Peripheral T-cell Lymphomas

Blood Reviews (2007) 21, 201–216

www.elsevierhealth.com/journals/blre

REVIEW

Peripheral T-cell Lymphomas Kerry J. Savage British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada

KEYWORDS

Summary Peripheral T-cell lymphomas (PTCLs) are a biologically diverse and uncommon group of diseases. Compared to their B-cell counterparts, PTCLs remain largely unexplored and the optimal treatment ill-defined due to disease rarity and biological heterogeneity. With the notable exception of ALK-pos anaplastic large cell lymphoma (ALCL), the prognosis of most PTCL subtypes is extremely is poor with a 5 y overall survival of approximately 15-30% in most series. The international prognostic index has been useful in defining different risk groups within some PTCL subtypes, including PTCL unspecified (PTCLU). Attempts have been made to define disease subgroups within the biologically heterogeneous PTCLU based on T-helper chemokine receptor profile and/or gene expression profiling which may aid in tailoring new therapies. Future clinical trials are needed that focus specifically on PTCL to advance our understanding and define the optimal management in this disease. c 2007 Elsevier Ltd. All rights reserved.

Peripheral T-cell lymphomas; Prognosis; Treatment

 Introduction

Peripheral T-cell lymphomas, so-called by their post-thymic orgin, represent approximately 12–15% of all non-Hodgkin lymphomas in Western populations. In recent years, the importance of the T-cell phenotype has been highlighted through the application of routine immunophenotyping and molecular diagnostics. These techniques, coupled with disease-specific clinical and pathologic features led to the recognition of the full spectrum of T-cell neoplasms, in the REAL (Revised European – American Lymphoma) classification and provided the basis for the recently published WHO (World Health Organization)1 classification with several E-mail address: [email protected]



notable changes: (Table 1): division into predominantly leukemic, extranodal and nodal types; separation of cutaneous and systemic anaplastic large cell lymphomas (ALCL); updated terminology for some diseases; inclusion of lymphomatoid papulosis (LyP) in the spectrum of CD30+ T-cell lymphoproliferative disorders; recognition of subcutaneous panniculitis-type and hepatosplenic c d T-cell lymphomas as separate entities2 (Table 1). Although earlier reports, based on older classification schemes, described similar prognoses amongst B and T-cell lymphomas,3 more recent studies utilizing newer classification systems have consistently demonstrated that the T-cell phenotype imparts a negative impact on overall surviva14–6 Fig. 1. The discrepancies in prognosis between studies may be due to inclusion in some

0268-960X/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.blre.2007.03.001

202 Table 1

K.J. Savage REAL and WHO Classifications of T-cell and NK neoplasms.

REAL Classification

WHO Classification

Precursor T-cell neoplasm Precursor T-lymphoblastic lymphoma/leukemia Peripheral T-cell and NK-cell neoplasms T-cell chronic lymphocytic leukemia/ Prolymphocytic leukemia Large granular lymphocyte leukemia T-cell type and NK-cell type Adult T-cell lymphoma/leukemia (HTLV1+)

Precursor T-cell neoplasm Precursor T-lymphoblastic lymphoma/leukemia Mature (peripheral) T-cell neoplasms Predominantly leukemic/disseminated T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia NK-cell leukemia Adult T-cell lymphoma/leukemia (HTLV1 +)

Predominantly nodal Angioimmunoblastic T-cell lymphoma Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, unspecified Peripheral T-cell lymphoma, unspecified Anaplastic large cell lymphoma, T/null-cell types Anaplastic large-cell lymphoma, T/null-cell, primary systemic type Mycosis fungoides/Sezary syndrome

Angiocentric lymphoma Intestinal T-cell lymphoma

Predominantly extranodal Mycosis fungoides/Sezary syndrome Anaplastic large-cell lymphoma, T/null-cell, primary cutaneous type Extranodal NK/T-cell lymphoma nasal and nasal type Enteropathy-type T-cell lymphoma Hepatosplenic cd T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma

earlier studies of disease entities that are now appreciated to have a more favorable prognosis such as ALCL Fig. 1. Understanding of the biology and optimal treatment of PTCLs has been limited due to only recent recognition of PTCLs in addition to disease rarity and histologic subtype heterogeneity. Frequently, dissimilar T-cell lymphomas have been combined under the term ‘PTCL’ potentially obscuring their distinct natural histories and limiting comparison of studies that focus on prognostic factors and survival analyses. This review will highlight some of the more commonly encountered subtypes with a

Figure 1 Survival of patients with PTCL compared with anaplastic large cell lymphoma and diffuse large B-cell lymphoma (reproduced with permission).74

further discussion of prognostic markers and treatment strategies.

Peripheral T-cell lymphoma, Unspecified Peripheral T-cell lymphoma, unspecified (PTCLU) represents the largest PTCL subtype in North America.7 In the WHO classification it encompasses all of the PTCLs not classifiable as a specific disease entity in contrast to the rare, but ‘specified’ subtypes (Table 1). Pathologically there is typically a diffuse atypical infiltrate of intermediate and large lymphoid cells that are CD4 +, CD2+ and CD3 + but they often lack mature T-cell antigens such as CD7. Approximately a third may be CD30+ (Ki-1 Ag) or EBV+ however, the relevance is unknown. Multiple other morphologic subtypes can occur, including the histiocyte-rich ‘Lennert’s’ or ‘lymphoepithelioid’ lymphoma, however, the prognostic significance is not fully understood. Given the biological heterogeneity encountered in PTCLU, it is widely believed that PTCLU is made up of more than one disease type but how to best differentiate these is unknown. Despite being classified in as a nodal PTCL in the WHO, the majority of patients have extranodal site involvement including the gastrointestinal tract, liver, bone marrow and skin. The majority of patients present with advanced stage disease often

Peripheral T-cell Lymphomas

203

with elevated LDH and B symptoms.7 The 5 y survival of patients with PTCLU is approximately 30% using standard chemotherapy.4,5,7–9

some 2.14 Several variant translocations have since been recognized that similarly result in expression of ALK which has constitutive tyrosine kinase activity (ALK-pos). Importantly, several independent studies have demonstrated that those tumors that are ALK-pos have a 5 y survival that is far superior to those that lack expression (ALK-neg)(Table 3, Fig. 2).15–17

Anaplastic Large Cell Lymphoma Anaplastic large-cell lymphoma was initially identified in 1985 by the highly pleomorphic appearance, propensity to invade lymph node sinuses and hallmark uniform expression of CD30 on the tumor cells.10 Since the original description of ALCL, several additional morphologic variants have since been identified. In the WHO classification, cutaneous ALCL is distinguished from the systemic type as a result of genetic, immunophenotypic and clinical differences (Tables 1 and 2).11

Primary Cutaneous ALCL Primary cutaneous ALCL (CUTALCL) belongs to a spectrum of diseases referred to as CD30+ lymphoproliferative disorders which also includes lymphomatoid papulosis, a chronic recurring benign entity as well as so-called borderline lesions. It typically occurs in older men as solitary, asymptomatic cutaneous or subcutaneous reddish-violet nodules/tumors < 2cm in size. Extracutaneous disease can occur in 10% of patients, mainly in regional lymph nodes and most often in patients with multiple lesions.11 Distinguishing between CUTALCL and lymphomatoid papulosis (LyP), can be difficult (Table 4) and requires communication between the clinician and pathologist for accurate diagnosis as the pathology can be identical in both disorders. Lymphomatoid papulosis generally presents as more diffuse small lesions (< 1 cm) and spontaneous regression is the rule, usually occurring within 12 weeks. Spontaneous regression can also occur in approximately 25% of CUTALCL.11 Since secondary cutaneous involvement by systemic ALCL can occur, full staging investigations are required.

Systemic Anaplastic Large Cell Lymphoma Primary systemic ALCLs display either a T- or nullcell phenotype, the latter inferring that although the typical T-cell antigen markers are absent a clonally rearranged T-cell receptor can be identified and like their T-cell counterparts, they demonstrate a cytotoxic profile Table 2.11 Most cases also are CD2+ and CD4+ but CD3 expression can be more variable. Epithelial membrane antigen (EMA) and clusterin can also be useful diagnostic markers11,12 (Table 2). Systemic ALCL has a superior survival to other PTCLs, with outcomes at least comparable to, if not better than, that of diffuse large B-cell lymphoma (DLBCL)5,8,13 (Fig. 1). However, since the original recognition ALCL it was determined that a large proportion of cases are associated with a translocation between chromosome 2 and 5 [t(2;5)(p23;q35] which generates a fusion gene between nucleophosmin (NPM) on chromosome 5 and the receptor tyrosine kinase gene, ALK on chromo-

NK/T-cell Lymphoma In the REAL classification extranodal NK/T cell lymphomas, nasal-type (NK/TCL) were referred to as

Table 2 Clinical and pathologic features used to distinguish primary cutaneous anaplastic lymphoma and systemic ALCL, ALK-pos and ALK-neg subtypes. Features

ALK-pos systemic ALCL

ALK-neg systemic ALCL

Primary cutaneous ALCL

T-cell phenotype ALK protein CD30 Clusterin EMA Cytotoxic proteins Median age Sex 5-year survival

CD4+/CD8+ + + + + (80%) <30 M>F 65-90%

CD4+/-/CD8-

CD4+/CD8-

+ +

+

/+ + (50%) >50 M=F 30-40%

Classn = classification. Cytotoxic proteins = granzyme B, perforin, TIA-1 (T-cell intracytoplasmic antigen). EMA = epithelial membrane antigen.

+ (70%) >50 M>F >90%

Figure 2 Survival of ALCL patients by ALK expression (reproduced with permission).16

71

15 p < .0007

angiocentric lymphomas due to the vascular localization and destructive properties. The updated terminology in the WHO classification is intended to provide a better reflection of the disease process. The designation ‘NK/T’ rather than ‘NK’ cell lymphoma is used since although most cases appear to be NK-cell derived (CD2+, CD56+, CD3e (cytoplasmic)+, EBV+), rare cases with identical clinical and cytologic features exhibit an EBV+CD56- cytotoxic T-cell phenotype.11 EBV is thought to play a role in tumor pathogenesis, however, the mechanism is unknown. The qualifier ‘nasal-type’ is assigned due to the common presentation in the nasal region and associated structures, however, other identical tumors can also occur at ‘extranasal sites’ such as the skin, soft tissue GI tract and testis (WHO).11 NK/TCLs, uncommon in North America, are the dominant PTCL type in Asian populations.11 NK/ TCLs are typically very locally aggressive with 5 y overall survival rates ranging in the literature from 25% to 50%,18 the variability likely reflecting inconsistent reporting of immunophenotyping and EBV status and more favorable outcomes observed in those individuals with truly localized disease. In most analyses, the EFS approximates OS suggesting that salvage treatments in this population are ineffective. Nasal-type NK/TCL often present with advanced stage disease and appear to have an inferior survival to nasal NK/TCL with long-term remissions achieved in only 10-15% of cases.18

Angioimmunoblastic T-cell lymphoma Classn = classification.

82 (DFS) Combination chemotherapy Pediatric protocols REAL

60%

28 p < .0001

37 p < .00001 93 37 p < .0001 88 CHOP

Gascoyne 1999 (57)16,17 Falini 1999 (78)

REAL

54%

35 p = .0003 90 – – Not stated ten Berge, 2000 Europe (85)15

REAL

38%

ALK-pos ALK neg ALK pos

ALK-neg

Comment OS EFS ALK-pos Treatment Classn Study

Selected outcome studies of ALK-pos and ALK-neg ALCL. Table 3

Some pediatric cases included

K.J. Savage

Outcome of ALK-neg ALCL poor in nodal and extranodal sites Some pediatric cases included Estimates only for T and null-cell ALCL

204

Angioimmunoblastic T-cell lymphoma (AILT) was initially described in the 1970s as a clinical syndrome characterized by generalized lymphadenopathy, rash, heptatosplenomegaly, fever and hypergammaglobulinemia and believed to be reactive process.11 However, with the development of immunophenotypic, genetic molecular techniques,

Peripheral T-cell Lymphomas Table 4

205

Cutaneous anaplastic large cell lymphoma and Lymphomatoid papulosis.

Cutaneous ALCL

Lymphomatoid papulosis

Malignant M > F, median age 60 ALK-neg, EMA neg Non-epidermotropic, large CD30+ cells

Benign, chronic recurrent disorder M > F, median age 45 ALK-neg, EMA neg Pathology heterogeneous with 3 subtypes: A Prominent inflammatory infiltrate, RS like cells B Epidermotropic infiltrate with small atypical cells C Large CD30+ cells Usually multiple papules

Usually limited, solitary lesions > 2cm Spontaneous Regression in up to 25%

Spontaneous regression in all (3-12 wks) Up to 20% may be preceded or followed by another malignant lymphoma (cut ALCL, MF, Hodgkin lymphoma.

clonality is established in the majority of cases, strongly supporting that AILT is a distinct PTCL subtype.11 Patients are typically elderly often with multiple extranodal sites of involvement at presentation and autoimmune phenomena can occur. Immunophenotypically, an expansion of the interfollicular regions of CD3+, usually CD4+, cells are found. Distinguishing AILT from PTCLU can often be difficult, however, features favoring AILT are prominent vascularization by arborizing venules, expansion of CD21 positive follicular dendritic cell (FDC) networks and the recent identification of CD10 as phenotypic marker of the neoplastic T-cells.19 Further CXCL13, a chemokine upregulated in germinal center (GC) T-helper cells, may also be a useful diagnostic marker in AILT and supports derivation from a GC T-helper cell.20,21 Evidence of immune activation can be found in the peripheral blood and lymph nodes however, despite this, functional studies performed on T-cells from these regions support a defective T-cell response consistent with an underlying immunodeficiency.22 EBV infected cells are seen in the majority of cases and virtually all infected cells are B-cells. It is hypothesized that the underlying immunodeficiency maybe responsible for the expansion of the EBV-infected cells. Oligoclonal or monoclonal B-cell population can be found and secondary EBV positive B-cell lymphomas have been described in some patients.11 The outcome of AILT is poor with most series reporting a 5 y OS of approximately 30% and median survival of three years.7 Infectious complications can be problematic due to the underlying immunodeficiency and can compromise delivery of chemotherapy.

Other Uncommon PTCL subtypes Adult T-cell lymphoma/leukemia (ATLL) is associated with infection by the human T-cell lymphotropic virus (HTLV-1) and occurs in endemic areas of infection (e.g., Caribbean basin and southwestern Japan).23 Pathologically, the malignant cells have a distinct ‘‘cloverleaf’’ appearance and lack CD7, and the majority are CD4+/CD8 . The retroviral gene Tax has been shown to have a critical role in the pathogenesis of ATLL. Several clinical variants have been recognized: acute type with a rapidly progressive clinical course, bone marrow and peripheral blood involvement, hypercalcemia with or without lytic bone lesions, skin rash, generalized lymphadenopathy, hepatosplenomegaly and pulmonary infiltrates; lymphoma type with prominent adenopathy but lacking peripheral blood involvement but also associated with an aggressive course; chronic type with lymphocytosis and occasionally associated with lymphadenopathy, hepatosplenomagaly, and cutaneous lesions but having an indolent course; and smoldering type with < 5% circulating neoplastic cells, skin involvement, and prolonged survival. Survival times in the acute and lymphomatous variants range from 2 weeks to over a year. The chronic and particularly the smoldering subtypes have a longer survival but can transform into the more acute forms. Underlying immunodeficiency associated with ATLL leads to a high rate of infections throughout the course of the disease. Enteropathy type T-cell lymphoma is a rare PTCL subtype that can complicate an established history of gluten-sensitive enteropathy but most often occurs following a short history of celiac disease and/

206 or dermatitis herpetiformis.23 Even in the absence of a known history of celiac disease, there is usually histologic evidence of villous atrophy and crypt hyperplasia in the adjacent bowel when the tumor is excised. Malignant cells are CD3+, CD7+, CD4 and are usually CD8 , but despite this, they do not express the c d T-cell receptor. Clinically, it affects older males who present with abdominal pain and diarrhea and intestinal perforation or obstruction can occur either at presentation or can complicate treatment delivery. Although most patients have clinical stage I or IIE disease, dissemination to the liver, spleen, lung, skin, and bone marrow can occur. Treatment is often compromised by poor nutrition and significant risk of bowel perforation. Consequently, survival is extremely poor, with rare long-term survivors.2 Hepatosplenic c d T-cell lymphoma (HSTCL) is a recently recognized and uncommon PTCL subtype. Most tumor cells are CD4 and CD8 , and many are associated with isochrome 7q.24 The majority of patients are young men (median age 34) who present with hepatosplenomegaly and bone marrow involvement. Rare cases of HSTCL expressing the a b chain have been reported, but the prognostic relevance is unknown.24 Many patients have a history of immunosuppression (eg. Renal transplant) and recently, a higher than expected frequency of this unusual entity has been reported in Crohn’s patients receiving infliximab, an antibody directed against TNF a, supporting that immunosuppression plays a role in disease pathogenesis. The survival is extremely poor and the majority of patients with rare long term survivors.24 The c d phenotype has been rarely identified in primary cutaneous T-cell lymphoma and is a marker of poor prognosis (median survival 15 months vs. 166 months in ab subtypes).25 Unlike HSTCL, which express TIA1 but are negative for granzyme B and perforin cytotoxic proteins, primary cutaneous c d TCL express all

K.J. Savage cytotoxic proteins, thus demonstrating an activated T-cell phenotype which may contribute to their aggressive behavior.25 Subcutaneous panniculitis-like TCL (SCTCL), is the least well-defined and rarest subtype of PTCL. The neoplastic cells are most often CD8+ a b and express cytotoxic granules, although in 25% of cases, a cd T-cell phenotype is identified and may be associated with a more aggressive clinical course.26 Patients often have a preceding course of waxing and waning nodules, resembling lipomas. Hemophagocytic syndrome with pancytopenia, fever, and hepatosplenomegaly has been reported in association with SCPTCL and is often a fatal complication. Durable remissions are uncommon; however, some cases can have a more indolent course.

Prognostic Factors in Peripheral T-cell Lymphomas Clinical Factors The International Prognostic Index (IPI) provides a prognostic score based on clinical and laboratory factors but was developed in aggressive lymphomas (intermediate or high grade, defined by the working formulation) before routine immunophenotyping was utilized.27 Thus the influence of the T-cell phenotype on the applicability of the IPI is not known from this large study. Interpretation of older studies evaluating the usefulness of the IPI retrospectively in PTCL are complicated by the usage of outdated lymphoma classification systems and frequent ‘lumping’ of histologic subtypes, obscuring the impact of the IPI in specific disease entities {Gisselbrecht, 1998 #85; Melnyk, 1997 #79;}. However, several reports have confirmed the IPI’s usefulness in at least some of the specific PTCL subtypes including ALCL, (ALK-pos and ALKneg) and PTCLU.7–9 Recently, the IPI has been applied PTCLU according to the WHO classification

Figure 3a Overall survival of PTCLU according to the IPI. Low risk 0,1, 5 y OS 59%; low-intermediate risk 2, 5 yOS 46%; high intermediate risk 3, 5 y OS 40%; high risk 18% p < .0001.9

Peripheral T-cell Lymphomas

Figure 3b Overall survival of PTCLU according to proposed new prognostic index (age >60, performance status P2, elevated LDH, bone marrow involvement). Group 1, 0 factors, 5 y OS 62%; Group 2, 1 factor, 5 y OS 53%; Group 3, 2 factors, 5 y OS 33%; Group 4, 3 factors, 5 y OS 18%.9

and found to be predictive of survival.7,9 Fig. 3a. A new prognostic model for PTCLU has also been developed which incorporates many of the current IPI factors (age, PS, LDH) in addition to bone marrow involvement.9 In this model, survival ranged from 18% (4 factors) to 62% (1 factor) Fig. 3b. Unfortunately, many patients with PTCLU fall into the high risk categories with poor survival emphasizing the urgent need for better therapies. Attempts to use the IPI to define risk groups within NK/T-cell lymphoma have also been met with variable results.7,29 Again, study heterogeneity with inclusion of other PTCL and, less often, B-cell lymphomas presenting in the nasal region in some analyses and a predominance of localized disease may explain discrepant results. Application of the IPI in the remaining subtypes has not been verified. However, it is unlikely that the IPI will be effective in risk stratification in those subtypes that present almost exclusively with high risk factor scores (eg. AILT, enteropathy-type and hepatosplenic cd).

207 expression of TH1 and/or TH2 surface chemokine receptors.30 In one analysis, two distinct subgroups with PTCLU were identified.based on the chemokine receptor profile: Group 1 positive for any of ST2(L)(TH2 marker, IL-1R family member), CCR5 (TH1) , CXCR3 (TH1); group 2 negative for all these markers.31 Group 1 cases, considered ‘functional’ based on the receptor expression had a more favorable prognosis compared to group 2 cases, however, adjustment for known clinical prognostic factors was not incorporated into this analysis.31 Of interest, in this study, cases of AILT demonstrated a TH1 profile (CXCR3+) and ALCL had a TH2 marker pattern (CCR4+) Tsuchiya, 2004 #194}. In a separate report the prognostic significance of CXCR3 was confirmed and CCR4 (TH2) expression was associated with a unfavorable outcome and remained significant after adjustment for the IPI.30 The functional significance of these chemokine receptor profiles remains unknown and confirmation of the prognostic value awaits further study. Optimistically, they may provide rationale new targets for novel therapies in this poor risk population.30,32

ALCL Other biological markers beyond the ALK phenotype have been determined to have prognostic significance in ALCL. Expression of CD56 and or/ survivin are associated with a inferior outcome in both ALK-pos and ALK-neg ALCL.33,34 In ALK-neg ALCL several other biological prognostic factors have been determined to impact clinical outcome. High numbers of activated (granzyme B+) cytotoxic T-lymphocytes and BCL2 expression are associated with a poor prognosis.28,35 Conversely, expression of caspase 3, a critical component in the pro-death pathways, is associated with a favourable outcome suggesting that alterations in apoptotic pathways may in part explain the prognostic differences between ALKpos and ALK-neg ALCL subtypes.35

Biological and Molecular Prognostic Factors

Gene Expression Profiling of PTCLs

PTCLU Attempts have been made to identify biologically and prognostically distinct subgroups within the morphologically and clinically heterogeneous PTCLU subtype. Most cases of PTCLU are CD4+CD8-, prompting speculation that within the CD4+, T-helper (TH) phenotype some of the biological heterogeneity may be explained by variable

Due to disease rarity, histological variability and frequent misclassification of T-cell lymphomas with other conditions, gene expression studies have been much less extensive in the T-cell lymphomas than in B-cell lymphomas. One of the first studies to gene expression profiling to explore the biology of PTCL tumors utilized the CNIO Oncochip to evaluate the gene signature of 42 newly diagnosed

208 T-cell lymphomas that included 34 PTCLs of various histologic subtypes and compared the gene expression pattern signature to normal cellular counterparts in addition to lymphoblastic lymphoma.36 Within the PTCL tumors, upstream and downstream targets of the NFjB pathway were featured in the molecular signature36 and a subsequent study focused only on the PTCLU and AILT subtypes, determined that those cases lacking an expression pattern of NFjB-related genes may have an inferior outcome.37 Another recent study evaluated 59 specimens of T-cell lymphomas including 32 cases of PTCLU using cDNA microarrays demonstrated clear separation of AILT and ALCL by gene expression profiling, however, not surprisingly, PTCLU did not share a single molecular profile. A mutli-class predictor was then utilized to distinguish three PTCLU subtypes by differences in their molecular signature: U1 (genes associated with poor outcome in other tumors eg. CCDN2); U2 (genes associated with T-cell activation and apoptosis eg. BCL2); U3 (genes associated with IFN/JAK STAT1 pathway and included Lennert’s lymphoma).38 There was a trend to worse outcome in the U1 group, however, validation of these results awaits a larger analysis. In a separate analysis focused exclusively on PTCLU, platelet derived growth factor alpha (PDGFRA) was determined to be differentially expressed using the Affymetrix U133 platform. Immunohistochemistry performed in 160 cases confirmed PDGFRA expression by the malignant cells, raising the possibility that this may be a therapeutic target in the disease.

Primary treatment approaches in PTCLs CHOP-type (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy is considered the standard therapy for PTCLs however, with the notable exception of ALK-pos ALCL, outcomes utilizing anthracycline-based regimens has been uniformly disappointing. The large intergroup trial established CHOP as equivalent but less toxic than 2nd and 3rd generation regimens in diffuse large-cell lymphoma, however this study was conducted prior to the routine use of immunophenotyping and thus the impact of specific regimens in the subgroup of patients with T-cell lymphomas was not assessable.39 There have been no randomized phase III studies since this landmark analysis that have compared CHOP to an alternate treatment regimen exclusively in PTCLs. However, a limited number of studies have evaluated doseintensive regimens in all aggressive lymphomas,

K.J. Savage including a subset with a T-cell phenotype. The German Non-Hodgkin’s Lymphoma Group (DSHNHL) recently evaluated whether the reduction of treatment intervals from 3 (CHOP-21) to 2 weeks (CHOP14) and/or the addition of etoposide (CHOEP) would improve outcome in elderly patients or young ‘good prognosis’ patients with aggressive lymphomas.40,41 In this pre-rituximab era, CHOP14 and CHOEP improved EFS and OS in elderly patients (NHL-B2) and young patients (NHL-B1), respectively.40,41 Although, a proportion of patients in each of these trials did have an aggressive lymphoma with a T-cell phenotype (5.8% (n = 40) NHL-B2; 13.7% (n-97) NHL-B1), most of the patients had anaplastic large cell lymphoma (without ALK status information) and further, insufficient numbers in each treatment group precluded analysis of the subset of patients with T-cell lymphoma in these two 4-arm trials.40,41 Other randomized studies in aggressive lymphomas also have only a small fraction of patients with T-cell lymphoma and fail to report outcome analyses for this patient subgroup. The remaining studies are retrospective in nature and have not demonstrated any definite superiority of any alternate chemotherapy regimen in T-cell lymphomas.7,42 It has been postulated that some of the chemoresistance in PTCLs relates to the expression of Pglycoprotein which has been previously shown to be higher in normal T-cells than B-cells.43 Consistent with this, there is some emerging evidence that anthracyclines may not influence outcome, at least in PTCLU,44 suggesting that CHOP may not be the appropriate chemotherapy backbone in this disease. As a result, some groups are exploring alternate chemotherapy regimens that employ agents that bypass the P-glycoprotein. Generally, treatment approaches to date have been similar among the PTCL subtypes. One exception is extranodal NK/T-cell lymphoma where radiotherapy appears to be the key treatment modality with more favorable outcomes observed in treatment regimens that incorporate radiotherapy.45–47 A recent large analysis of 105 patients from China with localized NK/TCL demonstrated that patients treated with primary radiotherapy had an equivalent 5 y OS (66% vs 76%) and PFS (61% vs 66%) to patients treated with combined modality strategies, suggesting that chemotherapy did not provide any additional benefit.48 Frequent progression during anthracycline-based chemotherapy has been observed in several studies of NK/T nasal type lymphoma suggesting an inherent resistance of these tumors to conventional systemic therapy that again, may be related to expression of P-glycoprotein resulting in multi-drug

Peripheral T-cell Lymphomas resistance.47 Because of this some groups have advocated the use of front-line radiotherapy in localized NK/T-cell lymphoma.47 Although there are limitations due to the retrospective nature of these analyses and biases introduced by the selection of patients for specific treatments, all of the studies demonstrated either equivalent or superior outcomes for radiotherapy alone compared to CMT. Collectively, these results suggest that radiation should be the primary therapy in localized NK/ T-cell lymphoma. However, both local and systemic relapse remain problematic, particularly in those with stage II disease, suggesting that new approaches are needed, perhaps combining radiotherapy with alternate, radiosensitizing chemotherapy.18 Further, survival in patients with more widespread disease at presentation is extremely poor, underscoring the need for improved chemotherapy. The other exception to the treatment paradigm for PTCLs is cut ALCL. This subtype typically has an indolent natural history and propensity to relapse. Most patients can be treated with localized excision with or without radiotherapy, reserving systemic chemotherapy to those patients with disseminated or extracutaneous disease.49

The role of high dose chemotherapy and stem cell transplant in PTCL Several small uncontrolled trials in PTCL have attempted to evaluate the role of high dose chemotherapy (HDC) and stem cell transplant (SCT) but are extremely heterogeneous making interpretation and study comparisons difficult. Some of these differences include: usage of varied lymphoma classification systems; combining distinct PTCL subtypes in outcome analyses; evaluation of both allogeneic and autologous transplants; combining those with primary and relapsed/refractory disease in survival analyses; use of variable salvage and conditioning regimens and; inclusion of pediatric cases in some analyses.2

Primary high dose chemotherapy and stem cell transplant in PTCL With poor outcomes in most patients with PTCL using CHOP-type treatment, several investigators have attempted to add consolidate treatment for patients with PTCL with HDC and SCT.50,51 (Table 5). The recent results of long term follow-up of two phase II studies evaluating HDC and SCT in

209 the primary therapy of PTCL demonstrated a 12 y EFS and OS of 30% and 34%, respectively.52 Not surprisingly, patients with ALK-pos ALCL had a superior EFS (54%) and OS (62%) compared to the other subtypes (19% 10 y EFS, 21% OS%), thus outcomes using this approach appear comparable to studies evaluating CHOP-type chemotherapy.52 In another study, 37 patients were transplanted in first CR with an encouraging 5 year OS of 80%50 (Table 5). However, this was a highly selected population of patients in a CR after CHOP chemotherapy, including some pediatric patients and a proportion of cases were ALCL with no information regarding ALK status.53 Reimer and colleagues prospectively evaluated primary transplant in patients in first remission (CR or PR) and published their initial resuls of 30 PTCL patients, excluding ALK-pos ALCL.54 With a median follow-up of 15 months, the transplantation rate was 70% and 72% of patients were in continuous CR (CCR). However, the updated results of 65 patients with longer follow-up demonstrates a transplant rate of 62% and a CCR of only 42%.55 This highlights the difficulty of early progression in PTCL and the need for improved initial chemotherapy. Several randomized phase III studies have been performed in aggressive lymphomas, including a subset of patients with T-cell lymphoma, comparing consolidative HDC SCT to various ‘standard’ therapies. The GELA study, LNH-93 evaluated a protocol of shortened chemotherapy course followed by HDC and SCT in comparison with ACVBP and sequential consolidative chemotherapy and found no benefit overall of transplant, including in those patients with a T-cell phenotype56 (Table 5). A matched control study was then performed using patients with T-cell lymphoma from this trial as well as from the LNH-87 trial (consolidative sequential chemotherapy vs HDC SCT) confining the analysis to patients who achieved a CR/ CRu and who were able to receive either HDC SCT (case group) or sequential chemotherapy (control group)57 (Table 5). Cases and controls were matched 1:1 by treatment protocol, histology (anaplastic or non-anaplastic PTCL), aaIPI, bone marrow involvement and number of extranodal sites. Among the 29 patients with non-anaplastic (including 2 lymphoblastic lymphoma), there was no difference in DFS (45% vs 38%) or OS (49% vs 44%) between the two groups (Table 5). In the absence of randomized trials proving superiority to conventional chemotherapy, use of HDC and SCT in the primary treatment remains experimental in any histological subtype.

210 Table 5 Selected Studies in the last 5 years evaluating the outcome of PTCL patients who have received High dose chemotherapy and autologous or allogeneic stem cell transplant as primary therapy. Publication First author

n

PTCL Subtype (n)

EFS/PFS

OS

Comments

52

Corradini, 2006 Prospective ph II

62

PTCL-U(28) ALK + ALCL(19) Other

30% (12 y)

34% (12 y)

2 prospective phase II trials 74% tranasplant rate Superior EFS ALK-pos ALCL (54 v 18% p = .006)

Reimer, 200454 Prospective ph II

30

PTCL-U(12) AILT (12)

–

76% CCR transplanted patients (median f/u 15 mos)

70% transplant rate 42% CCR in update at ASH 2005

Rodriguez (2003)50 Retrospective

37

PTCLU ALCL AILD Other

79% (5y)

80% (5y)

ALK status unknown; median age 31 for primary transplant

Mounier, 200272 item Randomized ph III

34

PTCL-U (23) AILT (3) ALCL(8)

56% (sequential consolidation) vs 54.5% (HDC SCT)

67% (sequential consolidation) vs 64% (HDC SCT)

Randomized phase III of high dose sequential vs HDC SCT in aggressive lymphomas first CR Matched-control analysis – HDC SCT vs sequential consolidation in CR/CRu patients ALK status unknown

Gisselbrecht, 200256

76

Non-anaplastic PTCL (55) Anaplastic (29)

30% (sequential consoliation) vs 20% (HDC SCT) p = .4

39% (ACVBP)vs 32% (HDC SCT)_p = .5

Randomized phase III trial of ACVB vs shortened chemotherapy and HDC SCT in aggressive lymphomas Included 12 patients with LBL Trial stopped early due to inferior results in transplant arm ALK status unknown

LBL (lymphoblastic lymphoma); CHT chemotherapy; HDC SCT (High dose chemotherapy and stem cell transplantation); EFS event free survival; PFS progression free survival; OS overall survival; CCR continuous complete remission.

K.J. Savage

Peripheral T-cell Lymphomas

Transplant in relapsed/refractory PTCL The PARMA study randomized controlled study established that HDC and SCT was superior to salvage chemotherapy alone in patients with relapsed, chemosensitive, bone marrow and CNS negative, aggressive lymphomas.58 Tumors were classified by the Working Formulation as either intermediate or high grade and immunophenotyping was not performed.58 Thus, this study does not address the value of HDC and SCT specifically in relapsed PTCL and there have been no prospective randomized studies since this report comparing transplantation to conventional salvage therapy in relapsed or refractory PTCL. In several retrospective series, patients with relapsed PTCL with chemosensitive disease respond favorably to HDC and SCT with long term survival rates of approximately 35–45% (Table 6).2 Two studies suggest that transplant success in non-ALCL patients is comparable to DLBCL, in the pre-rituximab treatment era59,60 (Table 6). One study found an inferior survival if only PTCLU is considered,61 however, as the survival estimates in all of these studies are comparable the differences likely reflect limitations by study size. In all analyses, patients with ALCL and in particular, ALK-pos, have superior salvage rates, often exceeding that observed in DLBCL (Table 6). The results in patients with refractory PTCL are less consistent with some studies reporting no long-term survivors and others reporting similar results to patients with relapsed disease if chemosensitivity is demonstrated (Table 6). Experience with allogeneic SCT in PTCL is limited. It is unknown whether a graft vs lymphoma effect in PTCL exists. Reduced intensity conditioning has recently emerged as an attractive strategy for patients at increased risk of treatment-related toxicity, although it has not been extensively evaluated in aggressive lymphomas. A small pilot study (n = 17) was recently performed evaluating RIC in patients with PTCL62 (Table 6). The majority of cases were PTCL-U9 and many had relapsed after autologous HDC SCT. Although this was a highly selected population including many with a history of late relapse and all demonstrating chemosensitive disease, the 3 y overall and progression-free survival were encouraging at 81% and 64%, respectively, and responses were observed after donor lymphocyte infusion suggesting that a graft-versus-T-cell lymphoma effect may exist.62

Novel Treatment Approaches For many PTCL patients current treatment strategies are largely ineffective and new therapies are being

211 explored. Limited success has been achieved in PTCLs with anthracycline-containing regimens since in most series only a small fraction enjoy long term survival. Nucleoside analogs have been recently gaining interest in this disease. Gemcitabine has shown activity in relapsed PTCLs as a single agent,63 and is currently being explored in combination with other agents in the primary treatment of PTCL. IL2-receptor (IL-2R) is a marker of T-cell differentiation and the CD25 subunit of this receptor is expressed in a subset of patients with PTCLU and CD30+ ALCL. Denileukin diftitox (ONTAK) is a fusion molecule of IL-2 to diphtheria toxin and has been shown to have efficacy in patients with cutaneous T-cell lymphoma and limited reports have also demonstrated tumor responses in relapsed PTCLs64 Table 4. Studies are ongoing combining this agent with CHOP. Antibodies directed at the CD25 subunit (human anti-TAC antibody, daclizumab) and an anti-CD25 recombinant immunotoxin are also currently been evaluated as potential therapeutic agents (Table 7). Histone deacetylase inhibitors (HDIs) are a new class of anti-neoplastic agents currently being evaluated in cancer clinical trials. Histone acetylation modulates gene expression, cellular differentiation and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deaceylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. Depsipeptide, an inhibitor of histone deacetylation has demonstrated activity in relapsed PTCL patients with a ORR 26% (Table 7).65 Recently, immunotherapy has emerged as an important adjunct to traditional cytotoxic chemotherapy in B-cell lymphomas. Alemtuzumab, a humanized monoclonal antibody directed against the CD52 antigen, present on most malignant T-cells making it an attractive target for PTCL. Additional widespread CD52 expression on normal T/B-cells, monocytes and macrophages results in profound immunosuppression and has restricted combination with chemotherapy. As a single agent in heavily pretreated patients with PTCL the overall response rate with alemtuzumab was 36% in one report.66 Combination of alemtuzumab with fludarabine, cyclophosphamide and doxorubicin in untreated and relapsed patients was evaluated in a variety of PTCLs.67 Of 18 evaluable patients, the majority had PTCLU (n = 10) with an overall response rate of 61% and those patients treated primarily with this regimen had a CR rate of 78%, however survival outcome measurements await longer follow-up. Of concern, over half of the patients developed CMV reactivation. Several other

212

Table 6

Selected studies high dose chemotherapy and allogeneic and autologous stem cell transplant for relapsed and refractory PTCL.

Publication first author Kelaramani, 2006

59

Jagasia (2004)60

n

PTCL Subtype (n)

EFS/PFS

OS

Comments

24

PTCLU (14) ALK-neg ALCL (4) AILT (4) Other PTCLU (6) ALCL (16) ALK-pos (7) ALK-neg (4) CUTALCL (5) AILD (3) NK/T-cell (3)

24%

33%

Included only patients with chemosensitive (PR/CR) disease Similar EFS (p = .14) and OS (p = .64) to DLBCL No difference relapsed vs refractory disease

50% (3y)

43% (6y)

Outcome analysis combined auto and allo transplants

Non-ALCL 38% (3y)

Non-ALCL 47% (3y)

ALK-pos ALCL 100%(3y) ALK-neg ALCL 0% (3y)

ALK-pos ALCL 100% (3y) ALK-neg ALCL 50% (3y)

ALK-pos ALCL superior outcome to other PTCLs and DLBCL

PTCLU (9) ALK-neg ALCL (4) AILD (4) PTCLU(*) ALCL AILD Other *not available

64% (3y)

81% (3y)

May include ALK-neg ALCL that were primary cutaneous

39% (5y)

45% (5y)

ALK status unknown; median age 31 for primary transplant No patient salvaged with refractory disease

PTCLU (18) ALCL (9)

37% (3y)

48% (3y)

ALCL (ALK status unknown) superior outcome to PTCLU and DLBCL

PTCLU 23% (3y) ALCL 67% (3y)

PTC U 35% (3y) ALCL 78% (3y)

28

Corradini (2004)62

17

Rodriguez (2003)53

78

Song (2003)61

36

AILD (2) NK/T (4) ETTL (1)

K.J. Savage

Peripheral T-cell Lymphomas Table 7

213

Targeted novel therapies in relapsed/refractory PTCLs Tox=toxicity; ORR = overall response rate.

Agent (s)

Nucleoside analogs Gemcitabine

Target

Histological subtypes evaluated

Clinical studies

Nucleoside analog; non-specific DNA syntheis inhibition

PTCL

60% ORR63

PTCL

Ph II ORR 14%73 Tox: 2 early deaths

IL2 receptor

PTCL

Ph II ORR 50%64

Histone de-aceylation

PTCL

Ph II ORR 26%65

CD52

PTCL

AraG 506U78 (Nelarabine)-pro-drug Immunotoxin Denileukin difitox Histone deaceylase Inhibitors Depsipeptide SAHA Immunotherapy Alemtuzumab

Alemtuzumab + fludarabine, cyclophosphamide + doxorubicin

CD52

Antibody to CD30 SGN30 (chimeric monoclonal antibody MDX-060 (fully human anti-CD30) 5F11 (fully human anti-CD30)

CD30

studies are ongoing evaluating alemtuzmab in combination with CHOP or CHOP-like therapy. Of concern, limited studies suggest that not all PTCLs uniformly express CD52 and this marker should be evaluated in all studies incorporating alemtuzumab.68 CD30 is uniformly expressed in ALCL and a subset of patients with PTCLU. With minimal expression on normal cells, it is the ideal therapeutic target. Phase I/II studies have been initiated with chimeric (SGN30) and fully humanized antibodies directed against CD30 (MDX-060, 5F11) in ALCL69,70 (Table 7). Several objective responses have been reported in Phase II reports, and ongoing studies with these agents suggest that an additive benefit in combination with chemotherapy. Unfortunately, the majority of PTCLs do not express this antigen and better targets, with limited expression on normal tissue, are needed. With recent studies demonstrating that a subset of patients with PTCLU express CCR4 which in turn correlates with poor outcome, studies are ongoing evaluating a monoclonal antibody directed against this target. Finally, studies are ongoing evaluating tumor vac-

Pilot ORR 36%66 Tox: CMV reactivation 43%; 36% TRM – study closed early Pilot ORR 61%; CR 78% primary PTCL except therapy67 ALK-pos ALCL (9 patients Tox: 81% grade III/IV leukocytopenia; primary) 56% CMV reactivation ALCL SGN30 -Ph II OR 33%69 Tox: well tolerated

ALCL CD30 pos ALCL

MDX-060 ORR 33% Tox: no MTD70 5F11 – Ph I study ongoing in CD30+ lymphomas

cines in PTCLs directed against the idiotypic TCR particularly in cutaneous TCLs and in ALK-pos ALCL, targeting the ALK protein.71 In summary PTCLs represent a heterogenous group of diseases which in most instances have a disappointing prognosis. Therapeutic progress has been slow due to disease rarity and inclusion in studies focused on B-cell NHL. With the development of microarray technology, the molecular heterogeneity of these diseases, particularly the very diverse subgroup PTCLU, may be better understood and provide clues as to new biological subtypes and highlight novel therapeutic targets. Future studies must focus on PTCLs in isolation, preferably as individual disease entities due to their unique clinical behavior, an effort that will require multi-institution collaboration.

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