jueves, 7 de marzo de 2019

Adult Non-Hodgkin Lymphoma Treatment (PDQ®) 2/3 —Health Professional Version - National Cancer Institute

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

National Cancer Institute



Extranodal Natural Killer (NK)-/T-cell Lymphoma

Extranodal natural killer (NK)-/T-cell lymphoma (nasal type) is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region.[69] Other extranodal sites include the palate, trachea, skin, and gastrointestinal tract. Hemophagocytic syndrome may occur; historically, these tumors were considered part of lethal midline granuloma.[70] In most cases, Epstein-Barr virus (EBV) genomes are detectable in the tumor cells and immunophenotyping shows CD56 positivity. Cases with blood and marrow involvement are considered NK-cell leukemia.
The increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, concurrently, before the start of chemotherapy or between cycle two and three of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.[71-78] A retrospective review of 1,273 early-stage patients stratified them into a low-risk group and high-risk group using stage, age, LDH, performance status, and primary tumor invasion. Low-risk patients fared best with radiation therapy alone,[79] while high-risk patients fared best with a strategy of radiation therapy concurrent with chemotherapy, following cycle two of chemotherapy, or followed by chemotherapy.[77,80,81] Higher doses of radiation therapy administered at more than 50 Gy are associated with improved outcomes according to anecdotal reports.[77] The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced-stage disease or extranasal presentation, has led some investigators to recommend autologous or allogeneic peripheral SCT consolidation.[78,82-86] L-asparaginase-containing regimens have shown anecdotal response rates greater than 50% for relapsing, refractory, or newly diagnosed stage IV patients.[78,87,88] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[89] A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy can be distinguished from NK-/T-cell lymphoma.[90]

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[91,92] The histology shows association with angioinvasion and vasculitis, usually manifesting as pulmonary lesions or paranasal sinus involvement.
Patients are managed like others with diffuse large cell lymphoma and require doxorubicin-based combination chemotherapy.

Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL or ATCL) was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma.[93-96] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia.[70] (Refer to the information on night sweats in the PDQ summary on Hot Flashes and Night Sweats, information on weight loss in the in the PDQ summary on Nutrition in Cancer Care, and information on skin rash in the PDQ summary on Pruritus.) Opportunistic infections are frequent because of an underlying immune deficiency. B-cell EBV genomes are detected in most affected patients.[97]
Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is recommended as it is for other aggressive lymphomas.[93,96] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[58][Level of evidence: 1iiD] (Refer to the Anaplastic Large Cell Lymphomasection of this summary for more information.) The International Peripheral T-Cell Lymphoma Project involving 22 international centers identified 243 patients with AITL or ATCL; the 5-year OS and failure-free survival rates were 33% and 18%, respectively.[98] Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[85,99,100] Anecdotal responses have been reported for cyclosporine,[101] pralatrexate,[102] bendamustine,[103] the histone deacetylase inhibitor romidepsin, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[63,104][Level of evidence: 3iiiDiv] Occasional spontaneous remissions and protracted responses to steroids only have been reported.

Peripheral T-cell Lymphoma

Patients with peripheral T-cell lymphoma have diffuse large cell or diffuse mixed lymphoma that expresses a cell surface phenotype of a postthymic (or peripheral) T-cell expressing CD4 or CD8 but not both together.[105] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[70,106] This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells.

Prognosis

Most investigators report worse response and survival rates for patients with peripheral T-cell lymphomas than for patients with comparably staged B-cell aggressive lymphomas.[106,107] Most patients present with multiple adverse prognostic factors (i.e., older age, stage IV, multiple extranodal sites, and elevated LDH), and these patients have a low (<20%) failure-free survival and OS at 5 years.[106,107] As with other lymphomas (e.g., diffuse large B-cell lymphoma or follicular lymphoma), event-free survival at 24 months predicts a 5-year OS of 78%.[108]

Therapeutic approaches

Therapy involves doxorubicin-based combination chemotherapy (such as CHOP or CHOPE [CHOP plus etoposide]), which is also used for DLBCL.[109] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[58][Level of evidence: 1iiD] (Refer to the Anaplastic Large Cell Lymphomasection of this summary for more information.) For patients with early-stage disease, anecdotal retrospective series disagree on the value of consolidative radiation therapy after combination chemotherapy.[110][Level of evidence: 3iiiDiv] Consolidation using high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell support has been applied to patients with advanced-stage peripheral T-cell lymphoma after induction therapy with CHOP-based regimens and after response to reinduction therapy at first relapse. Evidence for this approach is anecdotal.[85,99,111,112] For relapsing patients, pralatrexate has shown a 30% response rate and a median 10-month duration of response for 109 evaluable patients in a prospective trial.[63,113][Level of evidence: 3iiiDiv] Also for relapsing patients, similar response rates were seen for romidepsin for 130 evaluable patients in a prospective trial.[63][Level of evidence: 3iiiDiv] Anecdotal responses have been seen with a combination of pralatrexate and romidepsin,[102] single-agent bendamustine,[103] belinostat,[114] and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[104][Level of evidence: 3iiiDiv] Incorporation of these new agents with CHOP chemotherapy is under clinical evaluation.[58,106] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, after relapse from previous chemotherapy.[115] The median PFS after first relapse was less than 6 months in one series of 163 patients with peripheral T-cell lymphoma.[116]
An unusual type of peripheral T-cell lymphoma occurring mostly in young men, hepatosplenic T-cell lymphoma, appears to be localized to the hepatic and splenic sinusoids, with cell surface expression of the T-cell receptor gamma/delta.[117-121] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[122-125] These patients have cells that express alpha-beta phenotype. Those with gamma-delta phenotype have a more aggressive clinical course and are classified as cutaneous gamma-delta T-cell lymphoma.[126-128] These patients may manifest involvement of the epidermis, dermis, subcutaneous region, or mucosa. These entities have extremely poor prognoses with an extremely aggressive clinical course and are treated within the same paradigm as the highest-risk groups with DLBCL.[85] An indolent T-cell lymphoproliferative disease of the gastrointestinal tract must be distinguished from peripheral T-cell lymphoma because no therapy may be indicated.[129]

Enteropathy-type Intestinal T-cell Lymphoma

Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[70,130-132] Because a gluten-free diet prevents the development of lymphoma, patients diagnosed with celiac sprue in childhood rarely develop lymphoma. The diagnosis of celiac disease is usually made by finding villous atrophy in the resected intestine. Surgery is often required for diagnosis and to avoid perforation during therapy.
Therapy is with doxorubicin-based combination chemotherapy, but relapse rates appear higher than for comparably staged diffuse large cell lymphoma.[131-133] Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. (Refer to the PDQ summaries on Gastrointestinal Complications and Nutrition in Cancer Care for more information on parenteral nutrition.) Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. High-dose therapy with hematopoietic stem cell rescue has been applied in first remission or at relapse.[85,131,134][Level of evidence: 3iiiDiii] Evidence for this approach is anecdotal.

Intravascular Large B-cell Lymphoma (Intravascular Lymphomatosis)

Intravascular lymphomatosis is characterized by large cell lymphoma confined to the intravascular lumen. The brain, kidneys, lungs, and skin are the organs most likely affected by intravascular lymphomatosis.
With the use of aggressive combination chemotherapy, the prognosis is similar to more conventional presentations.[135,136]

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.[137] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-Myc gene on chromosome 8.[138] A subgroup of patients with dual translocation of C-Myc and BCL2 appear to have an extremely poor outcome despite aggressive therapy (5-month OS).[139][Level of evidence: 3iiiA]
In some patients with larger B cells, there is morphologic overlap with DLBCL. These Burkitt-like large cell lymphomas show C-Myc deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[140-142] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing EBV genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high LDH but are potentially curable with intensive doxorubicin-based combination chemotherapy.

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).[143-146] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[147-150] 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.[151] Patients with HIV-associated Burkitt lymphoma also benefit from less-toxic modification of the aggressive multidrug regimens in combination with rituximab.[152][Level of evidence: 3iiiDiv] (Refer to the PDQ summaries on Primary CNS Lymphoma Treatment and AIDS-Related Lymphoma Treatment for more information.)

Lymphoblastic Lymphoma

Lymphoblastic lymphoma (precursor T-cell) is a very aggressive form of NHL. It often, but not exclusively, occurs in young patients.[153] It is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the CNS.
Treatment is usually patterned after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without bone marrow transplantation is the standard treatment for this aggressive histologic type of NHL.[154-156] Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

Adult T-cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus human T-lymphotrophic virus 1 and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to combination chemotherapy.[157,158] ATL has been divided into four clinical subtypes:[159,160]
  • Acute (aggressive course with leukemia, with or without extranodal or nodal involvement).
  • Lymphoma (aggressive course with lymphadenopathy and no leukemia).
  • Chronic (indolent course with leukemia and lymphadenopathy).
  • Smoldering (indolent course with only leukemia).
The acute and lymphoma types of ATL have done poorly with strategies of combination chemotherapy and allogeneic SCT with a median OS under 1 year.[161-163] Using combination chemotherapy, less than 10% of 807 patients were alive after 4 years.[163] Anecdotal durable remissions have been reported after allogeneic SCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[164][Level of evidence: 3iiiDiv] Among 815 patients who underwent allogeneic SCT in two retrospective reviews, the 3-year OS rates were 36% and 26%.[165,166][Level of evidence: 3iiiA]
The combination of zidovudine and interferon-alpha has activity against ATL, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in the majority of presenting patients with this combination but are not seen in patients with the lymphoma subtype of ATL.[167-171] In a multicenter phase II study of 26 relapsed patients, 42% responded to lenalidomide (including four CR).[172][Level of evidence: 3iiiDiv] Symptomatic local progression of all subtypes responds well to palliative radiation therapy.[173] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[58][Level of evidence: 1iiD] (Refer to the Anaplastic Large Cell Lymphoma section of this summary for more information.)

Mantle Cell Lymphoma

Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[174] Mantle cell lymphoma is characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein.[174]
Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemotherapy and occurs in older patients with generally asymptomatic advanced-stage disease. The median survival, however, is significantly shorter (5–7 years) than that of other lymphomas, and this histology is now considered to be an aggressive lymphoma.[175] 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.[176] A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[177,178]

Therapeutic approaches

Asymptomatic patients with low-risk scores on the IPI may do well when initial therapy is deferred.[179,180][Level of evidence: 3iiiDiv] There is no standard approach to mantle cell lymphoma. Several induction chemotherapy regimens may be employed for symptomatic progressing disease. These regimens range in intensity from rituximab alone to rituximab plus bendamustine, to R-CHOP, to high-dose intensive regimens such as R-hyper C-VAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine). Some physicians use autologous SCT or allogeneic SCT consolidation next, while others prefer rituximab maintenance, reserving high-dose consolidation for a later time. Ibrutinib, lenalidomide, and bortezomib have shown activity in relapsing patients, and these drugs are being incorporated upfront.[181-184]
It is unclear which therapeutic approach offers the best long-term survival in this clinicopathologic entity. In a prospective randomized trial, 532 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.[185] With a median follow-up of 37 months, the OS was significantly shorter after R-FC than after R-CHOP (47% vs. 62%, P = .005; HRdeath, 1.50; 95% CI, 1.13–1.99).[185][Level of evidence: 1iiA] Event-free survival favored rituximab over interferon-alpha (57% PFS at 4 years vs. 34%, P = .01; HR, 0.55; 95% CI, 0.36–0.87), but OS did not differ significantly (79% vs. 67% at 4 years, P= .13).[185][Level of evidence: 1iiDi] However, patients who received R-CHOP induction showed an OS benefit for rituximab maintenance over interferon-alpha maintenance (87% vs. 63% at 4 years, P = .005).[185][Level of evidence: 3iiiA] 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.[186][Level of evidence: 1iiDiii] However, this trial failed to show any benefit for rituximab maintenance after BR. A prospective, randomized trial of 487 patients compared VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) with R-CHOP.[187] With a median follow-up of 40 months, the median PFS favored VR-CAP (24.7 months vs. 14.4 months, HR, 0.63; P <.001), but the 4-year OS was not significantly different (64% vs. 54%, P = .17).[187][Level of evidence: 1iiDiii]
A prospective randomized trial of 497 patients younger than 65 years compared six cycles of R-CHOP to six cycles of alternating R-CHOP and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), with both groups then receiving autologous SCT.[188][Level of evidence: 1iiDiii] With a median follow-up of 6.1 years, the time to treatment failure (TTF) was longer in the cytarabine group, with a median TTF follow-up of 9.1 years (95% CI, 6.3 years to not reached) compared with 3.9 years (95% CI, 3.2‒4.4 years) (HR, 0.56; corrected P= .038) for the control group. Despite this surprising difference in TTF, the OS was not different.
Many investigators are exploring high-dose chemoradiation immunotherapy with stem cell/bone marrow support or nonmyeloablative allogeneic SCT.[189-194] Thus far, randomized trials have not shown OS benefits from these newer approaches.[190]
In a prospective trial (NCT00921414) of 299 patients who were previously untreated for mantle cell lymphoma, 257 responders received four courses of R-DHAP and autologous SCT. The patients were randomly assigned to receive rituximab maintenance therapy for 3 years versus no maintenance therapy. After randomization, a median follow-up at 50.2 months showed the rate of PFS at 4-years favored the rituximab-maintenance arm at 83% (95% CI, 73%–88%) versus the no-maintenance arm at 64% (95% CI, 55%–73%; P < .001). The 4-year OS rate also favored the rituximab-maintenance arm at 89% (95% CI, 81%–94%) versus the no-maintenance arm at 80% (95% CI, 72%–88%; P = .04).[195][Level of evidence: 1iiA]
Lenalidomide with or without rituximab also shows response rates of around 50% in relapsed patients, with even higher response rates for previously untreated patients.[182,196,197][Level of evidence: 3iiDiv]
The B-cell receptor-inhibitor, ibrutinib, showed a response rate of 86% (21% CR rate) in previously treated patients with a median PFS time of 14 months.[183][Level of evidence: 3iiiDiv] In a prospective randomized trial of 280 patients with relapsed/refractory mantle cell lymphoma, patients received either ibrutinib or temsirolimus.[198] 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).[198][Level of evidence: 1iiDiii] Ibrutinib has been combined with another active agent, venetoclax, in a phase II study of 23 patients with relapsed or refractory mantle cell lymphoma.[199] An unprecedented 71% of patients had CR and 78% of responding patients maintained response at 15 months.[199][Level of evidence: 3iiiDiv]
Acalabrutinib (another B-cell receptor inhibitor via the Bruton tyrosine kinase pathway) was studied in 124 patients with relapsed/refractory mantle cell lymphoma.[200] In a phase II study, there was an 81% objective response rate, 40% CR rate, and the 1-year PFS rate was 67%.[200][Level of evidence: 3iiiDiv] Rituximab, lenalidomide, ibrutinib, acalabrutinib, and venetoclax represent directed biologic agents that may lead the way to chemotherapy-free strategies for patients with mantle cell lymphoma.[201]

Posttransplantation Lymphoproliferative Disorder

Patients who undergo transplantation of the heart, lung, liver, kidney, or pancreas usually require lifelong immunosuppression. This may result in posttransplantation lymphoproliferative disorder (PTLD) in 1% to 3% of recipients, which appears as an aggressive lymphoma.[202] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[203]

Prognosis

Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[204,205]

Therapeutic options

In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[206,207] 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.[206,208,209] If these measures fail, doxorubicin-based combination chemotherapy (R-CHOP) is recommended, although some patients can avoid cytotoxic therapy.[209,210] Localized presentations can be controlled with surgery or radiation therapy alone. These localized mass lesions, which may grow over a period of months, are often phenotypically polyclonal and tend to occur within weeks or a few months after transplantation.[203] Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV.[211] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[211-213] 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.[214] 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).[215] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[216]

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.[217,218] Care must be taken with immunophenotypic tests to exclude ALCL or hemophagocytic syndromes caused by viral infections, especially EBV.

Therapeutic options

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

Primary Effusion Lymphoma

Primary effusion lymphoma presents exclusively or mainly in the pleural, pericardial, or abdominal cavities in the absence of an identifiable tumor mass.[219] Patients are usually HIV seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.

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.[220] Anecdotal reports suggest using aggressive chemotherapy for Burkitt or lymphoblastic lymphoma, followed by SCT consolidation in responding patients, when feasible.[220-222]
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  172. Ishida T, Fujiwara H, Nosaka K, et al.: Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. J Clin Oncol 34 (34): 4086-4093, 2016. [PUBMED Abstract]
  173. Simone CB 2nd, Morris JC, Stewart DM, et al.: Radiation therapy for the management of patients with HTLV-1-associated adult T-cell leukemia/lymphoma. Blood 120 (9): 1816-9, 2012. [PUBMED Abstract]
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  175. Herrmann A, Hoster E, Zwingers T, et al.: Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27 (4): 511-8, 2009. [PUBMED Abstract]
  176. Majlis A, Pugh WC, Rodriguez MA, et al.: Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants. J Clin Oncol 15 (4): 1664-71, 1997. [PUBMED Abstract]
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  179. Martin P, Chadburn A, Christos P, et al.: Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27 (8): 1209-13, 2009. [PUBMED Abstract]
  180. Cohen JB, Han X, Jemal A, et al.: Deferred therapy is associated with improved overall survival in patients with newly diagnosed mantle cell lymphoma. Cancer 122 (15): 2356-63, 2016. [PUBMED Abstract]
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  189. Khouri IF, Lee MS, Saliba RM, et al.: Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol 21 (23): 4407-12, 2003. [PUBMED Abstract]
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  191. Geisler CH, Kolstad A, Laurell A, et al.: Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood 112 (7): 2687-93, 2008. [PUBMED Abstract]
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Stage Information for Adult NHL

Stage is important in selecting a treatment for patients with non-Hodgkin lymphoma (NHL). Chest and abdominal computed tomography (CT) scans are usually part of the staging evaluation for all lymphoma patients. The staging system is similar to the staging system used for Hodgkin lymphoma (HL).
Common among patients with NHL is involvement of the following:
  • 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).
Cytologic examination of cerebrospinal fluid may be positive in patients with aggressive NHL. Involvement of hilar and mediastinal lymph nodes is less common than in HL. Mediastinal adenopathy, however, is a prominent feature of lymphoblastic lymphoma and primary mediastinal B-cell lymphoma, entities primarily found in young adults.
The majority of patients with NHL present with advanced (stage III or stage IV) disease that can often be identified with limited staging procedures such as CT scanning and biopsies of the bone marrow and other accessible sites of involvement. Laparoscopic biopsy or laparotomy is not required for staging but may be necessary to establish a diagnosis or histologic type.[1] Positron emission tomography (PET) with fluorine F 18-fludeoxyglucose can be used for initial staging and for follow-up after therapy as a supplement to CT scanning.[2] Interim PET scans after two to four cycles of therapy did not provide reliable prognostic information because of problems of interobserver reproducibility in a large cooperative group trial (ECOG-E344 [NCT00274924]) and lack of difference in outcome between PET-negative and PET-positive/biopsy-negative patients in two prospective trials [3-5] and in a meta-analysis.[6] 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.[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.[8] Bone marrow biopsies are required for some clinical trials and when the identification of marrow involvement would change the therapeutic plan.

Staging Subclassification System

Lugano Classification

The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma.[9] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[10] with some modifications 18 years later from the Cotswolds meeting.[11,12]
Table 1. Lugano Classification for Hodgkin and Non-Hodgkin Lymphomaa
StageStage Description
CSF = cerebrospinal fluid; CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
aHodgkin and Non-Hodgkin Lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 937–58.
bStage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors.
cThe definition of disease bulk varies according to lymphoma histology. In the Lugano classification, bulk ln Hodgkin lymphoma is defined as a mass greater than one-third of the thoracic diameter on CT of the chest or a mass >10 cm. For NHL, the recommended definitions of bulk vary by lymphoma histology. In follicular lymphoma, 6 cm has been suggested based on the Follicular Lymphoma International Prognostic Index-2 and its validation. In DLBCL, cutoffs ranging from 5 cm to 10 cm have been used, although 10 cm is recommended.
Limited stage
IInvolvement of a single lymphatic site (i.e., nodal region, Waldeyer’s ring, thymus, or spleen).
IESingle extralymphatic site in the absence of nodal involvement (rare in Hodgkin lymphoma).
IIInvolvement of two or more lymph node regions on the same side of the diaphragm.
IIEContiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm.
II bulkybStage II with disease bulk.c
Advanced stage
IIIInvolvement of lymph node regions on both sides of the diaphragm; nodes above the diaphragm with spleen involvement.
IVDiffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or noncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease; or any extralymphatic organ involvement in nodal stage III disease. Stage IV includes any involvement of the CSF, bone marrow, liver, or multiple lung lesions (other than by direct extension in stage IIE disease).
Note: Hodgkin lymphoma uses A or B designation with stage group. A/B is no longer used in NHL.
Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.
The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.
Table 2. Notation to Identify Specific Sites
N = nodesH = liverL = lungM = bone marrow
S = spleenP = pleuraO = boneD = skin
Current practice assigns a clinical stage based on the findings of the clinical evaluation and a pathologic stage based on the findings made as a result of invasive procedures beyond the initial biopsy.
For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be clinical stage IIA, pathologic stage IVA(H+)(M+).
A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:
  • 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 five significant risk factors prognostic of OS:[13]
  • 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 LDH normalized: 0; >1x–3x: 1; >3x: 2.
  • Number of extranodal sites ≥2: 1.
Risk scores:
  • Low (0 or 1): 5-year overall survival (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.[14] Shorter intervals of time between diagnosis and treatment appear to be a surrogate for poor prognostic biologic factors.[15]
The BCL2 gene and rearrangement of the MYC gene or dual overexpression of the MYCgene, or both, confer a particularly poor prognosis.[16,17] Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[18] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[19-21]
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  17. Horn H, Ziepert M, Becher C, et al.: MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood 121 (12): 2253-63, 2013. [PUBMED Abstract]
  18. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329 (14): 987-94, 1993. [PUBMED Abstract]
  19. Rosenwald A, Wright G, Chan WC, et al.: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346 (25): 1937-47, 2002. [PUBMED Abstract]
  20. Abramson JS, Shipp MA: Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 106 (4): 1164-74, 2005. [PUBMED Abstract]
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Treatment Option Overview for Adult NHL

Treatment of non-Hodgkin lymphoma (NHL) depends on the histologic type and stage. Many of the improvements in survival have been made using clinical trials (experimental therapy) that have attempted to improve on the best available accepted therapy (conventional or standard therapy).
In asymptomatic patients with indolent forms of advanced NHL, treatment may be deferred until the patient becomes symptomatic as the disease progresses. When treatment is deferred, the clinical course of patients with indolent NHL varies; frequent and careful observation is required so that effective treatment can be initiated when the clinical course of the disease accelerates. Some patients have a prolonged indolent course, but others have disease that rapidly evolves into more aggressive types of NHL that require immediate treatment.
Radiation techniques differ somewhat from those used in the treatment of Hodgkin lymphoma. The dose of radiation therapy usually varies from 25 Gy to 50 Gy and is dependent on factors that include the histologic type of lymphoma, the patient’s stage and overall condition, the goal of treatment (curative or palliative), the proximity of sensitive surrounding organs, and whether the patient is being treated with radiation therapy alone or in combination with chemotherapy. Given the patterns of disease presentations and relapse, treatment may need to include unusual sites such as Waldeyer ring, epitrochlear, or mesenteric nodes. The associated morbidity of the treatment must be considered carefully. The majority of patients who receive radiation are usually treated on only one side of the diaphragm. Localized presentations of extranodal NHL may be treated with involved-field techniques with significant (>50%) success.
Table 4. Standard Treatment Options for Non-Hodgkin Lymphoma (NHL)
StageStandard Treatment Options
IF-XRT = involved-field radiation therapy; P13K = phosphatidylinositol 3-kinase; R-CHOP = rituximab, an anti-CD20 monoclonal antibody, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Indolent Stage I and Indolent, Contiguous Stage II Adult NHLRadiation therapy
Rituximab with or without chemotherapy
Watchful waiting
Other therapies as designated for patients with advanced-stage disease
Indolent, Noncontiguous Stage II/III/IV Adult NHLWatchful waiting for asymptomatic patients
Rituximab with or without chemotherapy
Maintenance rituximab
Obinutuzumab
P13K inhibitors
Lenalidomide and rituximab
Radiolabeled anti-CD20 monoclonal antibodies
Indolent, Recurrent Adult NHLChemotherapy (single agent or combination)
Rituximab
Obinutuzumab
Lenalidomide
Radiolabeled anti-CD20 monoclonal antibodies
Palliative radiation therapy
Aggressive Stage I and Aggressive, Contiguous Stage II Adult NHLR-CHOP with or without IF-XRT
Aggressive, Noncontiguous Stage II/III/IV Adult NHLR-CHOP
Other combination chemotherapy
Lymphoblastic Lymphoma/Acute Lymphocytic LeukemiaIntensive therapy
Radiation therapy
Diffuse, Small, Noncleaved-Cell/Burkitt LymphomaAggressive multidrug regimens
Central nervous system (CNS) prophylaxis
Aggressive, Recurrent Adult NHLBone marrow or stem cell transplantation
Re-treatment with standard agents
Palliative radiation therapy
Even though standard treatment in patients with lymphomas can cure a significant fraction, numerous clinical trials that explore improvements in treatment are in progress. If possible, patients can be included in these studies. Standardized guidelines for response assessment have been suggested for use in clinical trials.[1]
Several retrospective reviews suggest routine surveillance scans after attaining clinical complete remission after induction therapy for diffuse large B-cell lymphoma offer little to no value. Prognostic value is also difficult to identify for an interim positron emission tomography-computed tomography scan during induction therapy for diffuse large B-cell lymphoma.[2-5]
Aggressive lymphomas are increasingly seen in HIV-positive patients; treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C can be assessed before treatment with rituximab and/or chemotherapy.[6,7] Even patients with undetectable hepatitis B viral loads after remote past infection benefit from prophylaxis with entecavir in the context of rituximab therapy.[8,9] Similarly, prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually applied with rituximab with or without combination chemotherapy.
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] Even patients with undetectable hepatitis B viral loads after remote past infection benefit from prophylaxis with entecavir in the context of rituximab therapy.[8,9] Similarly, prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually applied with rituximab with or without combination chemotherapy.
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,[10-18] thyroid,[19,20] spleen,[21] testis,[22-24] paranasal sinuses,[25-28] bone,[29,30] orbit,[31-35] and skin.[36-45]
(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information.)

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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