

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Adult Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Go to Patient Version

General Information About Adult Non-Hodgkin Lymphoma (NHL)

The non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.[1]
Like Hodgkin lymphoma, NHL usually originates in lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a far greater predilection to disseminate to extranodal sites. The prognosis depends on the histologic type, stage, and treatment.

Incidence and Mortality

Estimated new cases and deaths from NHL in the United States in 2019:[2]
  • New cases: 74,200.
  • Deaths: 19,970.

Anatomy

NHL usually originates in lymphoid tissues.
ENLARGELymph 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: the indolent lymphomas and the aggressive lymphomas.
Indolent NHL types have a relatively good prognosis with a median survival as long as 20 years, but they usually are not curable in advanced clinical stages.[3] Early-stage (stage I and stage II) indolent NHL can be effectively treated with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology.
The aggressive type of NHL has a shorter natural history, but a significant number of these patients can be cured with intensive combination chemotherapy regimens.
In general, with modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 2 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.[4]
While indolent NHL is responsive to immunotherapy, radiation therapy, and chemotherapy, a continuous rate of relapse is usually seen in advanced stages. Patients, however, can often be re-treated with considerable success as long as the disease histology remains low grade. Patients who present with or convert to aggressive forms of NHL may have sustained complete remissions with combination chemotherapy regimens or aggressive consolidation with marrow or stem cell support.[5,6]

Related Summaries

Other PDQ summaries containing information related to non-Hodgkin lymphoma treatment include the following:
References
  1. Shankland KR, Armitage JO, Hancock BW: Non-Hodgkin lymphoma. Lancet 380 (9844): 848-57, 2012. [PUBMED Abstract]
  2. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed January 23, 2019.
  3. Tan D, Horning SJ, Hoppe RT, et al.: Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood 122 (6): 981-7, 2013. [PUBMED Abstract]
  4. Cabanillas F, Velasquez WS, Hagemeister FB, et al.: Clinical, biologic, and histologic features of late relapses in diffuse large cell lymphoma. Blood 79 (4): 1024-8, 1992. [PUBMED Abstract]
  5. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PUBMED Abstract]
  6. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PUBMED Abstract]

Late Effects of Treatment for Adult NHL

Late effects of treatment for non-Hodgkin lymphoma (NHL) have been observed. Pelvic radiation therapy and large cumulative doses of cyclophosphamide have been associated with a high risk of permanent sterility.[1] For as many as three decades after diagnosis, patients are at a significantly elevated risk for second primary cancers, especially the following:[1-3]
  • 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.[4,5]
Myelodysplastic syndrome and acute myelogenous leukemia are late complications of myeloablative therapy with autologous bone marrow or peripheral blood stem cell support, as well as conventional chemotherapy-containing alkylating agents.[1,6-13] Most of these patients show clonal hematopoiesis even before the transplantation, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy.[8,14,15] With a median 10-year follow-up after autologous bone marrow transplantation (BMT) with conditioning using cyclophosphamide and total-body radiation therapy, in a series of 605 patients, the incidence of a second malignancy was 21%, and 10% of those were solid tumors.[16]
Successful pregnancies with children born free of congenital abnormalities have been reported in young women after autologous BMT.[17]
Some patients have osteopenia or osteoporosis at the start of therapy; bone density may worsen after therapy for lymphoma.[18]
References
  1. Mudie NY, Swerdlow AJ, Higgins CD, et al.: Risk of second malignancy after non-Hodgkin's lymphoma: a British Cohort Study. J Clin Oncol 24 (10): 1568-74, 2006. [PUBMED Abstract]
  2. Travis LB, Curtis RE, Glimelius B, et al.: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85 (23): 1932-7, 1993. [PUBMED Abstract]
  3. Hemminki K, Lenner P, Sundquist J, et al.: Risk of subsequent solid tumors after non-Hodgkin's lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26 (11): 1850-7, 2008. [PUBMED Abstract]
  4. Haddy TB, Adde MA, McCalla J, et al.: Late effects in long-term survivors of high-grade non-Hodgkin's lymphomas. J Clin Oncol 16 (6): 2070-9, 1998. [PUBMED Abstract]
  5. Moser EC, Noordijk EM, van Leeuwen FE, et al.: Long-term risk of cardiovascular disease after treatment for aggressive non-Hodgkin lymphoma. Blood 107 (7): 2912-9, 2006. [PUBMED Abstract]
  6. Darrington DL, Vose JM, Anderson JR, et al.: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12 (12): 2527-34, 1994. [PUBMED Abstract]
  7. Stone RM, Neuberg D, Soiffer R, et al.: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12 (12): 2535-42, 1994. [PUBMED Abstract]
  8. Armitage JO, Carbone PP, Connors JM, et al.: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21 (5): 897-906, 2003. [PUBMED Abstract]
  9. André M, Mounier N, Leleu X, et al.: Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood 103 (4): 1222-8, 2004. [PUBMED Abstract]
  10. Oddou S, Vey N, Viens P, et al.: Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution. Leuk Lymphoma 31 (1-2): 187-94, 1998. [PUBMED Abstract]
  11. Lenz G, Dreyling M, Schiegnitz E, et al.: Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22 (24): 4926-33, 2004. [PUBMED Abstract]
  12. McLaughlin P, Estey E, Glassman A, et al.: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105 (12): 4573-5, 2005. [PUBMED Abstract]
  13. Morton LM, Curtis RE, Linet MS, et al.: Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 28 (33): 4935-44, 2010. [PUBMED Abstract]
  14. Mach-Pascual S, Legare RD, Lu D, et al.: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: a single institution study. Blood 91 (12): 4496-503, 1998. [PUBMED Abstract]
  15. Lillington DM, Micallef IN, Carpenter E, et al.: Detection of chromosome abnormalities pre-high-dose treatment in patients developing therapy-related myelodysplasia and secondary acute myelogenous leukemia after treatment for non-Hodgkin's lymphoma. J Clin Oncol 19 (9): 2472-81, 2001. [PUBMED Abstract]
  16. Brown JR, Yeckes H, Friedberg JW, et al.: Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 23 (10): 2208-14, 2005. [PUBMED Abstract]
  17. Jackson GH, Wood A, Taylor PR, et al.: Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK. Leuk Lymphoma 28 (1-2): 127-32, 1997. [PUBMED Abstract]
  18. 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. [PUBMED Abstract]

Cellular Classification of Adult NHL

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

Historical Classification Systems

Historically, uniform treatment of patients with non-Hodgkin lymphoma (NHL) has been hampered by the lack of a uniform classification system. In 1982, results of a consensus study were published as the Working Formulation.[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 leukemiaDiffuse lymphocytic, well-differentiated
B. Follicular, predominantly small-cleaved cellNodular lymphocytic, poorly differentiated
C. Follicular, mixed small-cleaved, and large cellNodular mixed, lymphocytic, and histiocytic
Intermediate grade 
D. Follicular, predominantly large cellNodular histiocytic
E. Diffuse, small-cleaved cellDiffuse lymphocytic, poorly differentiated
F. Diffuse mixed, small and large cellDiffuse mixed, lymphocytic, and histiocytic
G. Diffuse, large cell, cleaved, or noncleaved cellDiffuse histiocytic
High grade 
H. Immunoblastic, large cellDiffuse histiocytic
I. Lymphoblastic, convoluted, or nonconvoluted cellDiffuse lymphoblastic
J. Small noncleaved-cell, Burkitt, or non-BurkittDiffuse undifferentiated Burkitt or non-Burkitt

Current Classification Systems

As the understanding of NHL has improved and as the histopathologic diagnosis of NHL has become more sophisticated with the use of immunologic and genetic techniques, a number of new pathologic entities have been described.[4] In addition, the understanding and treatment of many of the previously described pathologic subtypes have changed. As a result, the Working Formulation has become outdated and less useful to clinicians and pathologists. Thus, European and American pathologists have proposed a new classification, the Revised European American Lymphoma (REAL) classification.[5-8] Since 1995, members of the European and American Hematopathology societies have been collaborating on a new World Health Organization (WHO) classification, which represents an updated version of the REAL system.[9,10]
The WHO modification of the REAL classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma (HL). Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For example, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma are simply different manifestations of the same neoplasm, as are lymphoblastic lymphomas and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.[9,10]

Updated REAL/WHO classification

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.
  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. Refer to the following PDQ summaries for more information:

PDQ modification of REAL classification of lymphoproliferative diseases

  1. Plasma cell disorders. (Refer to the PDQ summary on Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment for more information.)
    1. Bone.
    2. Extramedullary.
      1. Monoclonal gammopathy of undetermined significance.
      2. Plasmacytoma.
      3. Multiple myeloma.
      4. Amyloidosis.
  2. HL. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
    1. Nodular sclerosis HL.
    2. Lymphocyte-rich classical HL.
    3. Mixed-cellularity HL.
    4. Lymphocyte-depleted HL.
  3. Indolent lymphoma/leukemia.
    1. Follicular lymphoma (follicular small-cleaved cell [grade 1], follicular mixed small-cleaved, and large cell [grade 2], and diffuse, small-cleaved cell).
    2. Chronic lymphocytic leukemia/small lymphocytic lymphoma. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
    3. Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).
    4. Extranodal marginal zone B-cell lymphoma (MALT lymphoma).
    5. Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma).
    6. Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes).
    7. Hairy cell leukemia. (Refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information.)
    8. Mycosis fungoides (including Sézary syndrome). (Refer to the PDQ summary on Mycosis Fungoides (Including Sézary Syndrome) Treatment for more information.)
    9. T-cell granular lymphocytic leukemia. (Refer to the PDQ summary on Chronic Lymphocytic Leukemia Treatment for more information.)
    10. Primary cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis (CD30-positive).
    11. Nodular lymphocyte–predominant Hodgkin lymphoma. (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
  4. Aggressive lymphoma/leukemia.
    1. Diffuse large cell lymphoma (includes diffuse mixed-cell, diffuse large cell, immunoblastic, and T-cell rich large B-cell lymphoma).
      Distinguish:
      1. Mediastinal large B-cell lymphoma.
      2. Follicular large cell lymphoma (grade 3).
      3. Anaplastic large cell lymphoma (CD30-positive).
      4. Extranodal NK-/T-cell lymphoma, nasal type/aggressive NK-cell leukemia/blastic NK-cell lymphoma.
      5. Lymphomatoid granulomatosis (angiocentric pulmonary B-cell lymphoma).
      6. Angioimmunoblastic T-cell lymphoma.
      7. Peripheral T-cell lymphoma, unspecified.
        • Subcutaneous panniculitis-like T-cell lymphoma.
        • Hepatosplenic T-cell lymphoma.
      8. Enteropathy-type T-cell lymphoma.
      9. Intravascular large B-cell lymphoma.
    2. Burkitt lymphoma/Burkitt cell leukemia/Burkitt-like lymphoma.
    3. Precursor B-cell or T-cell lymphoblastic lymphoma/leukemia. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)
    4. Primary central nervous system (CNS) lymphoma. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)
    5. Adult T-cell leukemia/lymphoma (HTLV 1+).
    6. Mantle cell lymphoma.
    7. Posttransplantation lymphoproliferative disorder.
    8. AIDS-related lymphoma. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
    9. True histiocytic lymphoma.
    10. Primary effusion lymphoma.
    11. B-cell or T-cell prolymphocytic leukemia. (Refer to the PDQ summary onChronic Lymphocytic Leukemia Treatment for more information.)
    12. Plasmablastic lymphoma.
References
  1. Zeppa P, Marino G, Troncone G, et al.: Fine-needle cytology and flow cytometry immunophenotyping and subclassification of non-Hodgkin lymphoma: a critical review of 307 cases with technical suggestions. Cancer 102 (1): 55-65, 2004. [PUBMED Abstract]
  2. Young NA, Al-Saleem T: Diagnosis of lymphoma by fine-needle aspiration cytology using the revised European-American classification of lymphoid neoplasms. Cancer 87 (6): 325-45, 1999. [PUBMED Abstract]
  3. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 49 (10): 2112-35, 1982. [PUBMED Abstract]
  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. [PUBMED Abstract]
  6. Pittaluga S, Bijnens L, Teodorovic I, et al.: Clinical analysis of 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group subtyped according to the Revised European-American Classification of Lymphoid Neoplasms: a comparison with the Working Formulation. Blood 87 (10): 4358-67, 1996. [PUBMED Abstract]
  7. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PUBMED Abstract]
  8. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PUBMED Abstract]
  9. Pileri SA, Milani M, Fraternali-Orcioni G, et al.: From the R.E.A.L. Classification to the upcoming WHO scheme: a step toward universal categorization of lymphoma entities? Ann Oncol 9 (6): 607-12, 1998. [PUBMED Abstract]
  10. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.

Indolent NHL

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

Follicular Lymphoma

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

Prognosis

Despite the advanced stage, the median survival ranges from 8 to 15 years, leading to the designation of being indolent.[5-7] Patients with advanced-stage follicular lymphoma are not cured with current therapeutic options. The rate of relapse is fairly consistent over time, even in patients who have achieved complete responses to treatment.[8] Watchful waiting, i.e., the deferring of treatment until the patient becomes symptomatic, is an option for patients with advanced-stage follicular lymphoma.[9,10] An international index for follicular lymphoma (i.e., the Follicular Lymphoma International Prognostic Index [FLIPI]) [11-13] identified five significant risk factors prognostic of overall survival (OS):
  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 one risk factor or none have an 85% 10-year survival rate, and three or more risk factors confer a 40% 10-year survival rate.[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. Gene expression profiles of tumor biopsy specimens suggest that follicular lymphoma that is surrounded by infiltrating T-lymphocytes has a much longer median survival (13.6 years) than follicular lymphoma that is surrounded by dendritic and monocytic cells (3.9 years) (P< .001).[15]
Two retrospective analyses identified a high-risk group that had a 50% OS rate at 5 years when relapse occurred after induction chemoimmunotherapy at 24 or 30 months; this has not been validated in prospective studies or an independent cohort.[16,17] These higher-risk patients represent a target population for clinical trials.
Follicular, small-cleaved cell lymphoma and follicular mixed small-cleaved and large cell lymphoma do not have reproducibly different disease-free survival or OS.

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 employed in varying sequences with an OS equivalence at 5 to 10 years.[9,18-20] Rituximab can be given alone or in combination with various chemotherapy options.[9,18-20] Rituximab can also be combined with the immunomodulating-agent lenalidomide to avoid the short- and long-term toxicities of cytotoxic agents.[21,22] Another anti-CD20 monoclonal antibody, obinutuzumab, can be administered with combination chemotherapy.[23] Inhibitors of phosphatidylinositol 3-kinase (PI3K) are also effective in patients with relapsed or refractory disease.[24-27] Consolidation therapy for relapsed disease after reinduction therapy using autologous stem cell transplant (SCT) or allogeneic SCT can be considered.[28]
Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress and rarely require therapy.[29,30] A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histologic variant are characterized by a lack of BCL2rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.[31]
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.[32] Documentation of conversion to a more aggressive histology requires an appropriate change to a therapy applicable to that histologic type.[33] Rapid growth or discordant growth between various disease sites may indicate a histologic conversion.[32] The risk of histologic transformation was 30% by 10 years in a retrospective review of 325 patients from diagnosis between 1972 and 1999.[34] In this series, high-risk factors for subsequent histologic transformation were advanced stage, high-risk FLIPI, and expectant management (as opposed to treatment being initiated at diagnosis). The 5-year OS rate was more than 50% for patients who had biopsy-proven, aggressive-histology transformation in several multicenter cohort studies employing rituximab plus anthracycline or platinum-based chemotherapy, or similar therapy followed by autologous or allogeneic SCT.[32,35,36]
In a prospective nonrandomized study, at a median follow-up of 6.8 years, 379 (14%) of 2,652 patients subsequently transformed to a more aggressive histology after an initial diagnosis of follicular lymphoma.[37][Level of evidence: 3iiiDiv] The median OS after subsequent transformation was 5 years; however, among 47 patients with evidence of transformation in conjunction with follicular lymphoma at the time of initial diagnosis, the OS was no worse than that of the other nontransformed patients (5-year OS, 88%; 95% confidence interval [CI], 74%–95%).

Lymphoplasmacytic Lymphoma (Waldenström Macroglobulinemia)

Lymphoplasmacytic lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M (IgM) type (Waldenström macroglobulinemia).[38] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hyperviscosity syndrome. Most patients with Waldenström macroglobulinemia carry the MYD88 mutation, which some pathologists consider pathognomonic for the disease.[39] Other lymphomas may also be associated with serum paraproteins.
Asymptomatic patients can be monitored for evidence of disease progression without immediate need for chemotherapy.[9,40,41]
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.[40]

Therapeutic approaches

The management of lymphoplasmacytic lymphoma is similar to that of other low-grade lymphomas, especially diffuse, small lymphocytic lymphoma/chronic lymphocytic leukemia.[40,42-44] If the viscosity relative to water is greater than four, the patient may have manifestations of hyperviscosity. Plasmapheresis is useful for temporary, acute symptoms (such as retinopathy, congestive heart failure, and central nervous system [CNS] dysfunction) but can be combined with chemotherapy for prolonged control of the disease. Symptomatic patients with a serum viscosity of not more than four are usually started directly on chemotherapy. Therapy may be required to correct hemolytic anemia in patients with chronic cold agglutinin disease; rituximab, cyclophosphamide, and steroids are often employed.[41] Occasionally, a heated room is required for patients whose cold agglutinins become activated by even minor chilling.
First-line regimens include rituximab and ibrutinib, rituximab alone, the nucleoside analogs, and alkylating agents, either as single agents or as part of combination chemotherapy.[45-49] In a randomized prospective trial, 150 symptomatic patients (including previously untreated and relapsing patients) received either ibrutinib and rituximab or rituximab and a placebo. With a median follow-up of 2.5 years, the PFS favored the ibrutinib-and-rituximab arm (82%) versus the rituximab-and-placebo arm (28%) (hazard ratio, 0.20; 95% CI, 0.11–0.38; P < .001), and the OS at 30 months was no different in the two arms (OS, 92%–94%).[49][Level of evidence: 1iDiii] A phase II trial of 30 patients studied single-agent ibrutinib in previously untreated Waldenström macroglobulinemia patients. With a median follow-up of 15 months, the objective response rate was 83%, and the 18-month PFS rate was 92% (95% CI, 73%–98%).[50][Level of evidence: 3iiiDiv] Rituximab showed 60% to 80% response rates in previously untreated patients, but close monitoring of the serum IgM is required because of a sudden rise in this paraprotein at the start of therapy.[45,51,52][Level of evidence: 3iiiDiv] The rise of IgM after rituximab can be avoided with the concomitant use of an alkylating agent, such as cyclophosphamide or the proteosome inhibitor bortezomib.[41,53,54] A combination of bortezomib, dexamethasone, and rituximab has been used with avoidance of an IgM rebound.[55-57] The nucleoside analogs 2-chlorodeoxyadenosine and fludarabine have shown similar response rates for previously untreated patients with lymphoplasmacytic lymphoma.[48,58,59][Level of evidence: 3iiiDiv] Single-agent alkylators, bendamustine, bortezomib, and combination chemotherapy with or without rituximab also show similar response rates.[48,53,60-63][Level of evidence: 3iiiDiv]
Interferon-alpha also shows activity in this disease, in contrast to poor responses in patients with multiple myeloma.[64] Myeloablative therapy with autologous or allogeneic hematopoietic stem cell support is under clinical evaluation.[65-68] Candidates for this approach should avoid long-term use of alkylating agents or purine nucleoside analogs, which can deplete hematopoietic stem cells or predispose patients to myelodysplasia or acute leukemia.[45,69] After relapse from alkylating-agent therapy, 92 patients with lymphoplasmacytic lymphoma were randomly assigned to either fludarabine or cyclophosphamide, doxorubicin, and prednisone. Although relapse-free survival favored fludarabine (median duration of 19 months vs. 3 months, P < .01), no difference was observed in OS.[70][Level of evidence: 1iiDii] Among patients with concomitant hepatitis C virus (HCV) infection, some will attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[71][Level of evidence: 3iiiDiv]

Marginal Zone Lymphoma

Marginal zone lymphomas were previously included among the diffuse, small lymphocytic lymphomas. When marginal zone lymphomas involve the nodes, they are called monocytoid B-cell lymphomas or nodal marginal zone B-cell lymphomas, and when they involve extranodal sites (e.g., gastrointestinal tract, thyroid, lung, breast, orbit, and skin), they are called mucosa-associated lymphatic tissue (MALT) lymphomas.[72,73]

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 pyloriinfection may resolve most cases of localized gastric involvement.[74,75] 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.[76] The clinical implication of this finding is unknown. Translocation t(11;18) in patients with gastric MALT predicts for poor response to antibiotic therapy, for H. pylori–negative testing, and for poor response to oral alkylator chemotherapy.[77-79] Stable asymptomatic patients with persistently positive biopsies have been successfully followed on a watchful waiting approach until disease progression.[75] Patients who progress are treated with radiation therapy,[80-83] rituximab,[84] surgery (total gastrectomy or partial gastrectomy plus radiation therapy),[85] chemotherapy,[86] or combined–modality therapy.[87] The use of endoscopic ultrasonography may help clinicians to follow responses in these patients.[88] Four case series (encompassing more than 100 patients with stage IE or IIE diffuse large B-cell lymphoma (DLBCL) with or without associated MALT (but H. pylori-positive) reported durable complete remissions in more than 50% of the patients after treatment of H. pylori.[89-92]

Extragastric MALT

Localized involvement of other sites can be treated with radiation or surgery.[81-83,93-96] Patients with extragastric MALT lymphoma have a higher relapse rate than patients with gastric MALT lymphoma in some series, with relapses many years and even decades later.[97] Many of these recurrences involve different MALT sites than the original location.[98] When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.[99,100] A prospective, randomized trial of 401 patients with nongastric, extranodal MALT compared chlorambucil alone versus rituximab plus chlorambucil versus rituximab alone.[101] With a median follow-up of 7.4 years, the event-free survival was better for the rituximab-plus-chlorambucil arm (68%) than for the rituximab-alone arm (51%) and for the chlorambucil-alone arm (50%) (P = .0009); however, the 5-year OS was 90% in all arms.[101] 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.[102][Level of evidence: 3iiiDiv] These responses to doxycycline are mainly seen in Italian trials and less often in trials conducted in other geographic sites.[103] Large B-cell lymphomas of MALT sites are classified and treated as diffuse large cell lymphomas.[104] 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.[105]

Nodal marginal zone lymphoma

Patients with nodal marginal zone lymphoma (monocytoid B-cell lymphoma) are treated with the same paradigm of watchful waiting or therapies as described for follicular lymphoma.[106] Among patients with concomitant HCV infection, the majority attain a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[71][Level of evidence: 3iiiDiv]

Mediterranean abdominal lymphoma

The disease variously known as Mediterranean abdominal lymphoma, heavy–chain disease, or immunoproliferative small intestinal disease (IPSID), which occurs in young adults in eastern Mediterranean countries, is another version of MALT lymphoma, which responds to antibiotics in its early stages.[107] Campylobacter jejuni has been identified as one of the bacterial species associated with IPSID, and antibiotic therapy may result in remission of the disease.[108]

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.[109,110] This type of lymphoma is otherwise known as splenic lymphoma with villous lymphocytes. Splenectomy may result in prolonged remission.[72,111]
Management is similar to that of other low-grade lymphomas and usually involves rituximab alone or rituximab in combination with purine analogs or alkylating agent chemotherapy.[112] Splenic marginal zone lymphoma responds less well to chemotherapy, which would ordinarily be effective for chronic lymphocytic leukemia.[109,112,113] Among small numbers of patients with splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes) and infection with HCV, the majority attained a complete or partial remission after loss of detectable HCV RNA with treatment using interferon-alpha with or without ribavirin.[71,114]; [115][Level of evidence: 3iiiDiv] In contrast, no responses to interferon were seen in six HCV-negative patients.

Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous anaplastic large cell lymphoma presents in the skin only with no pre-existing lymphoproliferative disease and no extracutaneous sites of involvement.[116-118] Patients with this type of lymphoma encompass a spectrum ranging from clinically benign lymphomatoid papulosis, marked by localized nodules that may regress spontaneously, to a progressive and systemic disease requiring aggressive doxorubicin-based combination chemotherapy. This spectrum has been called the primary cutaneous CD30-positive T-cell lymphoproliferative disorder.
Patients with localized disease usually undergo radiation therapy. With more disseminated involvement, watchful waiting or doxorubicin-based combination chemotherapy is applied.[116-118]
(Refer to the PDQ summaries on Chronic Lymphocytic Leukemia Treatment; Mycosis Fungoides (Including Sézary Syndrome) Treatment; Hairy Cell Leukemia Treatment; and Adult Hodgkin Lymphoma Treatment for more information.)
References
  1. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16 (8): 2780-95, 1998. [PUBMED Abstract]
  2. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89 (11): 3909-18, 1997. [PUBMED Abstract]
  3. Society for Hematopathology Program: Society for Hematopathology Program. Am J Surg Pathol 21 (1): 114-121, 1997.
  4. López-Guillermo A, Cabanillas F, McDonnell TI, et al.: Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood 93 (9): 3081-7, 1999. [PUBMED Abstract]
  5. Peterson BA, Petroni GR, Frizzera G, et al.: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 21 (1): 5-15, 2003. [PUBMED Abstract]
  6. Swenson WT, Wooldridge JE, Lynch CF, et al.: Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23 (22): 5019-26, 2005. [PUBMED Abstract]
  7. Liu Q, Fayad L, Cabanillas F, et al.: Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 24 (10): 1582-9, 2006. [PUBMED Abstract]
  8. Kahl BS, Yang DT: Follicular lymphoma: evolving therapeutic strategies. Blood 127 (17): 2055-63, 2016. [PUBMED Abstract]
  9. Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003. [PUBMED Abstract]
  10. Armitage JO, Longo DL: Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood 127 (23): 2804-8, 2016. [PUBMED Abstract]
  11. Solal-Céligny P, Roy P, Colombat P, et al.: Follicular lymphoma international prognostic index. Blood 104 (5): 1258-65, 2004. [PUBMED Abstract]
  12. Perea G, Altés A, Montoto S, et al.: Prognostic indexes in follicular lymphoma: a comparison of different prognostic systems. Ann Oncol 16 (9): 1508-13, 2005. [PUBMED Abstract]
  13. Buske C, Hoster E, Dreyling M, et al.: The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108 (5): 1504-8, 2006. [PUBMED Abstract]
  14. Federico M, Bellei M, Marcheselli L, et al.: Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol 27 (27): 4555-62, 2009. [PUBMED Abstract]
  15. Dave SS, Wright G, Tan B, et al.: Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351 (21): 2159-69, 2004. [PUBMED Abstract]
  16. Casulo C, Byrtek M, Dawson KL, et al.: Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol 33 (23): 2516-22, 2015. [PUBMED Abstract]
  17. Shi Q, Flowers CR, Hiddemann W, et al.: Thirty-Month Complete Response as a Surrogate End Point in First-Line Follicular Lymphoma Therapy: An Individual Patient-Level Analysis of Multiple Randomized Trials. J Clin Oncol 35 (5): 552-560, 2017. [PUBMED Abstract]
  18. Brice P, Bastion Y, Lepage E, et al.: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1110-7, 1997. [PUBMED Abstract]
  19. Young RC, Longo DL, Glatstein E, et al.: The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol 25 (2 Suppl 2): 11-6, 1988. [PUBMED Abstract]
  20. Luminari S, Ferrari A, Manni M, et al.: Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma. J Clin Oncol 36 (7): 689-696, 2018. [PUBMED Abstract]
  21. Morschhauser F, Fowler NH, Feugier P, et al.: Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med 379 (10): 934-947, 2018. [PUBMED Abstract]
  22. Leonard JP, Trnený M, Izutsu K, et al.: Augment: a phase III randomized study of lenalidomide Plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory indolent non-Hodgkin lymphoma. [Abstract] Blood 132 (Suppl 1): A-445, 2018.
  23. Marcus R, Davies A, Ando K, et al.: Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med 377 (14): 1331-1344, 2017. [PUBMED Abstract]
  24. Dreyling M, Santoro A, Mollica L, et al.: Phosphatidylinositol 3-Kinase Inhibition by Copanlisib in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol 35 (35): 3898-3905, 2017. [PUBMED Abstract]
  25. Gopal AK, Kahl BS, de Vos S, et al.: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370 (11): 1008-18, 2014. [PUBMED Abstract]
  26. Gopal AK, Kahl BS, Flowers CR, et al.: Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy. Blood 129 (22): 3037-3039, 2017. [PUBMED Abstract]
  27. Flinn IW, Miller CB, Ardeshna KM, et al.: Dynamo: a phase 2 study demonstrating the clinical activity of duvelisib in patients with relapsed refractory indolent non-Hodgkin lymphoma. [Abstract] Blood 128 (22): A-1218, 2016.
  28. Schaaf M, Reiser M, Borchmann P, et al.: High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 1: CD007678, 2012. [PUBMED Abstract]
  29. Schmatz AI, Streubel B, Kretschmer-Chott E, et al.: Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J Clin Oncol 29 (11): 1445-51, 2011. [PUBMED Abstract]
  30. Jegalian AG, Eberle FC, Pack SD, et al.: Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 118 (11): 2976-84, 2011. [PUBMED Abstract]
  31. Louissaint A Jr, Ackerman AM, Dias-Santagata D, et al.: Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement. Blood 120 (12): 2395-404, 2012. [PUBMED Abstract]
  32. Sarkozy C, Trneny M, Xerri L, et al.: Risk Factors and Outcomes for Patients With Follicular Lymphoma Who Had Histologic Transformation After Response to First-Line Immunochemotherapy in the PRIMA Trial. J Clin Oncol 34 (22): 2575-82, 2016. [PUBMED Abstract]
  33. Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]
  34. Montoto S, Davies AJ, Matthews J, et al.: Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25 (17): 2426-33, 2007. [PUBMED Abstract]
  35. Villa D, Crump M, Panzarella T, et al.: Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group. J Clin Oncol 31 (9): 1164-71, 2013. [PUBMED Abstract]
  36. Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
  37. Wagner-Johnston ND, Link BK, Byrtek M, et al.: Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood 126 (7): 851-7, 2015. [PUBMED Abstract]
  38. Leblond V, Kastritis E, Advani R, et al.: Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia. Blood 128 (10): 1321-8, 2016. [PUBMED Abstract]
  39. Treon SP, Xu L, Yang G, et al.: MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med 367 (9): 826-33, 2012. [PUBMED Abstract]
  40. Dhodapkar MV, Hoering A, Gertz MA, et al.: Long-term survival in Waldenstrom macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood 113 (4): 793-6, 2009. [PUBMED Abstract]
  41. Ansell SM, Kyle RA, Reeder CB, et al.: Diagnosis and management of Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc 85 (9): 824-33, 2010. [PUBMED Abstract]
  42. Leblond V, Ben-Othman T, Deconinck E, et al.: Activity of fludarabine in previously treated Waldenström's macroglobulinemia: a report of 71 cases. Groupe Coopératif Macroglobulinémie. J Clin Oncol 16 (6): 2060-4, 1998. [PUBMED Abstract]
  43. Foran JM, Rohatiner AZ, Coiffier B, et al.: Multicenter phase II study of fludarabine phosphate for patients with newly diagnosed lymphoplasmacytoid lymphoma, Waldenström's macroglobulinemia, and mantle-cell lymphoma. J Clin Oncol 17 (2): 546-53, 1999. [PUBMED Abstract]
  44. Baldini L, Goldaniga M, Guffanti A, et al.: Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenstrom's macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: proposal for a common prognostic scoring system. J Clin Oncol 23 (21): 4662-8, 2005. [PUBMED Abstract]
  45. Gertz MA, Anagnostopoulos A, Anderson K, et al.: Treatment recommendations in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 30 (2): 121-6, 2003. [PUBMED Abstract]
  46. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al.: Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol 25 (22): 3344-9, 2007. [PUBMED Abstract]
  47. Treon SP, Branagan AR, Ioakimidis L, et al.: Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood 113 (16): 3673-8, 2009. [PUBMED Abstract]
  48. Leblond V, Johnson S, Chevret S, et al.: Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated Waldenström macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol 31 (3): 301-7, 2013. [PUBMED Abstract]
  49. Dimopoulos MA, Tedeschi A, Trotman J, et al.: Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia. N Engl J Med 378 (25): 2399-2410, 2018. [PUBMED Abstract]
  50. Treon SP, Gustine J, Meid K, et al.: Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia. J Clin Oncol 36 (27): 2755-2761, 2018. [PUBMED Abstract]
  51. Dimopoulos MA, Zervas C, Zomas A, et al.: Treatment of Waldenström's macroglobulinemia with rituximab. J Clin Oncol 20 (9): 2327-33, 2002. [PUBMED Abstract]
  52. Treon SP, Branagan AR, Hunter Z, et al.: Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom's macroglobulinemia. Ann Oncol 15 (10): 1481-3, 2004. [PUBMED Abstract]
  53. Dimopoulos MA, Chen C, Kastritis E, et al.: Bortezomib as a treatment option in patients with Waldenström macroglobulinemia. Clin Lymphoma Myeloma Leuk 10 (2): 110-7, 2010. [PUBMED Abstract]
  54. Gavriatopoulou M, García-Sanz R, Kastritis E, et al.: BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years. Blood 129 (4): 456-459, 2017. [PUBMED Abstract]
  55. Treon SP, Ioakimidis L, Soumerai JD, et al.: Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol 27 (23): 3830-5, 2009. [PUBMED Abstract]
  56. Dimopoulos MA, García-Sanz R, Gavriatopoulou M, et al.: Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood 122 (19): 3276-82, 2013. [PUBMED Abstract]
  57. Treon SP, Tripsas CK, Meid K, et al.: Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia. Blood 124 (4): 503-10, 2014. [PUBMED Abstract]
  58. Dimopoulos MA, Alexanian R: Waldenstrom's macroglobulinemia. Blood 83 (6): 1452-9, 1994. [PUBMED Abstract]
  59. Laszlo D, Andreola G, Rigacci L, et al.: Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study. J Clin Oncol 28 (13): 2233-8, 2010. [PUBMED Abstract]
  60. García-Sanz R, Montoto S, Torrequebrada A, et al.: Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol 115 (3): 575-82, 2001. [PUBMED Abstract]
  61. Buske C, Hoster E, Dreyling M, et al.: The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Leukemia 23 (1): 153-61, 2009. [PUBMED Abstract]
  62. Ghobrial IM, Hong F, Padmanabhan S, et al.: Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol 28 (8): 1422-8, 2010. [PUBMED Abstract]
  63. Rummel MJ, Niederle N, Maschmeyer G, et al.: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381 (9873): 1203-10, 2013. [PUBMED Abstract]
  64. Rotoli B, De Renzo A, Frigeri F, et al.: A phase II trial on alpha-interferon (alpha IFN) effect in patients with monoclonal IgM gammopathy. Leuk Lymphoma 13 (5-6): 463-9, 1994. [PUBMED Abstract]
  65. Dreger P, Glass B, Kuse R, et al.: Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia. Br J Haematol 106 (1): 115-8, 1999. [PUBMED Abstract]
  66. Desikan R, Dhodapkar M, Siegel D, et al.: High-dose therapy with autologous haemopoietic stem cell support for Waldenström's macroglobulinaemia. Br J Haematol 105 (4): 993-6, 1999. [PUBMED Abstract]
  67. Martin P, Chadburn A, Christos P, et al.: Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies. Ann Oncol 19 (7): 1327-30, 2008. [PUBMED Abstract]
  68. Kyriakou C, Canals C, Cornelissen JJ, et al.: Allogeneic stem-cell transplantation in patients with Waldenström macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 28 (33): 4926-34, 2010. [PUBMED Abstract]
  69. Leleu X, Soumerai J, Roccaro A, et al.: Increased incidence of transformation and myelodysplasia/acute leukemia in patients with Waldenström macroglobulinemia treated with nucleoside analogs. J Clin Oncol 27 (2): 250-5, 2009. [PUBMED Abstract]
  70. Leblond V, Lévy V, Maloisel F, et al.: Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease. Blood 98 (9): 2640-4, 2001. [PUBMED Abstract]
  71. Vallisa D, Bernuzzi P, Arcaini L, et al.: Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol 23 (3): 468-73, 2005. [PUBMED Abstract]
  72. Bertoni F, Zucca E: State-of-the-art therapeutics: marginal-zone lymphoma. J Clin Oncol 23 (26): 6415-20, 2005. [PUBMED Abstract]
  73. Zucca E, Bertoni F: The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood 127 (17): 2082-92, 2016. [PUBMED Abstract]
  74. Zullo A, Hassan C, Andriani A, et al.: Eradication therapy for Helicobacter pylori in patients with gastric MALT lymphoma: a pooled data analysis. Am J Gastroenterol 104 (8): 1932-7; quiz 1938, 2009. [PUBMED Abstract]
  75. Nakamura S, Sugiyama T, Matsumoto T, et al.: Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan. Gut 61 (4): 507-13, 2012. [PUBMED Abstract]
  76. Wündisch T, Thiede C, Morgner A, et al.: Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 23 (31): 8018-24, 2005. [PUBMED Abstract]
  77. Ye H, Liu H, Raderer M, et al.: High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood 101 (7): 2547-50, 2003. [PUBMED Abstract]
  78. Lévy M, Copie-Bergman C, Gameiro C, et al.: Prognostic value of translocation t(11;18) in tumoral response of low-grade gastric lymphoma of mucosa-associated lymphoid tissue type to oral chemotherapy. J Clin Oncol 23 (22): 5061-6, 2005. [PUBMED Abstract]
  79. Nakamura S, Ye H, Bacon CM, et al.: Clinical impact of genetic aberrations in gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence in situ hybridisation. Gut 56 (10): 1358-63, 2007. [PUBMED Abstract]
  80. Schechter NR, Yahalom J: Low-grade MALT lymphoma of the stomach: a review of treatment options. Int J Radiat Oncol Biol Phys 46 (5): 1093-103, 2000. [PUBMED Abstract]
  81. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Stage I and II MALT lymphoma: results of treatment with radiotherapy. Int J Radiat Oncol Biol Phys 50 (5): 1258-64, 2001. [PUBMED Abstract]
  82. Tsang RW, Gospodarowicz MK, Pintilie M, et al.: Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21 (22): 4157-64, 2003. [PUBMED Abstract]
  83. Tsai HK, Li S, Ng AK, et al.: Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma. Ann Oncol 18 (4): 672-8, 2007. [PUBMED Abstract]
  84. Martinelli G, Laszlo D, Ferreri AJ, et al.: Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 23 (9): 1979-83, 2005. [PUBMED Abstract]
  85. Cogliatti SB, Schmid U, Schumacher U, et al.: Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 101 (5): 1159-70, 1991. [PUBMED Abstract]
  86. Zinzani PL, Magagnoli M, Galieni P, et al.: Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients. J Clin Oncol 17 (4): 1254, 1999. [PUBMED Abstract]
  87. Thieblemont C, Bastion Y, Berger F, et al.: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 15 (4): 1624-30, 1997. [PUBMED Abstract]
  88. Pavlick AC, Gerdes H, Portlock CS: Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors. J Clin Oncol 15 (5): 1761-6, 1997. [PUBMED Abstract]
  89. Morgner A, Miehlke S, Fischbach W, et al.: Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection. J Clin Oncol 19 (7): 2041-8, 2001. [PUBMED Abstract]
  90. Chen LT, Lin JT, Shyu RY, et al.: Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol 19 (22): 4245-51, 2001. [PUBMED Abstract]
  91. Chen LT, Lin JT, Tai JJ, et al.: Long-term results of anti-Helicobacter pylori therapy in early-stage gastric high-grade transformed MALT lymphoma. J Natl Cancer Inst 97 (18): 1345-53, 2005. [PUBMED Abstract]
  92. Kuo SH, Yeh KH, Wu MS, et al.: Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood 119 (21): 4838-44; quiz 5057, 2012. [PUBMED Abstract]
  93. Uno T, Isobe K, Shikama N, et al.: Radiotherapy for extranodal, marginal zone, B-cell lymphoma of mucosa-associated lymphoid tissue originating in the ocular adnexa: a multiinstitutional, retrospective review of 50 patients. Cancer 98 (4): 865-71, 2003. [PUBMED Abstract]
  94. Bayraktar S, Bayraktar UD, Stefanovic A, et al.: Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients. Br J Haematol 152 (1): 72-80, 2011. [PUBMED Abstract]
  95. Stefanovic A, Lossos IS: Extranodal marginal zone lymphoma of the ocular adnexa. Blood 114 (3): 501-10, 2009. [PUBMED Abstract]
  96. Vazquez A, Khan MN, Sanghvi S, et al.: Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the salivary glands: a population-based study from 1994 to 2009. Head Neck 37 (1): 18-22, 2015. [PUBMED Abstract]
  97. Raderer M, Streubel B, Woehrer S, et al.: High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res 11 (9): 3349-52, 2005. [PUBMED Abstract]
  98. Sretenovic M, Colovic M, Jankovic G, et al.: More than a third of non-gastric malt lymphomas are disseminated at diagnosis: a single center survey. Eur J Haematol 82 (5): 373-80, 2009. [PUBMED Abstract]
  99. Nathwani BN, Drachenberg MR, Hernandez AM, et al.: Nodal monocytoid B-cell lymphoma (nodal marginal-zone B-cell lymphoma). Semin Hematol 36 (2): 128-38, 1999. [PUBMED Abstract]
  100. Raderer M, Wöhrer S, Streubel B, et al.: Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol 24 (19): 3136-41, 2006. [PUBMED Abstract]
  101. Zucca E, Conconi A, Martinelli G, et al.: Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. J Clin Oncol 35 (17): 1905-1912, 2017. [PUBMED Abstract]
  102. Kiesewetter B, Raderer M: Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature. Blood 122 (8): 1350-7, 2013. [PUBMED Abstract]
  103. Grünberger B, Hauff W, Lukas J, et al.: 'Blind' antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa. Ann Oncol 17 (3): 484-7, 2006. [PUBMED Abstract]
  104. Kuo SH, Chen LT, Yeh KH, et al.: Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas. J Clin Oncol 22 (17): 3491-7, 2004. [PUBMED Abstract]
  105. Desai A, Joag MG, Lekakis L, et al.: Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study. Blood 129 (3): 324-332, 2017. [PUBMED Abstract]
  106. Thieblemont C, Molina T, Davi F: Optimizing therapy for nodal marginal zone lymphoma. Blood 127 (17): 2064-71, 2016. [PUBMED Abstract]
  107. Isaacson PG: Gastrointestinal lymphoma. Hum Pathol 25 (10): 1020-9, 1994. [PUBMED Abstract]
  108. Lecuit M, Abachin E, Martin A, et al.: Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350 (3): 239-48, 2004. [PUBMED Abstract]
  109. Arcaini L, Paulli M, Boveri E, et al.: Splenic and nodal marginal zone lymphomas are indolent disorders at high hepatitis C virus seroprevalence with distinct presenting features but similar morphologic and phenotypic profiles. Cancer 100 (1): 107-15, 2004. [PUBMED Abstract]
  110. Arcaini L, Rossi D, Paulli M: Splenic marginal zone lymphoma: from genetics to management. Blood 127 (17): 2072-81, 2016. [PUBMED Abstract]
  111. Parry-Jones N, Matutes E, Gruszka-Westwood AM, et al.: Prognostic features of splenic lymphoma with villous lymphocytes: a report on 129 patients. Br J Haematol 120 (5): 759-64, 2003. [PUBMED Abstract]
  112. Arcaini L, Lazzarino M, Colombo N, et al.: Splenic marginal zone lymphoma: a prognostic model for clinical use. Blood 107 (12): 4643-9, 2006. [PUBMED Abstract]
  113. Iannitto E, Ambrosetti A, Ammatuna E, et al.: Splenic marginal zone lymphoma with or without villous lymphocytes. Hematologic findings and outcomes in a series of 57 patients. Cancer 101 (9): 2050-7, 2004. [PUBMED Abstract]
  114. Hermine O, Lefrère F, Bronowicki JP, et al.: Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347 (2): 89-94, 2002. [PUBMED Abstract]
  115. Kelaidi C, Rollot F, Park S, et al.: Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia 18 (10): 1711-6, 2004. [PUBMED Abstract]
  116. de Bruin PC, Beljaards RC, van Heerde P, et al.: Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology 23 (2): 127-35, 1993. [PUBMED Abstract]
  117. Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28 (6): 973-80, 1993. [PUBMED Abstract]
  118. Kempf W, Pfaltz K, Vermeer MH, et al.: EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood 118 (15): 4024-35, 2011. [PUBMED Abstract]

Aggressive NHL

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

Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common NHL and comprises 30% of newly diagnosed cases.[1] Most patients present with rapidly enlarging masses, often with both local and systemic symptoms (designated B symptoms with fever, recurrent night sweats, or weight loss). (Refer to the PDQ summary on Hot Flashes and Night Sweats and the PDQ summary on Nutrition in Cancer Care for more information on weight loss.)
Some cases of large B-cell lymphoma have a prominent background of reactive T cells and often of histiocytes, so-called T-cell/histiocyte-rich large B-cell lymphoma. This subtype of large cell lymphoma has frequent liver, spleen, and bone marrow involvement; however, the outcome is equivalent to that of similarly staged patients with DLBCL.[2-4] Some patients with DLBCL at diagnosis have a concomitant indolent small B-cell component; while overall survival (OS) appears similar after multidrug chemotherapy, there is a higher risk of indolent relapse.[5]

Prognosis

The vast majority of patients with localized disease are curable with combined–modality therapy or combination chemotherapy alone.[6] For patients with advanced-stage disease, 50% of presenting patients are cured with doxorubicin-based combination chemotherapy and rituximab.[7-9]
The National Comprehensive Cancer Network International Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) identifies five significant risk factors prognostic of OS:[10]
  • Age <40 years: 0; 41–60 years: 1; 61–75 years: 2; >75 years: 3.
  • Stage III/IV: 1.
  • Performance status 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, 96%; progression-free survival (PFS), 91%.
  • Low intermediate (2 or 3): 5-year OS, 82%; PFS, 74%.
  • High intermediate (4 or 5): 5-year OS, 64%; PFS, 51%.
  • High (>6): 5-year OS, 33%; PFS, 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 biologic factors.[12]
The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYCgene, or both, confer a particularly poor prognosis.[13-15] Dose-intensive therapies, infusional therapies, and stem cell transplantation consolidation are being explored in this high-risk group.[16,17] A retrospective review evaluated 159 patients with previously untreated DLBCL who underwent double-hit genetic testing by fluorescence in situhybridization (FISH) and achieved complete response (CR).[18] The induction therapy did not alter 3-year relapse-free survival or OS when autologous stem cell transplantation (SCT) was employed.
In a retrospective review of 117 patients with relapsed or refractory DLBCL who underwent autologous SCT, the 4-year OS was 25% for double-hit lymphomas (rearrangement of BCL2and MYC), 61% for 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 may be considered 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.[21-26] Patients who have DLBCL with coexpression of CD20 and CD30 may define a subgroup with a unique molecular signature, a more favorable prognosis, and possible therapeutic implication for the use of anti-CD30–specific therapy, such as brentuximab vedotin.[27] 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.[28]

Central nervous system (CNS) prophylaxis

CNS prophylaxis (usually with four to six injections of methotrexate intrathecally) is recommended for patients with testicular involvement. Some clinicians are employing high-dose intravenous methotrexate (usually four doses) as an alternative to intrathecal therapy because drug delivery is improved and patient morbidity is decreased.[29] CNS prophylaxis for bone marrow involvement is controversial; some investigators recommend it, others do not.[30,31]
A retrospective analysis of 605 patients with diffuse large cell lymphoma who did not receive prophylactic intrathecal therapy identified an elevated serum LDH and more than one extranodal site as independent risk factors for CNS recurrence. Patients with both risk factors have a 17% probability of CNS recurrence at 1 year after diagnosis (95% confidence interval [CI], 7%–28%) versus 2.8% (95% CI, 2.7%–2.9%) for the remaining patients.[32][Level of evidence: 3iiiDiii]
The CNS-IPI is a tool used to predict which patients have a risk of CNS relapse above 10%. It was developed by the German Lymphoma Study Group and validated by the British Columbia Cancer Agency database. Four to six of the IPI risk factors (refer to the Prognosissection of this summary for more information) and involvement of the kidneys or adrenal glands were used to define the high-risk group that might benefit from CNS prophylaxis.[33]
The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-based regimens has significantly reduced the risk of CNS relapse in retrospective analyses.[34,35] Patients with CNS dissemination at diagnosis or at relapse usually receive rituximab and highdoses of methotrexate and/or cytarabine followed by autologous SCT, but this approach has not been assessed in randomized trials.[36,37][Level of evidence: 3iiiDiv]

Primary Mediastinal Large B-cell Lymphoma

Primary mediastinal (thymic) large B-cell lymphoma is a subset of DLBCL with molecular characteristics that are most similar to nodular-sclerosing Hodgkin lymphoma (HL). Mediastinal lymphomas with features intermediate between primary mediastinal B-cell lymphoma and nodular-sclerosing HL are called mediastinal gray-zone lymphomas.[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 is the same as for other comparably staged patients with DLBCL. Uncontrolled, phase II studies employing dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) show high cure rates while avoiding any mediastinal radiation.[39-43][Level of evidence: 3iiiA] These results suggest that patients who receive R-CHOP–-based regimens may avoid the serious long-term complications of radiation therapy when given with chemotherapy. Posttreatment fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET-CT) scans are controversial; it remains unclear if PET scans can reliably identify patients who can take or omit radiation therapy consolidation.[40,44-46] The only randomized trial showing an OS advantage for combined modality therapy was retracted. In situations where mediastinal radiation would encompass the left side of the heart or would increase breast cancer risk in young female patients, proton therapy may be considered to reduce radiation dose to organs at risk.[47] (Refer to the Superior Vena Cava Syndrome section in the PDQ summary on Cardiopulmonary Syndromes for more information.)

Follicular Large Cell Lymphoma

Prognosis

The natural history of follicular large cell lymphoma remains controversial.[48] While there is agreement about the significant number of long-term disease-free survivors with early-stage disease, the curability of patients with advanced disease (stage III or stage IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma).[49] Other investigators report a plateau in freedom from progression at levels expected for an aggressive lymphoma (40% at 10 years).[50,51] This discrepancy may be caused by variations in histologic classification between institutions and the rarity of patients with follicular large cell lymphoma. A retrospective review of 252 patients, all treated with anthracycline-containing combination chemotherapy, showed that patients with more than 50% diffuse components on biopsy had a worse OS than other patients with follicular large cell lymphoma.[52]

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.[53][Level of evidence: 3iiiA]

Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphomas (ALCL) may be confused with carcinomas and are associated with the Ki-1 (CD30) antigen. These lymphomas are usually of T-cell origin, often present with extranodal disease, and are found especially in the skin.[54]
The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin-anaplastic lymphoma kinase (ALK).[54,55]
Patients whose lymphomas express ALK (immunohistochemistry) are usually younger and may have systemic symptoms, extranodal disease, and advanced-stage disease; however, they have a more favorable survival rate than that of ALK-negative patients.[56,57]
In a prospective randomized trial of 452 patients with CD30-positive T-cell lymphoma, 70% of whom had ALCL (22% ALK-positive and 48% ALK-negative patients), the previously used standard regimen, CHOP, was compared with brentuximab vedotin (an anti-CD30 monoclonal antibody conjugated to a cytotoxic agent) combined with cyclophosphamide, doxorubicin, and prednisone.[58] With a median follow-up of 35 months, the brentuximab combination (3-year OS, 77%) showed an OS advantage over CHOP (3-year OS, 68%); (hazard ratio [HR], 0.66; 95% CI, 0.46–0.95; P = .02).[58][Level of evidence: 1iiA] This established brentuximab plus cyclophosphamide, doxorubicin, and prednisone as a new option for patients with anaplastic large cell lymphoma and other CD30-positive T-cell lymphomas, such as angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. For patients with relapsed disease, anecdotal responses have been reported for brentuximab vedotin (anti-tubulin agent attached to a CD30-specific monoclonal antibody),[59-62] romidepsin,[63] and pralatrexate.[64][Level of evidence: 3iiiDiv] In a phase II study (NCT00866047), 66% of 58 patients attained a CR with brentuximab vedotin. At a median follow-up of 58 months, the 5-year PFS was 57% (95% CI, 41%–74%), and the 5-year OS was 79% (95% CI, 65%–92%) with 42% of these patients undergoing hematopoietic SCT.[62][Level of evidence: 3iiiDiv] For patients with relapsed disease, autologous or allogeneic SCT showed a 50% 3-year PFS for 39 patients in a retrospective review.[65][Level of evidence: 3iiiDiii]
ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy.[66] Patients with breast implant–associated ALCL may do well without chemotherapy after capsulectomy and implant removal if the disease is confined to the fibrous capsule, and no associated mass is present.[67,68]
Publicado por en

No hay comentarios:

Publicar un comentario

Suscribirse a: Enviar comentarios (Atom)