martes, 30 de julio de 2019

Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute 4/9

Adult Non-Hodgkin Lymphoma Treatment - National Cancer Institute

National Cancer Institute

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

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]


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 high doses 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


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.[67-69]

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

Extranodal natural killer (NK)-/T-cell lymphoma (nasal type) is an aggressive lymphoma marked by extensive necrosis and angioinvasion, most often presenting in extranodal sites, in particular the nasal or paranasal sinus region.[70] Other extranodal sites include the palate, trachea, skin, and gastrointestinal tract. Hemophagocytic syndrome may occur; historically, these tumors were considered part of lethal midline granuloma.[71] In most cases, Epstein-Barr virus (EBV) genomes are detectable in the tumor cells and immunophenotyping shows CD56 positivity. Cases with blood and marrow involvement are considered NK-cell leukemia.
The increased risk of CNS involvement and of local recurrence has led to recommendations for radiation therapy locally, concurrently, before the start of chemotherapy or between cycle two and three of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.[72-79] A retrospective review of 1,273 early-stage patients stratified them into a low-risk group and high-risk group using stage, age, LDH, performance status, and primary tumor invasion. Low-risk patients fared best with radiation therapy alone,[80] while high-risk patients fared best with a strategy of radiation therapy concurrent with chemotherapy, following cycle two of chemotherapy, or followed by chemotherapy.[78,81,82] Higher doses of radiation therapy administered at more than 50 Gy are associated with improved outcomes according to anecdotal reports.[78] The highly aggressive course, with poor response and short survival with standard therapies, especially for patients with advanced-stage disease or extranasal presentation, has led some investigators to recommend autologous or allogeneic peripheral SCT consolidation.[79,83-87] L-asparaginase-containing regimens have shown anecdotal response rates greater than 50% for relapsing, refractory, or newly diagnosed stage IV patients.[79,88,89] NK-/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.[90] A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy can be distinguished from NK-/T-cell lymphoma.[91]

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is an EBV-positive large B-cell lymphoma with a predominant T-cell background.[92,93] The histology shows association with angioinvasion and vasculitis, usually manifesting as pulmonary lesions or paranasal sinus involvement.
Patients are managed like others with diffuse large cell lymphoma and require doxorubicin-based combination chemotherapy.

Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL or ATCL) was formerly called angioimmunoblastic lymphadenopathy with dysproteinemia. Characterized by clonal T-cell receptor gene rearrangement, this entity is managed like diffuse large cell lymphoma.[94-97] Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia.[71] (Refer to the information on 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.[98]
Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is recommended as it is for other aggressive lymphomas.[94,97] For CD30-positive cases, brentuximab combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care.[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.[99] Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports.[86,100,101] Anecdotal responses have been reported for cyclosporine,[102] pralatrexate,[103] bendamustine,[104] the histone deacetylase inhibitor romidepsin, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[63,105][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.[106] Peripheral T-cell lymphoma encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.[71,107] This includes the so-called Lennert lymphoma, a T-cell lymphoma admixed with a preponderance of lymphoepithelioid cells.


Most investigators report worse response and survival rates for patients with peripheral T-cell lymphomas than for patients with comparably staged B-cell aggressive lymphomas.[107,108] 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.[107,108] 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%.[109]

Therapeutic approaches

Therapy involves doxorubicin-based combination chemotherapy (such as CHOP or CHOPE [CHOP plus etoposide]), which is also used for DLBCL.[110] 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.[111][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.[86,100,112-114] 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.[63,115][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,[103] single-agent bendamustine,[104] belinostat,[116] and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).[105][Level of evidence: 3iiiDiv] Incorporation of these new agents with CHOP chemotherapy is under clinical evaluation.[58,107] Anecdotal responses have also been seen with alemtuzumab, an anti-CD52 monoclonal antibody, after relapse from previous chemotherapy.[117] The median PFS after first relapse was less than 6 months in one series of 163 patients with peripheral T-cell lymphoma.[118]
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.[119-123] Another variant, subcutaneous panniculitis-like T-cell lymphoma, is localized to subcutaneous tissue associated with hemophagocytic syndrome.[124-127] 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.[128-130] 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.[86] An indolent T-cell lymphoproliferative disease of the gastrointestinal tract must be distinguished from peripheral T-cell lymphoma because no therapy may be indicated.[131]

Enteropathy-type Intestinal T-cell Lymphoma

Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue).[71,132-134] 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.[133-135] 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.[86,133,136][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.[137,138]

Burkitt Lymphoma/Diffuse Small Noncleaved-cell Lymphoma

Burkitt lymphoma/diffuse small noncleaved-cell lymphoma typically involves younger patients and represents the most common type of pediatric NHL.[139] These types of aggressive extranodal B-cell lymphomas are characterized by translocation and deregulation of the C-Myc gene on chromosome 8.[140] 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).[141][Level of evidence: 3iiiA]
In some patients with larger B cells, there is morphologic overlap with DLBCL. These Burkitt-like large cell lymphomas show C-Myc deregulation, extremely high proliferation rates, and a gene-expression profile as expected for classic Burkitt lymphoma.[142-144] Endemic cases, usually from Africa, involve the facial bones or jaws of children, mostly containing EBV genomes. Sporadic cases usually involve the gastrointestinal system, ovaries, or kidneys. Patients present with rapidly growing masses and a very high LDH but are potentially curable with intensive doxorubicin-based combination chemotherapy.

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).[145-148] Aggressive combination chemotherapy, which is patterned after that used in childhood Burkitt lymphoma, has been very successful for adult patients with more than 60% of advanced-stage patients free of disease at 5 years.[149-152] Adverse prognostic factors include bulky abdominal disease and high serum LDH. Patients with Burkitt lymphoma have a 20% to 30% lifetime risk of CNS involvement. Prophylaxis with intrathecal chemotherapy is required as part of induction therapy.[153] Patients with HIV-associated Burkitt lymphoma also benefit from less-toxic modification of the aggressive multidrug regimens in combination with rituximab.[154][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.[155] It is commonly associated with large mediastinal masses and has a high predilection for disseminating to bone marrow and the CNS.
Treatment is usually patterned after that for acute lymphoblastic leukemia. Intensive combination chemotherapy with or without bone marrow transplantation is the standard treatment for this aggressive histologic type of NHL.[156-158] Radiation therapy is sometimes given to areas of bulky tumor masses. Because these forms of NHL tend to progress quickly, combination chemotherapy is instituted rapidly once the diagnosis has been confirmed. Careful review of the pathologic specimens, bone marrow aspirate, biopsy specimen, cerebrospinal fluid cytology, and lymphocyte marker constitute the most important aspects of the pretreatment staging workup. (Refer to the PDQ summary on Adult Acute Lymphoblastic Leukemia Treatment for more information.)

Adult T-cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is caused by infection with the retrovirus human T-lymphotrophic virus 1 and is frequently associated with lymphadenopathy, hypercalcemia, circulating leukemic cells, bone and skin involvement, hepatosplenomegaly, a rapidly progressive course, and poor response to combination chemotherapy.[159,160] ATL has been divided into four clinical subtypes:[161,162]
  • 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.[163-165] Using combination chemotherapy, less than 10% of 807 patients were alive after 4 years.[165] Anecdotal durable remissions have been reported after allogeneic SCT and even after subsequent donor lymphocyte infusion for relapses after transplant.[166][Level of evidence: 3iiiDiv] Among 815 patients who underwent allogeneic SCT in two retrospective reviews, the 3-year OS rates were 36% and 26%.[167,168][Level of evidence: 3iiiA]
The combination of zidovudine and interferon-alpha has activity against ATL, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in the majority of presenting patients with this combination but are not seen in patients with the lymphoma subtype of ATL.[169-173] In a multicenter phase II study of 26 relapsed patients, 42% responded to lenalidomide (including four CR).[174][Level of evidence: 3iiiDiv] Symptomatic local progression of all subtypes responds well to palliative radiation therapy.[175] 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).[176] 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.[176] Mantle cell lymphoma may be divided into two clinical subtypes: a classical version with lymphadenopathy with high SOX-11 expression that manifests with an aggressive clinical course and a worse prognosis versus a leukemic, non-nodal version with low SOX-11 expression and a more indolent course and a better prognosis.[177] There is frequent overlap on presentation with these subtypes, and the therapeutic implication remains unclear. However, both of these versions can converge later in their course into a blastoid phenotype or treatment-resistant phenotype due to genomic instability and selection.[178]
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.[179] 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.[180] A high cell-proliferation rate (increased Ki-67, mitotic index, beta-2-microglobulin) may be associated with a poorer prognosis.[181,182]

Therapeutic approaches

Asymptomatic patients with low-risk scores on the IPI may do well when initial therapy is deferred.[183,184][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.[185] Ibrutinib, lenalidomide, and bortezomib have shown activity in relapsing patients, and these drugs are being incorporated upfront.[186-190]
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.[191] 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).[191][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).[191][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).[191][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.[192][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.[193] 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).[193][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.[194][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.[195-200] Thus far, randomized trials have not shown OS benefits from these newer approaches.[196]
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).[201][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.[187,190,202,203][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.[188][Level of evidence: 3iiiDiv] In a prospective randomized trial of 280 patients with relapsed/refractory mantle cell lymphoma, patients received either ibrutinib or temsirolimus.[204] 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).[204][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.[205] An unprecedented 71% of patients had CR and 78% of responding patients maintained response at 15 months.[205][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.[206] In a phase II study, there was an 81% objective response rate, 40% CR rate, and the 1-year PFS rate was 67%.[206][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.[207]

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.[208] Pathologists can distinguish a polyclonal B-cell hyperplasia from a monoclonal B-cell lymphoma; both are almost always associated with EBV.[209]


Poor performance status, grafted organ involvement, high IPI, elevated LDH, and multiple sites of disease are poor prognostic factors for PTLD.[210,211]

Therapeutic options

In some cases, withdrawal of immunosuppression results in eradication of the lymphoma.[212,213] 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.[212,214,215] If these measures fail, doxorubicin-based combination chemotherapy (R-CHOP) is recommended, although some patients can avoid cytotoxic therapy.[215,216] 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.[209] Multifocal, rapidly progressive disease occurs late after transplantation (>1 year) and is usually phenotypically monoclonal and associated with EBV.[217] These patients may have durable remissions using standard chemotherapy regimens for aggressive lymphoma.[217-219] 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.[220] 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).[221] An anti-interleukin-6 monoclonal antibody is also under clinical evaluation.[222]

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.[223,224] 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.[225] Patients are usually HIV seropositive, and the tumor usually contains Kaposi sarcoma–associated herpes virus/human herpes virus 8.[226]


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.[227] Anecdotal reports suggest using aggressive chemotherapy for Burkitt or lymphoblastic lymphoma, followed by SCT consolidation in responding patients, when feasible.[227-229]

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