THE TIME TO TARGET AND TERMINATE THE THREAT OF PTCL

Oliver Karanfilski

University Hematology Hospital, Medical Faculty, University “Ss.Kiril and Metodij”, Skopje, Republic of Macedonia

Whenever professional interest is directed The final word in labeling these neoplasms towards this particular type of lymphoma, some belongs to the pathologist, regardless whether only terms are evidently present more than others: morphology is going to be decisive, or immunophe- heterogeneous, aggressive, dismal prognosis, stan- notyping, molecular analyses and/or genetics are dard treatment not established, poor outcome ..., going to be included in the process of establishing something that does not make any hematologist the diagnosis. Many problems lie in the path for very happy. If some breakthroughs in hematolo- the pathologists. Firstly, due to the not clearly dis- gy in the past two decades brought smiles to our tinct clinical manifestations, parallel to the aggres- faces, this area of expertise is certainly not among sive and rapidly advancing disease course, the those. pathologist might not even receive any substrate Let’s have a look at the definition of Peripheral for examination, only leaving the opportunity for Lymphomas. establishing the diagnosis following autopsy. When substrate is available, the problems arise from the Although the term “peripheral” could associate growing number of entities that are introduced to to “not central”, or “distal”, in means of occurrence, this segment of pathology in the successive clas- localization of the disease, or eventually to the sifications of lymphoproliferative disorders, which zone in the lymph node where it develops and/or becomes the basis for naming this group of disor- grows, that is not what it refers to. Peripheral is an ders heterogeneous, diverse and complex. In such attribute for the T cells, aiming to explain that the a situation, when not so many cases of PTCL are essence of these lymphomas is the mature T cell, scattered around the World, and are being classi- one that has been introduced to its destined func- fied in a growing number of distinct categories, the tions in the human organism. If it had been still suffering end is the level of concordance in pathol- immature, and taken a turn towards malignant ogist’s opinions. Even in the vast field of B-cell proliferation, the result would be a lymphoblastic lymphoma (only approximately 10% of these are lymphomas pathologists have a certain level of of B lineage origin), or an ATLL. In a smaller pro- disagreement regarding final diagnoses, but it has portion, these lymphomas can have their origin in been observed that the accord, confidentiality and a subset of lymphocytes of the natural killer type. reproducibility levels decline for around further 10% in the area of PTCL. Utilizing contemporary In explaining the previous, we have also estab- available lab techniques gives rise to the possi- lished that the pathognomonic substance of these bilities for precise diagnosis of a certain type of neoplasms are the T lymphocytes. PTCL, but characteristics obtained by these are not The last of the terms simply delineates that attributable to all subtypes. Therefore, for some these disorders are inevitably of malignant nature, types of PTCL, molecular analyses of immunophe- lymphoproliferative neoplasms, very aggressive, notype or genetic distinctions can be the decisive fast growing, quite resistant to known therapies, factor, but for others it will still remain a matter of and very frequently fatal. professional opinion.

23-26 Ekim 2013, Antalya 125 Table 1. Classification and characteristics of T/NK-cell lymphoproliferative disorders Entity Immunology Genetics Cutaneous Mycosis fungoides Sezary syndrome CD4+, CD5+, CD7- Primary cutaneous CD30+ T-cell lym- phoproliferative disorders Primary cutaneous ALCL Primary cutaneous γδ TCL Primary cutaneous CD8+ aggressive epider- motropic lymphoma (provisional) Primary cutaneous CD4+ small/medium TCL (provisional) Nodal TCR αβ; AITL (18.5%) CD10+ Gains 2 5 13q22; TCR αβ; Translocation (2;5); Gain 1q; Loss ALCL ALK+ (6.6%) CD30+, CD4+/CD8-. 6q 13q; ALCL ALK- (provisional) (5.5%) CD15- ; Pax5-; TCR αβ; TCR αβ; PTCL NOS (25.9%) Loss of CD5/CD7 Loss 13q22; Gains 8q 9p 19q; Loss 3q 9p; Extranodal Systemic EBV+ T-cell childhood lymphoproliferative disorder Hydroa vacciniforme-like lymphoma Extranodal NK/T-cell lymphoma, nasal type CD56+, cytoplasmic CD3+ TCR αβ: CD3+, CD7+, CD56-, may be Gains Enteropathy associated TCL CD8+, CD56+ (monomorphic) 9q33-q34 TCR γδ; CD2+, CD3+, CD4-, CD5-, Hepatosplenic TCL CD7+, CD8+ or CD8-, Isochromosome 7q CD56 may be + TCR αβ: CD3+, CD4-, CD8+, CD56- 5q Gains Subcutaneous panniculitis-like TCL TCR γδ; CD3+, CD8-, CD56+/- 13q Gains Leukemic T-cell prolymphocytic leukemia CD2+, CD5+, CD7++, CD52+ T-cell LGL leukemia CD3+, CD8+, CD16+, CD57+ Adult T-cell leukemia/lymphoma precursor CD4+/CD25+ Aggressive NK-cell leukemia CD3-, CD16+, CD56+ Indolent large granular NK-cell lymphopro- CD3-, CD16+, CD56+ liferative disorder (provisional) *bold frame marks the most frequent subtypes

The relatively small overall number of PTCL rising number of agents that are introduced as cases definitely handicaps progress in managing therapeutic possibilities for PTCLs. In summary: this area of hematology. Prospective randomized too few cases, too many centers, too many treat- studies have since long ago become the verified ment alternatives ... not a fruitful field for random- basis for advances in the field of establishing suc- ized studies. The conclusion is inevitable: progress cessful treatment options for any kind of disease. When PTCLs are in question, not much success can be achieved only through multicentre inves- is observed. According to different reports, the tigational programs and protocols, such as is the whole segment of PTCLs account for not more than International PTCL project. 12-15% of all lymphomas, which, when distributed To make the issue even worse, PTCL patients to the existent and growing number of hematol- ogy centers, hardly comprise patient populations tend to relapse very often, and within a short mar- sufficient for randomized studies. Even more, this gin of time, in which situations their prognosis option is made more implausible, because of the becomes even more dismal.

126 XXXIX. Ulusal Hematoloji Kongresi At present, the number of entities comprising the designated treatment approach for all of those the circle of PTCLs is a result of joint efforts of the would be the same. WHO classification and the International PTCL When we come to the point of treatment, we project consortium. Some of the entities are better must once more emphasize that a total relative- characterized and firmly established, and a minor ly small number of cases denies possibilities for number are labeled as provisional entries. There performing successful randomized studies. Small is a total of 22 entities, T-cell and NK-cell derived numbers deny the analyzes the statistical power to neoplasms, distributed in several groups (Table 1). prove a hypothesis, and they also demand greater A few of the entities are diagnosed with great differences in order to assign the attribute of signif- confidentiality, based solely on morphology, espe- icance to the findings. cially the cutaneous types of PTCL, since clinical Nevertheless, clinical experience has come to presentation patterns and characteristics contrib- some revelations. It is now well established that ute considerably to the process. Immunopheno- the subset of anaplastic lymphoma kinase protein typing, whether performed by immunohistology (ALK) positive ALCL (which can be T-cell or NK-cell or flow cytometry, can aid the categorization, but derived) have a better prognosis with today’s “stan- also of a certain number of entities, and maybe dard” treatments, i.e. with alone, help in distinction of certain subtypes. Since we even better than cases with DLBCL: ~70% for 5-y have largely entered the era of genomics, efforts OS. Also, it is almost without exceptions shown are introduced to utilize this methodology in better that the cutaneous forms of PTCLs tend to have a characterizing the PTCL’s also, but definite genetic better outcome and vital statistics. associations in the area of PTCLs are still anecdot- al. This is why most of the diagnosed PTCLs are Worldwide, CHOP chemotherapy regimen is framed in the category of “not otherwise specified”. still recognized as the “standard” first line treat- ment option for all PTCLs, everywhere quoted as Some of the entities are definitely associated producing results that are not even close to those with the presence of the HTLV-1 virus, in partic- obtained in B-cell neoplasms. With the exception of ular the Adult T-cell leukemia/lymphoma type. ALK+ ALCL, all other PTCL subtypes have OS rates Since this virus is much more frequently present below 50%, some expressed as 5-y rates, but some in the population of the Far East, the Caribbe- as only 2- or 3-y rates. In some types, PFS and/ an and the Middle East, chances for acquiring or OS are expressed only in months, when first- a consequent PTCL of this particular type range line treatment is analyzed. The dismal prognosis from 2-4%, but by no means does it state that becomes even shorter, and finally inevitably fatal, a person with the HTLV-1 will certainly develop in virtually all relapsed patients. a PTCL. Considering the Asian region again, the intestinal PTCLs on that continent are far more When one tries to improve on treatment results, frequently associated with an EBV infection. On there are two basic options: a. increase treatment the other hand, some PTCLs are associated with intensity by elevating drug dosage or by shorten- other disorders, as is the enteropathy associated ing the intervals of chemotherapy administration, TCL, which arises more frequently in individuals or b. expand the “coverage” area of chemotherapy with celiac disease, making it more prevalent in by adding drugs to the regimen. Most such efforts Northern Europe. Therefore, the PTCLs also have, have been performed by the Nordic and the German to some extent, a particular geographical pattern Lymphoma Study Group, resulting in the CHOEP of distribution. (adding of Etoposide) regimen, and eventually in the Mega-CHOEP (dose escalated) regimen, now Considering most of the previously stated, it standard treatments for PTCLs by their guidelines. is not a surprise at all, that the largest number Many investigators would recommend HyperCVAD of PTCLs are categorized as NOS, a wastebasket as the more aggressive chemotherapy regimen. that encircles all the diagnosed PTCLs, with no Others have tried, or would prefer EPOCH, ICE, specific morphological, immunological, genetic, DHAP, ESHAP, or similar combinations. clinical or prognostic feature. This simply leads to the conclusion that we have still not found The issue of “standard” treatment is completed the common denominator for a large proportion by the wide acknowledgement and recommenda- of these disorders. It also reveals that, not being tion that all PTCL cases, except the ones with low able to distinguish any differences between them, risk disease, if remission is achieved, continue to

23-26 Ekim 2013, Antalya 127 high dose chemotherapy followed by autologous No doubt that hematologists would be extreme- PBSC rescue. Although the transplant issue is still ly happy to know that a new , probably not with a high level of evidence support, this is the named T-, has been synthesized. Unfor- current “general” recommendation. As for the issue tunately, no such news are emerging on the sci- of allogeneic SCT in PTCLs, it is still quite debated, entific horizon. Nevertheless, some of the PTCLs controversial and hampered by the low number of (AITL) express CD20 on the surface of some of the cases and the wide variety of subtypes submitted cells involved, which favors adding Rituximab to to such treatment. the treatment. However, desirable results are lim- ited to individual cases. Of the newer agents, several are more widely explored, while others are confined to single center Following this line of investigations, other anti- attempts or incidental observations. Common for bodies and conjugates have been employed in the the newer agent reports is that almost all of them quest for better management of PTCLs: alemtu- express results with an emphasis on response zumab, CCR4 antibody, , , rates, not remission rates, which most often is denileukin diftitox, bevacizumab, etc. derived from shrinking in tumor size as the mea- In view of the somewhat encouraging results surable effect, regardless of how short-lived that with the newer drugs, further attempts to improve effect had been. As is the case with most of the efficacy in PTCLs are represented by many tests new drugs, investigations have started dominantly of combinations of newer agents with “classical” in relapsed patients. The obtained results in such chemotherapy regimens: Pral-CHOP, Romi-CHOP, cases have led to the approval by relevant author- Bren-CHOP, However, new “standards” are not ities for some of the drugs to be utilized in the emerging. setting of relapsed disease. Side effects, in some instances very detrimental, further hamper the Some well known agents have been explored successful prospects of such drugs. for treatment of PTCLs also: , Ben- damustine, Belinostat (HDAC inhibitor), MLN8237 Pralatrexate, a folate antagonist similar to (Aurora kinase inhibitor). As a specific type of , is the first agent approved for a virus associated PTCL, treatment of HTLV-a relapsed PTCL patients, based on the results of the associated T-cell lymphoma/leukemia has been phase II PROPEL study. The observed ORR was attempted with AZT (sometimes in combination 28%, with a median duration of 9.4 months and a with IFN). median OS of 14.7 months. Emergence of new drugs in other fields of Many reports are released on the use of Romide- hematology and/or oncology, inspires clinicians psin, a novel bicyclical HDAC inhibitor. Based on and researchers to try them in new areas, with results as second line therapy, it has approvals the hope that a certain signaling pathway can be for PTCL since 2011: ORR = 26%, CR = 13%. In crucial not only in a single disorder, but maybe subsequent trials, the ORR has risen to 34%, in different settings as well. Such a “modern” with as many as 15% CR’s, and around 10% approach is challenging the PTCLs with Dasatinib having longer lasting (48+ months) uninterrupted (TKI). Research evidence prompted attempts with responses. Romidepsin has also been tried in the JAK-STAT inhibitors (Ruxolitinib and others) as setting of maintenance for good responders to ini- well. Others have been investigated also, some as tial treatment. a primary option, but mostly in the relapsed or The other agent approved for the relapsed set- refractory settings: Bexarotene (retinoid), Bortezo- ting in the US is vorinostat. mib (proteasome inhibitor), Sunitinib, Sorafenib, nucleoside analogs, signaling inhibitors, etc. PTCL cases that express the CD30 have been treated with considerable success with an Clinical research has made attempts to catego- agent, initially tested on patients with HD: bren- rize patients with PTCL in risk categories, estab- tuximab vedotine. Used as third line therapy, and lishing prognostic criteria, scores and indexes. It in a cohort of 72% ALK negative ALCL, it produced is important to acknowledge that most of these an 86% ORR, but with a median duration of 12.6 systems have been based on relatively small, often months. The CR rate observed was 57%, but again selected populations of PTCL patients, and treated the duration of it only 13.2 months. Another such with various regimens. They have certainly con- agent is iratumumab. tributed to delineating patients with low risk, who

128 XXXIX. Ulusal Hematoloji Kongresi would benefit even from “standard” treatment, as faces, nor does it show the light at the end of the well as those with high risk, who would need to tunnel for our patients. I believe that we would receive treatment designed for patients with poor all love to ultimately witness another revolution prognosis. Nevertheless, categorization is mostly in the management of the serious diseases which made difficult by the enormous number of agents, comprise our everyday professional life, as we have so far explored in the treatment of comparably seen with Hairy-cell leukemia, non-Hodgkin’s lym- variable PTCL’s subtypes, which impedes general, phomas, and especially with Chronic myelogenous universal conclusions. leukemia. I am a believer in targeted therapy. A In conclusion, a hematologist cannot be very hematologist has no alternative options in his satisfied with what we have learned and achieved work, but to be an irrevocable optimist, posing so far regarding patients with PTCL. It is one of the only possible question: not “if”, but WHEN the those areas that does not bring a smile to our dream will become reality?

References 14. Horwitz SM: Update on Peripheral T-Cell Lympho- ma. Virtual Lecture, Presentation, Q&A Session 1. Armitage JO: The Aggressive Peripheral T-Cell (hosted by Berger L). The Leukemia and Lymphoma Lymphomas. Contemporary Oncology 2010: 7 pages Society. Telephone, Web. 14 Mar 2012. Lecture 2. Armitage JO et al: Peripheral T-Cell Lymphoma. 15. Jacobsen E, Freedman AS. Treatment of relapsed or Cancer 1989 (63): 158-163 refractory peripheral T-cell lymphoma. www.uptoda- 3. Armitage JO et al: Towards understanding the te.com. Ed. Andrew Lister. Wolters Kluwer Health, peripheral T-cell lymphomas. Annals of Oncology 29 Jan. 2013 2004 (15): 1447-1449 16. Jagadeesh D, Smith MR: Novel Targeted Therapies 4. Bisig B et al: CD30-positive peripheral T-cell in Peripheral T-Cell Lymphoma. Discovery Medicine lymphomas share molecular and phenotypic featu- 2013; 15 (85): 367-378 res. Haematologica 2013; 98 (8): 1250-1258 17. Lin H-N et al: How to predict the outcome in matute 5. Choi MY, Lechowicz MJ: Management of the Cuta- T and NK cell lymphoma by currently used prog- neousPeripheral T-Cell Lymphomas. When Subtypes nostic models? Blood Cancer Journal 2 e93 doi Matter. The Cancer Journal 2012; 18 (5): 439-444 10.1038/bcj 2012 23 6. Coiffier B et al: Romidepsin Induces Durable Res- 18. Mak V et al: Survival of Patients With Peripheral ponses in Patients with Peripheral T-cell Lympho- T-Cell Lymphoma After First Relapse or Progression: ma: GPI-006-0002 Study Update. Blood (ASH Annu- Spectrum of Disease and Rare Long-Term Survivors. al Meeting Abstracts) 2012; 120 (21): Abstract 3641 Journal of Clinical Oncology 2013; 31 (16): 1970- 7. Cuneo A et al: Peripheral T-cell lymphoma not 1976 otherwise specified (PTCLNOS). Atlas of Genetics 19. Ly M et al: Peripheral T-cell lymphoma expressing and Cytogeneticsin Oncology and Haematology. July IRF4. http://www.cancer-amcc.org/FICHIERS/ 2009 files/PERIPHERAL T-CELL LYMPHOMA EXPRES- 8. Dearden CE et al: Guidelines for the management SING IRF4.pdf. of mature T-cell and NK-cell neoplasms (excluding 20. Moskowitz A et al: Should Patients With Aggressi- cutaneous T-cell lymphoma). British Journal of ve Peripheral T-Cell Lymphoma All Be Treated the Hematology 2011; 153 (4): 451-485 Same? The Cancer Journal 2012; 18 (5): 445-449 9. Dragos L: Lymphoma - Non B cell neoplasms T/NK 21. Peripheral T-Cell Lymphoma. www.lymphoma.org. cell disorders Peripheral T cell lymphoma, not other- Ed. Julie M. Vose. N.p., n.d. Web. 18 July 2013 wise specified. www,PathologyOutlines.com. N.p., 7 22. Pileri SA, Piccaluga PP: New molecular insights into Feb. 2012. Web. 18 July 2013. peripheral T cell lymphomas. The Journal of Clinical 10. Foss F: Evolving therapy of peripheral T-cell lympho- Investigation 2012; 122 (10): 3448-3455 ma: 2010 and beyond. Therapeutic Advances in 23. Robles M et al: Allogeneic SCT for patients with Hematology 2011; 2 (3): 161-173 high-risk peripheral T-cell lymphoma in first relap- 11. Foss FM: Treatment strategies for peripheral T-cell se. Bone Marrow Transplantation doi 10:1038/ lymphoma. Best Practice & Research Clinical Hema- bmt.2013.86 tology 2013 (26): 43-56 24. Rüdiger T et al: Peripheral T-cell lymphoma (exclu- 12. Foss FM et al: Peripheral T-cell lymphoma. Blood ding anaplastic large-cell lymphoma): Results from 2011; 117 (25): 6756-6767 the Non-Hodgkin’s Lymphoma Classifiction Project. 13. Gallamini A et al: Peripheral T-cell lymphoma uns- Annals of Oncology 2002 (13): 140-149 pecified (PTCL-U): a new prognostic model from 25. Savage KJ, Reiman T: Peripheral T-cell lymphomas: a retrospective multicentric clinical study. Blood progress and challenges. Oncology Exchange 2012; 2004; 103 (7): 2474-2479 11 (3): 10-18

23-26 Ekim 2013, Antalya 129 26. Savage KJ: Update on peripheral T-cell lymphomas. 30. Vasmatzis G et al: Genome-wide analysis reveals 10th Annual Indy Hematology Review. St.Vincent recurrent structural abnormalities of TP63 and Cancer Care. Indiana, Indianapolis. 09 Mar 2013. other p53-related genes in peripheral T-cell lympho- Lecture mas. Blood 2012; 120 (11): 2280-2289 27. Skarbnik AP et al: Peripheral T-cell lymphomas: a 31. Vose JM. T-Cell Lymphomas: Moving Forward, Imp- review of current approaches and hopes for the futu- roving Outcomes (An Expert Interview by Berman re. Frontiers in Oncology / Hematology Oncology S). Medscape, Jan 23 2013 2013 (3): 138. doi: 10.3389/fonc.2013.00138 32. Vose JM: Update on Novel Treatments for Peripheral 28. Tang T et al: Peripheral T-Cell Lymphoma: Review T-Cell Lymphoma (Report by Stenger M). The ASCO and Updates of Current Management Strategies. Post 2012; 3 (1): 3 pages Advances in Hematology 2010, Article ID 624040: 8 33. Zain J, Sawey K: Peripheral T cell lymphoma: cli- pages; doi 10.1155/2010/624040 nical utility of romidepsin. Blood and Lymphatic 29. Van Den Neste E: Peripheral T-cell lymphomas Cancer: Targets and Therapy 2012 (2): 109-115 (PTCL) Specified and Unspecified. BHS Training 34. Zelenetz AD et al: Non-Hodgkin’s Lymphomas, Ver- Course and Seminars, Seminar 11 - Hodgkin’s sion 1.2013. Journal of the National Comprehensive lymphoma and aggressive lymphoma. Belgian Cancer Network 2013; 11(3): 257-273 Hematological Society. Belgium, Brussels. 09 Mar 2013. Lecture.

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