The non-Hodgkin lymphoma (NHL) T-cell lymphomas are a heterogeneous group of T-cell lymphoproliferative malignancies, which account for less than 15% of NHLs. About 85% of NHL cases are B-cell lymphomas. For more information, see B-Cell Non-Hodgkin Lymphoma Treatment.

T-cell lymphoma can be divided into cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and T-cell lymphoblastic lymphoma/acute lymphocytic leukemia (T-LBL/ALL).

T-LBL/ALL arises from very early T cells, often involves the thymus, and is more common in young adults. The lymphoma form is often treated similarly to the leukemia form. For more information, see Acute Lymphoblastic Leukemia Treatment.

CTCL starts in the skin and includes mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, and others. For more information, see Mycosis Fungoides (Including Sézary Syndrome) Treatment.

PTCL originates from mature T cells. It usually arises from lymphoid tissues but can spread to other organs. Subsets of PTCL include anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), extranodal natural killer/T-cell lymphoma (ENK/TCL), PTCL not otherwise specified (PTCL-NOS), adult T-cell leukemia/lymphoma (ATLL), enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell lymphoma (HSTCL), T-cell prolymphocytic leukemia (T-PLL), and others.

Incidence and Mortality

T-cell lymphomas make up less than 15% of NHL cases. Most T-cell lymphoma subtypes are associated with worse outcomes than those of B-cell lymphomas.

Anatomy

NHL usually originates in lymphoid tissues.

Prognosis and Survival

Prognosis in PTCL varies depending on subtype, stage, and other factors. In general, PTCL is associated with a poor prognosis, with a 5-year survival rate of approximately 30% to 40%. While outcomes are better for patients with ALK-positive ALCL, with a median 5-year overall survival (OS) closer to 70% to 80%, other subsets are associated with worse survival, such as ALK-negative ALCL, AITL, PTCL-NOS, HSTCL, EATL, and ENK/TCL.

Unlike B-cell NHLs, which include both indolent and aggressive forms, most PTCLs are considered aggressive. As with most other aggressive lymphomas, PTCLs are often curable with systemic therapy, though effective treatment options are more limited, particularly in the relapsed or refractory setting.

Even though existing treatments cure a significant fraction of patients with lymphoma, numerous clinical trials that explore treatment improvements are in progress. If possible, patients can be included in these studies.

In addition to screening for HIV among patients with aggressive lymphomas, active hepatitis B or hepatitis C can be assessed before treatment with chemotherapy. Patients with detectable hepatitis B virus (HBV) benefit from prophylaxis with entecavir. Patients with a resolved HBV infection (defined as hepatitis B surface antigen-negative but hepatitis B core antibody-positive) are at risk of reactivation of HBV and require monitoring of HBV DNA. Prophylactic nucleoside therapy lowered HBV reactivation from 10.8% to 2.1% in a retrospective study of 326 patients. Prophylaxis for herpes zoster with acyclovir or valacyclovir and prophylaxis for pneumocystis with trimethoprim/sulfamethoxazole or dapsone are usually given to patients receiving combination chemotherapy.

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

• 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.

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. Most of these patients show clonal hematopoiesis even before the transplant, suggesting that the hematologic injury usually occurs during induction or reinduction chemotherapy. A series of 605 patients who received autologous bone marrow transplant (BMT) with cyclophosphamide and total-body radiation therapy (as conditioning) were followed for a median of 10 years. The incidence of a second malignancy was 21%, and 10% of those malignancies were solid tumors.

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

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

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

Current Classification Systems

Updated REAL/WHO classification

The World Health Organization (WHO) modification of the Revised European American Lymphoma (REAL) classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma (HL). Both lymphomas and lymphoid leukemias are included in this classification because both solid and circulating phases are present in many lymphoid neoplasms and distinction between them is artificial. For example, B-cell chronic lymphocytic leukemia (CLL) and B-cell small lymphocytic lymphoma are simply different manifestations of the same neoplasm, as are lymphoblastic lymphomas and acute lymphocytic leukemias. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.

B-cell neoplasms

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

T-cell and putative NK-cell neoplasms

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

HL

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

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

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

Subtypes of Peripheral T-Cell Non-Hodgkin Lymphoma

Peripheral T-cell non-Hodgkin lymphoma includes the following subtypes, among others:

• Anaplastic large cell lymphoma.
• Angioimmunoblastic T-cell lymphoma.
• Peripheral T-cell lymphoma, not otherwise specified.
• Extranodal NK/T-cell lymphoma.
• Enteropathy-type intestinal T-cell lymphoma.
• Hepatosplenic T-cell lymphoma.
• Adult T-cell leukemia/lymphoma.
• T-cell prolymphocytic leukemia.
• Cutaneous T-cell lymphoma (including mycosis fungoides and Sézary syndrome, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous anaplastic large cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, and others).
• T-cell granular lymphocytic leukemia.

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

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

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

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

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

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

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

Staging Subclassification System

Lugano classification

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

Table 1. Lugano Classification for Hodgkin and Non-Hodgkin Lymphomaa

Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.

The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathological proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Table 2. Notation to Identify Specific Sites

Current practice assigns a clinical stage based on the findings of the clinical evaluation and a pathological stage based on the findings from invasive procedures beyond the initial biopsy.

For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might have involvement of the liver and bone marrow. The precise stage of such a patient would be clinical stage IIA, pathological stage IVA(H+)(M+).

Several other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:

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

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

• Age.
  • 40 years: 0.
  • 41–60 years: 1.
  • 61–75 years: 2.
  • >75 years: 3.
• Stage III/IV: 1.
• Performance status (PS) 2/3/4: 1.
• Serum lactate dehydrogenase (LDH).
  • Normalized: 0.
  • >1x–3x: 1.
  • >3x: 2.
• Number of extranodal sites ≥2: 1.

Risk scores:

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

Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma associated with the CD30 antigen. The translocation of chromosomes 2 and 5 creates a unique fusion protein with a nucleophosmin–anaplastic lymphoma kinase (ALK). Patients whose lymphomas express ALK by immunohistochemistry are usually younger and may have systemic symptoms, extranodal disease, and advanced-stage disease. However, they have a more favorable survival rate than patients with ALK-negative disease.

• A prospective randomized trial included 452 patients with CD30-positive T-cell lymphoma (CD30 expression >10%). Of these patients, 70% had ALCL (22% with ALK-positive disease and 48% with ALK-negative disease). The trial compared the previously used standard regimen, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), with brentuximab vedotin (an anti-CD30 monoclonal antibody conjugated to a cytotoxic agent) combined with cyclophosphamide, doxorubicin, and prednisone (A+CHP regimen).
  • With a median follow-up of 47.6 months, the 5-year overall survival (OS) rates were 70.1% (95% confidence interval , 63.3%–75.9%) for patients who received A+CHP and 61.0% (95% CI, 54.0%–67.3%) for patients who received CHOP (hazard ratio , 0.72; 95% CI, 0.53–0.99).
  • The 5-year progression-free survival (PFS) rates were 51.4% (95% CI, 42.8%–59.4%) for patients who received A+CHP and 43.0% (95% CI, 35.8%–50.0%) for patients who received CHOP (HR, 0.70; 95% CI, 0.53–0.91).
  • This established A+CHP as a new option for patients with ALCL or 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, romidepsin, and pralatrexate.
• In a phase II study (NCT00866047), 66% of 58 patients attained a complete response with brentuximab vedotin.
  • At a median follow-up of 58 months, the 5-year PFS rate was 57% (95% CI, 41%–74%), and the 5-year OS rate was 79% (95% CI, 65%–92%). Of the patients achieving a complete response, 42% underwent hematopoietic stem cell transplant (SCT).
• In a retrospective review, 39 patients with relapsed disease had a 3-year PFS rate of 50% after autologous or allogeneic SCT.
• A retrospective review of 84 patients with ALK-negative ALCL suggested a survival benefit with autologous SCT. This hypothesis requires confirmation in a randomized prospective trial.
• A retrospective study included 182 patients with relapsed or refractory ALCL (23% ALK-positive, 21% ALK-negative, and 56% ALK-unknown) who underwent allogeneic SCT.
  • The 5-year PFS rate was 41% (95% CI, 34%–49%), and the 5-year OS rate was 41% (95% CI, 49%–64%).
  • On multivariate analysis, African American race (HR, 2.7; 95% CI, 1.6–4.8; P .001) and refractory disease at time of allogeneic SCT (HR, 3.2; 95% CI, 1.6–6.2; P .001) were predictive factors for inferior OS.
  • Despite ALK positivity being a favorable prognostic factor, outcomes after allogeneic SCT in this study did not vary significantly according to ALK status.

ALCL in children is usually characterized by systemic and cutaneous disease and has high response rates and good OS with doxorubicin-based combination chemotherapy. The ALK inhibitor crizotinib has been combined with chemotherapy for previously untreated pediatric patients, and crizotinib has been used to control disease in multiply relapsed pediatric patients. Crizotinib is associated with a high risk (around 25%) of thromboembolism, especially pulmonary embolism, and prophylaxis is recommended. There are no reports supporting the use of crizotinib in adults.

Patients with breast implant–associated ALCL may do well without chemotherapy after capsulectomy and implant removal if the disease is confined to the fibrous capsule, and no associated mass or lymphadenopathy is present. Most patients with breast implant–associated ALCL have a characteristic deletion at 20Q13.13 that may help to diagnostically distinguish it from cutaneous or systemic ALCL.

Primary cutaneous ALCL is a distinct entity that is typically ALK-negative and has a very indolent/low-grade clinical course.

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 treated like diffuse large B-cell lymphoma, using cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (without rituximab). Patients present with profound lymphadenopathy, fever, night sweats, weight loss, skin rash, a positive Coombs test, and polyclonal hypergammaglobulinemia. Opportunistic infections are frequent because of an underlying immune deficiency. B-cell Epstein-Barr virus genomes are detected in most affected patients. For more information about weight loss, see Nutrition in Cancer Care and for more information about skin rash, see Pruritus.

Doxorubicin-based combination chemotherapy, such as the CHOP regimen, is commonly used for AITL, as it is for other aggressive lymphomas. For CD30-positive cases, brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone is the proposed standard of care. Patients with AITL were included in the clinical trial involving mostly patients with anaplastic large cell lymphoma; a benefit for this smaller AITL subgroup cannot be established. For more information, see the Treatment of Anaplastic Large Cell Lymphoma section.

The International Peripheral T-Cell Lymphoma Project involving 22 international centers identified 243 patients with AITL or ATCL; the 5-year overall survival rate was 33% and the failure-free survival rate was 18%. Myeloablative chemotherapy and radiation therapy with autologous or allogeneic peripheral stem cell support has been described in anecdotal reports. Anecdotal responses have been reported for cyclosporine, pralatrexate, bendamustine, the histone deacetylase inhibitor romidepsin, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma). Occasional spontaneous remissions and protracted responses to steroids only have been reported.

Patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) 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. PTCL-NOS encompasses a group of heterogeneous nodal T-cell lymphomas that will require future delineation.

Prognosis

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

Therapeutic Approaches

Therapy involves doxorubicin-based combination chemotherapy such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus etoposide (CHOPE). Doses are the same as those used for DLBCL. For CD30-positive cases, brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone is the proposed standard of care. Patients with PTCL-NOS were included in the clinical trial involving mostly patients with anaplastic large cell lymphoma; a benefit for this smaller PTCL-NOS subgroup cannot be established. For more information, see the Treatment of Anaplastic Large Cell Lymphoma section.

For patients with early-stage disease, anecdotal retrospective series disagree on the value of consolidative radiation therapy after combination chemotherapy. Consolidation therapy using high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell transplant (SCT) has been given to patients with advanced-stage PTCL after induction therapy in multiple phase II or retrospective trials. Evidence for this approach is anecdotal.

• A randomized prospective trial included 104 patients younger than 61 years with stage II, III, or IV PTCL (excluding ALK-positive anaplastic large cell lymphoma). Patients received either autologous SCT or allogeneic SCT as consolidation therapy after induction with CHOPE followed by DHAP (dexamethasone, cytarabine, and cisplatin).
  • With a median follow-up of 42 months, the 3-year EFS rate was 43% for patients who received allogeneic SCT and 38% for patients who received autologous SCT.
  • The 3-year OS rate was 57% for patients who received allogeneic SCT and 70% for patients who received autologous SCT (P = nonsignificant).
  • None of the 21 responding patients who proceeded to allogeneic SCT relapsed, and 36% of patients who proceeded to autologous SCT relapsed.
  • Eight of 26 patients (31%) who received allogeneic SCT died of graft-versus-host disease, and none of the 41 patients who received autologous SCT died of toxicity.
  • The benefit of graft-versus-lymphoma effect was negated by increased transplant-related mortality.
• In a prospective trial of 109 evaluable patients with relapsing disease, treatment with pralatrexate resulted in a 30% response rate and a median 10-month duration of response.
• Similar response rates were seen in 130 evaluable patients with relapsing disease who received romidepsin in a prospective trial.
• Anecdotal responses have been seen with a combination of pralatrexate and romidepsin, single-agent bendamustine, belinostat, and brentuximab vedotin (even if there is little or no CD30 expression on the lymphoma).

  Incorporation of these new agents with CHOP chemotherapy is under clinical evaluation.

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. 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. 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. A benign NK-cell enteropathy (EBV negative) on endoscopic biopsy can be distinguished from NK/T-cell lymphoma.

The increased risk of central nervous system involvement and of local recurrence has led to recommendations for local radiation therapy given before the start of chemotherapy or between cycle two and three of chemotherapy, and for intrathecal prophylaxis and/or prophylactic cranial radiation therapy.

• A retrospective review included 1,273 patients with early-stage disease. Patients were stratified into a low-risk group and high-risk group using stage, age, lactate dehydrogenase level, performance status, and primary tumor invasion.
  • Low-risk patients fared best with radiation therapy alone, while high-risk patients fared best with a strategy of radiation therapy combined with chemotherapy.
• A retrospective review included 303 previously untreated patients from an international consortium who received nonanthracycline chemotherapy.
  • The overall survival rates were identical (72%−74% at 5 years) for patients with early-stage disease who received either concurrent chemotherapy and radiation therapy or chemotherapy followed by radiation therapy.

Higher doses of radiation therapy administered at more than 50 Gy are associated with improved outcomes according to anecdotal reports. 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 stem cell transplant consolidation. Asparaginase-containing regimens have shown anecdotal response rates greater than 50% for patients with relapsing, refractory, or newly diagnosed disease. Because of the lack of randomized clinical trials with more than 100 patients for this rare type of T-cell lymphoma, regimens containing pegaspargase have become the standard for systemic therapy. Pegaspargase is a less toxic formulation of asparaginase with less hypersensitivity reactions and a longer half-life. NK/T-cell lymphoma that presents only in the skin has a more favorable prognosis, especially in patients with coexpression of CD30 with CD56.

• In a phase II trial, the anti-programmed death-ligand 1 (PD-L1) antibody avelumab was given to 21 patients with relapsed or refractory disease.
  • The complete response rate was 24% and the overall response rate was 38%. The responses correlated with tumor PD-L1 expression.

Treatment with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody, resulted in similar responses in patients with relapsed or refractory disease.

Enteropathy-type intestinal T-cell lymphoma involves the small bowel of patients with gluten-sensitive enteropathy (celiac sprue). Because a gluten-free diet prevents the development of lymphoma in patients with celiac disease, patients diagnosed 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. Complications of treatment include gastrointestinal bleeding, small bowel perforation, and enterocolic fistulae; patients often require parenteral nutrition. For more information on parenteral nutrition, see Nutrition in Cancer Care. Multifocal intestinal perforations and visceral abdominal involvement are seen at the time of relapse. High-dose therapy with hematopoietic stem cell rescue has been used at first remission or at relapse. Evidence for this approach is anecdotal.

Hepatosplenic T-cell lymphoma (HSTCL) is an unusual type of peripheral T-cell lymphoma occurring mostly in young men. HSTCL appears to be localized to the hepatic and splenic sinusoids, with cell surface expression of the T-cell receptor gamma/delta. This lymphoma has an extremely poor prognosis and an extremely aggressive clinical course. HSTCL is treated with induction chemotherapy and stem cell transplant (SCT) consolidation.

• A meta-analysis of 118 patients with HSTCL compared CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CHOP-like induction regimens.
  • Non–CHOP-based regimens (containing cytarabine, etoposide, and/or platinum-based treatment) were associated with improved outcomes, including an overall response rate of 82% versus 52% (P = .006) and a median overall survival (OS) of 36.5 months versus 18 months (P = .00014).
  • Consolidation with allogeneic SCT was associated with an improved median OS of 33 months, versus 27 months (P = .016) for autologous SCT.

The use of ICE (ifosfamide, carboplatin, and etoposide) or IVAC (ifosfamide, etoposide, and high-dose cytarabine) has resulted in improved responses when compared with CHOP in other smaller studies as well. Given the inadequate responses to CHOP or CHOP-like regimens, many clinicians are using ICE chemotherapy as front-line induction therapy, followed by consolidative allogeneic SCT for patients achieving a first remission. However, the efficacy of this approach is undetermined.

Adult T-cell leukemia/lymphoma (ATLL) 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. ATLL has been divided into four clinical subtypes:

• 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 ATLL respond poorly to combination chemotherapy and allogeneic stem cell transplant (SCT), with a median overall survival (OS) under 1 year. Less than 10% of 807 patients who received combination therapy were alive after 4 years. Anecdotal durable remissions have been reported after allogeneic SCT and even after subsequent donor lymphocyte infusion for relapses after transplant. Among 815 patients who underwent allogeneic SCT in two retrospective reviews, the 3-year OS rates were 36% and 26%.

The combination of zidovudine and interferon-alpha has activity against ATLL, even for patients who failed previous cytotoxic therapy. Durable remissions are seen in most patients treated with this combination, but are not seen in patients with the lymphoma subtype of ATLL. In a multicenter phase II study of 26 relapsed patients, 42% responded to lenalidomide (including four complete responses). Symptomatic local progression of all subtypes responds well to palliative radiation therapy. In the relapsed setting, an overall response rate above 50% was seen using mogamulizumab, a humanized monoclonal antibody against the C-C chemokine receptor 4 (CCR4). For CD30-positive cases, brentuximab vedotin combined with cyclophosphamide, doxorubicin, and prednisone is the standard of care. Patients with ATLL were included in the clinical trial involving mostly patients with anaplastic large cell lymphoma; a benefit for this smaller ATLL subgroup cannot be established.

Treatment Options for Relapsed or Refractory Peripheral T-Cell Lymphoma

Treatment options for relapsed or refractory peripheral T-cell lymphoma include the following:

1. Combination chemotherapy.
   • ICE (ifosfamide, carboplatin, and etoposide).
   • GEMOX (gemcitabine, oxaliplatin, and dexamethasone).
   • DHAP (dexamethasone, high-dose cytarabine, and cisplatin).
   • ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin).
   • Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone).
2. Antibody conjugates.
   • Brentuximab vedotin (for CD30-positive patients).
3. Histone deacetylase inhibitors.
   • Romidepsin.
   • Belinostat.
4. Dihydrofolate reductase inhibitors.
   • Pralatrexate.
5. Anti-CD52 monoclonal antibodies.
   • Alemtuzumab (only available through a restricted distribution program).
6. Stem cell transplant.