Critical Reviews in Oncology/Hematology 71 (2009) 181–198

Current and future aggressive peripheral T-cell lymphoma treatmentparadigms, biological features and therapeutic molecular targets

J. Rodríguez a,∗, A. Gutiérrez b, B. Martínez-Delgado c, G. Perez-Manga a

a Service of Oncology, General University Hospital Gregorio Maranon, Madrid, Spainb Service of Hematology, University Hospital Son Dureta, Palma de Mallorca, Spain

c Centro Nacional de Investigaciones Oncológica (CNIO), Madrid, Spain

Accepted 15 October 2008

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822. Genomic profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1823. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1834. Chromosomal abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1835. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1846. Results of conventional regimens in PTCL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1857. Autologous stem cell transplantation in PTCL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

7.1. Frontline ASCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1867.2. Salvage therapy with ASCT in PTCL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1877.3. Results with transplant in other PTCL subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

8. Allogeneic stem cell transplantation experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1889. Conventional and new drugs in PTCL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

9.1. Nucleoside analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1899.2. Pralatrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1909.3. Histone-deacetylase inhibitors (HDAI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1909.4. Other drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

10. Other immune-based strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19010.1. Alemtuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19110.2. Ontak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19210.3. Anti-CD30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

11. Therapeutic strategy model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19212. Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Abstract

Prognosis of PTCL is generally poor when treated with conventional chemotherapy regimens used in B-cell aggressive lymphomas. Recentadvances in genomic and molecular profiling of PTCL have allowed to further insight this heterogeneous group of neoplasias and their mainprognostic factors. This review will try to summarize the main clinical problems related to standard frontline and salvage therapy, including

∗ Corresponding author at: Service of Oncology, General University Hospital Gregorio Maranon, C/ Doctor Esquerdo, 46. 28007 Madrid, Spain.Tel.: +34 91 586 80 00; fax: +34 91 586 80 18.

E-mail address: joseguez89@hotmail.com (J. Rodríguez).

1040-8428/$ – see front matter © 2008 Published by Elsevier Ireland Ltd.doi:10.1016/j.critrevonc.2008.10.011

182 J. Rodríguez et al. / Critical Reviews in Oncology/Hematology 71 (2009) 181–198

the use of conventional chemotherapy and high-dose, dose-dense and immunotherapeutic strategies, as well as new approaches based on

biological knowledge and the use of new drugs or immunotherapy.© 2008 Published by Elsevier Ireland Ltd.

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eywords: Peripheral T-cell lymphoma; Genomic profiling; Pathology; Tre

. Introduction

Peripheral T-cell lymphoma (PTCL) constitutes a rarend biologically heterogeneous group of lymphomas [1]Table 1). Prognosis is generally poor when treatedith conventional chemotherapy regimens used in B-

ell aggressive counterparts [2]. Moreover, the T-cellmmunophenotype is an independent prognostic factor in

ajor series of aggressive non-Hodking lymphoma (NHL)3–6]. However, not all PTCL display such a poor prog-osis. In fact, anaplastic large-cell lymphoma (ALCL)LK positive displays a better prognosis, not only with

espect to other aggressive PTCL subtypes, but also withespect to the corresponding aggressive B-cell lymphomas7].

This review will try to summarize the main clinicalroblems related to standard frontline and salvage therapy,ncluding the use of conventional chemotherapy and high-ose, dose-dense and immunotherapeutic strategies, as wells new approaches based on biological knowledge.

. Genomic profiling

Expression profiling using DNA microarrays has dramat-cally improved the knowledge of lymphoma pathobiology8–11] (Table 2). Among this group of lymphomas unspec-

able 1HO histological classification of mature T/NK-cell neoplasms.

odalPeripheral T-cell lymphoma, unspecifiedAnaplastic large cell lymphomaAngioimmunoblastic T-cell lymphoma

utaneousMycosis fungoides/Sézary syndromePrimary cutaneous CD30-positive T-cell lymphoproliferative disorders:

Primary cutaneous anaplastic large cell lymphomaLymphomatoid papulosisBorderline lesions

ther extranodalExtranodal NK/T cell lymphoma, nasal typeEnteropathy-type T-cell lymphomaHepatosplenic T-cell lymphomaSubcutaneous panniculitis-like T-cell lymphoma

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Hematopoietic stem cell transplantation; Immunotherapy; Target therapy

fied PTCL (PTCL-u) is the most frequent, accounting for0–70% of cases. However this group, as its own namendicates, is no more than an array of biologically differ-nt entities, as shown by recent molecular biology studies12–16]. Although, there is a great overlapping between enti-ies some authors have found particular differences in someTCL such as AIL and ALCL [12,17].

Indeed, different molecular subgroups within PTCL-uave been described by different studies. Martinez-Delgadot al. [18] were able to differentiate two different groups basedn the expression level of NF-�B pathway genes. Interest-ngly, these two groups differ both in response and prognosisith a worse prognosis for the group that do not express NF-B. This is surprising given the fact that in one of the genomicubgroups of diffuse large-cell lymphoma (DLCL) namely,he activated B-cell-like (ABC) subtype, the characteristiconstitutive overexpression of NF-�B confers a significantlyorse prognosis compared to the other Germinal Center sub-

ype which do not express it [9,11].One of the drawbacks of genomic profiling studies is

ecause of the lack of suitable cell lines in most of the

hoblastic T-cell lymphoma. Nevertheless recent studies are

able 2enomic profiling data on T-cell lymphomas.

ain studies Achievements

artinez-Delgado et al. [21] PTCL and lymphoblastic T-celllymphomas showed a completelydifferent gene expression profiles.

iccaluga et al. [91] PDGFR� is overexpressed in neoplasticcells of PTCL, and it is suggested as apotential therapeutic target.

artinez-Delgado et al. [18] Differentiate two groups of PTCL basedon the expression of NF-�B pathwayrelated genes.

hompson et al. [17] ALK+ and ALK− ALCL showeddifferent gene expression profiles.

allester et al. [13] Subdivided PTCL-u into three subgroups(U1, U2 and U3) characterized byspecific expression profiles.

e Leval et al. [12] Identification of a characteristic AILexpression profile and their putativenormal counterpart.

uadros et al. [24] Defined a proliferation signatureassociated to survival of nodal PTCL.

TCL: peripheral T-cell lymphoma; PDGFR�: platelet-derived growthactor receptor alpha; NF-�B: nuclear factor-kappa-B; ALK: anaplasticymphoma kinase; ALCL: anaplastic large-cell lymphoma; PTCL-u: PTCL-nspecified; AIL: angioimmunoblastic lymphoma.

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hedding light on the biological complexity of these dis-rders [19–21]. Another recent genomic profiling analysisy Ballester et al. [13] allowed the division of PTCL-u intohree discrete groups, which the authors named U1, U2, and3, respectively. The U1 gene expression signature includedenes associated with a poor outcome, including CCND2 rep-esenting a group with a predominance of proliferation overther tumor phenomena according to the Hanahan and Wein-erg model [22]. The U2 group was associated with a higherxpression of genes related to T-cell activation and apopto-is such as NF-�B1 and bcl-2. Finally the third group, called3, was defined by the overexpression of genes involved

n the IFN/JAK/STAT pathway and interestingly comprisedistiocyte-rich samples that are translated into a typical mor-hological variant, earlier called Lennert T-cell lymphoma23]. It is interesting to note that in this work, there is ane correlation between genomic and immunohistochem-

stry (IH) data, suggesting the feasibility of dividing thisype of lymphoma into three biological entities, which mayacilitate both diagnosis and therapeutic approaches. How-ver, although the U1 group tends to have worse prognosishan the other groups, there were no statistically signifi-ant survival differences among groups. Nevertheless, themall number of cases and the heterogeneity of clinicaleatures and treatment make it unrealistic to try to drawlinical relevance from the biological differences. The valuef this work relies on the identification of biological path-ays amenable to be targeted by specific drugs. In this vein,ur recently reported observation of a proliferative signa-ure associated with worse prognosis in these lymphomas24] confirms the findings of Ballester et al. in their U1roup.

In a small sample number study by Mahadevan et al., theuthors were able to establish differences between PTCL-und DLCL on the basis of genes involved in the relevantancer-related processes such as proliferation, apoptosis,ngiogenesis or invasion. In this study platelet derived growthactor alpha (PDGFR�), MET and STK6 emerged as theore discriminative genes and thereby subject to therapeutic

argeting in this PTCL-u [25]. Recently, in another gene-xpression profiling microarrays study, differences in ALCLith or without ALK expression have been established. In

act, a molecular signature of overexpression of four genes,CR7, CNTFR, IL22 and IL21 in patients with ALCL ALK−as shown. The corresponding overexpressed genes in theLK+ group were BCL-6, PTPN12, CEBPB and SERPINA1

17]. Accordingly, this study establishes important oncogenicifferences in these two ALCL entities with or without ALKxpression. The fact that these two entities have a differentrognosis might be explained by these molecular differences26]. PDGFR� was identified by Piccaluga et al. [16] as theost differentially expressed gene in a study analyzing the

xpression of 17 cases of PTCL-u. As it is possible to detectDGFR� by IH, this marker might be used to target this

yrosine kinase with the small molecule inhibitors alreadyvailable [27,28].

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logy/Hematology 71 (2009) 181–198 183

. Pathology

Several attempts have been made in order to functionallylassify PTCL into different subtypes based on the presencef cytotoxic granules and/or the type of T-cell, namely naiver memory T-cell [29,30]. Other complementary criteria haveeen made on the basis of the chemokine pattern expressed byhe T-cells in the different subtypes of PTCL [31]. Indeed, inonforming these criteria three discrete groups emerge [32],ne is represented by cytotoxic-memory T-cell (CD45RO)nd/or NK/T-cell extranodal lymphoma other than mycosisungoides (MF). A second group of non-cytotoxic memory-cell lymphoma encompasses nodal and cutaneous tumorsuch as angioimmunoblastic lymphoma (AIL), adult T-celleukemia/lymphoma and MF. The third group is representedy ALCL ALK+ tumors that express cytotoxic granules andre a naïve T-cell population (CD45RA). Oshima et al. [33]rouped PTCL grouped into 3 distinct subtypes accordingo the expression of CCR4, CCR3 and CXCR3 respectively.nterestingly, AIL constantly express CXCR3 [34]. Accord-ng to the chemokine receptor this division confers prognosticnformation. In fact, the prognosis of the group expressingCR4 is poor and the one expressing CCR3 is favourable.

Another method of classifying these tumors is based onypical Th1 or Th2 markers. In this vein, CD69 stainingorrelated with Th1 markers facilitating the division of the T-ell population conformed this marker available by IH [35].n this vein, AIL, Lennert-variant of PTCL and MF are allD69+. Similarly, another work separated PTCL into severalroups: OX40, CXCR3 identify cases of AIL, as 89% of casesxpress these markers; in ALCL, OX40−, CXCR3+ (24%)nd ST2(L)+ were found in 94% of cases. Accordingly, twoiscrete prognostic groups emerged: one of favourable prog-osis expressing ST2(L), CCR5 or CXCR3 and the other oforse prognosis being ST2(L), CCR5 AND CXCR3 negative

36].

. Chromosomal abnormalities

There have been a few studies describing the chromoso-al alterations observed in these lymphomas and possible

orrelations with both pathogenic mechanisms and progno-is [15,37,38]. In a recent study, 36 patients with de novoTCL were studied. There were losses in chromosome 13q in6%. Other losses were seen in 25–30% of cases in chromo-omes: 6q, 9p, 10q, 12q and 5q. Gains in chromosome 7q22ere observed in 31% of the cases. Amplifications in chro-osome 12p13 were also observed in cytotoxic PTCL. Other

enetic alterations typically present in ALCL were gains inq in 46% of cases, losses in 6q in 31% and losses of 13qn 23%. Interestingly, losses of 5q, 10q and 12q identified a

D5-positive PTCL discrete group [15].

Recently, specific genomic alterations in AIL and PTCL-uave been described pointing out marked differences amonghese groups. Interestingly, in both diseases more gains than

1 n Oncology/Hematology 71 (2009) 181–198

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Prognostic factors Values

Clinical variablesHistologic subtype Good: ALCL ALK+

Intermediate: PTCL-u, AIL,ALCL ALK-Worse: all other

Prognostic scores Adverse factors:Prognostic index for PTCL Age >60, high LDH, ECOG

PS > 1, BM infiltrationInternational prognostic index Age >60, AA stage III-IV, High

LDH, >1 ES, ECOG PS>1M.D. Anderson Tumor score B-symptoms, bulky mass, AA

stage III-IV, High LDH and highB2M

a-IPI + beta-2-microglobulin No versus 1 versus 2 adversefactors (a-IPI>1; high B2M)

Age + ECOG PS + LDH + Ki-67 Age >60 years, ECOG PS > 1,high LDH, Ki-67 ≥ 80

Biological variablesCCND2 AdverseNF-�B FavourableBCL-2/BCL-xL AdverseIFN/JAK/STAT pathway Not definedp53/p21 AdverseEBV AdverseCD26 Adverse

Detoxifying agents expressionGST-Pi AdverseTopo2-alfa Adverse

General resistance mechanismsMDR Adverse

Chemokine receptorsCCR3 FavourableCCR4 AdverseCXCR3 Medium

ALCL: anaplastic large-cell lymphoma; ALK: anaplastic lymphoma kinase;PTCL: peripheral T-cell lymphoma; AIL: angioimmunoblastic lymphoma;LDH: lactate dehydrogenase; ECOG PS: Eastern Cooperative OncologyGroup performance status; BM: bone marrow; AA: Ann Arbor; ES:extranodal sites, B2 M: beta-2-microglobulin; a-IPI: adjusted internationalper

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84 J. Rodríguez et al. / Critical Reviews i

osses, such as genetic imbalances, were observed [12]. Inhe same direction goes a work of Nelson et al identifyingecurrent chromosomal abnormalities in AIL, ALK− ALCLnd PTCL-u, showing a worst prognosis for cases with com-lex karyotypes, most frequently observed in ALK−, ALCLnd PTCL-u patients [38].

The transcripts of these defined alterations in these rareeported series of chromosomal abnormalities might provideasic information regarding molecular pathways involved inhese diseases and also potential therapeutic targets.

. Prognostic factors

Aside from the pathologic characterization according toifferent cytokine and chemokine expression by the differentTCL subtypes aforementioned, several other clinical andiological prognostic factors have been drawn from differ-nt series in this type of lymphomas. Table 3 depicts theseactors, grouping them into several classes, either clinical oriological. One of the most interesting recently describedndings is the identification of a proliferative signature able

o discriminate several subtypes of T-cell lymphoma. Further-ore, this signature is associated with prognosis [24]. Indeed,

he relationship between the overexpression of p53 and Ki-67as been highlighted as representative of high proliferationnd subsequently worse prognosis. In one report, overex-ression of p53 was present in 29% of the cases and theseases were associated with increased proliferation, bcl-2 pos-tivity in tumor cells and decreased p21 expression, linkingurvival signals to proliferation. Moreover in a multivariatenalysis the expression of p53 was the most important inde-endent prognostic factor [39]. Interestingly, 61% of p53+atients overexpress p-glycoprotein, which is associated withesistance to most major drugs effective in the aggressive lym-homas, such as anthracyclins, etoposide or vincristine [40].hus, this marker, easily available by IH, is useful to predict

esponse but also to inform of resistant mechanisms to theasic chemotherapy drugs used against these lymphomas.

Another basic lymphoma barrier to effective therapy is theverexpression of antiapoptotic proteins by the lymphomaell. Interestingly, 40–60% of patients with PTCL expresscl-2 and bcl-xL antiapoptotic proteins [41]. Of note is theact that ALK+ ALCL and enteropathy-type T-cell lymphomaave a distinctive pattern of expression, being bcl-2− andCL-1+. In the case of ALK+ ALCL, the presence of less

ntiapoptotic active mechanisms than in the other subtypesay explain the better prognosis with standard chemother-

py. However, enteropathy-type T-cell lymphoma with theame pattern has a poor prognosis that may be explained byhe coexistence of other resistance mechanisms.

Other single prognostic factors have been described. For

nstance, the expression of Epstein-Barr virus (EBV) in lym-homa cells has been associated with an adverse prognosisn PTCL but not in the corresponding aggressive B-cell lym-homas [42]. Other predictors of chemotherapy efficacy have

aai

rognostic index; CCND2: cyclin D2; NF-�B: nuclear factor-kappa B; EBV:pstein-Barr virus; GST-Pi: glutathione S-transferase-pi; MDR: multidrugesistance.

een reported including the expression of topo2-alfa andther detoxifying agents such as glutathione s-transferase-piGST-pi), which are associated to resistance to anthracyclinend alkylating agents commonly used in lymphoma therapy.his is interesting because recent retrospective data question

he role of doxorubicin or cisplatin in these types of lym-homa [43]. However, the heterogeneity of the populationegarding treatment, prognostic factors and the inclusion inhe analysis of different subtypes with different prognosis

akes this suggestion speculative at present.

Another interesting marker is CD26, which has been

ssociated to prognosis in these malignancies. CD26 isn exopeptidase with dipeptidyl peptidase enzymatic activ-ty, involved in purine metabolism. In fact, it catalyzes

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he deamination of Adenosine and 2′deoxyadenosine in theorresponding inosine and 2′deoxy-inosine. Its role as anctivation T-cell marker lies in its function as the surfaceipeptidyl peptidase IV (DPPIV) enzymatic functioning asbinding protein to extracellular matrix components [44].oreover, CD26 has been identified as the adenosine deam-

nase (ADA) binding protein that is expressed on the cellurface along with ADA [45]. Its role as unfavourable prog-ostic factor has been reported [46,47], as well as beingssociated with higher proliferative activity. Expression ofD26 has been reported in some T-cell entities especially

n ��+ T-cell malignancies, and T-cell lymphoblastic lym-homa, ALCL CD30+ and other PTCL lymphoma in variableroportions.

Some reports establish an association of CD26 expres-ion by the lymphoma cells and a lack of response to′-deoxycoformycin, although some other reports establishhe opposite [48]. Conversely, it has been argued that tumorells expressing CD26 are sensitive to doxorubicin [49]. Inhis regard the finding of no therapeutic benefit for PTCLatients treated with doxorubicin in retrospective data pro-ided by the International T group, may give the opportunityo test whether this was predicted by the CD26 condition ofhe tumor cells. In summary, CD26 could be a prognosticactor as well as a response predictor to important agents inhe treatment of this disease.

Recently, positive regulatory domain 1 (PRDM1) hasmerged as an unfavourable prognosis factor in PTCL. Its upregulated in PTCL-u, ALCL and in T/NK lymphomasnd is characteristically lost in AIL. Moreover its overexpres-ion is associated with overexpression of m-myc and IRF4.nterestingly Bortezomib, a proteasome inhibitor with majorctivity in multiple myeloma and mantle cell lymphomaespectively downregulates the positive regulatory domain(PRDM1), suggesting that this drug could be active in these-cell malignancies [50].

Apart from individual markers associated with prognosisn this type of lymphomas, no specific risk system had beeneported for these lymphomas until recently. In fact in mostublished works, usually retrospective studies, the lack ofniform treatment and the small number of cases of most ofhese series have made impossible to build on a robust systemrognosticator similar to the larger group of aggressive B-ell lymphomas. However, the most widely used risk systemor aggressive lymphomas, the international prognostic indexIPI) system, provides important prognostic information inhis group of nodal PTCL. In fact, the 4-year overall survivalOS) of the low risk group was 78% versus 0% for the high-isk group, with the low/intermediate and high/intermediateroups around 38% OS [51]. Of note is the characteristicistribution of patients with these lymphomas, with approxi-ately 60% of the patients belonging to the adverse groups.

ecently the Italian Group has presented two risk systems

hat allocate patients in different, widely differentiated prog-ostic groups, which allow the therapeutic decision process52,53]. In these systems, the bone marrow involvement and

pt

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logy/Hematology 71 (2009) 181–198 185

umor cell proliferation measured by IH with the Ki-67 mon-clonal antibody are proposed respectively. The other factorsn both systems are variables present in the IPI.

In an encouraging effort by the international PTCLroject a retrospective analysis on a large group of patientsith newly diagnosed PTCL and other non-PTCL subtypesas performed. Three independent factors emerged in theultivariate analysis: age greater than 60 years, Easternooperative Oncology Group performance status (ECOGS) higher than 1 and a lower than 150 thousand plateletumber were associated with poor prognosis with only 12%urvival in patients presenting the three adverse factors. How-ver, patients with no factors still only had 42% survival, thuso good prognosis group has been identified with this sys-em [43]. Other risk systems have been associated with theutcome in these type of lymphomas and the bottom line ofhis issue is that all of them provide valid information, whichs important not only for evaluation of therapeutic modal-ties in retrospective studies, but much more important forrospective studies that are now finally emerging. In the sal-age setting using high dose chemotherapy with autologoustem cell transplantation (ASCT) rescue a system based onhe a-IPI and beta-2-microglobuline has been proposed by theEL-TAMO (Spanish Lymphoma Group) on the basis of a

etrospective multivariate analysis of 123 patients with PTCLincluding 31% of cases of T-ALCL with unknown ALK),here no survivors at 5 years were found in patients present-

ng 2–3 factors of the a-IPI and high beta-2-microglobuline atransplant [54]. In this line, beta-2-microglobuline is a prog-ostic factor included in the M.D. Anderson Tumor Score.lthough not widely tested in PTCL, there are also several

vidences pointing to an adverse prognostic role in this groupf lymphomas [51,55].

. Results of conventional regimens in PTCL

Aggressive nodal and extranodal T-cell lymphomas haveworse prognosis than the corresponding aggressive B-

ell lymphomas. Moreover, the role of major drugs, suchs anthracycline and platinum, in aggressive lymphomas isuestionable in these T-cell malignancies [43]. Therefore, upo now there is no standard regimen for these malignancies.urthermore, the fact that different biological and clinicalntities cohabit inside the so-called group of PTCL preventshe finding of effective regimens in these diseases. In thisegard the three nodal aggressive T-cell lymphomas: PTCL-, nodal ALCL ALK− and AIL have been grouped togethern the clinical series described, despite the fact that thesentities present with distinct biological and clinical features.owever, as previously mentioned, until recently all of themere treated in the same way, due to the generally dismal

rognosis of this illness, along with a paucity of clinical trialsargeting these relatively low frequent neoplasias.

Frontline standard regimens such as CHOP or CHOP-ike regimens offer inferior results in all risk groups of the

1 n Oncology/Hematology 71 (2009) 181–198

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PI system compared to the corresponding B-cell aggressiveymphomas. In fact, the survival rate at 5 years with thesetandard regimens ranges from 20 to 35% [56]. Other regi-ens based on Ara-C or Platinum frequently used in salvage

hemotherapy regimens have not reflected superior resultso CHOP based regimens [57]. Therefore intense therapeu-ic modalities are being tested in order to improve theseesults.

. Autologous stem cell transplantation in PTCL

Cumulative experience shows that high dose chemother-py is the most effective salvage therapy in B-cell aggressiveymphoma [58]. However, the role of this therapeutic modal-ty is not as well defined in the corresponding PTCL. Herein,e review the most relevant experience with this treatment

n patients with this rare type of lymphoma, both as frontlineherapy in patients presenting with high risk features at diag-osis, and also as salvage therapy in primary refractory andelapsing patients. Finally, we will review the initial experi-nce with allogeneic stem cell transplantation as well as inhis type of disorders.

.1. Frontline ASCT

There is a paucity of data from retrospective studies con-erning the outcome of patients with PTCL treated withSCT as consolidation of chemosensitive response to ini-

ial induction treatment. The largest retrospective series waseported by the GEL-TAMO consisting of 74 patients withigh-risk features at diagnosis, who were transplanted atrst complete remission. In this study, with a prolongededian follow-up, these investigators reported an OS and

rogression-free survival (PFS) of 68 and 63%, respectively.n this retrospective study only the Prognostic Index for PTCLPIT) described by Gallamini et al. [52], showed prognosticalue for identification of a poor risk group who did not bene-t from this therapeutic modality. In spite of these rather goodesults, caution should be taken because this is a retrospectivetudy and thus subject to selection bias.

Prospective data with ASCT in patients with aggressiveTCL, excluding ALCL ALK+ cases, as frontline therapyre available although rare as only a few series [59–64], mostf them in abstract form, with enough number of patientsnd acceptable median observation time have been reportedTable 4). Therefore, no firm conclusions can be drawn fromhese preliminary data. Reimer et al. [65] reported prelim-nary data in 75 patients who underwent the procedure.orty-nine percent of the patients belonging to the higherisk groups of the IPI received the procedure as consolidationf frontline conventional chemotherapy. With a very short

edian observation time of 10 months, 42% of the patients

re in sustained remission. Of note, only 62% of the patientsere actually consolidated with ASCT due to progression or

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Recently at the ASH meeting, D’Amore et al. [61,66] inhe Nordic group, presented data of the largest series so farith 121 patients treated with ASCT as consolidation of an

nduction regimen based on dose dense CHOEP. In this studyith a short follow-up (2 years) 73% of the patients planned

o be transplanted underwent the procedure. Pretransplant,5% of the patients were in response: complete responseCR) (50%) or partial response (PR) (35%). In an inten-ion to treat analysis, therefore not excluding those patientsho, because of progression or toxicity, did not undergo therocedure, the actuarial OS at 3 years is 67%. However, inommon with Reimer’s study, around 30% of the patientslanning to receive the transplant failed to do so mainly due torogression or toxicity. Moreover, in a recent Spanish series63,64] of 41 patients with PTCL planned to receive ASCTs consolidation of an objective response to conventionalhemotherapy, the outcome of patients who did receive theransplant was quite good, with 86% disease free at 4 years of

edian follow up. Strikingly only 41% of the patients wereble to receive the transplant. This series also showed a 2.5-old more relapses in the chemosensitive non-transplantedroup, as well as a 2-fold more 4-year event-free survival inhe chemosensitive-transplanted sample, supporting the rolef frontline ASCT in high-risk PTCL.

In the same vein and in the longest median observationime study, Italian investigators [62] reported the outcomef 62 patients with PTCL, including 30% of patients withLCL ALK+. In this series the event-free survival (EFS) andS at 5 years was around 40% and 50%, respectively. Once

gain and similarly to the other series, 26% of the patientsailed to be transplanted for the same reasons: early progres-ion and/or toxicity. In another approach based on adjustinghe therapy depending on the response determined by Gal-ium scan after three cycles of conventional chemotherapy inn effort to diminish the number of early progressions, theEL-TAMO introduced the concept of early rescue at mid-

reatment in patients who are not in CR evaluated by bothallium scan and computerized tomography (CT) scan [60].ith this maneuver these investigators reported an encour-

ging 72 and 53% of survival and PFS, respectively, in 26atients with a median follow up of 35 months from diagno-is, and 24 months since the transplant. In this series only 23%f the patients did not get the transplant because of toxicity orrogression, suggesting that an early switch to an alternativective salvage therapy in patients not in CR at mid-treatmentight be a valid strategy to rescue a fraction of resistant

atients. However, the small number of patients and shortollow-up make it difficult to come to stronger conclusions.

Nevertheless, several lessons emerge from these frontlinetudies. The first one is that this procedure is relatively safe ashe transplant related mortality is consistently below 5% in allve series. Second, results with transplant as consolidation

eem to improve the outcome of these patients with high-riskeatures in PTCL. Indeed, the results of the patients who inact were transplanted are very similar in all series and strik-ngly are basically identical to the results in the retrospective

itlt

logy/Hematology 71 (2009) 181–198 187

eries of patients who received the transplant as consolida-ion of first CR. The third lesson is that around 30–60% ofatients do not reach transplantation due to early progressionr toxicity and 20–30% relapse after the transplant.

Thus, today with this therapeutic modality as consolida-ion of frontline therapy, approximately only 40–50% of theatients enjoy a prolonged survival. However, caution shoulde taken, as the follow-up of these series is still too short andnly a randomized trial could confirm whether ASCT is bet-er than other less intensive therapies. From these data wean infer that any therapeutic maneuver able to increase theumber of patients available to receive the transplant mayramatically improve the results. For this reason, new reg-mens able to increase both the number of remissions and,

ore importantly, the strategies focusing on diminishing theumber of early progressions and reducing the toxicity areagerly needed.

Another part of the problem is to identify the approxi-ately 25% of patients who eventually relapse after having

een in remission after the transplant. However, at presente do not know who these patients are, as no study has been

pecifically designed to identify the clinical and biologicalariables able to provide predictive information. Further-ore, due to the relatively small number of patients in these

rospective series at present it is not possible to identifyhis group of patients. Nevertheless, in the large retrospec-ive analysis reported by the GEL-TAMO [67] group, theIT system [52] was able to select a group of patients whoo not benefit from transplantation. Once again prospectivetudies with vast numbers of patients are needed to identifyiological and clinical variables. International efforts in thisirection are planned for the near future.

.2. Salvage therapy with ASCT in PTCL

Several series [68–74] with ASCT as salvage therapy inTCL has been published. In most of them similar resultsompared with the corresponding aggressive B-cell lym-homas were obtained. Blistad et al. [71] in one of the firsteries reported, showed a 58 and 48% survival and EFS in 40atients who underwent the procedure most of them as sal-age therapy in relapsing or refractory disease. Other seriesrom the GEL-TAMO group [68] and Memorial group [74]howed similar results.

The largest series with longer follow-up have beenecently reported by the Spanish GEL-TAMO group [75].n this series, 123 patients in refractory or relapsing diseaseere transplanted as salvage therapy. With a median followp of more than 5 years (61 months) the authors reported that1% of the patients were rendered CR after the transplant.nterestingly the OS and PFS at 5 years with such a pro-onged follow-up was 45 and 33%, respectively. Once again,

n the salvage setting, results with ASCT are equivalent tohe results obtained in the corresponding aggressive B-cellymphomas. Prognostic factors in this salvage setting withhis therapeutic modality have been rarely reported [73–75],

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s most series do not have enough statistic power to identifyiscrete risk groups.

However, in the GEL-TAMO series [75] of 123 patientsnew system is proposed, which is able to identify three

ery distinct risk groups. In fact, these investigators proposescore system based on the only variables significant in theultivariate analysis: the IPI system, taken as a binary covari-

te (0–1 versus 2–3) and elevated beta-2-microglobulin.urthermore, the population with no risk factors, which con-titutes 50% of the cases, have a 60% OS at 5 years versus8% for those 38% of the patients population who presentedith one risk factor at transplant. Interestingly, no patientith the presence of both factors at transplant, representing% of the population, was alive at 5 years. If confirmed inn independent series, this simple friendly system may allowhe adoption of other strategies in those patients who do notenefit from transplantation.

But perhaps the most unfavourable important factor iden-ified in this and most other series [69,71,76] as a surrogate ofransplant failure is refractoriness to the salvage regimen prioro the transplant. In fact, the outcome of patients transplantedn that situation is very poor with basically no survivors.his is best emphasized in another study reported by theame group, GEL-TAMO [68], where patients who did notbtain a CR with the frontline induction therapy were trans-lanted. While the outcome for the patients transplanted inrst PR is similar to chemosensitive patients treated in the sal-age setting, the outcome for the patients primarily refractoryas very poor. From these studies, a firm conclusion can berawn and this is the need for better salvage regimens. In fact,he regimens used in the largest group of B-cell lymphomas

ight not be so useful in PTCL.

.3. Results with transplant in other PTCL subtypes

There are a wide number of series available in ASCTn patients with ALCL [77,78]. Most studies do not spec-fy whether lymphoma cells display ALK or not. Howeverhe available series show excellent results in patients treatedn chemosensitive disease either as consolidation or as sal-age therapy in relapsing disease in both ALK+ and ALKnspecified. Moreover, given the excellent results obtainedith conventional anthracycline-based chemotherapy regi-ens in ALCL ALK+ [56,79,80], ASCT should be offered

nly to the rare primarily refractory patients of this type ofTCL. However, in the salvage setting, results in this sub-

ype of lymphomas do not seem to differ from the PTCL-uroup [75]. In fact, patients ALCL ALK− constitute a dif-erent entity [81,82] to those ALCL ALK+, with a poorerrognosis in most series [83] but appearing to be better thanTCL-NOS [84]. However, more series are needed in order

o establish a different outcome with ASCT since as men-

ioned previously most available series do not inform of theLK condition.The outcome with ASCT in the other extranodal PTCL

s anecdotal, as most information is based on case reports

e4pt

logy/Hematology 71 (2009) 181–198

r series with a very small number of patients. Neverthe-ess, the information available suggests results similar to theargest groups of PTCL. The two largest series in the litera-ure from Finland [85] and the United Kingdom [86] of 5 andpatients respectively, in enteropathy-associated T-cell lym-homa have opposite results. The Finland series has very pooresults in these patients with 40% tumor related mortality,hile the UK series reported no mortality by the procedure

nd high rate of CR with the transplant. Obviously more infor-ation is needed before concluding whether ASCT has a

ole in this extremely infrequent type of lymphomas. Otherisorders such as gamma-delta hepatosplenic lymphomas,ubcutaneous panniculitis-like subtype, etc., are representedn the literature by case reports [87,88] with a typical biaso report favourable results. Therefore no conclusions can berawn.

In AIL, there are several series [89,90] reported in the liter-ture offering data with transplant both as front-line therapys consolidation of first remission and as salvage therapy.nterestingly, results in both settings do not differ from theesults obtained in PTCL. In fact around 60% of OS at 5ears were reported in retrospective studies of patients whonderwent the procedure as front-line therapy [90]. How-ver, these retrospective studies are again biased by patientelection and only prospective studies can offer a more validicture of the reality with this treatment. Once again in thealvage setting the results are similar to those obtained inTCL. Moreover, most series include patients with this par-

icular group of nodal PTCL into the group of patients withransplanted PTCL [85]. Nevertheless, taking into accounthe uniqueness of this disorder with respect to biology and

olecular features [13,14,91,92], and more interestingly theffect of new therapy approaches [93–96], the role of this ther-peutic modality is undefined. Nevertheless, it may remains an option for patients with primary refractory or relapsingisease or as consolidation of first remission in patients pre-enting with unfavourable features at diagnosis. Althoughn this last setting more studies are needed to confirm thereliminary good results in the small current series.

. Allogeneic stem cell transplantation experience

At present, the experience with this therapeutic transplantodality in PTCL is limited although cumulative evidences

f a graft versus PTCL are being reported [70,97–100]. How-ver, patient population is usually highly selected; thereforet is difficult to have an insight into what this treatment reallyffers. Corradini et al. reported 17 patients with relapsed orefractory disease with an impressive OS of 80% and PFSf 60% at 3 years with only 6% transplant-related mortal-ty (TRM). Recently these investigators have updated their

xperience in 35 patients with a median follow-up now of4 months, a PFS of 49% and OS of 54%. Moreover, CRatients postransplant had a 72% PFS versus only 25% inhose chemorefractory at transplant.

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In addition, the European Group for Blood and Mar-ow Transplantation (EBMT) experience is very illustrativeoncerning the existence of a graft versus PTCL effectmanuscripts in preparation). They reported on 45 patientsith relapsing/refractory AIL who underwent a full condi-

ioned in 24 patients and a reduced intensity conditionedllo-SCT in the other 21 patients. With a median follow-upf 29 months OS and PFS at 5 years were 64 and 57%, respec-ively, with a plateau in the survival curve after the first yearrom the transplant. A large difference was observed betweenhe chemosensitive and refractory group in reference to OSnd PFS. Interestingly, the refractory group at transplant had36% PFS, suggesting that some of these patients can ben-

fit from this therapy. TRM was 24.5% with no differencesetween conventional versus low intensity procedure. How-ver, refractoriness at transplant predicted for a higher TRM.he corresponding experience in PTCL pertains to 91 patients

egistered. Of these 91 patients, 35 had failed an ASCT pre-iously. With a prolonged follow up of 50 months, the PFSt 4 years was 39% and the OS 43%. The TRM was 39% andnterestingly and similar to other series a plateau in the PFSnd OS curve were shown after two 2 years of the procedure.

Le Gouill et al. [101] have recently reported another largeeries in 77 patients with several subtypes of PTCL. Resultsgain were encouraging with a 57% 5-year OS and a corre-ponding 53% EFS. The TRM was 33%. Predictors of poorutcome in this series were refractory disease at transplantnd appearance of acute graft-versus-host disease (GVHD)rade III–IV by multivariate analysis. In accordance withost series results, several points need to be highlighted.irst, the presence of a plateau after 18–24 months after the

ransplant in the PFS and OS curve suggests cure of theisease. Second, a graft versus lymphoma effect is againuggested in this series as two patients relapsing after theransplant entered in a new remission with donor lymphocytenfusion (DLI). Third, although chemorefractory transplantare worse than the corresponding chemosensitive patients,till around 30% of these patients in this and the other seriestill benefit from the procedure. Fourth, disease status at trans-lant is a major predictor of the outcome with around 70%f patients in CR cured of their disease according to data ofhese three largest series.

On the basis of this encouraging data, two Europeanroups are launching randomized studies comparing bothutologous and allogeneic myeloablative procedures inatients with this group of lymphoma as consolidation ofrontline therapy. However, outside a formal trial this treat-ent modality should be limited to patients who fail anSCT. Moreover, some investigators reasoned that given

he poor results with conventional chemotherapy regimensnd even with ASCT as frontline therapy, where a sizableumber of patients succumb to their disease, it is proposed

hat if a donor is available, patients with high-risk features

ay be consolidated with a reduced intensity allogeneic non-yeloablative procedure. Trials testing this hypothesis are

ngoing and results are eagerly expected.

Ppid

logy/Hematology 71 (2009) 181–198 189

. Conventional and new drugs in PTCL

Disease-specific therapeutic strategies will require sub-tantial efforts. Up to now only a few drugs seem to havepecific toxicity in these malignant T-cells.

.1. Nucleoside analogues

In the past Pentostatin was the nucleoside analogue withhe most experience in these malignancies. Several studiesave shown an important level of activity in T-cell lym-homas. However, the number of PTCL cases is too smallo properly evaluate the activity of this drug. Nevertheless,n the largest series published so far by M.D. Anderson Can-er Centre investigators an important percentage of responsesas observed in refractory and relapsed patients with PTCL,

lthough the response duration was usually short [102,103].nfortunately, there is a lack of experience with com-inations incorporating this drug into conventional activehemotherapy regimens. Predictors of response to Pento-tatin are not known. However some reports establish anssociation of CD26 expression by the lymphoma cells andack of response to 2′-deoxycoformycin, while others estab-ish just the opposite [48,49]. Thus, different entities or initro conditions may explain these opposite results. This issuehould be resolved in order to establish CD26 as a predictorarker of Pentostatin response.Newer compounds of this type of drugs with impor-

ant activity, more relevant and relatively specific activity inhese malignancies are gemcitabine, nelarabine and clofara-ine [104,105]. However, other nucleoside analogues suchs fludarabine and clorodeoxiadenosine that have substan-ial activity in some B-cell malignancies do not have suchmportant activity in this group of lymphomas. As mentioned,reclinical activity indicates that nelarabine could be selec-ively toxic to T cells. In fact preliminary data in phase Itudies show excellent activity in pediatric T-lymphoblasticymphoma [106,107]. Similar activity has been observedn adult phase II studies in patients with PTCL [108,109].lthough in vitro data and preliminary experience withew nucleoside analogues (nelarabine and clofarabine) areppealing, safety data and efficacy in acceptable number ofatients are lacking.

Efficacy of gemcitabine data in these disorders is wide.inzani et al. [110] report data in a phase II study of4 patients previously treated, 30 of them with mycosisungoides and 14 cases with PTCL-u with exclusive skinnvolvement. More than 80% of the patients respondedith 11% CR. There were interestingly no differences in

esponse between patients with both histologies. Updatedesults by the same group demonstrated meaningful activ-ty of this drug in both cutaneous T-cell lymphomas and

TCL. Other series with heterogeneous types of T-cell lym-homas confirmed the activity of this nucleoside analoguen these disorders [111]. Interestingly the toxicity of thisrug is very manageable with neutropenia and thrombocy-

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openia grade III in around 20% of the cases and less than0% of the patients showing hematological grade IV toxic-ty.

A major point in designing regimens including theseucleoside analogues is to test whether there may be syn-rgism if administered with other chemotherapy drugs inombination. In this respect the effect in the activation ofpoptosis in response to inhibition of DNA repair processesriggering by DNA damaging agents such as alkylating, tri-zine compounds (dacarbazine, procarbazine, etc.) or thosehat elicit larger DNA adducts such as platinum derivativesre appealing [112]. Accordingly, the interaction of nucle-side analogues with DNA damaging agents that initiatexcision DNA repair mechanisms are a new mechanism ofell toxicity in T-cell lymphoma cells that merit being testedn the clinic [105]. Moreover, feasibility studies of these com-inations are eagerly needed, due to the lack of specific activeombinations in T-cell malignancies.

Forodesine is an inhibitor of purine nucleoside phospho-ylase (PNP), which is the key enzyme that phosphorylates′-deoxy guanosine to guanine [113]. Interestingly, mutationsf PNP cause T-cell lymphopenia. Furthermore, the obser-ation that pediatric patients with genetic PNP deficiencyresented with profound T-cell lymphopenia [114] gave riseo interest in testing PNP inhibitors in the treatment of T-cellisorders.

Several inhibitors are known: acyclovir, allopurinol,-mercaptopurine, etc. However, the deazanucleoside ana-ogues termed immunocillins are the only ones endowedith therapeutically appealing PNP inhibition power. Among

hese derivates, Forodesine (immunocillin-H) is the bestositioned [115]. Preclinical studies have shown promisingesults, which will foster clinical studies [116]. Followingphase I study that shows safety and feasibility to obtain

ppropriate pharmacokinetics parameters; ongoing phase IItudies are exploring the efficacy of protracted intravenousormulations. Meanwhile, a phase I with an oral formulations ongoing.

.2. Pralatrexate

Pralatrexate is one of the most promising drugs with activ-ty in PTCL. Indeed this drug seems to be very specific tohis type of lymphomas according to phase I studies [117].his is a new antifolate with a high affinity for the reduced

olate carrier type 1 (RFC-1) [118]. This increased affinityor the carrier compared to the other antifolates significantlymproves its intrusion into the cell, increasing its cytotoxic-ty. The dose-limiting toxicity in the available phase I studyas mucositis that was substantially abrogated by the con-

omitant treatment with vit B12 and leucovorin. Preliminaryata in 16 patients show encouraging 63% responses, all but

ne CR. If confirmed these data offer an outstanding levelf activity in this heavily resistant patient population. More-ver, it seems that this drug could be a very specific agent forTCL.

1

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logy/Hematology 71 (2009) 181–198

.3. Histone-deacetylase inhibitors (HDAI)

Abnormal activity of histone deacetylases resulting inberrant gene transcription is commonly observed in lym-homa and other tumor cells [119]. Histone deacetylasenhibitors induce changes in gene expression that lead to cel-ular differentiation and may eventually reverse the tumor cellhenotype [120]. This new type of drugs by inducing acety-ation of histones, transcription factors and other key cellroteins elicit differentiation, cell cycle arrest and apoptosis121].

Among the different classes of HDAI, two drugshow meaningful if not dramatic effects. Depsipeptide anduberoylanilide hydroxamic acid (SAHA), in a phase II study,1 patients with CTCL and 34 with PTCL entered into thetudy. Depsipeptide was administered as a 4 h infusion onays 1, 8 and 15 of a 28 days cycle at doses of 14 mg/m2.omplete and partial responses were seen in both cohorts ofatients [122]. Specifically in 26 patients with PTCL, thereere 24% responses including 12% complete responses.oxicity was mild and manageable with fatigue, nausea,omiting, and transient granulocytopenia, lymphopenia andhrombocytopenia the most reported. However, concern haseen aroused regarding potential cardiac events triggeredy this drug. In fact since the beginning in animal studiesepsipeptide has been associated with by electrocardiogramhanges occurring in patients treated with this drug. However,o organic miocardial injury associated with these changesas been shown so far [123]. All the cardiac disorders, inome cases lethal, which occur during depsipeptide trials,ave occurred in patients with prior cardiac risk factors.evertheless, the presence of cardiac disorders may exclude

hese patients from either entering into HDAI trials or if con-rmed making them unable to be treated with these importantgents. Results with the other most investigated HDAI SAHAre encouraging in PTCL as well, although most experienceome from CTCL [124].

.4. Other drugs

Gallium nitrate, bortezomib, temsirolimus and others areubject to active investigation, although only in vitro pre-iminary information is available [125,126]. Other agentsurrently investigated in these lymphomas are listed inable 5. Among them immunomodulatory agents, such as

halidomide and lenalidomide, have shown activity in caseeports. Moreover the multiple mechanisms of action includ-ng antiangiogenesis of these drugs and the pathogenichenomena characteristic of most of these lymphomas offerheoretical rationality to further test these drugs [127].

0. Other immune-based strategies

Monoclonal antibodies or immunotoxins represent a newind of therapy in lymphomas. After the massive implemen-

J. Rodríguez et al. / Critical Reviews in Onco

Table 5New agents in PTCL.

Nucleoside analogues/antimetabolitesNelarabine, clofarabine, gemcitabinePralatrexate

Inhibitors of PNPForodesine

HDAIDesipeptideSAHA

Immunomodulatory/antiangiogenic drugsThalidomideLenalidomide

Molecular targetsNF-�B inhibition: Bortezomibm-Tor inhibition: temsirolimusApoptotic molecules: anti-BCL-2 agents

PTCL: peripheral T-cell lymphoma; PNP: purine nucleoside phosphorylase;Ha

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ation of Rituximab in CD20 expressing B-cell lymphomas,everal antigens present in normal and malignant counter-arts have been targeted by designed monoclonal antibodiesr immunotoxins. In general terms these agents mediateheir anti-tumor effects throughout three major mechanismsncluding antibody-dependent cellular toxicity (ADCC),omplement dependent cytotoxicity and less well knownntrinsic pro-apoptotic actions which may be potentiatedhen coupled with active chemotherapeutic agents. Alem-

uzumab, Ontak and the anti-CD30 are the most developedgents in this category for treating these disorders.

0.1. Alemtuzumab

Alemtuzumab is a humanized IgG1 MoAb targeting thelycosylated peptide cell surface antigen CD52 that is presentn variable density in the cell surface of normal and malig-ant B and T cells, but is notably absent in the hematopoietictem cell [128]. After its approval by the FDA for the treat-ent of refractory B-CLL, alemtuzumab has been developed

s a therapeutic agent in T-cell malignancies. Most experi-nce comes from cutaneous T-cell lymphomas where it hasmportant activity. In a phase II multicentric study reportedy Lundin et al. [129], the overall response in 22 patientsxtensively treated with a median of 3 previous regimensas 55 with 32% complete responses. Doses of Alem-

uzumab were based on the doses previously used in theLL experience. Of note, in this study there was substan-

ial toxicity, mainly infections related with CMV activation.owever, other types of infections were observed includ-

ng herpes simplex, mycobacterium pneumoniae and some

ases of fatal aspergillosis. Hematologic toxicity affected8% of the patients. However, all grade 4 cytopenias wereeversible once alemtuzumab treatment was discontinued.everal considerations should be known before treatment

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logy/Hematology 71 (2009) 181–198 191

ith this agent is designed: first, the need for frequent CMVesting according to well-known guidelines from the allo-eneic stem cell transplantation universe; second, the needor prophylaxis with antiviral and antimycotic agents. Insingle study of Alemtuzumab in 14 patients with PTCL

elapsing after 1 or two lines of chemotherapy, Enblad etl. reported 36% response rate with three patients achievingR. However, substantial toxicity including five treatment-

elated deaths lead to the closing of the study prematurely130].

Based on this and other smaller studies proving Alem-uzumab activity in refractory/relapsing T-cell malignancies,ecent studies using Alemtuzumab combinations with activehemotherapy regimens generally in a less treated populationr less advanced disease have been reported. In a recent studyf patients with PTCL at first diagnosis or at relapse, Alem-uzumab in combination with a regime including fludarabine,yclophosphamide, and doxorubicin was performed. Dosesf Alemtuzumab given intravenously were 30 mg twice perycle. A striking 73% CR rate was reported in the naïve PTCLatients. Results in the salvage setting were substantiallyorse and the toxicity in this later population was notable

131].Other recent studies combining Alemtuzumab and CHOP

ave been reported with preliminary data. Although theesponse rate is acceptable (50–70%), the toxicity is still anssue. Recently Gallamini et al. [132] reported data of 24atients with PTCL who received treatment with CHOP andlemtuzumab in combination as primary treatment. Alem-

uzumab at 30 mg subcutaneously at day −1 was added tohe conventional CHOP regimen. A reported 71% of CRas obtained and at a median observation time of 16 months3 patients out of 24 remain free of disease with a medianuration of response of 11 months. Even though these datas encouraging, the toxicity of the regimen was substantials severe infections with Pneumocistis carinii, pulmonaryspergillosis and Staphylococcus sepsis and pneumonia wereocumented. Furthermore, severe neutropenia was observedn 34% of the cycles. Despite this degree of mainly infec-ion side effects due to the combination, the authors claimhat with infectious prophylaxis and caution the toxicity is

anageable and the activity rate is encouraging in this poorrognosis group of lymphomas.

As a whole, Alemtuzumab is an active drug in PTCLhat can be combined with active chemotherapy regimensnd offers an encouraging remissions rate. However, exper-ise and caution in its use is mandatory as potentially severenfection complications may result. The schedule of admin-stration, duration, pharmacokinetic and pharmacodynamicssues remain unknown and should be actively investigatedn order to incorporate this important drug into the treatmentf these rare types of lymphoma. Furthermore the expres-

ion of the target CD52 by immunohistochemistry is notniform in different subtypes of lymphomas and, more impor-antly, in some cases the expression level is as low as 35%f the cases in PTCL-u in a recent study [128,133]. Thus,

1 n Oncology/Hematology 71 (2009) 181–198

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Addressing induction failures and early relapsesThe precise role of high-dose therapy and ASCTIs consolidation with ASCT necessary always in first-line complete or

good partial responders?The precise role of dose-dense strategiesDefining the utility of new drugs alone or in combinationImplementing in the routine molecular tools to assess response and

minimal residual disease

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92 J. Rodríguez et al. / Critical Reviews i

se of Alemtuzumab in this setting is questionable. By thether hand, responses have been observed (unpublished data)n CD52 negative cases, considering them as pitfalls of theD52 technic. Anyhow, this important drug needs to be for-ally tested and, in this respect an international randomized

tudy is being launched testing the superiority of Alem-uzumab combined to dose dense CHOP14 versus CHOP14lone.

0.2. Ontak

Denileukin diftitox (Ontak) is an immunotoxin: a genet-cally engineered recombinant fusion protein composed ofhe full-length interleukin 2 and the catalytic domain ofiphtheria toxin. Ontak received approval by the FDA forhe treatment of cutaneous T-cell Lymphoma in 1999, aftermpressive activity observed in a phase III multicentric study134]. Since then, it has been extensively tested in severalematologic and immunological diseases with an encourag-ng activity and most importantly low toxicity [135–137].xperience with this agent in PTCL is anecdotal but stud-

es are ongoing to test the safety and efficacy of this drugn several T-cell lymphomas subtypes. In fact, Dang et al.eported [138] a response rate of 48% with 20% CR raten 25 valuable patients with PTCL treated with this com-ound. Amazingly responses were seen in CD25-negativeases.

Since the toxicity profile of Ontak is very favourablend basically there is no myelotoxicity and its activity levels shown is important, this compound could ideally bencorporated into active combinations. In this respect theOMPACT trial is testing a combination of Ontak and CHOP

n patients with newly diagnosed aggressive T-cell lym-homa. In an Interim analysis presented at the ASH-2006eeting, an impressive 87% response rate was observed in

5 evaluable patients, most of them CR. Interestingly in thisnalysis the toxicity profile is very favourable [139]. Thus,his combination may represent an interesting regimen in theery small therapeutic armamentarium of these malignan-ies.

0.3. Anti-CD30

Anti-CD30 is another monoclonal antibody that is cur-ently being studied in T-cell lymphomas expressing CD30,hich is mostly restricted to ALCL. Activity has beenbserved [140] but the small number of patients treated soar and the short follow-up makes a valid appraisal of itsctivity and feasibility difficult.

1. Therapeutic strategy model

There are some clinical tenets, which we should take intoonsideration in order to establish a rational therapeutic strat-gy. Table 6 depicts some of these observations. First, the

t

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TCL: peripheral T-cell lymphoma; ASCT: autologous stem cell transplan-ation.

act that in spite of a relatively high response rate with novelose dense chemotherapy combinations, a sizable percentagef patients (25–50%) progress during the treatment or ear-ier after stopping. This fact should guide the correspondingtrategies in order to address this situation. The GEL-TAMOroup reported data of a small study of 26 patients that inrder to reduce this problem (early progression) were eval-ated for response after three cycles and then if not in CRere switched to an alternative active salvage regimen. This

trategy may save some patients from early progression dur-ng the treatment. Other strategies to increase the stability ofhe response should be proposed.

There are other questions still remaining; for example,hould all patients who achieved a complete response orgood partial response be consolidated with ASCT? Here

he problem is that several studies show that patients doot benefit from this consolidation. However, there are noandomized studies that might point out which patient sub-roup would do equally well without the transplant. This ismportant, because it is possible that with the current intensehemoimmunotherapy regimens a good prognosis group maymerge and in this group consolidation with ASCT may note needed, eliminating substantial toxicity in a percentage ofhe population. However, at present there is no such ongo-ng study. This randomized study should be a priority, but its important to remain conscious of the difficulties of carry-ng out such a study, which would only be possible with annternational effort.

Combinations of some of these new agents with stan-ard therapy should be tested in the near future as theseombinations could increase the complete response rate andopefully make these responses more stable. Proliferation haseen identified in genomic profiling studies as the predictorf responses and also shown before early progression. Thiss a typical phenomenon observed in patients who initiallyespond to the treatment, and thus theoretically dose-denseegimens such as CHOP14 or CHOEP14 could be of ben-fit to these patients. In this regard chemoimmunotherapyith dose-dense CHOP and Alemtuzumab or Ontak are being

ested in two international randomized studies.

In this vein the German Group has recently presented the

nal analysis of a Phase II study of dose dense CHOP14n elderly patients or CHOEP14 in the younger ones with

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onsolidation with Alemtuzumab [141]. Even though the EFSs modest at 2 years (32%), it is interesting that for thoseatients that were consolidated with Alemtuzumab (70% ofhe patients) the EFS at 2 years was 44%, suggesting thatf toxicity is conveniently managed or if Alemtuzumab isncorporated into the chemotherapy regimen rather than at thend of the treatment as consolidation, when toxicity by therevious chemotherapy administered is at play, there coulde room for improvement.

Other combinations with drugs of interesting rational inhis kind of lymphomas are equally appealing. For instance,evazizumab and other antiangiogenic agents are of theo-etical interest. The current dilemma is how to incorporatehese drugs: as single agents or in combinations with con-entional chemotherapy in frontline regimens. Moreover, theare but ongoing molecular information shows genetic alter-tions involved in the malignant lymphoma transformation.his knowledge, similarly to what happens in the B-cell

ymphomas, sheds light on the new therapeutic targets thatould eventually be drugable. Other immunomodulators withroad action mechanisms; such as lenalidomide or thalido-ide, with preliminary activity in some subtypes of these

ymphomas, should also be studied in meaningful combina-ions.

According to most studies, approximately a quarter of theatients who enter into complete remission still relapse. Thus,he issue of maintenance treatment with relatively non-toxicffective agents also apply in these lymphomas. However,uch agents are not yet ready to test this hypothesis. Fur-hermore, the importance of minimal residual disease in theutcome of these lymphomas has not been established, andeither has it in other B-cell lymphomas. Implementing meth-ds to measure residual disease by the typical T-cell receptorlonal marker by polymerase chain reaction (PCR) tech-iques should be studied. In this setting finding a clonalarker in either blood or bone marrow would be instrumental.ailoring therapies to obtain molecular remission and show-

ng the importance of molecular remission in the outcome areound questions of real clinical importance.

Answers to the questions in the different phases of thereatment may in fact provide important information thatill transfer into future strategies that improve current

esults in these malignancies. Another important questions whether different biologies that start to emerge fromenomic profile studies can be specifically targeted. In thisegard delineate the nodal T-cell lymphoma conforming tohe Hanahan–Weinberg schema may provide information ofpecific targets which can be drugable. Furthermore on theasis of the biological heterogeneity the new active agentsn this broad group of lymphomas can be more efficientlyvaluated to grade their activity in the different biologicalroups. Extensive research is eagerly needed as PTCL are

ehind other more frequent lymphomas in therapy. There-ore the challenge for the near future is magnificent. Table 6how some of these research questions whose answers mayramatically change the outcome of these.

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logy/Hematology 71 (2009) 181–198 193

2. Conclusion and future perspectives

Although infrequent, these types of lymphomas are behindhe other lymphomas in both molecular biology knowledgend treatment results. Only recently international efforts areutting into motion both biological studies and targeted newreatments for this type of lymphomas. At present, front-ine therapy with consolidation with ASCT offers the bestesults according to recent phase II studies. However, noandomized study has ever been performed, therefore thishould be a priority in order to show whether this promisingpproach really improves the outcome of these unfavourableisorders.

Moreover, similarly with the corresponding aggressive-cell lymphomas, where the role of active monoclonalntibodies as purging drugs to obtain a tumor-free inocu-um seems to improve the outcome [142], this strategyan also be tested in PTCL by using monoclonal antibod-es against T lymphoma cells with known activity such aslemtuzumab [143]. Moreover, in an effort to decrease theercentage of patients who progress early, even when onreatment owing to early tumor repopulation, dose-denseormulations may favourably impact in this regard. Thus,hemoimmunotherapy regimens, which incorporate activeonoclonal antibodies such as Alemtuzumab in these T-cell

ymphomas coupled with dose-dense chemotherapy activeegimens, are appealing maneuvers in the treatment of thisisease.

Finally, it seems that light is starting to be noticed con-erning the care of these patients. However, as always withelatively rare diseases, only well organized internationalfforts are able to advance in the treatment of these disor-ers. As genomic and molecular studies of this group of rareumors are increasingly being reported, novel therapeutic tar-ets are being elucidated. Accordingly, biological markersf the disease can be defined. Moreover, it might be usefulo divide them into discrete prognostic groups, according tohe biological markers representative of the basic biologi-al phenomena described by Hanahann and Weinberg. Thisould define key specific biological targets of the differentubgroups of these lymphomas and, more importantly, leado meaningful new therapies to improve the current dismalrognosis of most of these disorders.

eviewers

Fernando Cabanillas, M.D., Clinical Professor, MDnderson Cancer Center, Medical Director, Auxilio Mutuoancer Center, P.O. Box 191227, San Juan 00919-1227,uerto Rico.

Michael J. Robertson, M.D., Professor, Indiana Univer-

ity School of Medicine, Dept. of Medicine, Division ofematology/Oncology, Indiana Cancer Pavilion, Room 473,35 Barnhill Drive, Indianapolis, IN 46202-5289, Unitedtates.

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onflict of interest statement

We state that we have nothing to declare in terms of conflictf interest, including any financial or personal relationshipsith other people or organizations that could inappropriately

nfluence (bias) this work.

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iographies

Dr. Jose Rodriguez, M.D., Ph.D., is an oncologist formedn the M.D. Anderson Cancer Centre (USA). During sev-ral years first in M.D. Anderson Cancer Centre and after

1 n Onco

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g(wtis

pAai

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of the Service of Medical Oncology of the General Univer-

98 J. Rodríguez et al. / Critical Reviews i

n Spain inside GEL-TAMO (Spanish Lymphoma Group)eveloped several lines of work on lymphomas and specif-cally on peripheral T-cell lymphoma including the largeretrospective series using autologous stem cell transplanta-ion and the third published prospective phase II trial of therontline use of ASCT in PTCL. Currently he works in theeneral University Hospital Gregorio Maranon of Madrid

nd directed several clinical and translational research pro-rams in PTCL in collaboration with the GEL-TAMO andNIO.

Dr. Antonio Gutierrez, M.D., Ph.D., is an hematolo-ist formed in the Clinical University Hospital of ValenciaSpain). Together with Dr. Jose Rodriguez he has actively

orked in the field of PTCL studying biological events in

heir pathogenesis, immunotherapy and the value of ASCTn the treatment of PTCL, including the larger retrospectiveeries using autologous stem cell transplantation and the third

sts

logy/Hematology 71 (2009) 181–198

ublished prospective phase II trial of the frontline use ofSCT in PTCL. Currently he develops several translational

nd clinical lines of work in lymphomas, with special interestn PTCL and other neoplasms.

Dra. Beatriz Martínez-Delgado is a Ph.D. in Biologic Sci-nces, staff in the Human Genetics Department of the CNIO,adrid (Spain). She has great experience in molecular biol-

gy and genomic profiling in lymphomas and counts withome of the most important contributions in the genomicrofiling of PTCL.

Dr. Gumersindo Perez-Manga, M.D. Ph.D., is the Head

ity Hospital Gregorio Maranon and Associate Professor ofhe University Complutense, Madrid. Currently he directedeveral research lines in medical oncology.