The Aggressive Peripheral T-Cell Lymphomas

INTRODUCTION

The aggressive peripheral T-cell lymphomas make up less than 10% of all lymphomas diagnosed each year in the United States. They provide a wide variety of clinical syndromes, many of which have been well defined only in the past few decades. The results of therapy for patients with aggressive peripheral T-cell lymphomas have been much worse than observed for patients with aggressive B-cell lymphomas. This undoubtedly reflects, at least in part, that only a minority of patients with aggressive peripheral T-cell lymphoma are included in clinical trials. It is not surprising that the most effective therapy for diffuse large B-cell lymphoma—the most common of the aggressive lymphomas—was the most effective treatment in these trials. Since peripheral T-cell lymphomas are clinically and biologically distinct entities, there would have been no reason to expect that the same treatment would work equally for them.

The aggressive peripheral T-cell lymphomas, despite their relative infrequency, include a wide variety of illnesses (Table 1).¹ These tumors can be subdivided into those developing primarily in (1) lymph nodes and (2) extranodal sites. The subtypes of aggressive peripheral T-cell lymphomas will be dealt with in the rest of this paper, and are divided into those of primary nodal and primary extranodal origin.

The ability of pathologists to diagnose aggressive peripheral T-cell lymphoma has been much less reproducible than their ability to diagnose aggressive B-cell lymphomas. For example, expert hematopathologists using modern classification systems are able to diagnose aggressive B-cell lymphomas, with few exceptions, in a highly reproducible manner.² However, a recent study of the WHO classification system for the aggressive T-cell lymphomas found an approximately 10% lower rate of agreement by expert hematopathologists than was seen for B-cell lymphomas (Table 2).³ The application of gene expression studies has the potential to improve our ability to diagnose aggressive peripheral T-cell lymphomas. A recent review suggested that gene expression patterns will have an impact on our ability to classify aggressive peripheral T-cell lymphomas and are likely to be particularly important with certain subtypes.⁴ For example, it appears that angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma, and adult T-cell leukemia/lymphoma have robust and reproducible molecular signatures.⁵ In contrast, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) was molecularly heterogeneous, with some tumors showing the molecular signature of angioimmunoblastic T-cell lymphoma.

PRIMARILY NODAL AGGRESSIVE PERIPHERAL T-CELL LYMPHOMAS

Peripheral T-Cell Lymphoma Not Otherwise Specified

Patients with PTCL-NOS present at a median age of 60 years with a striking male predominance (Table 3). About 70% of patients will have widespread disease. The distinction between these patients and those with diffuse large B-cell lymphoma can be made on biopsy only when the tumor cells mark as mature T-cells. Unfortunately, the treatment outcome for patients with PTCL-NOS has been much poorer, with shorter survival and one-third to one-fourth the chance to remain free of disease for 5 years.

We now know that not all tumors with a PTCL-NOS diagnosis are the same. Some of them have gene expression patterns characteristic of angioimmunoblastic T-cell lymphoma.⁵ There appears to be more than one other subgroup, though these are not yet well defined. It obviously confounds the interpretation of clinical trials and suggests that not all patients will benefit maximally from the same treatment.

The most common treatment for patients with PTCL-NOS has been an anthracycline-containing regimen like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Because of the poor results seen to date, many physicians offer an autologous transplant in first remission, although it is unclear that this yields a significant advantage. A number of new drugs are being studied in these patients (Table 4), although none have yet made it into first-line therapy. For patients with aggressive peripheral T-cell lymphomas, we are in desperate need of an improved treatment regimen that could serve as a standard in the same way that CHOP has for patients with diffuse large B-cell lymphoma. For patients who relapse, both autologous and allogeneic hematopoietic stem cell transplantation can be curative.^6,7 At least one report suggested that for patients with recurrent disease, allogeneic transplantation is superior.⁸

Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma is the second most common of the aggressive peripheral T-cell lymphomas.³ It occurs more frequently in northern Europe.³ The typical patient with this tumor is aged >60 years, presents with systemic symptoms, and has widespread disease and an elevated level of lactate dehydrogenase. As might be expected, survival has been poor, with a large international review³ showing a 5-year failure-free rate of 18% and a 5-year overall rate of 32%.

The optimal treatment for patients with angioimmunoblastic T-cell lymphoma is not certain. Only a minority of patients will benefit in the long term from traditional anthracycline-based therapy. New treatment approaches have included the addition of alemtuzumab to a CHOP-like regimen and the use of early autologous hematopoietic stem cell transplantation. A small series that combined CHOP with alemtuzumab had a high rate of complete remission.⁹ Autologous hematopoietic stem cell transplantation can induce long-term disease-free survival and is most likely to be effective when patients are transplanted in complete remission.¹⁰ A series using allogeneic hematopoietic stem cell transplantation for patients with relapsed angioimmunoblastic T-cell lymphoma showed that either myeloablative or reduced-intensity allogeneic transplantation can produce long-term disease-free survival.¹¹

A variety of other treatments have been utilized in patients with angioimmunoblastic T-cell lymphoma. One report showed that some patients responded to cyclosporine and obtained a complete response with maintenance cyclosporine.¹² In addition, a small report suggested that combining rituximab with the CHOP regimen might benefit patients with angioimmunoblastic T-cell lymphoma—perhaps by eliminating CD20-positive cells and interfering with intercellular signaling.¹³

Anaplastic Large Cell Lymphoma

The tumors that we now call anaplastic large cell lymphoma are characterized pathologically by large anaplastic cells that like carcinomas tend to grow cohesively and frequently invade lymph node sinuses. As a result, these tumors were frequently misclassified as undifferentiated carcinomas, malignant melanomas, or malignant histiocytosis until the discovery in 1985 of the Ki-1 (now CD30) marker.¹⁴ CD30 was known to be a marker for Reed-Sternberg cells, but this led to the discovery of anaplastic large cell lymphoma, which uniformly expresses CD30. (A cutaneous variant of anaplastic large cell lymphoma has a much less aggressive course and will not be dealt with in this section.¹)

The ALK gene on chromosome 2 is fused with the nucleophosmin gene on chromosome 5 in the t(2;5) translocation that characterizes a subset of anaplastic large cell lymphomas.¹⁵ Patients whose anaplastic large cell lymphomas overexpress the ALK protein and have the characteristic translocation are younger and have a better survival.^16,17 It is not completely clear whether the expression of ALK or the younger age of the ALK-positive patients is the major factor in determining their better outcome.¹⁷

In a recent international study, patients with ALKpositive anaplastic large cell lymphoma had a median age of 34 years, in contrast to 58 years in those whose tumors were ALK negative. Males predominated in both groups, and 35% to 40% of patients had stage I or II disease.¹⁷ Five-year failure-free survival was 60% in ALK-positive patients and 36% in ALK-negative patients (Table 3), with the International Prognostic Index Score¹⁸ being predictive in both groups.¹⁷

Patients with anaplastic large cell lymphoma have the best treatment outcomes among patients with any of the aggressive peripheral T-cell lymphomas. However, the optimal therapy remains uncertain. Treatment has usually included the CHOP regimen, which remains the standard approach for most physicians. Although patients with relapsed peripheral T-cell lymphoma often benefit from autologous bone marrow transplantation, this treatment is not widely included as part of primary therapy. A number of trials are being conducted of antibodies, including those against CD52, CD25, and CD30. In some patients, alemtuzumab has been combined with CHOP.⁹ SGN-30 and SGN-35 have both been shown to be active in relapsed anaplastic large cell lymphoma,^19,20 with some complete responses. It is unclear whether this approach will benefit patients in combination with standard chemotherapy as the initial treatment.

Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma is one result of infection by the virus HTLV-1. While infection is asymptomatic in most patients, adult-cell leukemia/lymphoma occurs in about 3% of patients. The ensuing syndrome can be predominantly a leukemia or lymphoma, and the clinical course can be smoldering, chronic, or acute.²¹ Most patients present with disseminated disease and have an aggressive course. This disease is seen most frequently in southern Japan and the Caribbean but can be found throughout the world. The infection can be passed vertically from mother to child or spread through blood products. The management of patients with adult T-cell leukemia/lymphoma is difficult, and most patients presenting with the acute form have a short survival. Patients frequently respond to a variety of chemotherapy regimens but rarely have long-term disease-free survival. There is some evidence that more intensive regimens, including transplantation, are more beneficial.²²

PRIMARILY EXTRANODAL AGGRESSIVE PERIPHERAL T-CELL LYMPHOMAS

Extranodal Natural Killer/T-Cell Lymphomas

Most natural killer (NK)/T-cell lymphomas present in the nose and nasal sinuses and are termed nasal NK/Tcell lymphoma in the WHO classification. These are the tumors that were once included in the category of lethal midline granuloma, which was not known to be a cancer but was responsive to radiotherapy. Other NK/T-cell lymphomas can present involving other sites in the body and are referred to as extranasal NK/T-cell lymphomas in the WHO classification. Lymphomas presenting in the nose and nasal sinuses are more likely to be localized (73% vs 32%) and have a better 5-year survival (45% vs 10%) than those presenting in other sites.²³

Nasal NK/T-cell lymphomas are seen most frequently in Southeast Asia, Korea, and parts of Latin America. In the United States, immigrants from those areas represent a significant proportion of the cases. The presenting symptoms for nasal NK/T-cell lymphomas are usually reflective of the localized nature of the disease. A minority of the patients have systemic symptoms.³ This is an aggressive lymphoma, and patients must be evaluated and treated promptly. When staging evaluation shows evidence of disseminated disease, the chances for cure become greatly diminished.

Therapy for nasal NK/T-cell lymphoma has been the subject of debate. For patients with localized disease, radiotherapy seems to be the most important component of therapy and is necessary for cure.^24,25 This may be one of the unusual situations in treating lymphomas where radiotherapy should be administered before chemotherapy, though there is no consensus on this point. For example, some clinicians favor the use of radiotherapy alone for localized disease.²⁶ At least one report suggested that concurrent chemotherapy along with radiation, in a manner similar to what is used in some carcinomas, might benefit patients with this disorder.²⁷

Patients who have disease that presents in other sites, or disseminated nasal NK/T-cell lymphoma, have a much poorer outlook. Although most patients will respond at least transiently to chemotherapy, cure is uncommon. There are reports of activity of methotrexate and L-asparaginase, and there are hints that their inclusion in treatment might improve outcomes.^28,29 Some patients have been reported to benefit from autologous and allogeneic hematopoietic stem cell transplantation.^30-32

Enteropathy Type Peripheral T-Cell Lymphomas

Enteropathy-associated T-cell lymphoma is a rare lymphoma that arises in the small intestine; patients usually present with abdominal pain and weight loss. People with celiac disease seem to be at higher risk for this disorder.³ Note, however, that many patients with this disorder do not have a history of celiac disease and that lymphomas of the small intestine in patients with celiac disease can also be diffuse large B-cell lymphoma.

Patients with enteropathy-associated T-cell lymphoma have a poor survival rate (Table 3). They are often very ill by the time of diagnosis, and intestinal perforation is not uncommon at presentation. These poor presenting characteristics often limit treatment options. Patients are often treated initially with surgery, but it rarely yields long-term disease-free survival. Anthracycline-based chemotherapy regimens have poor outcomes, with many patients unable to tolerate a full course of therapy.³³ However, a recent report of intensive chemotherapy followed by autologous hematopoietic stem cell transplantation in patients healthy enough to tolerate this approach showed a much better outcome than previously seen. About 50% of patients survived 3 years free of disease,³⁴ in contrast to 5-year failure-free survival of 4% in a large international study that utilized several different treatment approaches.³

Hepatosplenic Peripheral T-Cell Lymphoma

Hepatosplenic T-cell lymphoma is a rare disease that typically presents with systemic symptoms such as fevers, night sweats, and malaise combined with liver and spleen enlargement and peripheral blood cytopenias. The initial clinical impression is often of an infectious disease, and the diagnosis of lymphoma is sometimes not made until autopsy—if at all. These patients typically do not have lymphadenopathy, and the tumor cells usually have a sinusoidal growth pattern, which makes pathological diagnosis difficult. The first description of the disease might be a 1990 report of 2 patients who briefly responded to therapy and then died. Unfortunately, the treatment options for these patients have not improved much in recent years.

Most hepatosplenic T-cell lymphomas display the gamma/delta T-cell receptor rather than the alpha/beta T-cell receptor. It may be that tumors expressing the latter have a somewhat better prognosis. Finding a T-cell gene rearrangement is sometimes the key to diagnosis. Familiarity with the disease, as well as a high degree of suspicion on the part of both clinician and pathologist, increases the likelihood of timely diagnosis.

Unfortunately, hepatosplenic T-cell lymphoma continues to have a dismal survival rate. In a large international study of T-cell lymphomas, 5-year overall survival was only 7% (Table 3).3 CHOP-based therapies often yield a response, but it is usually transient. Patients have been reported to benefit from alemtuzumab, pentostatin, and fludarabine, but the only therapy that appears to be curative is allogeneic bone marrow transplantation.^35,36

Subcutaneous Panniculitis-Like Peripheral T-Cell Lymphoma

Subcutaneous panniculitis-like T-cell lymphoma is usually included among the aggressive peripheral T-cell lymphomas. However, a recent report3 of a large number of patients with T-cell lymphomas from around the world showed that patients with this disorder have a much more indolent course than might have been expected. It does appear that patients with the gamma/delta subtype of subcutaneous panniculitis-like T-cell lymphoma do have a more aggressive course than those whose tumors express the alpha/beta T-cell receptor.³⁷ It is likely that many patients with subcutaneous panniculitis-like peripheral T-cell lymphoma are followed for much of their clinical course by dermatologists and are seen by oncologists only when they develop systemic disease.

The optimal treatment for patients with subcutaneous panniculitis-like T-cell lymphoma is uncertain. Radiotherapy is extremely effective for sites of disease to which it can be applied. Combination chemotherapy regimens such as CHOP can yield remissions, but the chance of remaining in remission for 5 years was only 4%3 (Table 3). Some patients might benefit from autologous or allogeneic hematopoietic stem cell transplantation.^38,39

CONCLUSION

Aggressive peripheral T-cell lymphomas represent a wide variety of clinical syndromes. However, they are diseases that practicing oncologists will occasionally see. To maximize the chances that patients will benefit from effective therapies, it is important that clinicians be acquainted with these diseases and be aware of treatment advances as they occur. Currently, major lymphoma study groups are focusing on identifying improved treatments for patients with these disorders. There is every reason to believe that the outcome of this work will be a significant improvement in survival—perhaps approaching that seen for patients with the aggressive B-cell lymphomas.