Anaplastic large cell lymphoma, ALK-positive

Critical Reviews in Oncology/Hematology 83 (2012) 293–302

Anaplastic large cell lymphoma, ALK-positive Andrés J.M. Ferreri a,b,∗ , Silvia Govi a,b , Stefano A. Pileri c , Kerry J. Savage d a Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy Haematopathology Unit, Department of Haematology and Oncological Sciences “L. and A. Seràgnoli”, Bologna University School of Medicine, Bologna, Italy d Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada b

c

Accepted 14 February 2012

Contents 1.

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3. 4. 5. 6.

General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Incidence and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Anaplastic lymphoma kinase (ALK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Immunophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Genetic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging system and procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. First-line treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Treatment of relapsed or refractory disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. New drugs or experimental approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) is an aggressive CD30-positive T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene and the expression of ALK protein. No particular risk factor has been clearly identified for ALCL. ALK+ ALCL shows a broad morphologic spectrum, but all cases contain a variable proportion of cells with eccentric, horseshoe- or kidney-shaped nuclei often with an eosinophilic region near the nucleus (hallmark cells). Five morphologic patterns can be recognized. ALK+ ALCL occurs in young subjects (median age ∼35 years), with male predominance, and frequently presents at an advanced stage, with systemic symptoms and extranodal involvement. Near 40% of patients are low risk according to the International Prognostic Index (IPI). Overall, the prognosis of ALK+ ALCL is remarkably better than other T-cell lymphomas. The IPI and the PIT scores in general predict survival in patients with ALK+ ALCL. Standard first-line treatment for ALK+ ALCL consists of doxorubicin-containing

∗ Corresponding author at: Unit of Lymphoid Malignancies, Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Tel.: +39 02 26437649; fax: +39 02 26437625. E-mail address: [email protected] (A.J.M. Ferreri).

1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2012.02.005

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polychemotherapy, which is associated with an overall response rate of ∼90%, a 5-year relapse-free survival of ∼60%, and a 5-year overall survival of 70%. Excellent results have been reported with a variety of anthracycline-based chemotherapy regimens including CHOP, CHOEP or MACOP-B. Consolidative high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) has also been evaluated in patients in first remission with favourable results, however, superiority to standard chemotherapy is unproven and this approach remains investigational. Following universally accepted guidelines for the treatment of failed aggressive lymphomas, HDC/ASCT can effectively salvage a proportion of patients with relapsed or refractory ALK+ ALCL. Recently, the development of novel therapies targeting CD30 and ALK appear promising. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Anaplastic lymphoma; CD30; ALK; ALK inhibitors; Autologous transplant; Allogeneic transplant

1. General information 1.1. Definition Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) was first described by Stein et al. in 1982 [1]. It is a peripheral T-cell lymphoma (PTCL) consisting usually of large neoplastic cells with abundant cytoplasm and pleomorphic, often horseshoe-shaped, nuclei, with a translocation involving the ALK gene, and expression of ALK protein, as well as of CD30. ALCL with similar morphologic and phenotypic features, but lacking the ALK rearrangement and the ALK protein, are considered as a separate category (ALK-negative (ALK-) ALCL) ALK+ ALCL must be distinguished from primary cutaneous ALCL which is usually ALK- and other subtypes of T- or B-cell lymphoma with anaplastic features and/or CD30 expression. Of note, ALK+ ALCL with a Bcell phenotype is considered a subtype of diffuse large B-cell lymphoma (DLBCL) [2].

1.2. Incidence and risk factors ALK+ ALCL accounts for about 3% of adult non-Hodgkin lymphomas (NHL) and 10–15% of childhood lymphomas. No particular risk factors have been clearly identified for ALCL. Presently, there is no convincing evidence that viruses causing NHL in humans, such as Epstein–Barr virus, human T-cell leukaemia/lymphoma virus family, or others are involved in the origin of ALCL. The pathogenetic implication of the t(2;5) chromosomal translocation and NPM (nucleophosmin)-ALK fusion product are matter of study. ALK, a receptor tyrosine kinase (RTK) in the insulin receptor superfamily, was originally identified as the oncogenic NPM-ALK fusion protein due to a t(2;5) in ALCL. Many other chromosomal rearrangements or gene mutations/amplification leading to enhanced ALK activity have subsequently been identified and characterized in a number of human cancer types (see below). No particular correlation between ALCL and inherited immunological deficiency disease, or other immunological disorders has been reported. There are no convincing data concerning the role of chronic antigenic stimulation in the genesis of ALCL. Several chemical substances such as solvents, pesticides and fertilizers, as

well as dusts and particles, hair dye, smoking and diet have been suggested as possible aetiological factors in NHL [2]. Although specific studies have not been undertaken in ALCL patients, all histotypes of NHL have been described as occurring in people whose work involves application of solvents, pesticides and fertilizers [3–6]. T-cell lymphomas represent 3% of the lymphomas related to HIV infection [7]. Some reported T-cell lymphomas were actually CD30+ B-cell lymphomas with down-regulation of B-cell antigens due to Epstein–Barr virus-coinfection [8] or PTCL with large cells [9]. ALCL is not included among WHO-classification of HIV-correlated lymphomas, but at least 20 cases have been reported, with rare cases of ALK expression [10]. HIV-related ALCLs were characterized by poor prognosis, rapid clinical deterioration, nosocomial infections, and diagnostic delay [11].

1.3. Anaplastic lymphoma kinase (ALK) ALK is an orphan receptor tyrosine kinase first identified as part of the t(2;5) associated with most ALCL and a subset of T-cell [12] ALK signalling can be activated by the establishment of unique oncogenic fusions of the ALK gene at chromosomal band 2p23 with a variety of partners through chromosomal translocation events [12], resulting in the generation of oncogenic ALK fusion genes and their encoded proteins. ALK is one of the few oncogenes activated in both haematopoietic and non-haematopoietic malignancies. Approximately 70–80% of ALK+ ALCL express the NPM-ALK fusion protein derived from the t(2;5)(p23;q35), and about the same frequency of ALCLs stain positive for ALK by immunohistochemistry (see below) [13,14]. These oncogenic fusion proteins and ALK kinase domain activation have been also identified in various solid tumours, like non-small cell lung cancers and neuroblastoma [15,16]. The extracellular region of ALK shows significant homology to the leukocyte tyrosine kinase [19], which places ALK in the insulin receptor superfamily of RTKs. The ALK gene encodes a 1,620-amino acid protein that undergoes posttranslational N-linked glycosylation to a fully mature form weighing 220 kDa. ALK expression is restricted to the developing central and peripheral nervous system with a postulated role in participating in the regulation of neuronal differentiation [17]. Although constitutive ALK signalling has

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been shown in these contexts to induce cell transformation in vitro and in vivo by controlling key cellular processes, the canonical signalling pathways and cell-type specificities of signalling remain poorly defined. A variety of mechanisms that lead to aberrant ALK signalling in a variety of human cancers have been characterized, and these include translocations or structural rearrangements, ALK gene amplification, mutations, and overexpression. Translocations are the most common known cause of genomic ALK aberration, while ALK mutations can be somatically acquired [18,19]. In physiological ALK signalling, ligand-induced homo-dimerization of the extracellular domains is hypothesized to bring the tyrosine kinase domains into sufficient proximity to enact trans-phosphorylation and kinase activity. By contrast, translocations resulting in pathogenic fusion partners provide dimerization domains that are ligand independent, leading to unregulated constitutive kinase activity and malignant transformation. The critical pathways involved in transformation because of deregulated ALK are best characterized by translocations that juxtapose ALK to dimerization partners. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signalling network. Among the potential combinations of proteins phosphorylated by ALK kinase activity, it has been postulated that the most important effects involve activation of STAT3, AKT/PI3K, and RAS/ERK pathways, which control cell proliferation, survival, and cell cycling. Recent work has shown that the sonic hedgehog signalling pathway (SHH/GLI1) is also activated in ALK+ ALCL [20]. Inhibition of this pathway induces apoptosis and cell cycle arrest, which may present a rational therapeutic approach in ALK+ ALCL. Different ALK aberrations produce diverse pathogenic anomalies through a combination of differentially activating common signal transduction pathways and unique pathogenic mechanisms. These variations could arise because of multiple mechanisms, including: variable subcellular localizations of activated ALK, altered sequences of tyrosine autophosphorylation, altered kinase substrate specificity, tissue context, autocrine or paracrine ligand effects, and by breakpoints disrupting the original loci in which truncated genes are translocated from.

2. Pathology and biology 2.1. Morphology ALK+ ALCL show a broad morphologic spectrum. However, all cases contain a variable proportion of cells with eccentric, horseshoe- or kidney-shaped nuclei often with an eosinophilic region near the nucleus. These cells have been referred to as hallmark cells. Five morphologic patterns can be recognized. The “common pattern” accounts for 60% of cases [21,22]. The tumour almost exclusively consists of large-sized cells, frequently with hallmark appearance and

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at times resembling Reed-Sternberg cells. When the lymph node architecture is only partially effaced, cells characteristically grow within the sinuses and thus, may resemble a metastatic tumour. The “lymphohistiocytic pattern” (10%) is characterized by tumour cells admixed with a large number of reactive histiocytes [23]. The latter may mask the malignant cells which are often smaller than in the common pattern and cluster around blood vessels, as highlighted by immunostaining using antibodies to CD30 and/or ALK. The “small cell pattern” (5–10%) shows a predominant population of small to medium-sized neoplastic cells with irregular nuclei [21,22]. Hallmark cells are always present and are often concentrated around blood vessels. The “Hodgkin-like pattern” (3%) is characterized by morphological features mimicking nodular sclerosing Hodgkin’s lymphoma [24]. More than one pattern may be seen in a single lymph node biopsy (“composite pattern”) (15%). Relapses may reveal morphologic features different from those seen initially. 2.2. Immunophenotype The tumour cells are positive for CD30 on the cell membrane and in the Golgi region [25]. Smaller tumour cells may be only weakly positive or even negative for CD30 [21]. In the majority of the cases that have the t(2;5)/NPM-ALK translocation, ALK staining of large cells is both cytoplasmic and nuclear [21,22,26]. In the small cell variant, ALK positivity is usually restricted to the nucleus of tumour cells. In cases with variant translocations, the sub-cellular distribution of ALK staining varies (membranous or cytoplasmic), depending on the translocation [21,22,26]. The majority of ALK+ ALCL is positive for EMA and expresses one or more T-cell antigens, although some may have “null” phenotype. Most ALK+ ALCL are immunoreactive for cytotoxic markers (TIA1, Granzyme B, Perforin) [27,28]. 2.3. Genetic features Approximately 90% of ALK+ ALCL show clonal rearrangement of the TCR genes. The most frequent genetic alteration is a translocation, t(2;5)(p23;q35), between the ALK gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5 [29–31]. Variant translocations involving ALK and other partner genes on chromosomes 1, 2, 3, 17, 19, 22 and X also occur. All these translocations result in up-regulation of ALK. ALK+ ALCL is consistently negative for Epstein–Barr virus [32]. Comparative genomic hybridization (CGH) analysis shows that ALK+ ALCL carry frequent secondary chromosomal imbalances. Supervised analysis by class comparison between ALK+ ALCL and ALCL-ALK- tumours provided distinct molecular signatures. Chromosomal imbalances have been detected in 58% of ALK+ ALCL and in 65% of ALCL-ALK- cases [33]. ALCL carrying NPM-ALK or other translocations involving ALK showed a similar profile of secondary genetic alterations. In ALK+ ALCL cases recurrent

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gains of 17p and 17q24 and losses of 4q13-q21 and 11q14 were identified, whereas in ALCL-ALK- gains of 1q and 6p21 were recognized more frequently [33]. A few recurrent chromosomal imbalances were found in both types of tumours (gains of 7 and 6q and 13q losses). ALK+ ALCL and ALCL-ALK- have different gene expression profiling (GEP) signatures [34]. Among 117 genes over-expressed in ALK+ ALCL, BCL6, PTPN12 (tyrosine phosphatase), serpinA1 and C/EBP were the four top genes, and some of these data were validated by immunohistochemistry. Moreover, GEP identified a cluster of genes that differentiates common-type ALCL and other morphological variants (small cell and ‘mixed’ variants). However, this technique did not provide any clear information about the molecular mechanisms responsible for the pathogenesis of ALCL-ALK-. Shared genes highly expressed in both ALK+ ALCL and ALCL-ALK- were identified in the analysis of transcriptome, suggesting that some pathogenetic mechanisms might be shared by these two entities [35]. GEP identifies gene cluster classifiers capable of differentiating ALK+ ALCL from normal T-cells, ALCL-ALK- and other PTCL. Among other genes selectively expressed in ALK+ ALCL, GAS1 was found to be one of the most highly ALKsignalling dependent genes. ALK or STAT3 GEP signatures obtained from ALK+ ALCL cell lines recently demonstrated that primary systemic ALK+ ALCL express a distinct profile, mainly dictated by STAT3 signalling [36]. The preferential expression of a limited number of genes was sufficient to recognize ALK+ ALCL from other T-cell NHL, independent from ALK expression. On the contrary, no significant markers specifically expressed in ALCL-ALK- were identified. However, ALCLs share a cluster of transcripts, which allow their stratification and distinction from other T-cell lymphomas, suggesting a common ALCL signature and possibly unique origin.

3. Diagnosis 3.1. Clinical presentations ALK+ ALCL is an aggressive lymphoma that occurs in young subjects (median age: 34 years), with a male predominance (M:F ratio = 1.5) [13,36]. Patients with ALK+ ALCL frequently present with advanced stage disease (stage III–IV 65% of cases) and systemic symptoms (75%), especially fever. It mostly affects lymph nodes, with extranodal involvement observed in 60% of cases, mostly commonly in the soft tissue and bone [37,38]. Central nervous system localization is rare [39]. Bone marrow involvement consists of infiltration as single neoplastic cells. This is identified in 11% of the cases when assessed by haematoxylin and eosin staining, and in 30% if immunohistochemistry is performed [40]. Approximately 50% present with low risk disease according to the International Prognostic Index (IPI) [37].

4. Staging system and procedures Similar to most NHLs, the standard staging system used for ALK+ ALCL is the same as that proposed for Hodgkin’s disease at the Ann Arbor Conference in 1971 [41]. This staging system reflects both the number of sites of involvement and the presence of disease above or below the diaphragm, according to four stages of disease. Patients are divided into two subsets according to the presence (A) or absence (B) of systemic symptoms (fever with no evident cause, night sweats and weight loss >10% of body weight). The presence of a bulky mass, such as a lesion of 10 cm or more in the longest diameter is signalled as “X”, while the extranodal involvement should be identified by an “E” and a site-specific symbol. Complete staging and work-up for ALCL is similar to that routinely used for nodal NHL. It includes an accurate physical examination, complete haematological and biochemical exams, total-body computerized tomography, and bone marrow aspirate and biopsy. Indirect evidence from retrospective series of patients with NK/T-cell lymphomas, including a few cases of ALCL, performed in Eastern countries, suggests that FDG-PET may be useful as staging procedure in ALK+ ALCL [42,43]. Under certain rare circumstances, special procedures, like CNS MRI, CSF cytology examination, bone scan, gastrointestinal endoscopy or contrasted X-rays, are required.

5. Prognosis Overall, the prognosis of ALK+ ALCL is remarkably better than that of other T-cell lymphomas [44]. Thus, patients with ALK+ ALCL are usually excluded from trials evaluating new upfront therapies on these lymphomas. Approximately 90% of patients with ALK+ ALCL treated with anthracycline-based chemotherapy achieve a tumour response, with 60% of patients remaining relapse free at 5 years [37,45]. After relapse, some patients can be cured with intensive salvage therapy which includes autologous stem cell transplantation. Where lymphoma is the main cause of death the 5-year OS is 70%. Importantly, ALK protein expression has been proposed as an independent predictor of survival in ALCLs [38]. Overall survival of ALK+ ALCL is far better than that of ALKALCL, with 5-year OSs of 71% and 15%, respectively. In series limited to adult patients [37] the 5-year failure-free survival (FFS) was 60% and 36%, respectively, for ALK+ ALCL and ALCL-ALK-. The main prognostic indicators for ALCL are age, Ann Arbor stage, bulky disease, lactate dehydrogenase (LDH) level, performance status, histology, B symptoms, serum albumin level, bone marrow involvement, and extranodal involvement [36,46,47]. The IPI developed for aggressive lymphomas in general predicts survival in patients with ALK+ ALCL with the low risk IPI group having a 5 year FFS of 80% [37,38]. The new T-cell prognostic index (PIT) developed for PTCL-NOS [48] has also been

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applied to ALCLs and has been shown to be similarly predictive of FFS and OS in both groups [37]. The distribution of ALCL patients across the risk groups is very similar using either the IPI or PIT models [42]. ALCL has been reported to be associated with a more favourable prognosis in patients who are younger and have normal LDH levels, low IPI scores and CD56 negativity, and all of these factors are associated with the expression of ALK [49]. The favourable prognosis of ALK+ ALCL is in part related to the young age at presentation. In the International Peripheral T-cell Lymphoma Project (ITLP) [37], the FFS and OS were similar for ALKALCL and ALK+ ALCL patients <40 years. However, a young age at presentation is uncommon for ALK- patients. Similarly, the GELA group found that in patients <40 years, the survival of ALK+ and ALK- ALCL was similar. This group have recently proposed a new model in ALCL patients which incorporates age (<40 years) and Beta2 microglobulin to stratify patients [50]. The serum soluble CD30 level has also been reported as a negative prognostic indicator in these patients [51]. Patients with ALCL with variant translocations show similar outcome with respect to patients with NPM-ALK-positive tumours [38,52,53], while cases with small cell variant histology seem to show a less favourable prognosis. A novel fusion gene, ALO17/C-MYC, was recently identified, and C-MYC rearrangement may induce an aggressive phenotype in ALK+ ALCL [54].

6. Treatment 6.1. First-line treatment There is no defined chemotherapy combination for ALCL and the majority of prospective trials have been performed in children. Furthermore, in older studies when immunophenotyping was not routinely performed, cases of Hodgkin lymphoma, ALCL-ALK- and even DLBCL may have been included. Based on retrospective series, and modelled on the treatment of the more common DLBCL, doxorubicin-containing polychemotherapy, typically CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), is the standard first-line treatment for ALK+ ALCL on type C basis, which is associated with an overall response rate of ∼90% [37,38,55]. With this strategy, patients with ALK+ ALCL exhibit significantly better outcome than patients with ALK- ALCL, with 5-year OSs of 70–80% and 33–49%, respectively [13,37]. An Italian multicentre trial evaluated MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) compared with ABVD (doxorubicin, bleomycin, vincristine, dacarbazine) in ALCL-Hodgkin-like patients and the complete remission rate was high in both arms (90%); the probability of being relapse-free at almost 3 years was 94% for MACOP-B (methotrexate, adriamycin, vincristine, cyclophosphamide, prednisolone, bleomycin)

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and 91% for ABVD. However, it was likely that many of these patients had Hodgkin’s lymphoma by current lymphoma classification standards and ALK status was not reported, making this trial difficult to interpret [56]. A large retrospective series of 71 patients with aggressive lymphoma, including ALCL, diagnosed by the Kiel classification and with a low IPI score (0–2) treated with MACOP-B +/− radiotherapy had a 10-year OS of 80% [62]. However, stratification by ALK expression was not performed in this analysis. More recently, the German High-grade Non-Hodgkin’s Lymphoma Study Group (DSGNHL) performed a large retrospective analysis evaluating all patients with a T-cell lymphoma within aggressive lymphoma phase III studies that compared standard CHOP21 to CHOP-14 or to CHOP plus etoposide (CHOEP 14 or 21 day cycle) or CHEP to dose escalated (Hi-CHOEP) or a mega-dose (MegaCHOEP) with autologous stem cell transplant. In total, there were 78 of 320 patients with ALK+ ALCL and with a median follow-up of 44 months; the 3 year EFS and OS were 76% and 90%, respectively, which was far superior to the findings in other PTCL subtypes. It appeared that in younger patients (≤60 years) with a normal LDH, the addition of etoposide improved EFS in ALK+ ALCL. However, it should be emphasized that this was a subgroup analysis and the benefit of etoposide awaits further studies [57]. Overall results in paediatric series with ALK+ ALCL demonstrate that the cure rate is high in this population of patients. The Children’s Cancer Group Study 5941 reported the use of intensive chemotherapy for children and adolescents with ALCL (90% of cases were ALK-positive) [58]. The chemotherapy regimen consisted of a 3-week induction therapy (vincristine, prednisone, cyclophosphamide, daunomycin, asparaginase) followed by a 3-week consolidation period (vincristine, prednisone, etoposide, 6-thioguanine, cytarabine, asparaginase, methotrexate), followed by 6 courses of maintenance chemotherapy (cyclophosphamide, 6-thioguanine, vincristine, prednisone, asparaginase, methotrexate, etoposide, cytarabine) at 7weeks intervals. The total therapy duration was 48 weeks, and resulted in 5-year EFS of 68% and 5-year OS of 80%, but with significant haematological toxicity and 5% treatment-related mortality. Among risk factors, bone marrow involvement predicted a worse EFS. However, there have been no studies demonstrating that any dose intensive regimens are more effective than CHOP chemotherapy; thus it also remains the standard of care in the paediatric age group. Several studies have evaluated the use of consolidative high-dose chemotherapy supported by autologous stem cell transplantation (HDC/ASCT) in first remission. A French series evaluated 15 patients with ALCL, including 3 with a B-cell phenotype and 7 that were ALK+ who had received induction chemotherapy with an anthracyclinebased regimen followed by BEAM conditioning and ASCT and the 5-year EFS and OS were both 87% [59]. However, these patients fall into a low risk group by the IPI and it is unclear whether this approach is superior to

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standard anthracycline-based chemotherapy. A prospective study evaluating consolidative HDC/ASCT as part of firstline treatment, patients with PTCL, including ALK+ ALCL showed a significantly better outcome with respect to other T-cell lymphomas, with a 10-year OS of 62% and 21%, respectively [60]. Similar results have been seen with other trials using upfront ASCT [61,62] but the same potential biases interfere with interpretation and comparison with historical results with CHOP or other anthracycline-based regimens thus, upfront HDC/ASCT is still investigational in patients with ALK+ ALCL. 6.2. Treatment of relapsed or refractory disease The original PARMA study has established that HDC/ASCT is superior to conventional-dose chemotherapy as salvage treatment in patients with relapsed chemosensitive aggressive lymphoma [63]. The diagnosis of aggressive lymphoma in this study was based on the Working Formulation and as such would have contained some patients with ALCL. However, there has not been a similar phase III study exclusively in ALCL, including ALK+. Despite this, HDC/ASCT is recommended as salvage treatment in patients with relapsed or refractory ALK+ ALCL on type R bases, particularly since most of them are young and fit. Further, retrospective studies support that the salvage rate is good (3 year OS ∼80%) in ALCL compared to other PTCLs [62,64,65], particularly if restricted to those that are ALK+ [65]. Overall, patients with ALK+ ALCL that are resistant to primary chemotherapy or who relapse early have a worse prognosis In fact, 3-year disease free survival (DFS) after the first relapse is 28% for patients with early relapse (<12 months after diagnosis) versus 68% for patients with late relapse. The use of allogeneic SCT in patients with relapsed/refractory ALK+ ALCL is mostly supported by a few small retrospective studies in patients with various PTCL subtype categories, including rare cases of ALK+ ALCL. Sometimes, conclusions are limited by the fact that authors describe results in ALCL patients, where the ALK status is not reported. A large French study retrospectively evaluated the role of allogeneic transplant typically in relapsed or refractory patients, which included 27 patients (median age 12–55 years) with ALCL. Information on ALK status was available in 13 patients and 8 were ALK+. The 5 year EFS and OS for ALCL patients was 58% and 55%, respectively, which was comparable to the other PTCL subtypes [66]. Of note, chemotherapy-resistant patients also appeared to benefit from allogeneic SCT, with a 5-year OS of 29% for the whole group, and successful use of donor lymphocyte infusions suggested a graft-versus-lymphoma effect. Chemoresistant disease at the time of transplant and the occurrence of severe grade 3–4 acute graft-versus-host disease were the strongest adverse prognostic factors for OS, and an HLA-mismatched donor increased treatment-related mortality. Reduced-intensity conditioning and allogeneic transplantation has been evaluated in relapsed/refractory

PTCL with an over all 3-year PFS of 64% and OS of 81% in 17 patients, including 4 patients with ALCL (all ALK -). All of the latter remain event-free from 10–36 months [67]. Encouraging results have also been reported in paediatric patients [68]. This low-level evidence seems to suggest that allogeneic SCT is a treatment option for selected patients with relapsed refractory ALK+ ALCL, especially for younger patients. 6.3. New drugs or experimental approaches The challenges in studying new drugs in ALK+ ALCL are disease rarity and high cure rate with standard chemotherapy. However, some patients do present with high risk disease and sub-optimal remissions. Nevertheless, the development of novel therapies targeting CD30 and ALK is a major advance in the treatment of ALCL [69]. After an initial phase where several anti-CD30 antibodies showed considerable in vitro activity (i.e., the human Ig G1k antibody MDX-060 [70], the human antibody 5F11 [71], the humanized antibody XmAb 2513 [72], the chimeric antibody SGN-30, the immunotoxin ki-4dgA [73]), but modest clinical activity in patients with CD30-positive lymphomas (i.e., Hodgkin lymphoma and ALCL), recently reported studies showed relevant clinical activity with some interesting molecules. Brentuximab vedotin (SGN-35) seems to be the more promising one. This agent is a conjugate constituted by the antitubulin agent monomethyl auristatin E and a CD30-specific monoclonal antibody that has shown excellent activity both in Hodgkin lymphoma and ALCL. The phase I study evaluating this agent in relapsed or refractory CD30+ lymphomas included mostly patients with Hodgkin lymphoma, but also two patients with ALCL who achieved one CR and one PR, respectively, suggesting activity in this patient group as well. The treatment was well tolerated with mostly grade 1 and 2 toxicity, mainly peripheral neuropathy [74]. Pivotal phase II studies in both Hodgkin lymphoma and ALCL were recently reported in abstract form. In patients with relapsed or refractory ALCL (ALK+ 28%), the ORR was 86% including 53% CRs. The response rate was comparable in ALK+ and ALK- patients and the median duration of response had not yet been reached at the time of the analysis [75]. With these encouraging results, studies combining SGN-35 with CHOP in the up-front setting are planned. Small molecule inhibitors targeting ALK are under development in addition to anti-ALK vaccinations to treat ALK+ tumours, including ALCL. The first ALK inhibitor to enter phase I trials, the PF-02341066 (Crizotinib), is an orally bioavailable small molecule inhibitor that caused complete regression of NPM-ALK xenografts at pharmacologically relevant doses [76]. It is currently the only available ALK small-molecule inhibitor in clinical trials; however, the recent reports of EML4-ALK oncogenic proteins in non-small cell lung cancer and the identification of ALK activating point mutations and gene amplification in neuroblastoma have indicated ALK as a potential major therapeutic target for human

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cancers. In fact, crizotinib was associated with an ORR of 57%, and a 6-month PFS of 72% in 82 patients with relapsed ALK+ non small cell lung cancer [77]. The role of ALK mutations on the induction of resistance to small molecule inhibitors is an interesting open question. Co-development of small molecular and monoclonal antibody inhibitors of ALK activation seems an interesting strategy to avoid emerging resistance. It remains to be seen whether newer inhibitors designed with greater specificity against ALK will eventually prove superior to multikinase inhibitor. siRNA screens of the druggable genome in combination with ALK inhibitors, and preclinical testing for synergy and antagonism with existing chemotherapy backbones will be important to maximize efficacy. ALK would be a potential tumour antigen for vaccination therapies in human lymphomas. DNA-vaccination with plasmids that encode portions of the cytoplasmic domain of ALK induces an ALKspecific interferon-gamma response and CD8+ mediated

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cytotoxicity, and leads to growth arrest in mice models [78]. Several molecules targeting CD30 and ALK are being developed and they will be assessed in clinical trials shortly. The best location for these new target therapies is one of the most important research fields to improve treatment efficacy in patients with ALK+ ALCL.

Conflict of interest statement Authors have no conflict of interest to be disclosed.

Reviewer Michele Ghielmini, Head Medical Oncology Department, Oncology Institute of Southern Switzerland, San Giovanni Hospital, CH-6500 Bellinzona, Switzerland.

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Biographies Andrés J. M. Ferreri is Coordinator of the Unit of Lymphoid Malignancies and Vice Director of the Medical Oncology Unit, Department of Oncology, San Raffaele H Scientific Institute, Milan, Italy.

Silvia Govi is Member of the Unit of Lymphoid Malignancies, Department of Oncology, San Raffaele H Scientific Institute, Milan, Italy. Stefano A. Pileri is Full Professor of Pathologic Anatomy, Director of the Service of Haematopathology at Bologna University School of Medicine and Director of the Research Doctorate Project “Clinical and Experimental Haematology and Haematopathology”. Kerry Savage is Assistant Professor of Medicine with University of British Columbia, and a Medical Oncologist and Clinical Scientist at the British Columbia Cancer Agency with the Lymphoma Tumour Group in Vancouver, Canada.