The peripheral T-cell lymphomas (PTCLs) represent approximately 10 to 15 percent of non-Hodgkin lymphomas and are made up of 23 heterogeneous diseases (Table 104–1).¹ The most common entities, peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), and ALK-negative ALCL, account for approximately 60 percent of cases. This overview primarily pertains to these most common subtypes of PTCL and more detailed discussion of other subsets of PTCL follows this discussion.

As a result of the rarity of these disorders, there are no randomized controlled clinical trials to drive treatment decisions in PTCL. Our most comprehensive knowledge of the expected outcomes for patients with PTCL is mainly based upon three large retrospective series: the International Peripheral T-Cell Lymphoma Project (IPTCLP), the British Columbia Cancer Agency (BCCA) series, and a Swedish series which reported outcomes on 1314 cases, 199 cases, and 755 cases, respectively.^2,3,4 The prospective Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study is an ongoing registry of patients from the United States that has reported data on 253 subjects to date.⁵ These registries underscore the geographical variations in the incidence of these disorders (Table 104–2).

DIAGNOSIS OF PERIPHERAL T-CELL LYMPHOMA

The diagnosis of PTCL is based on histologic features, immunophenotype, molecular studies, and clinical presentation. While B-cell lymphomas are often characterized by a specific immunophenotypic profile, T-cell lymphomas are often characterized by antigen aberrancy that may vary within a subtype or even during the course of the disease.^6,7 In the IPTCLP, a consensus diagnosis (three of four expert pathologists arriving at the same diagnosis) was reached only 74 to 81 percent of the time for ALK-negative ALCL, PTCL-NOS, and AITL. Diagnoses were significantly refined in 154 out of 1314 cases when clinical information was available.³ In establishing the diagnosis of T-cell non-Hodgkin lymphoma, it is important to exclude a reactive process, particularly when the clinical picture is not congruent with the pathologic features, when the diagnostic biopsy is small, or when a clonal T-cell receptor (TCR) rearrangement is the primary or only reason for the diagnosis because reactive nonmalignant conditions often mimic PTCL.^8,9,10

INITIAL WORKUP

In addition to routine physical examination, initial evaluation should include systemic imaging (computed tomography [CT] of the chest, abdomen, and pelvis with contrast or positron emission tomography [PET]-CT), marrow aspirate/biopsy, and laboratory evaluation (including complete blood count, lactate dehydrogenase or lactate dehydrogenase [LDH], comprehensive metabolic panel). Serologic testing for human T-cell lymphotrophic virus (HTLV)-1 is particularly important in establishing a new diagnosis of PTCL in a person from an endemic area as adult T-cell leukemia/lymphoma (ATL) represents approximately 9 percent of PTCL, is associated with a different prognosis, and usually requires alternative therapy.³

Evaluating Prognosis in Peripheral T-Cell Lymphoma

The International Prognostic Index (IPI) established for evaluating aggressive lymphomas has been effective in risk stratifying patients with PTCL, although the utility in AITL is less clear (Table 104–3).¹¹ The “prognostic index for T-cell lymphoma (PIT),” is an improved index developed specifically for PTCL that includes age, performance status, LDH level, and marrow involvement.^7,12 Other prognostic indices, such as the IPTCLP score, have been suggested for PTCL. Each has some value, although none provides a significant improvement over IPI in terms of impacting clinical management.¹³ It is important to note that even patients identified as low risk by these indices often experience disappointing outcomes. For example, in the IPTCLP, the 5-year failure-free survival (FFS) for patients with 0 or 1 IPI risk factors were only 33 percent for PTCL-NOS and 34 percent for AITL. For this reason, the approach to management of PTCL patients usually does not differ significantly based on IPI alone. Nevertheless, in patients with ALK-positive ALCL, which tends to be more responsive to chemotherapy, the progression-free survivals for patients with zero/one, two, three, and four/five IPI risk factors are 80 percent, 60 percent, 40 percent and 25 percent, respectively.¹⁴ Consequently, patients with higher risk ALK-positive ALCL may be treated similarly to those with the less-favorable PTCL histologies.

APPROACH TO INITIAL THERAPY

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy remains the most commonly employed backbone for upfront therapy of PTCL, based on extrapolation from studies done in aggressive B-cell lymphomas. In the IPTCLP, more than 85 percent of patients received CHOP-based therapy, and in contrast to ALK-positive ALCL where the 5-year FFS was 60 percent, the 5-year FFS for PTCL-NOS, AITL, and ALK-negative ALCL, were only 20 percent, 18 percent, and 36 percent, respectively (see Table 104-3). Similar outcomes were observed in the BCCA series with 5-year progression-free survival (PFS) of 29 percent, 13 percent, and 28 percent for PTCL-NOS, AITL, and ALCL, respectively.² In the Swedish Registry study where 84 percent of patients were treated with CHOP-like therapy, 5-year PFSs were 21 percent, 20 percent, and 31 percent for PTCL-NOS, AITL, and ALK-negative ALCL, respectively, compared to 63 percent for ALK-positive ALCL.⁴

Several prospective clinical trials in PTCL are available to inform us on the expected response rate to CHOP. In a phase II study evaluating CHOP induction therapy followed by autologous stem cell transplantation (ASCT) for untreated PTCL, the overall response rate (ORR) to CHOP was 79 percent with a complete response (CR) rate of 39 percent.¹⁵ Similarly, a small phase III study of CHOP versus VIP-rABVD (etoposide, ifosfamide, cisplatin alternating with Adriamycin, bleomycin, vinblastine and dacarbazine) showed no significant difference in outcomes with an ORR of 70 percent and a CR rate of 35 percent.¹⁶

Although the majority of patients receive CHOP, there is currently no standard frontline treatment approach for PTCL, as there are no randomized data guiding a preferred approach. Many have sought to augment the efficacy of CHOP by adding agents to the CHOP backbone. Several phase II studies adding the anti-CD52 antibody, alemtuzumab, to CHOP demonstrated impressive CR rates of 65 to 71 percent. However, the addition of alemtuzumab conferred significant toxicity including Jacob-Creutzfeldt virus encephalitis, invasive aspergillosis, Pneumocystis carinii pneumonia, sepsis, Epstein-Barr virus (EBV)-related lymphoma and cytomegalovirus reactivation.^17,18,19 Similarly, in a phase II study of denileukin diftitox plus CHOP, the ORR and CR rates were 65 percent and 55 percent, respectively; however three deaths occurred following one cycle of therapy and four other patients were taken off study because of toxicity.²⁰

The German High-Grade non-Hodgkin Lymphoma Study Group (DSHNHL) evaluated the addition of etoposide to the CHOP regimen. They analyzed patients with PTCL treated on seven different prospective phase II or phase III protocols with either CHOP or CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone).²¹ Younger patients (<60 years old) with a normal LDH exhibited better outcomes if treated with CHOEP than with CHOP, with 3-year event-free survival (EFS) of 75.4 and 51 percent, respectively, although no difference in overall survival (OS) was observed. The benefits were greatest in the more favorable ALK-positive ALCL subtype but there was a trend toward improved EFS in favor of CHOEP in other subsets as well (p = 0.057). However, the addition of etoposide led to excessive toxicity in elderly patients. The Nordic group adopted CHOEP induction for subjects younger than age 60 years in a prospective study evaluating upfront stem cell transplantation for PTCL.²² In this phase II study, patients received biweekly CHOEP followed by ASCT for the responders. The ORR to CHOEP was 82 percent with a CR rate of 51 percent. Although one must be cautious when comparing results from different study populations, these results appear superior to those reported by Reimer and colleagues for patients treated with CHOP followed by ASCT, who achieved CR in only 39 percent of cases.¹⁵

There are no randomized trials assessing the controversial approach of performing ASCT in first remission for PTCL, although several prospective studies suggest the benefit of this strategy. The aforementioned Nordic study enrolled 160 patients with PTCL, including 39 percent with PTCL-NOS, 19 percent with ALK-negative ALCL, and 19 percent with AITL, while excluding ALK-positive ALCL.²² Patients were treated with CHOEP for six cycles (etoposide was omitted for patients >60 years of age) and those in CR or partial response (PR) proceeded to high-dose therapy with carmustine, etoposide, cytarabine, and melphalan (or cyclophosphamide) and ASCT. By intent-to-treat analysis, 71 percent of patients underwent ASCT and the 5-year OS and PFS were 51 percent and 44 percent. Reimer and colleagues conducted the second largest prospective study evaluating ASCT in first remission following CHOP, enrolling 83 patients.¹⁵ A 3-year OS rate of 48 percent was observed by intent-to-treat analysis. For those who were transplanted (66 percent of patients enrolled) outcomes were considerably more favorable with a 3-year OS of 71 percent. In a retrospective analysis performed at Memorial Sloan Kettering Cancer Center to evaluate patients treated with the intent to transplant in first remission, interim PET imaging was found to be the most powerful predictor of outcome. Of the 53 percent of patients who had a negative interim PET scan after four cycles, 59 percent were progression free after 5 years, including 53 percent of those with IPI of 3 or greater.²³

APPROACH TO RELAPSED OR REFRACTORY THERAPY

There are no randomized data or standard of care to guide treatment of patients with relapsed or refractory PTCL.²⁴ In the largest series of patients with PTCL-NOS, AITL, and ALCL treated from 1976 to 2010, those with relapsed or refractory disease who did not proceed to hematopoietic stem cell transplant demonstrated a median OS of 5.5 months.²⁶ However, the outlook for this patient population may improve as several new agents have been approved for this setting, including romidepsin, belinostat, and pralatrexate.^28,29 In addition, brentuximab vedotin is listed in the National Comprehensive Cancer Network (NCCN) compendium of appropriate therapeutic agents for CD30-positive T-cell lymphomas (Table 104–4).^30,31,32,33

For patients who are transplantation-eligible, allogeneic transplantation should be considered in the relapsed/refractory setting. Once a donor is identified, intensive salvage chemotherapy options should be considered, including ICE (ifosfamide, carboplatin, etoposide) or DHAP (dexamethasone, cytarabine, cisplatinum), as they have a high potential to induce major remissions that will optimize outcomes after transplantation.³⁰ However, these regimens are generally only tolerated for three to four cycles and should be followed promptly by consolidation with transplantation. Both myeloablative and reduced intensity allogeneic stem cell transplantation have demonstrated up to 60 percent 3-year PFS.^37,38,39 The role of ASCT in relapsed/refractory PTCL is controversial. Several series suggest that ASCT rarely results in long-term disease control of PTCL, with the exception of patients with ALCL.^34,35 Other series, however, including registry data from the Center for International Blood and Marrow Transplant Research, report more salutary results for ASCT after relapse.³⁶

For patients who are not transplantation-eligible, the goals of treatment are palliative, and therapy should be geared toward maintaining quantity and quality of life. Options for treatment include romidepsin, belinostat, pralatrexate, gemcitabine, bendamustine, and alemtuzumab.^{26,27,28,29,40,41,42} In addition, brentuximab vedotin should be considered as the first choice for relapsed CD30-expressing ALCL patients, who have not previously received this agent.^21–33

In view of the heterogeneity of PTCL, there is an increasing interest in individualizing therapy based on histology and other factors. For example, brentuximab vedotin, a CD30 antibody–drug conjugate, induced responses in patient with relapsed or refractory ALCL as well as those with CD30-positive AITL and PTCL-NOS.^32,33 Similarly, crizotinib, an ALK inhibitor, demonstrated significant activity in a small number of patients with relapsed ALK-positive ALCL and is being further investigated.^43,44,45 The histone deacetylase (HDAC) inhibitors, such as belinostat and romidepsin, appear to have preferential activity and duration of response in patients with AITL (see Table 104–4).^27,29

Gene-expression profiling has identified molecular classifiers that improve classification and prognostication in ALK-negative ALCL, AITL, and PTCL-NOS.^46,47,48,49 Furthermore, additional translocations and recurrent mutations have been identified that may help better classify PTCLs and identify potential treatment targets. Next-generation sequencing has identified a novel translocation within ALK-negative ALCL, t(6;7),⁵⁰ which potentially identifies a unique entity within ALK-negative ALCL associated with a better prognosis.⁵¹ This mutation typically leads to reduced expression of the DUSP22 gene, which likely functions as a tumor suppressor. A translocation producing an ITK-SYK fusion gene, t(5;9), was initially found in a subset of PTCL-NOS cases.⁵² SYK expression was subsequently evaluated in 141 PTCL cases by immunohistochemistry and found to be overexpressed in 94 percent, although the translocation was only detected in 39 percent.⁵³ These findings suggest a potential role for SYK inhibitors in these cases.⁵⁴ Mutations involving the TET2 gene appear to be common in AITL as well as PTCL-NOS expressing T-follicular helper (T_FH) cell markers; they are less frequent among the other PTCL-NOS cases (24 percent) and absent in ALCL.⁵⁵ TET2 is involved in epigenetic control of transcription through DNA methylation and inactivating mutations of this gene were first identified in myeloid malignancies. These mutations signify a biologic connection between AITL and PTCL-NOS with AITL features (T_FH-like PTCL-NOS) and suggest a role for hypomethylating agents.

DEFINITION

PTCLs that do not fit into any of the currently recognized histopathologic categories are designated PTCL, not otherwise specified (PTCL-NOS; Chap. 96.)

EPIDEMIOLOGY

PTCL-NOS is the most common of the mature T-cell neoplasms, representing approximately 25 to 30 percent of the total cases of T-cell lymphoma in Western countries.^56,57,58 In the United States, there are approximately 0.4 cases per 100,000 adults.⁶² In Asia, PTCL-NOS accounts for 20 to 25 percent of cases mature T-cell neoplasms (see Table 104–2).^3,57 The median age of diagnosis is 60 years with a male predominance (2:1).^3,7

CLINICAL FINDINGS

In general, patients with PTCL-NOS have aggressive, rapidly growing disease. Diffuse lymphadenopathy, constitutional symptoms, extranodal involvement, an elevated LDH level, and advanced stage disease are common.^56,57 Hepatomegaly and splenomegaly occur in 17 percent and 24 percent of patients, respectively. Stages I, II, III, and IV disease are observed in approximately 14 percent, 17 percent, 26 percent, and 43 percent of cases, respectively. The marrow is involved in approximately 20 percent of cases.^2,4 Pruritus, peripheral eosinophilia, hypercalcemia, and hemophagocytic syndrome may accompany PTCL.^60,61

LABORATORY FINDINGS

Histopathology

The majority of cases arise in lymph nodes, which exhibit mixtures of small and large atypical lymphoid cells, typically admixed with an inflammatory background (Chap. 96).⁶² The immunophenotype is typically that of a mature T-cell expressing either a CD4 or CD8 phenotype, most commonly CD4, although CD4/CD8 double-positive and double-negative cases have been reported.^6,63 Malignant cells are often characterized by antigen aberrancy that may vary from one patient to another or even vary during the course of the disease within a single patient.^6,7 Deletion of one or more pan–T-cell antigens is frequently observed,⁶⁴ along with rearrangements of the TCR.

TREATMENT AND PROGNOSIS

As discussed previously, patients with PTCL-NOS are most commonly treated with CHOP-based regimens, although there is no uniform standard of care for first-line treatment. Little prospective data exists for CHOP alone in PTCL, but based on clinical trials employing CHOP as a component of therapy, it appears that CHOP produces an ORR as high as 79 percent and a CR rate as high as 39 percent.¹⁵ However, with CHOP alone long-term remissions are uncommon, with PFS rates of 20 to 30 percent seen in the larger retrospective series.^2,3,4 Efforts to improve the efficacy of first-line therapy by adding new agents to CHOP, such as alemtuzumab, bortezomib, or denileukin diftitox, have not clearly resulted in significant benefit.^20,12,19 The addition of etoposide to CHOP appears to provide some benefit over CHOP in more favorable young patients, according to a retrospective analysis of seven prospective studies conducted by the DSHNHL.²¹ Moreover, in a prospective study of CHOEP followed by ASCT, the ORR to CHOEP was 82 percent, with 51 percent achieving a CR.²² Newer agents approved in the relapsed setting, such as romidepsin and brentuximab vedotin, are currently being combined with CHOP-based regimens and compared to standard CHOP in ongoing phase III clinical trials.

Another strategy for improving frontline therapy for PTCL-NOS has been through consolidation with ASCT in first remission, as discussed in “Approach to Initial Therapy” above. Even though there are no randomized trials of ASCT in first remission, three prospective phase II trials support this approach.^15,22,23 The largest of these studies demonstrated 5-year OS and PFS of 47 percent and 38 percent, respectively in patients with PTCL-NOS.²²

Allogeneic transplantation provides long-term disease control for a select group of patients with relapsed PTCL-NOS. Although transplant-related mortality is significant, retrospective studies have demonstrated up to 61 percent OS at 2 years in some trials. Consequently, allogeneic transplantation is often considered for fit patients who fail frontline therapy.^23,39,66

Several promising new agents, including belinostat, bendamustine, gemcitabine, and alemtuzumab, have become available for the treatment of PTCL-NOS in the relapsed setting.^28,40,41,42 Pralatrexate, romidepsin, and belinostat are approved broadly for PTCL, with an approximately 20 to 30 percent ORR in large phase II studies (see Table 104–4).^27,71,72

Overall, the 5-year FFS for PTCL-NOS is 20 percent with a 5-year OS of 32 percent in patients treated with CHOP-based therapy.⁶⁰ The IPI and PIT have been used to risk stratify patients with PTCL-NOS and estimate prognosis. For patients with PIT scores of 0, 1, 2, or 3 or greater, the 5-year FFSs are 34 percent, 22 percent, 13 percent, and 8 percent, respectively. For patients with IPI scores of 1 or less, 2, 3, or 4 or greater, 5-year FFSs are 36 percent, 18 percent, 15 percent, and 9 percent, respectively.⁷ PIT scores have not been used to direct treatment decisions, however (see Table 104–3).^13,12

DEFINITION

AITL was initially described as angioimmunoblastic lymphadenopathy with dysproteinemia in 1974. It is now known that these entities are identical.^1,68

EPIDEMIOLOGY

AITL represents approximately 1 percent of all cases of lymphoma and approximately 20 percent of all T-cell lymphomas.⁵⁷ International series show that AITL represents a higher portion of T-cell lymphomas in Europe than North America or Asia.³ The male-to-female ratio is approximately 1:1 and the median age at diagnosis is approximately 65 to 70 years.^3,4,7

CLINICAL FINDINGS

Common features at presentation include B symptoms (fever, drenching sweats, and weight loss), generalized lymphadenopathy, rash, polyclonal hypergammaglobulinemia, blood eosinophilia, and autoimmune hemolytic anemia (direct Coombs positive). Some patients experience waxing and waning of symptoms over several years before a diagnosis is made. Patients with AITL can develop diffuse large B-cell lymphoma, which evolves from EBV-positive B cells, which usually are present in the lymphoid infiltrate. Emergence of diffuse large B-cell lymphoma can occur concomitantly with AITL at the time of diagnosis or may be the primary histology at relapse; therefore, repeat biopsies are strongly encouraged whenever relapse is suspected in order to guide therapy.^69,70

LABORATORY FINDINGS

Histopathology

AITL is characterized histologically by effacement of the normal lymphoid architecture with a pleomorphic cellular infiltrate and proliferation of small arborizing blood vessels. Small lymphocytes, plasma cells, immunoblasts, histiocytes, and eosinophils infiltrate involved lymph nodes. As a result, the normal lymphoid architecture may be obliterated, with loss of germinal centers and extensive intranodal neovascularization and expansion of the follicular dendritic cell meshwork (CD21). Scattered EBV+ B cells are almost always present and reflect the accompanying immunodeficient state. The malignant cells are CD4+ αβ T cells with TCR-β and –γ rearrangements^70,71,72 and express CD10, a marker typical for AITL, approximately 90 percent of the time.⁷³ Abnormal karyotypes involving the X chromosome and chromosomes 1, 3, and 5 are frequently found in AITL. A complex karyotype is a negative prognostic factor for AITL.⁷⁷ The normal counterpart of AITL is suspected to be the follicular T-helper cell based on genomic profiling, which reveals overexpression of specific markers, including CXCL13 and PD1.^74,75 A subset of PTCL-NOS exhibits a similar gene-expression profile, suggesting it may behave similarly.⁷⁶

TREATMENT AND PROGNOSIS

Most patients with AITL are treated with CHOP-based regimens as discussed in the section Approach to Initial Therapy. The CR rate is similar to the rate observed with PTCL-NOS (approximately 50 to 60 percent). Nonrandomized data support upfront ASCT in patients who achieve a CR to first-line therapy.²² Rare patients may be managed with glucocorticoid monotherapy, which can induce remissions, although responses are rarely sustained.⁷⁸ Responses to low-dose methotrexate and cyclosporine have also been reported.^79,80,81 Finally, response rates as high as 50 percent have been reported in CD30-positive relapsed/refractory AITL treated with brentuximab vedotin.³²