**Monoclonal Antibody Therapy of T-Cell Leukemia and Lymphoma**

Tahir Latif and John C. Morris

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55122

#### **1. Introduction**

[146] Dixon DN, Izon DJ, Dagger S, et al. TLX1/HOX11 transcription factor inhibits differ‐ entiation and promotes a non-haemopoietic phenotype in murine bone marrow cells. *Br J Haematol*. 2007;138(1):54-67. Prepublished on 2007/06/09 as DOI 10.1111/j.

[147] Hawley RG, Fong AZ, Lu M, Hawley TS. The HOX11 homeobox-containing gene of human leukemia immortalizes murine hematopoietic precursors. *Oncogene*. 1994;9(1):

[148] Hawley RG, Fong AZ, Reis MD, Zhang N, Lu M, Hawley TS. Transforming function of the HOX11/TCL3 homeobox gene. *Cancer Res*. 1997;57(2):337-345. Prepublished on

[149] Riz I, Hawley TS, Luu TV, Lee NH, Hawley RG. TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells. *Mol Cancer*. 2010;9:181.

[150] Ntziachristos P, Tsirigos A, Van Vlierberghe P, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. *Nat Med*.

[151] Kraszewska MD, Dawidowska M, Larmonie NS, et al. DNA methylation pattern is altered in childhood T-cell acute lymphoblastic leukemia patients as compared with normal thymic subsets: insights into CpG island methylator phenotype in T-ALL. *Leukemia*. 2012;26(2):367-371. Prepublished on 2011/08/13 as DOI 10.1038/leu.2011.208.

[152] Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leuke‐ mia: where are we going and how do we get there? *Blood*. 2012;120(6):1165-1174.

Prepublished on 2012/06/26 as DOI 10.1182/blood-2012-05-378943.

2012;18(2):298-301. Prepublished on 2012/01/13 as DOI 10.1038/nm.2651.

Prepublished on 2010/07/14 as DOI 10.1186/1476-4598-9-181.

1365-2141.2007.06626.x.

32 T-Cell Leukemia - Characteristics, Treatment and Prevention

1997/01/15 as DOI.

1-12. Prepublished on 1994/01/01 as DOI.

T-cell leukemias and lymphomas are a heterogeneous group of uncommon tumors that account for 7-15% of lymphomas. [1] They represent approximately 6,500 new cases annually in the United States. Typically patients with malignant T-cell disorders present with highgrade lesions, advanced stage disease and have systemic or "B" symptoms at diagnosis. Until relatively recently these diseases were treated with the same anthracycline-based chemother‐ apy regimens used to treat B-cell lymphomas. With few exceptions, the outcomes are poorer with lower response rates, shorter times to progression, and shorter median survivals com‐ pared to B-cell lymphomas. A number of new agents have recently entered the clinic for the treatment of T-cell lymphomas. [2] These include the histone deacetylase inhibitors voronistat (Zolinza®) and romidepsin (Istodax®) approved for treatment of previously treated cutaneous T-cell lymphoma (CTCL), the antifolate, pralatrexate (Fotolyn®) indicated for the treatment of relapsed or resistant peripheral T-cell lymphoma (PTCL), and the immunotoxin brentuximab vedotin (Adcetris®) for the treatment of relapsed anaplastic large cell lymphoma (ALCL). These newer agents join a handful of drugs approved for the treatment of T-cell lymphomas including beraxotene (Targretin®) and the interleukin-2-diphtheria toxin fusion protein, denileukin diftitox (Ontak®).

The introduction of the chimerized anti-CD20 monoclonal antibody, rituximab (Rituxan®), was a major advance in the treatment of B-cell lymphoma improving the survival of patients with B-cell lymphoma. Unlike B-cell lymphomas no monoclonal antibody has received a similar indication for treatment of T-cell neoplasms. Presently an expanding number of antibodies targeting T-cells are being studied for the treatment of T-cell leukemia and lym‐ phoma. The current status of monoclonal antibody therapy of T-cell leukemia and lymphoma will be the focus of this chapter.

© 2013 Latif and Morris; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


their therapeutic efficacy. Modulation of surface receptor expression is an important physio‐ logical characteristic used by normal and malignant cells to control responsiveness to cytokines and other receptor ligands. For unmodified monoclonal antibodies ideally the antibody target should be non-modulating so that adequate target antigen is always available for antibody to exert its therapeutic effect. Modulating receptors internalize antibody-receptor complex leaving limited numbers of surface receptors causing relative resistance. Modulation; however, can be used to an advantage with immunotoxins and ligand-toxin fusion proteins that need internalization to exert their action, but in general, modulation reduces the effectiveness of

Monoclonal Antibody Therapy http://dx.doi.org/10.5772/55122 35

Other characteristics of the ideal monoclonal antibody should include that the targeting of the antigen by the antibody should not lead to serious side effects. In addition to their immuno‐ genicity causing infusion reactions and serum sickness, some monoclonal antibodies can stimulate the systemic release of inflammatory cytokines with serious consequences. A phase 1 dose-escalation trial testing an anti-CD28 monoclonal antibody (TGN1412) with 'superagonist' effects on T-lymphocytes caused near-lethal acute systemic inflammation requiring

Ideally the targeting antibody itself should be non-immunogenic, should act through several mechanisms of antitumor activity and have patient friendly dosing schedules and pharmaco‐ kinetics. [5] Current technologies has made it possible to engineer majority of antibodies in clinical use so that most of the molecule except for the receptor-binding domains is identical to that of a human antibody to reduce immunogenicity and the risk of neutralizing responses

Mechanisms of actions of monoclonal antibody action include induction of antibody-depend‐ ent cellular cytotoxicity (ADCC). A monoclonal antibody binds to its antigen target and recruits other components of cellular immune system such as NK cells, neutrophils, and eosinophils. These stimulated cells then attack and destroy the tumor cell. Some antibodies will directly bind to Fc receptors on effector cells such as macrophages and cytolytic T-cells

Complement-mediated cytotoxicity (CMC) is another Fc-mediated mechanism of monoclonal antibody action. [9] It has been shown to play a roll in the antitumor activity of a number of antibodies including alemtuzumab. [10] In addition to CMC, complement fixation is also involved in inflammation, chemotaxis and opsonization, all of which may aid in tumor cell

Monoclonal antibodies can also engage tumor cell surface receptors resulting into release of an apoptotic signal inducing tumor cell killing. Many of the cell surface markers including

hospitalization in six volunteers treated in a phase I study. [4]

causing destruction of the target cell through ADCC. [8]

monoclonal antibodies.

**3. Qualities of the antibody**

against the antibody. [6, 7]

**3.1. Mechanism of action**

killing.

**Table 1.** Monoclonal antibodies for the treatment of T-cell leukemia and lyumphoma.

#### **2. Characteristics of the ideal target for antibody-directed therapy**

Delivering maximum therapeutic benefits with minimal or no toxicity have been the main objective of any therapeutic strategy including antibody therapy. The choice of therapeutic target for antibody therapy is one of the most important variables in achieving this goal. The ideal target for antibody-directed therapy should have following characteristics: Including restriction of the target antigen expression to malignant T-cells. Toxicity and unintended effects of a ubiquitously present target is a significant hindrance in development of antibody therapy, an ideal target should have its expression restricted to malignant T-cell or if the target is expressed on other hematopoietic cells, the loss of these cells or their function should not result in serious complications such as life-threatening immunosuppression. If the target is broadly expressed on other T-cells or hematopoietic cells, treatment will not only eliminate the tumor cells, it will also cause depletion of functional T-cells allowing reactivation or susceptibility to a variety of serious infections. Alemtuzumab (Campath®), a monoclonal antibody directed against CD52 is an effective therapy against B-cell chronic lymphocytic leukemia (CLL); however, since CD52 is also expressed on T-cells, treatment results in the depletion of both CD4+ and CD8+ T-cell populations and an increased risk of opportunistic infections. [3]

The target antigen ideally should be expressed at high density on the malignant T-cells. Most antibodies deliver their therapeutic effect by binding to the target on the cell surface, activating complement, antibody dependent cellular cytotoxicity (ADCC) or inducing signals activating apoptosis. The target receptor must be present in significant numbers on the cell surface to provide an adequate number of binding sites for the antibody. Down modulation and mutations in surface receptors can reduce binding of monoclonal antibodies interfering with their therapeutic efficacy. Modulation of surface receptor expression is an important physio‐ logical characteristic used by normal and malignant cells to control responsiveness to cytokines and other receptor ligands. For unmodified monoclonal antibodies ideally the antibody target should be non-modulating so that adequate target antigen is always available for antibody to exert its therapeutic effect. Modulating receptors internalize antibody-receptor complex leaving limited numbers of surface receptors causing relative resistance. Modulation; however, can be used to an advantage with immunotoxins and ligand-toxin fusion proteins that need internalization to exert their action, but in general, modulation reduces the effectiveness of monoclonal antibodies.

Other characteristics of the ideal monoclonal antibody should include that the targeting of the antigen by the antibody should not lead to serious side effects. In addition to their immuno‐ genicity causing infusion reactions and serum sickness, some monoclonal antibodies can stimulate the systemic release of inflammatory cytokines with serious consequences. A phase 1 dose-escalation trial testing an anti-CD28 monoclonal antibody (TGN1412) with 'superagonist' effects on T-lymphocytes caused near-lethal acute systemic inflammation requiring hospitalization in six volunteers treated in a phase I study. [4]

### **3. Qualities of the antibody**

**Target Antigen Description Monoclonal Antibody** CD2 LFA-3 (CD58) Slipizumab (MEDI-507) CD3 (CD3ζ) TcR signaling chain muromonab-CD3 (Orthoclone®, OKT3) CD4 TcR co-receptor Zanolimumab (HuMax-CD4®)

CD5 Scavenger receptor family member Anti-Leu1

receptor

**2. Characteristics of the ideal target for antibody-directed therapy**

CCR4 Chemokine receptor-4 KW-0761

Delivering maximum therapeutic benefits with minimal or no toxicity have been the main objective of any therapeutic strategy including antibody therapy. The choice of therapeutic target for antibody therapy is one of the most important variables in achieving this goal. The ideal target for antibody-directed therapy should have following characteristics: Including restriction of the target antigen expression to malignant T-cells. Toxicity and unintended effects of a ubiquitously present target is a significant hindrance in development of antibody therapy, an ideal target should have its expression restricted to malignant T-cell or if the target is expressed on other hematopoietic cells, the loss of these cells or their function should not result in serious complications such as life-threatening immunosuppression. If the target is broadly expressed on other T-cells or hematopoietic cells, treatment will not only eliminate the tumor cells, it will also cause depletion of functional T-cells allowing reactivation or susceptibility to a variety of serious infections. Alemtuzumab (Campath®), a monoclonal antibody directed against CD52 is an effective therapy against B-cell chronic lymphocytic leukemia (CLL); however, since CD52 is also expressed on T-cells, treatment results in the depletion of both CD4+ and CD8+ T-cell populations and an increased risk of opportunistic

The target antigen ideally should be expressed at high density on the malignant T-cells. Most antibodies deliver their therapeutic effect by binding to the target on the cell surface, activating complement, antibody dependent cellular cytotoxicity (ADCC) or inducing signals activating apoptosis. The target receptor must be present in significant numbers on the cell surface to provide an adequate number of binding sites for the antibody. Down modulation and mutations in surface receptors can reduce binding of monoclonal antibodies interfering with

CD122 β-subunit of the IL-2 and IL-15

34 T-Cell Leukemia - Characteristics, Treatment and Prevention

**Table 1.** Monoclonal antibodies for the treatment of T-cell leukemia and lyumphoma.

infections. [3]

CD25 IL-2 receptor α-subunit Daclizumab (Zenapax®) CD30 TNF receptor family member Brentuximab vedotin (Adcetris®) CD52 GPI-anchored glycoprotein Alemtuzumab (Campath®)

T101

Mik-β1

Ideally the targeting antibody itself should be non-immunogenic, should act through several mechanisms of antitumor activity and have patient friendly dosing schedules and pharmaco‐ kinetics. [5] Current technologies has made it possible to engineer majority of antibodies in clinical use so that most of the molecule except for the receptor-binding domains is identical to that of a human antibody to reduce immunogenicity and the risk of neutralizing responses against the antibody. [6, 7]

#### **3.1. Mechanism of action**

Mechanisms of actions of monoclonal antibody action include induction of antibody-depend‐ ent cellular cytotoxicity (ADCC). A monoclonal antibody binds to its antigen target and recruits other components of cellular immune system such as NK cells, neutrophils, and eosinophils. These stimulated cells then attack and destroy the tumor cell. Some antibodies will directly bind to Fc receptors on effector cells such as macrophages and cytolytic T-cells causing destruction of the target cell through ADCC. [8]

Complement-mediated cytotoxicity (CMC) is another Fc-mediated mechanism of monoclonal antibody action. [9] It has been shown to play a roll in the antitumor activity of a number of antibodies including alemtuzumab. [10] In addition to CMC, complement fixation is also involved in inflammation, chemotaxis and opsonization, all of which may aid in tumor cell killing.

Monoclonal antibodies can also engage tumor cell surface receptors resulting into release of an apoptotic signal inducing tumor cell killing. Many of the cell surface markers including those of the tumor necrosis factor receptor (TNFR) family, Fas, and the receptors for TNFrelated apoptosis-inducing ligand (TRAIL) when engaged by their ligand deliver an apoptotic signal promoting apoptosis. Monoclonal antibodies can mimic the physiologic ligand of these receptors and can agonistically bind to receptor family members eliciting apoptotic responses on engagement. [11] A number of monoclonal antibodies are known to induce tumor cell apoptosis at least partially through direct engagement of their target receptor including SGN-30 a chimeric anti-CD30 antibody, and alemtuzumab (anti-CD52). [12, 13]

effects. Engineering of non-human monoclonal antibodies with human constant domains, so called chimerized or humanized monoclonal antibodies, or the generation of fully human monoclonal antibodies using transgenic or phage display technology has helped overcome

Monoclonal Antibody Therapy http://dx.doi.org/10.5772/55122 37

Chimeric monoclonal antibodies are generated by linking the rodent light and heavy chain variable domains to the human immunoglobulin constant domains using recombinant DNA technology. [20] This results in an antibody that contains approximately 65% human sequences that exhibits reduced immunogenicity and an increased serum half-life. Although the immu‐ nogenicity of chimeric monoclonal antibodies is significantly reduced, they are occasionally

Second generation monoclonal antibodies were further improved by incorporating the six complementarity-determining regions (CDR) of the rodent antibody-antigen binding site onto a human IgG antibody framework. Further improvements in maintaining the structure of the antigen-binding site and high affinity binding to the target were made by incorporating small number of amino acids in the murine antibody not directly involved in the CDR. [21] Alem‐ tuzumab is one such example. Although the binding between humanized antibodies and the dissociation constants (Kd) of humanized and the parental monoclonal antibody target is weaker than the murine parent, the differences between these are usually small enough to not be significant. [22, 23] Polymorphisms located in the constant regions, or to anti-idiotypic recognition of the variable domain can rarely result in human anti-human (HAHA) antibody

To further enhance efficacy, "fully human" monoclonal antibodies have been generated using transgenic mice expressing human immunoglobulin genes. Vaccination of these mice using the desired antigen induces B-cells producing a fully human antibody by the mouse. Panitu‐ mumab (Vectibix®) an anti-EGFR monoclonal antibody [26], and ofatumumab (Azerra®), an anti-CD20 monoclonal antibody, were generated using such an approach. Phage display technology has also made it possible to develop fully human monoclonal antibody with significant clinical activity. Phage display techniques have the added benefit of also allowing

Most antibodies in clinical use exert their antitumor effect through direct antibody-mediated killing. In an effort to increase cytotoxic effect of monoclonal antibodies other modifications were made to enhance their affinity or cell toxicity by combining the antibody with a toxin or

The antibody Fc region mediates effector function and may be altered to augment binding to FcRIII, a stimulatory receptor and reduce binding to FcRII, an inhibitory receptor, to enhance

the enhanced selection of therapeutically relevant features of antibodies. [27]

still capable of eliciting a human anti-chimera response (HACA) in some patients.

many of these issues of immunogenicity. [17-19]

*3.2.3. Chimerized monoclonal antibodies*

*3.2.4. Fully human monoclonal antibodies*

**3.3. Fully human monoclonal antibodies**

responses. [24, 25]

radioisotope.

Monoclonal antibodies can also hinder cell growth and regulation through blocking critical ligand-receptor interactions necessary for tumor survival and inducing receptor and downmodulation reducing pro-growth signaling. Daclizumab, the anti-CD25 antibody, exert its main cytotoxic effect by blocking the binding of IL-2 to its receptors depriving T-cells of a necessary growth factor resulting in cell death. [14]

#### **3.2. Immunogenicity of monoclonal antibodies**

#### *3.2.1. Non-human monoclonal antibodies*

Scientists have attempted to produce single specificity monoclonal antibodies for therapy for more than a century now. Despite early optimism the development of monoclonal antibodies as therapeutic modality remained elusive due to the immunogenicity of monoclonal antibod‐ ies. It was only with the introduction of hybridoma technology in 1975 the promise of selec‐ tively targeting cancers using monoclonal antibodies became a reality. [15] Early therapeutic monoclonal antibodies were derived primarily from rodents. These antibodies can be pro‐ duced in large amounts and have greater specificity to their single antigenic determinant compared to polyclonal antisera used for therapeutic purposes. Unfortunately early attempts to use these mouse or rodent antibodies for therapeutic purposes were unsuccessful in large part due to the dissimilarity between the rodent and human immune systems. Initially developed non-human antibodies, as foreign glycoproteins, had several issues hindering their effectiveness and development. These rodent hybridoma-derived antibodies exhibited short *in vivo* half-lives, were highly immunogenic in man often inducing neutralizing human antimouse antibodies (HAMA), and they could not engage Fc receptors expressed on human effector cells resulting in their inability at inducing ADCC making them relatively weak cytotoxic agents. Due to the foreign protein sequences serum sickness, infusion reactions and anaphylaxis were also common with these antibodies. In addition, many of these early nonhuman monoclonal antibodies were not directed against cell surface targets that were acces‐ sible to the antibody limiting their efficacy. First FDA approved monoclonal antibody in 1986 for treatment of allogeneic transplant rejection, Muromonab-CD3 (Orthoclone® OKT3), an anti-CD3 monoclonal antibody, is a non-human monoclonal antibody. [16]

#### *3.2.2. Chimerized antibodies*

Rapid neutralization of therapeutic antibodies due to formation of immune complexes between the non-human monoclonal antibody and induced host antibodies can severely limit tumor response and may alter antibody distribution and binding resulting in undesired side effects. Engineering of non-human monoclonal antibodies with human constant domains, so called chimerized or humanized monoclonal antibodies, or the generation of fully human monoclonal antibodies using transgenic or phage display technology has helped overcome many of these issues of immunogenicity. [17-19]

Chimeric monoclonal antibodies are generated by linking the rodent light and heavy chain variable domains to the human immunoglobulin constant domains using recombinant DNA technology. [20] This results in an antibody that contains approximately 65% human sequences that exhibits reduced immunogenicity and an increased serum half-life. Although the immu‐ nogenicity of chimeric monoclonal antibodies is significantly reduced, they are occasionally still capable of eliciting a human anti-chimera response (HACA) in some patients.

#### *3.2.3. Chimerized monoclonal antibodies*

those of the tumor necrosis factor receptor (TNFR) family, Fas, and the receptors for TNFrelated apoptosis-inducing ligand (TRAIL) when engaged by their ligand deliver an apoptotic signal promoting apoptosis. Monoclonal antibodies can mimic the physiologic ligand of these receptors and can agonistically bind to receptor family members eliciting apoptotic responses on engagement. [11] A number of monoclonal antibodies are known to induce tumor cell apoptosis at least partially through direct engagement of their target receptor including

Monoclonal antibodies can also hinder cell growth and regulation through blocking critical ligand-receptor interactions necessary for tumor survival and inducing receptor and downmodulation reducing pro-growth signaling. Daclizumab, the anti-CD25 antibody, exert its main cytotoxic effect by blocking the binding of IL-2 to its receptors depriving T-cells of a

Scientists have attempted to produce single specificity monoclonal antibodies for therapy for more than a century now. Despite early optimism the development of monoclonal antibodies as therapeutic modality remained elusive due to the immunogenicity of monoclonal antibod‐ ies. It was only with the introduction of hybridoma technology in 1975 the promise of selec‐ tively targeting cancers using monoclonal antibodies became a reality. [15] Early therapeutic monoclonal antibodies were derived primarily from rodents. These antibodies can be pro‐ duced in large amounts and have greater specificity to their single antigenic determinant compared to polyclonal antisera used for therapeutic purposes. Unfortunately early attempts to use these mouse or rodent antibodies for therapeutic purposes were unsuccessful in large part due to the dissimilarity between the rodent and human immune systems. Initially developed non-human antibodies, as foreign glycoproteins, had several issues hindering their effectiveness and development. These rodent hybridoma-derived antibodies exhibited short *in vivo* half-lives, were highly immunogenic in man often inducing neutralizing human antimouse antibodies (HAMA), and they could not engage Fc receptors expressed on human effector cells resulting in their inability at inducing ADCC making them relatively weak cytotoxic agents. Due to the foreign protein sequences serum sickness, infusion reactions and anaphylaxis were also common with these antibodies. In addition, many of these early nonhuman monoclonal antibodies were not directed against cell surface targets that were acces‐ sible to the antibody limiting their efficacy. First FDA approved monoclonal antibody in 1986 for treatment of allogeneic transplant rejection, Muromonab-CD3 (Orthoclone® OKT3), an

anti-CD3 monoclonal antibody, is a non-human monoclonal antibody. [16]

Rapid neutralization of therapeutic antibodies due to formation of immune complexes between the non-human monoclonal antibody and induced host antibodies can severely limit tumor response and may alter antibody distribution and binding resulting in undesired side

SGN-30 a chimeric anti-CD30 antibody, and alemtuzumab (anti-CD52). [12, 13]

necessary growth factor resulting in cell death. [14]

**3.2. Immunogenicity of monoclonal antibodies**

36 T-Cell Leukemia - Characteristics, Treatment and Prevention

*3.2.1. Non-human monoclonal antibodies*

*3.2.2. Chimerized antibodies*

Second generation monoclonal antibodies were further improved by incorporating the six complementarity-determining regions (CDR) of the rodent antibody-antigen binding site onto a human IgG antibody framework. Further improvements in maintaining the structure of the antigen-binding site and high affinity binding to the target were made by incorporating small number of amino acids in the murine antibody not directly involved in the CDR. [21] Alem‐ tuzumab is one such example. Although the binding between humanized antibodies and the dissociation constants (Kd) of humanized and the parental monoclonal antibody target is weaker than the murine parent, the differences between these are usually small enough to not be significant. [22, 23] Polymorphisms located in the constant regions, or to anti-idiotypic recognition of the variable domain can rarely result in human anti-human (HAHA) antibody responses. [24, 25]

#### *3.2.4. Fully human monoclonal antibodies*

To further enhance efficacy, "fully human" monoclonal antibodies have been generated using transgenic mice expressing human immunoglobulin genes. Vaccination of these mice using the desired antigen induces B-cells producing a fully human antibody by the mouse. Panitu‐ mumab (Vectibix®) an anti-EGFR monoclonal antibody [26], and ofatumumab (Azerra®), an anti-CD20 monoclonal antibody, were generated using such an approach. Phage display technology has also made it possible to develop fully human monoclonal antibody with significant clinical activity. Phage display techniques have the added benefit of also allowing the enhanced selection of therapeutically relevant features of antibodies. [27]

#### **3.3. Fully human monoclonal antibodies**

Most antibodies in clinical use exert their antitumor effect through direct antibody-mediated killing. In an effort to increase cytotoxic effect of monoclonal antibodies other modifications were made to enhance their affinity or cell toxicity by combining the antibody with a toxin or radioisotope.

The antibody Fc region mediates effector function and may be altered to augment binding to FcRIII, a stimulatory receptor and reduce binding to FcRII, an inhibitory receptor, to enhance ADCC. One strategy is to engineer Fc portions that exhibit reduced fucose glycosylation. [28] Alternatively, the Fc region may be engineered to reduce or enhance CMC by substituting antibody isotypes such as IgG4 that exhibit little complement activation or Fc receptor binding. An additional interaction of the Fc region is with the neonatal receptor FcRn that is involved with immunoglobulin turnover. This receptor interacts with IgG Fc in a saturable and pH dependent manner, this allows FcRn to bind IgG from acidic endosomes generated during pinocytosis, and recycle the IgG back to the cell surface where it is released in the slightly basic pH of the blood. This allows for an extended antibody half-life. This approach holds much promise for favorably altering the pharmacokinetics of monoclonal antibodies ultimately leading to the potential for less frequent administration of these expensive treatments.

**4. Antibody therapy for T-cell leukemias and lymphomas**

rituximab is used to prophylaxis against the risk of EBV-LPD.

CD2 is a surface glycoprotein that plays a key role in lymphocyte adhesion and signaling. [32] It is expressed on human T-lymphocytes, natural killer (NK) cells, and thymocytes, and its stimulation results in T-cell activation and antigen co-stimulation. It also potentiates the physical interaction between T-cells and antigen presenting cells, as well as between T-cells and NK-cells. In the cell membrane, CD2 associates with the T-cell receptor (TcR) and appears to enhance CD3 signaling during low affinity interactions with the major histocompatibility complex (MHC) molecules enhancing class I and class II-restricted antigen recognition. [33]

Monoclonal Antibody Therapy http://dx.doi.org/10.5772/55122 39

Siplizumab is humanized IgG1 monoclonal antibodies that binds to CD2 and inhibits Tcell responses and induced severe T-cell lymphopenia. It has primarily been studied as treatment for refractory psoriasis and treatment for graft-versus-host disease occurring during allogeneic bone marrow transplant. It has shown to increase disease-free survival of mice inoculated with human MET-1 adult T-cell leukemia cells. [34] In a phase I/II trial [35], 29 patients with various T-cell malignancies including HTLV-1-associated adult T-cell leukemia, peripheral T-cell lymphoma, cutaneous T-cells lymphoma, T-cell chronic lympho‐ cytic leukemia, and T-cell large granular lymphocyte leukemia were treated with siplizu‐ mab. Twenty-eight patients experienced a marked decline in circulating CD4+ and CD8+ Tcells, and NK-cells and there were two complete and nine partial responses. Unfortunately, four patients (13.7%) developed Epstein-Barr virus-related B-cell lymphoproliferative disease (EBV-LPD). [36] This complication has significantly hindered the development of siplizumab. A Phase I trial of siplizumab combined with rituximab and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH) for Tand NK cell lymphoma is currently ongoing at the National Cancer Institute, where the

CD3 represents a series of intermediate molecular weight polypeptide chains (CD3γ, CD3δ, CD3ε and CDζ) closely associated with α and β-subunits of the T-cell receptor (TcR) that recognizes antigen-peptide epitopes presented by MHC molecules in a class-restricted manner. [37] The intracellular regions of the CD3-subunits represent the signaling domains of the TcR complex that mediates T-cell activation. CD3 is expressed on most T-cells throughout development and thus represents a pan-T-cell antigen. The vast majority of T-cell neoplasms

Muromonab-CD3 (Orthoclone®, OKT3; Janssen Pharmaceutica, Ltd.), a murine IgG2a monoclonal antibody directed against the 20 kDa CD3ζ-subunit is approved for the reversal of acute allograft rejection in patients undergoing cardiac, hepatic and renal transplants. [39] It has also been used for the depletion of T-cells from stem cell and bone marrow allog‐ rafts to treat or reduce the risk of serious GvHD. [40] Administration of muromonab-CD3 results in the rapid disappearance of CD3+ T-cells from the peripheral circulation and

express CD3, although its expression may be reduced or lost in some lesions. [38]

**4.1. Anti-CD2 antibodies**

**4.2. Anti-CD3 antibodies**

#### **3.4. Immunotoxins**

Immunotoxins are conjugations of monoclonal antibodies with toxins that result in highly specific cytotoxicity. In this approach it is desirable for the target antigen to be internalized upon antibody binding delivering the toxin into the cell. These toxins, often derived from bacteria or plants sources, are extremely potent. Bacterial toxins such as diphtheria toxin (DT) and *Pseudomonas* exotoxin A inhibit cellular protein synthesis by the irreversible ADP ribosy‐ lation of elongation factor-2 (EF-2), while plant toxins such as ricin inactivate ribosomes. [29] Disadvantages of this approach include the increased immunogenicity of most of these toxins because of their microbial or plant origins. In addition, many immunotoxin conjugates are nonspecifically taken up by pinocytocysis by endothelial cell resulting in a vascular leak syndrome with edema and weight gain. In 2011, Brentuximab vendotin (Adcetris®), an immunotoxin composed of an anti-CD30 monoclonal antibody (SGN-30) and the potent anti-microtubule agent monomethylauristatin (MMAE) was approved for previously treated anaplastic large cell lymphoma and Hodgkin's lymphoma. [30] Denileukin difitox (Ontak®) approved for the treatment cutaneous T-cell lymphoma is often categorized as an immunotoxin; however, this agent is not antibody-based, but rather represents a fusion protein between the receptor binding domain of interleukin-2 and diphtheria toxin linked by short peptide sequence. [31]

#### **3.5. Radioimmunotherapy**

Radioimmunotherapy combines the specificity of monoclonal antibodies with the tumor killing effects of radiation, in theory sparing non-target cells from exposure to high doses of radiation. The choice of an appropriate antigen target and hence the specific monoclonal antibody is critical, as off target killing needs to be avoided. One consequence of this is the "bystander" or "cross-fire" effect, as radiation can also kill adjacent tumor cells that may not express the target antigen. The greatest clinical experience with radioimmunotherapy is in CD20-expressing lymphomas using radionuclides such as yttrium-90 (90Y) and iodine-131 (131I) labeled anti-CD20 monoclonal antibodies.

#### **4. Antibody therapy for T-cell leukemias and lymphomas**

#### **4.1. Anti-CD2 antibodies**

ADCC. One strategy is to engineer Fc portions that exhibit reduced fucose glycosylation. [28] Alternatively, the Fc region may be engineered to reduce or enhance CMC by substituting antibody isotypes such as IgG4 that exhibit little complement activation or Fc receptor binding. An additional interaction of the Fc region is with the neonatal receptor FcRn that is involved with immunoglobulin turnover. This receptor interacts with IgG Fc in a saturable and pH dependent manner, this allows FcRn to bind IgG from acidic endosomes generated during pinocytosis, and recycle the IgG back to the cell surface where it is released in the slightly basic pH of the blood. This allows for an extended antibody half-life. This approach holds much promise for favorably altering the pharmacokinetics of monoclonal antibodies ultimately

leading to the potential for less frequent administration of these expensive treatments.

Immunotoxins are conjugations of monoclonal antibodies with toxins that result in highly specific cytotoxicity. In this approach it is desirable for the target antigen to be internalized upon antibody binding delivering the toxin into the cell. These toxins, often derived from bacteria or plants sources, are extremely potent. Bacterial toxins such as diphtheria toxin (DT) and *Pseudomonas* exotoxin A inhibit cellular protein synthesis by the irreversible ADP ribosy‐ lation of elongation factor-2 (EF-2), while plant toxins such as ricin inactivate ribosomes. [29] Disadvantages of this approach include the increased immunogenicity of most of these toxins because of their microbial or plant origins. In addition, many immunotoxin conjugates are nonspecifically taken up by pinocytocysis by endothelial cell resulting in a vascular leak syndrome with edema and weight gain. In 2011, Brentuximab vendotin (Adcetris®), an immunotoxin composed of an anti-CD30 monoclonal antibody (SGN-30) and the potent anti-microtubule agent monomethylauristatin (MMAE) was approved for previously treated anaplastic large cell lymphoma and Hodgkin's lymphoma. [30] Denileukin difitox (Ontak®) approved for the treatment cutaneous T-cell lymphoma is often categorized as an immunotoxin; however, this agent is not antibody-based, but rather represents a fusion protein between the receptor binding domain of interleukin-2 and diphtheria toxin linked by short peptide sequence. [31]

Radioimmunotherapy combines the specificity of monoclonal antibodies with the tumor killing effects of radiation, in theory sparing non-target cells from exposure to high doses of radiation. The choice of an appropriate antigen target and hence the specific monoclonal antibody is critical, as off target killing needs to be avoided. One consequence of this is the "bystander" or "cross-fire" effect, as radiation can also kill adjacent tumor cells that may not express the target antigen. The greatest clinical experience with radioimmunotherapy is in CD20-expressing lymphomas using radionuclides such as yttrium-90 (90Y) and iodine-131 (131I)

**3.4. Immunotoxins**

38 T-Cell Leukemia - Characteristics, Treatment and Prevention

**3.5. Radioimmunotherapy**

labeled anti-CD20 monoclonal antibodies.

CD2 is a surface glycoprotein that plays a key role in lymphocyte adhesion and signaling. [32] It is expressed on human T-lymphocytes, natural killer (NK) cells, and thymocytes, and its stimulation results in T-cell activation and antigen co-stimulation. It also potentiates the physical interaction between T-cells and antigen presenting cells, as well as between T-cells and NK-cells. In the cell membrane, CD2 associates with the T-cell receptor (TcR) and appears to enhance CD3 signaling during low affinity interactions with the major histocompatibility complex (MHC) molecules enhancing class I and class II-restricted antigen recognition. [33]

Siplizumab is humanized IgG1 monoclonal antibodies that binds to CD2 and inhibits Tcell responses and induced severe T-cell lymphopenia. It has primarily been studied as treatment for refractory psoriasis and treatment for graft-versus-host disease occurring during allogeneic bone marrow transplant. It has shown to increase disease-free survival of mice inoculated with human MET-1 adult T-cell leukemia cells. [34] In a phase I/II trial [35], 29 patients with various T-cell malignancies including HTLV-1-associated adult T-cell leukemia, peripheral T-cell lymphoma, cutaneous T-cells lymphoma, T-cell chronic lympho‐ cytic leukemia, and T-cell large granular lymphocyte leukemia were treated with siplizu‐ mab. Twenty-eight patients experienced a marked decline in circulating CD4+ and CD8+ Tcells, and NK-cells and there were two complete and nine partial responses. Unfortunately, four patients (13.7%) developed Epstein-Barr virus-related B-cell lymphoproliferative disease (EBV-LPD). [36] This complication has significantly hindered the development of siplizumab. A Phase I trial of siplizumab combined with rituximab and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH) for Tand NK cell lymphoma is currently ongoing at the National Cancer Institute, where the rituximab is used to prophylaxis against the risk of EBV-LPD.

#### **4.2. Anti-CD3 antibodies**

CD3 represents a series of intermediate molecular weight polypeptide chains (CD3γ, CD3δ, CD3ε and CDζ) closely associated with α and β-subunits of the T-cell receptor (TcR) that recognizes antigen-peptide epitopes presented by MHC molecules in a class-restricted manner. [37] The intracellular regions of the CD3-subunits represent the signaling domains of the TcR complex that mediates T-cell activation. CD3 is expressed on most T-cells throughout development and thus represents a pan-T-cell antigen. The vast majority of T-cell neoplasms express CD3, although its expression may be reduced or lost in some lesions. [38]

Muromonab-CD3 (Orthoclone®, OKT3; Janssen Pharmaceutica, Ltd.), a murine IgG2a monoclonal antibody directed against the 20 kDa CD3ζ-subunit is approved for the reversal of acute allograft rejection in patients undergoing cardiac, hepatic and renal transplants. [39] It has also been used for the depletion of T-cells from stem cell and bone marrow allog‐ rafts to treat or reduce the risk of serious GvHD. [40] Administration of muromonab-CD3 results in the rapid disappearance of CD3+ T-cells from the peripheral circulation and lymphoid tissue through complement-mediated lysis, ADCC, apoptosis and the re-direc‐ tion of T-lymphocytes to other compartments. [41] Binding of muromonab-CD3 to its target receptor also stimulates TcR signaling, activation and proliferation of T-cells with in‐ creased expression of HLA-DR and CD25.

weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. [48]. Objective tumor responses were observed in 24% of the patients with two complete responses and three partial responses. In general, the drug was well tolerated with no major toxicity. Zanolimu‐ mab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be

Monoclonal Antibody Therapy http://dx.doi.org/10.5772/55122 41

CD5 (Leu-1) is a 67 kDa cysteine-rich scavenger receptor family glycoprotein expressed on T-cells and the B1a subset of B-cells. [49, 50] CD5 acts as a co-receptor and appears to regulate the signaling strength of the TcR signaling response. It may also play a similar role in modulating B-cell receptor signaling. [51] Current evidence indicates that CD5 is a key regulator of immune tolerance. Two small clinical trials have examined the use of anti-CD5 antibodies in patients with T-cell lymphoma. In one trial, 7 patients with refractory Leu-1+ (CD5+) T-cell lymphoma, six with CTCL and one with PTCL, were treated with murine anti-Leu-1 monoclonal antibody at doses of 0.25 to 100 mg administered 2-3 times per week. [52] A decrease in circulating T-cells was observed. The decline in T-cells was short-lived with a return to baseline occurring within 24-48 hours. The target antigen demonstrated down-modulation suggesting that CD5 might be a less suitable target for an unmodified antibody strategy. Five short-lived responses were reported and not surprising‐ ly the majority of patients treated developed neutralizing antibodies. In another trial, T101, a murine IgG2a anti-CD5 monoclonal antibody was administered to eight patients with CD5+ T-cell malignancies, four of which had CTCL. [53] Short-lived clinical improvements were noted in two CTCL patients. Again, the induction of neutralizing antibodies was limiting. More recent trials of CD5-targeted therapy have focused on treatment of B-cellinduced autoimmune diseases and purging of T-cells from bone marrow to prevent GvHD

CD25 (IL-2Rα) is the 55 kDa subunit of the interleukin-2 (IL-2) receptor, and plays a critical role mediating immune-modulatory function of IL-2 in the activation of T- and B-lymphocytes, NK-cells and macrophages. [57, 58]. Less than 5% of un-stimulated peripheral blood T-cells expresses the IL-2Rα; however, it is highly expressed on activated T-cells and on many B- and T-cell neoplasms such as ATL, ALCL, CTCL, hairy cell leukemia, and on the Reed-Sternberg

In 1981, Uchiyama and coworkers generated murine anti-Tac that defined the human IL-2Rα (CD25). [60] Daclizumab (Zenapax®; Hoffmann-La Roche, Inc.) is a recombinant monoclonal antibody where murine antigen-binding regions of the anti-Tac molecule were joined to a human immunoglobulin framework, approximately 90% of the murine IgG2a has been replaced with a human IgG1κ sequence. [61] Daclizumab has the advantages of a low frequency neutralizing antibodies, a significantly prolonged serum half-life compared to murine anti-

and have used immunotoxin conjugates of anti-CD5. [54-56]

investigated.

**4.5. Anti-CD25**

cells of Hodgkin's lymphoma. [59]

**4.4. Anti-CD5 antibodies**

In one report, a patient with refractory T-cell acute lymphoblastic leukemia that received muromonab-CD3 experienced a dramatic, albeit transient decline in circulating lymphoblasts and a reduction in splenomegaly. [42] Muromonmab-CD3 therapy is made difficult because engagement of the antibody with CD3ζ increases TcR signaling and can result in the release of inflammatory cytokines that can cause life-threatening cytokine release syndrome. In addition, muromonab-CD3 is also mitogenic for T-cells and its use may risk increasing the proliferation of malignant T-cells. Muromonmab-CD3 therapy is also associated with profound suppression of cell-mediated immunity and increased risk of opportunistic infections and secondary malignan‐ cies including EBV-LPD, lymphoma, skin cancer and Kaposi's sarcoma.

#### **4.3. Anti-CD4 antibodies**

CD4 is a 55 kDa membrane glycoprotein with four immunoglobulin-like domains, a hydro‐ phobic transmembrane domain and a long cytoplasmic tail. [43] CD4 acts as a co-receptor for the TcR complex. It is expressed on helper and regulatory T-cells, and it recognizes antigens presented by MHC class II molecules in association with the TCR. CD4 represents an attractive target since the majority of the post-thymic T-cell malignancies manifest a CD4+ phenotype.

In phase I study, seven CTCL patients were treated with a chimeric antibody composed of the IgG1κ human constant regions and the mouse variable regions directed against CD4 (anti-Leu3a). [44] Patients were dosed in cohorts of 10, 20, 40 or 80 mg intravenously twice a week for three weeks. At the 80 mg dose, the antibody was detected in skin lesions and also coating circulating CD4+ T-cells in the peripheral blood; however, with no significant depletion of CD4+ cells was observed. In a second study, this group administered a single intravenous dose of another chimeric murine anti-CD4 monoclonal antibody, cM-T412 (Centocor, Inc.), to eight previously treated CTCL patients. [45] Following the antibody infusion there was a significant suppression of peripheral blood CD4+ cells in seven of eight patients. Seven patients responded and the median duration of response was 25 weeks. One patient developed a neutralizing anti-chimeric antibody response. Toxicity was grade 2 or less and usually manifested as infusion reactions, mayalgias, and rashes.

More recently, zanolimumab (HuMax-CD4®; Genmab, Inc.), a fully human IgG1κ anti-CD4 monoclonal antibody was shown to deplete CD4+ T-cells from the skin, reduce dermal inflammatory infiltrates and induce remissions in psoriasis patients. [46] Zanolimumab was evaluated in two separate phase II trials in a total of 47 CTCL/Sezary syndrome patients. [47] Patients received between 280 and 980 mg weekly for up to 17 weeks. Zanolimumab resulted in a dose-dependent and profound CD4+ lymphocytopenia; however, the recov‐ ery of CD4+ cells. Overall 13 of 38 (34.2%) CTCL patients and 2 of 9 (22.2%) patients with Sezary cell leukemia responded to the antibody. Adverse events included nine infections attributed to therapy. In a second phase II study, 21 adult patients with relapsed or refractory CD4+ PTCL of non-cutaneous type were treated in a single-arm multicenter study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. [48]. Objective tumor responses were observed in 24% of the patients with two complete responses and three partial responses. In general, the drug was well tolerated with no major toxicity. Zanolimu‐ mab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.

#### **4.4. Anti-CD5 antibodies**

lymphoid tissue through complement-mediated lysis, ADCC, apoptosis and the re-direc‐ tion of T-lymphocytes to other compartments. [41] Binding of muromonab-CD3 to its target receptor also stimulates TcR signaling, activation and proliferation of T-cells with in‐

In one report, a patient with refractory T-cell acute lymphoblastic leukemia that received muromonab-CD3 experienced a dramatic, albeit transient decline in circulating lymphoblasts and a reduction in splenomegaly. [42] Muromonmab-CD3 therapy is made difficult because engagement of the antibody with CD3ζ increases TcR signaling and can result in the release of inflammatory cytokines that can cause life-threatening cytokine release syndrome. In addition, muromonab-CD3 is also mitogenic for T-cells and its use may risk increasing the proliferation of malignant T-cells. Muromonmab-CD3 therapy is also associated with profound suppression of cell-mediated immunity and increased risk of opportunistic infections and secondary malignan‐

CD4 is a 55 kDa membrane glycoprotein with four immunoglobulin-like domains, a hydro‐ phobic transmembrane domain and a long cytoplasmic tail. [43] CD4 acts as a co-receptor for the TcR complex. It is expressed on helper and regulatory T-cells, and it recognizes antigens presented by MHC class II molecules in association with the TCR. CD4 represents an attractive target since the majority of the post-thymic T-cell malignancies manifest a CD4+ phenotype. In phase I study, seven CTCL patients were treated with a chimeric antibody composed of the IgG1κ human constant regions and the mouse variable regions directed against CD4 (anti-Leu3a). [44] Patients were dosed in cohorts of 10, 20, 40 or 80 mg intravenously twice a week for three weeks. At the 80 mg dose, the antibody was detected in skin lesions and also coating circulating CD4+ T-cells in the peripheral blood; however, with no significant depletion of CD4+ cells was observed. In a second study, this group administered a single intravenous dose of another chimeric murine anti-CD4 monoclonal antibody, cM-T412 (Centocor, Inc.), to eight previously treated CTCL patients. [45] Following the antibody infusion there was a significant suppression of peripheral blood CD4+ cells in seven of eight patients. Seven patients responded and the median duration of response was 25 weeks. One patient developed a neutralizing anti-chimeric antibody response. Toxicity was grade 2 or

cies including EBV-LPD, lymphoma, skin cancer and Kaposi's sarcoma.

less and usually manifested as infusion reactions, mayalgias, and rashes.

More recently, zanolimumab (HuMax-CD4®; Genmab, Inc.), a fully human IgG1κ anti-CD4 monoclonal antibody was shown to deplete CD4+ T-cells from the skin, reduce dermal inflammatory infiltrates and induce remissions in psoriasis patients. [46] Zanolimumab was evaluated in two separate phase II trials in a total of 47 CTCL/Sezary syndrome patients. [47] Patients received between 280 and 980 mg weekly for up to 17 weeks. Zanolimumab resulted in a dose-dependent and profound CD4+ lymphocytopenia; however, the recov‐ ery of CD4+ cells. Overall 13 of 38 (34.2%) CTCL patients and 2 of 9 (22.2%) patients with Sezary cell leukemia responded to the antibody. Adverse events included nine infections attributed to therapy. In a second phase II study, 21 adult patients with relapsed or refractory CD4+ PTCL of non-cutaneous type were treated in a single-arm multicenter study, with

creased expression of HLA-DR and CD25.

40 T-Cell Leukemia - Characteristics, Treatment and Prevention

**4.3. Anti-CD4 antibodies**

CD5 (Leu-1) is a 67 kDa cysteine-rich scavenger receptor family glycoprotein expressed on T-cells and the B1a subset of B-cells. [49, 50] CD5 acts as a co-receptor and appears to regulate the signaling strength of the TcR signaling response. It may also play a similar role in modulating B-cell receptor signaling. [51] Current evidence indicates that CD5 is a key regulator of immune tolerance. Two small clinical trials have examined the use of anti-CD5 antibodies in patients with T-cell lymphoma. In one trial, 7 patients with refractory Leu-1+ (CD5+) T-cell lymphoma, six with CTCL and one with PTCL, were treated with murine anti-Leu-1 monoclonal antibody at doses of 0.25 to 100 mg administered 2-3 times per week. [52] A decrease in circulating T-cells was observed. The decline in T-cells was short-lived with a return to baseline occurring within 24-48 hours. The target antigen demonstrated down-modulation suggesting that CD5 might be a less suitable target for an unmodified antibody strategy. Five short-lived responses were reported and not surprising‐ ly the majority of patients treated developed neutralizing antibodies. In another trial, T101, a murine IgG2a anti-CD5 monoclonal antibody was administered to eight patients with CD5+ T-cell malignancies, four of which had CTCL. [53] Short-lived clinical improvements were noted in two CTCL patients. Again, the induction of neutralizing antibodies was limiting. More recent trials of CD5-targeted therapy have focused on treatment of B-cellinduced autoimmune diseases and purging of T-cells from bone marrow to prevent GvHD and have used immunotoxin conjugates of anti-CD5. [54-56]

#### **4.5. Anti-CD25**

CD25 (IL-2Rα) is the 55 kDa subunit of the interleukin-2 (IL-2) receptor, and plays a critical role mediating immune-modulatory function of IL-2 in the activation of T- and B-lymphocytes, NK-cells and macrophages. [57, 58]. Less than 5% of un-stimulated peripheral blood T-cells expresses the IL-2Rα; however, it is highly expressed on activated T-cells and on many B- and T-cell neoplasms such as ATL, ALCL, CTCL, hairy cell leukemia, and on the Reed-Sternberg cells of Hodgkin's lymphoma. [59]

In 1981, Uchiyama and coworkers generated murine anti-Tac that defined the human IL-2Rα (CD25). [60] Daclizumab (Zenapax®; Hoffmann-La Roche, Inc.) is a recombinant monoclonal antibody where murine antigen-binding regions of the anti-Tac molecule were joined to a human immunoglobulin framework, approximately 90% of the murine IgG2a has been replaced with a human IgG1κ sequence. [61] Daclizumab has the advantages of a low frequency neutralizing antibodies, a significantly prolonged serum half-life compared to murine antiTac, and the ability to mediate ADCC through its humanized Fc-domain. [62] It inhibits IL-2 induced activation of T-cells and it is approved for the prophylaxis of renal allograft rejection in combination with other immunosuppressive drugs.

**4.7. Alemtuzumab (anti-CD52)**

alemtuzumab treatment.

CD52 is a glycosylphosphatidylinositol (GPI)-anchored antigen expressed at high density on normal and malignant T- and B-cells, NK cells, monocytes, macrophages, eosinophils and epithelial cells of the male genital tract. It is not expressed on hematopoietic stem cells, granulocytes, erythrocytes, platelets, or plasma cells. Alemtuzumab (Campath®) a humanized rat monoclonal antibody targeting CD52 was approved by FDA for the treatment of relapsed/ refractory B-cell chronic lymphocytic leukemia (CLL). [67] Due to the presence of CD52 on Tcells and the antibody's ability to activate several mechanisms of cell death including ADCC,

Monoclonal Antibody Therapy http://dx.doi.org/10.5772/55122 43

T-cell prolymphocytic leukemia (T-PLL) carries a worse prognosis than CLL and has no established standard therapy and thus constituted a fitting model to study alemtuzumab. An initial trial in 39 T-PLL patients showed an overall response rate of 76%, including 60% complete responses to alemtuzumab. [68] A subsequent study reported the experience with alemtuzumab in 76 T-PLL patients. [69] The objective response rate was 51% with almost 40% patients achieving complete response with median response duration of 8.7 months. The most common treatment-related adverse events were acute infusion reactions. There were 2 treatment-related deaths, 15 infectious episodes in 10 patients during active treatment, and 8 patients experienced late-onset infections due to the long lasting lymphopenia associated with

These promising results in T-PLL lead to additional trials of alemtuzumab in both cutaneous T-cell lymphoma and other systemic T-cell malignancies either as a single agent or combined with chemotherapy. Single agent alemtuzumab is active in a variety of T-cell malignancies; however, responses are not durable and the risks of immunosuppression and development of opportunistic infections in patients poses a significant problem. In a phase II trial, alemtuzu‐ mab was administered to 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/ SS). The overall response rate was 55%, with 32% of patients achieving a complete remission. [70] Remarkably after treatment, Sézary cells were undetectable in blood in 6 of 7 (86%) SS patients and pruritis significantly improved in responding patients. Patients with erythroder‐

In a pilot study, 14 patients with heavily pretreated peripheral T-cell lymphoma (PTCL) that received alemtuzumab for a maximum of 12 weeks showed a response rate of 36%. [71] Toxicity included cytomegalovirus (CMV) reactivation in 6 patients, pulmonary aspergillosis in 2 patients, and pancytopenia in 4 patients. Another trial reported on the efficacy of the combi‐ nation of alemtuzumab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) as initial therapy for 24 PTCL patients. [72] The overall complete response rate was 71% (17 patients) and 1 patient a had partial remission. Grade 4 neutropenia and CMV reactivation was frequent. JC virus reactivation, invasive pulmonary aspergillosis, staphylo‐ coccal sepsis and pneumonia were also seen. In a recently reported phase II trial by the Dutch-Belgian HOVON group, 20 T-cell lymphoma patients were treated with 30 mg of alemtuzumab three times per week with every two week CHOP for eight courses. [73] The overall response was 90% and the median overall survival and event-free survival were 27 and 10 months, respectively. Although alemtuzumab-intensified CHOP achieved a high number of responses,

CMC and apoptosis it is an attractive agent to study in T-cell malignancies.

ma responded better than patients with thick plaque disease or skin tumors.

Daclizumab up to 8 mg/kg was administered to ATL patients in one phase I/II trial. [63] Cohorts of patients were treated with daclizumab 2 mg/kg on days 1 and 2, or 4, 6, or 8 mg/kg as a single intravenous dose every 2 or 3 weeks to complete six doses. Although Daclizumab showed modest clinical activity (2 partial response and 3 patients with improvement of their skin disease), flow cytometry analysis of the peripheral blood 72 hours after the first dose and at weeks 2, 5 and 14 showed that ≥95% saturation of IL-2Rα on circulating ATL cells could be achieved and maintained. In six patients that underwent lymph node fine needle aspiration, receptor saturation was documented in only half and it was not maintained suggesting that the impeded access of large antibody molecules into tumor is a potential blockade to receptor-directed therapy.

#### **4.6. Anti-CD30 antibodies**

CD30 is a cellular membrane protein member of the tumor necrosis factor receptor (TNFR) family expressed on activated T- and B-cells. It is highly expressed on HL Reed–Sternberg (RS) cells, in anaplastic large cell lymphoma (ALCL), embryonal carcinomas, and select subtypes of B-cell derived, non-Hodgkin's lymphomas and mature T-cell lymphomas. The immuno‐ toxin brentuximab vedotin (Adcetris®, SGN-35) was approved by the FDA in 2011 and became the first new treatment for HL in 30 years. Brentuximab vedotin is an antibody-drug conjugate between the antitubulin agent monomethylauristatin E (MMAE) and the anti-CD30 monoclo‐ nal antibody cAC10. Clinical studies with unconjugated anti-CD30 antibodies have shown disappointing clinical activity. [64] Objective responses were observed in 6% of patients with HL who were treated with MDX-060 and in none of those treated with cAC10 (SGN-30). However, the results of a pivotal phase II study of brentuximab vedotin in relapsed or refractory HL were impressive [65]. In this study, 102 patients with refractory or relapsed classical HL received brentuximab vedotin every 3 weeks for a median of 27 weeks. Almost all patients exhibited a reduction in tumor volume with 34% complete response and 40% partial response. A phase II multicenter trial evaluated the efficacy and safety of brentuximab vedotin in relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL) patients as CD30 is uniformly expressed in ALCL. [66] Fifty-eight patients received brentuximab vedotin 1.8 mg/ kg intravenously every 3 weeks and 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (median duration 13.2 months) and 17 patients (29%) achieved a partial remission. Grade 3 or 4 adverse events observed in ≥10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral neuropathy (12%). Based on these studies, brentuximab vedotin received accelerated approval for the treatment of Hodgkin lymphoma that has relapsed after autologous stem cell transplant and for the management of relapsed ALCL. Currently multiple studies are evaluating combination of brentuximab vedotin combined with standard chemotherapy options in management of both newly diagnosed and relapsed refractory ALCL patients.

#### **4.7. Alemtuzumab (anti-CD52)**

Tac, and the ability to mediate ADCC through its humanized Fc-domain. [62] It inhibits IL-2 induced activation of T-cells and it is approved for the prophylaxis of renal allograft rejection

Daclizumab up to 8 mg/kg was administered to ATL patients in one phase I/II trial. [63] Cohorts of patients were treated with daclizumab 2 mg/kg on days 1 and 2, or 4, 6, or 8 mg/kg as a single intravenous dose every 2 or 3 weeks to complete six doses. Although Daclizumab showed modest clinical activity (2 partial response and 3 patients with improvement of their skin disease), flow cytometry analysis of the peripheral blood 72 hours after the first dose and at weeks 2, 5 and 14 showed that ≥95% saturation of IL-2Rα on circulating ATL cells could be achieved and maintained. In six patients that underwent lymph node fine needle aspiration, receptor saturation was documented in only half and it was not maintained suggesting that the impeded access of large antibody molecules into

CD30 is a cellular membrane protein member of the tumor necrosis factor receptor (TNFR) family expressed on activated T- and B-cells. It is highly expressed on HL Reed–Sternberg (RS) cells, in anaplastic large cell lymphoma (ALCL), embryonal carcinomas, and select subtypes of B-cell derived, non-Hodgkin's lymphomas and mature T-cell lymphomas. The immuno‐ toxin brentuximab vedotin (Adcetris®, SGN-35) was approved by the FDA in 2011 and became the first new treatment for HL in 30 years. Brentuximab vedotin is an antibody-drug conjugate between the antitubulin agent monomethylauristatin E (MMAE) and the anti-CD30 monoclo‐ nal antibody cAC10. Clinical studies with unconjugated anti-CD30 antibodies have shown disappointing clinical activity. [64] Objective responses were observed in 6% of patients with HL who were treated with MDX-060 and in none of those treated with cAC10 (SGN-30). However, the results of a pivotal phase II study of brentuximab vedotin in relapsed or refractory HL were impressive [65]. In this study, 102 patients with refractory or relapsed classical HL received brentuximab vedotin every 3 weeks for a median of 27 weeks. Almost all patients exhibited a reduction in tumor volume with 34% complete response and 40% partial response. A phase II multicenter trial evaluated the efficacy and safety of brentuximab vedotin in relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL) patients as CD30 is uniformly expressed in ALCL. [66] Fifty-eight patients received brentuximab vedotin 1.8 mg/ kg intravenously every 3 weeks and 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (median duration 13.2 months) and 17 patients (29%) achieved a partial remission. Grade 3 or 4 adverse events observed in ≥10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral neuropathy (12%). Based on these studies, brentuximab vedotin received accelerated approval for the treatment of Hodgkin lymphoma that has relapsed after autologous stem cell transplant and for the management of relapsed ALCL. Currently multiple studies are evaluating combination of brentuximab vedotin combined with standard chemotherapy options in management of both

in combination with other immunosuppressive drugs.

42 T-Cell Leukemia - Characteristics, Treatment and Prevention

tumor is a potential blockade to receptor-directed therapy.

newly diagnosed and relapsed refractory ALCL patients.

**4.6. Anti-CD30 antibodies**

CD52 is a glycosylphosphatidylinositol (GPI)-anchored antigen expressed at high density on normal and malignant T- and B-cells, NK cells, monocytes, macrophages, eosinophils and epithelial cells of the male genital tract. It is not expressed on hematopoietic stem cells, granulocytes, erythrocytes, platelets, or plasma cells. Alemtuzumab (Campath®) a humanized rat monoclonal antibody targeting CD52 was approved by FDA for the treatment of relapsed/ refractory B-cell chronic lymphocytic leukemia (CLL). [67] Due to the presence of CD52 on Tcells and the antibody's ability to activate several mechanisms of cell death including ADCC, CMC and apoptosis it is an attractive agent to study in T-cell malignancies.

T-cell prolymphocytic leukemia (T-PLL) carries a worse prognosis than CLL and has no established standard therapy and thus constituted a fitting model to study alemtuzumab. An initial trial in 39 T-PLL patients showed an overall response rate of 76%, including 60% complete responses to alemtuzumab. [68] A subsequent study reported the experience with alemtuzumab in 76 T-PLL patients. [69] The objective response rate was 51% with almost 40% patients achieving complete response with median response duration of 8.7 months. The most common treatment-related adverse events were acute infusion reactions. There were 2 treatment-related deaths, 15 infectious episodes in 10 patients during active treatment, and 8 patients experienced late-onset infections due to the long lasting lymphopenia associated with alemtuzumab treatment.

These promising results in T-PLL lead to additional trials of alemtuzumab in both cutaneous T-cell lymphoma and other systemic T-cell malignancies either as a single agent or combined with chemotherapy. Single agent alemtuzumab is active in a variety of T-cell malignancies; however, responses are not durable and the risks of immunosuppression and development of opportunistic infections in patients poses a significant problem. In a phase II trial, alemtuzu‐ mab was administered to 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/ SS). The overall response rate was 55%, with 32% of patients achieving a complete remission. [70] Remarkably after treatment, Sézary cells were undetectable in blood in 6 of 7 (86%) SS patients and pruritis significantly improved in responding patients. Patients with erythroder‐ ma responded better than patients with thick plaque disease or skin tumors.

In a pilot study, 14 patients with heavily pretreated peripheral T-cell lymphoma (PTCL) that received alemtuzumab for a maximum of 12 weeks showed a response rate of 36%. [71] Toxicity included cytomegalovirus (CMV) reactivation in 6 patients, pulmonary aspergillosis in 2 patients, and pancytopenia in 4 patients. Another trial reported on the efficacy of the combi‐ nation of alemtuzumab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) as initial therapy for 24 PTCL patients. [72] The overall complete response rate was 71% (17 patients) and 1 patient a had partial remission. Grade 4 neutropenia and CMV reactivation was frequent. JC virus reactivation, invasive pulmonary aspergillosis, staphylo‐ coccal sepsis and pneumonia were also seen. In a recently reported phase II trial by the Dutch-Belgian HOVON group, 20 T-cell lymphoma patients were treated with 30 mg of alemtuzumab three times per week with every two week CHOP for eight courses. [73] The overall response was 90% and the median overall survival and event-free survival were 27 and 10 months, respectively. Although alemtuzumab-intensified CHOP achieved a high number of responses, many patients ultimately still relapsed, and this treatment was associated with frequent serious infection-related adverse events.

rashes (63%), which were manageable and reversible in all cases. Based on these results, a multicenter randomized phase II trial is ongoing comparing KW-0761 with standard secondline therapy according to investigator's choice of pralatrexate, gemcitabine and oxaliplatin, or

Monoclonal Antibody Therapy http://dx.doi.org/10.5772/55122 45

T-cell leukemias and lymphomas represent a heterogeneous group of uncommon diseases that often present with advanced stage disease and systemic symptoms. Historically they have been treated with combination chemotherapy similar to high-grade B-cell lymphomas; however, outcomes have been poorer. One of the reasons for this may be the lack of effective monoclonal antibody therapy for these diseases comparable to that of rituximab for the B-cell disorders. A number of antibodies targeting surface receptors on T-cells are being clinically studied. Alemtuzumab, a CD52-directed monoclonal antibody has demonstrated antitumor activity as a single agent and in combination with chemotherapy, but with increased risk of serious opportunistic infections. Zanolimumab and KW-0761 directed against CD4 and CCR4 expressed on T-cells, have also show an activity against CTCL and ATL, respectively and are being studied in ongoing clinical trials and offer hope for the future for patients with T-cell

Division of Hematology-Oncology, Department of Medicine, University of Cincinnati,

[1] Savage, KJ. Update: peripheral T-cell lymphomasCurr Hematol Malig Rep. (2011). ,

[2] Savage, KJ. Therapies for peripheral T-cell lymphomas. Hematology Am Soc Hema‐

[3] Nosari, A, Montillo, M, & Morra, E. Infectious toxicity using alemtuzumab. Haema‐

dexamethasone, cisplatin and cytarabine in previously treated relapsed ATL.

**5. Conclusions**

malignancies.

**Author details**

Cincinnati, OH, USA

6, 222-30.

**References**

Tahir Latif and John C. Morris\*

\*Address all correspondence to: morri2j7@ucmail.uc.edu

tol Educ Program. (2011). , 2011, 515-24.

tologica. (2004). , 89, 1414-9.

The combination of intravenous alemtuzumab 30 mg three times weekly and weekly pentos‐ tatin 4 mg/m2 was studied in 24 patients with a variety of T-cell leukemias and lymphomas. [74] This trial showed an overall response rate of 54% with 11 complete responses and median response duration was 19.5 months. As with other trials opportunistic infections due to severe T-cell dysfunction were common in spite of antimicrobial prophylaxis.

#### **4.8. Anti-CD122 (Mik-β1) antibodies**

CD122 (IL-2R/IL-15Rβ) is a 75 kDa glycoprotein that constitutes the β-subunit shared by the IL-2 and IL-15 receptors. During signal transduction, CD 122 and CD132, the common γ-chain of type I cytokine receptors, recruit janus kinase (JAK), that in turn activates the signal transducer and activator of transcription (STAT). Activated STAT transcription factors enhances specific gene expression after translocation to nucleus. T-cell large granular lym‐ phocyte (T-LGL) leukemia commonly presents with anemia, neutropenia and less frequently thrombocytopenia. IL-2 and IL-15 can stimulate T-LGL and NK cells and it is thought that the clinical cytopenias seen in T-LGL leukemia are a result of the enhanced NK activity of the leukemic cells. The Mik-β1 antibody (anti-CD122), directed against the IL-2R/IL-15Rβ, can inhibit IL-15-mediated effects *in vitro*. [75]

In a phase I trial, 12 patients with T-LGL leukemia received the murine Mik-β1 antibody and showed no responses in terms of decreases in T-LGL cell counts or improvement in their cytopenias. [76] Greater than 95% saturation of CD122 on circulating T-LGLs was achieved in all patients and down-modulation of CD122 was observed in seven patients. The lack of response may be the result of the short half-life of the murine antibody. In addition, downmodulation of CD122 after binding of the antibody reduced the amount of the receptor on the surface of the LGL cells and might have impacted the efficacy of the Mik-β1 antibody. A phase I safety and pharmacokinetic study of the humanized form of the antibody, HuMik-β1, in T-LGL leukemia patients was recently completed, but the results are not available.

#### **4.9. KW-0761 (anti-CCR4)**

Chemokine receptor-4 (CCR4) is over expressed on several T-cell neoplasms in addition to its normal expression on T-helper type 2 and regulatory T-cells. [77]. KW-0761 is a humanized IgG1 monoclonal antibody with a defucosylated Fc region that markedly enhances ADCC due to its increased binding affinity to the Fcγ receptor on effector cells. [78]. In a Phase I trial in 16 patients with relapsed CCR4-positive adult T-cell leukemia/lymphoma (ATL) or PTCL received KW-0761 once a week for 4 weeks by intravenous infusion. Toxicities included infusion reactions and skin rashes. The objective response rate was 31% with two complete and three partial responses. [79] Recently a multicenter phase II study conducted on 28 patients with relapsed ATL showed overall objective response rate of 50%, including eight complete responses, with a median progression-free and overall survival of 5.2 and 13.7 months, respectively. [80] The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases. Based on these results, a multicenter randomized phase II trial is ongoing comparing KW-0761 with standard secondline therapy according to investigator's choice of pralatrexate, gemcitabine and oxaliplatin, or dexamethasone, cisplatin and cytarabine in previously treated relapsed ATL.

#### **5. Conclusions**

many patients ultimately still relapsed, and this treatment was associated with frequent serious

The combination of intravenous alemtuzumab 30 mg three times weekly and weekly pentos‐

[74] This trial showed an overall response rate of 54% with 11 complete responses and median response duration was 19.5 months. As with other trials opportunistic infections due to severe

CD122 (IL-2R/IL-15Rβ) is a 75 kDa glycoprotein that constitutes the β-subunit shared by the IL-2 and IL-15 receptors. During signal transduction, CD 122 and CD132, the common γ-chain of type I cytokine receptors, recruit janus kinase (JAK), that in turn activates the signal transducer and activator of transcription (STAT). Activated STAT transcription factors enhances specific gene expression after translocation to nucleus. T-cell large granular lym‐ phocyte (T-LGL) leukemia commonly presents with anemia, neutropenia and less frequently thrombocytopenia. IL-2 and IL-15 can stimulate T-LGL and NK cells and it is thought that the clinical cytopenias seen in T-LGL leukemia are a result of the enhanced NK activity of the leukemic cells. The Mik-β1 antibody (anti-CD122), directed against the IL-2R/IL-15Rβ, can

In a phase I trial, 12 patients with T-LGL leukemia received the murine Mik-β1 antibody and showed no responses in terms of decreases in T-LGL cell counts or improvement in their cytopenias. [76] Greater than 95% saturation of CD122 on circulating T-LGLs was achieved in all patients and down-modulation of CD122 was observed in seven patients. The lack of response may be the result of the short half-life of the murine antibody. In addition, downmodulation of CD122 after binding of the antibody reduced the amount of the receptor on the surface of the LGL cells and might have impacted the efficacy of the Mik-β1 antibody. A phase I safety and pharmacokinetic study of the humanized form of the antibody, HuMik-β1, in T-

Chemokine receptor-4 (CCR4) is over expressed on several T-cell neoplasms in addition to its normal expression on T-helper type 2 and regulatory T-cells. [77]. KW-0761 is a humanized IgG1 monoclonal antibody with a defucosylated Fc region that markedly enhances ADCC due to its increased binding affinity to the Fcγ receptor on effector cells. [78]. In a Phase I trial in 16 patients with relapsed CCR4-positive adult T-cell leukemia/lymphoma (ATL) or PTCL received KW-0761 once a week for 4 weeks by intravenous infusion. Toxicities included infusion reactions and skin rashes. The objective response rate was 31% with two complete and three partial responses. [79] Recently a multicenter phase II study conducted on 28 patients with relapsed ATL showed overall objective response rate of 50%, including eight complete responses, with a median progression-free and overall survival of 5.2 and 13.7 months, respectively. [80] The most common adverse events were infusion reactions (89%) and skin

LGL leukemia patients was recently completed, but the results are not available.

T-cell dysfunction were common in spite of antimicrobial prophylaxis.

was studied in 24 patients with a variety of T-cell leukemias and lymphomas.

infection-related adverse events.

44 T-Cell Leukemia - Characteristics, Treatment and Prevention

**4.8. Anti-CD122 (Mik-β1) antibodies**

inhibit IL-15-mediated effects *in vitro*. [75]

**4.9. KW-0761 (anti-CCR4)**

tatin 4 mg/m2

T-cell leukemias and lymphomas represent a heterogeneous group of uncommon diseases that often present with advanced stage disease and systemic symptoms. Historically they have been treated with combination chemotherapy similar to high-grade B-cell lymphomas; however, outcomes have been poorer. One of the reasons for this may be the lack of effective monoclonal antibody therapy for these diseases comparable to that of rituximab for the B-cell disorders. A number of antibodies targeting surface receptors on T-cells are being clinically studied. Alemtuzumab, a CD52-directed monoclonal antibody has demonstrated antitumor activity as a single agent and in combination with chemotherapy, but with increased risk of serious opportunistic infections. Zanolimumab and KW-0761 directed against CD4 and CCR4 expressed on T-cells, have also show an activity against CTCL and ATL, respectively and are being studied in ongoing clinical trials and offer hope for the future for patients with T-cell malignancies.

#### **Author details**

Tahir Latif and John C. Morris\*

\*Address all correspondence to: morri2j7@ucmail.uc.edu

Division of Hematology-Oncology, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA

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normal and malignant T-cells. Science. (1986). , 232, 727-32.

als in seven patients with T-cell lymphoma. Blood. (1983). , 62, 988-95.

Oncol. (1984). , 2, 881-91.

50 T-Cell Leukemia - Characteristics, Treatment and Prevention

nol. (1994). , 1, 77-82.

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1393-7.

mic T cells. Blood. (1992). , 79, 1511-7.


[73] Kluin-nelemans, HC, van Marwijk Kooy, M, Lugtenburg, PJ, van Putten, WL, Luten, M, Oudejans, J, & van Imhoff, GW. Intensified alemtuzumab-CHOP therapy for pe‐ ripheral T-cell lymphoma. Ann Oncol. (2011). , 22, 1595-600.

**Chapter 3**

**T- and NK/T-Cell Leukemia in East Asia**

The relative frequency of lymphoma types varies in different geographic region. Human Tcell lymphotropic virus type I (HTLV-I) infection is endemic in south-western Japan which leads to a high frequency of adult T-cell leukemia/lymphoma (ATLL). As compared to the West, East Asian countries have higher relative frequencies of T- and natural killer (NK)-cell lymphomas, which account for about 15-20% of non-Hodgkin lymphoma after excluding ATLL in some Japanese series [1-5]. Accordingly, a higher frequency of T- and NK/T-cell leukemia would be expected in East Asia. As compared to B-cell lymphomas, T- and NK/Tcell neoplasms more frequently occur at extranodal locations, and may occasionally present

There are around 20 entities and variants of T- and NK/T-cell neoplasms in the 4th edition of World Health Organization (WHO) classification of lymphoid neoplasms [6]. Table 1 lists the T- and NK/T-cell neoplasms which may have leukemic presentation. The first category comprises entities that are predominantly leukemic including T-cell prolymphocytic leuke‐ mia (T-PLL), T-cell large granular lymphocytic leukemia (T-LGLL) and aggressive NK-cell leukemia (ANKL). The second category includes neoplasms that frequently present with concurrent lymphoma and leukemia such as T lymphoblastic leukemia/lymphoma (T-LBL), ATLL and Sézary syndrome. The third category includes T-cell lymphoma with secondary peripheral blood involvement such as unspecified peripheral T-cell lymphoma (PTCL-NOS) progressing to a leukemic phase and very rarely extranodal NK/T-cell lymphoma (ENKTL) with peripheral blood involvement, which might overlap with ANKL [7]. In the East Asian region other than Japan, ATLL is extremely rare and the discussion on this entity is covered in the other chapters. Sézary syndrome is extremely rare in this region as well. Accordingly

> © 2013 Lin et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Tsung-Hsien Lin, Yen-Chuan Hsieh,

http://dx.doi.org/10.5772/53743

**1. Introduction**

Sheng-Tsung Chang and Shih-Sung Chuang

Additional information is available at the end of the chapter

as leukemia, either with or without concomitant lymphoma.

we will not discuss these two entities in this chapter.


**Chapter 3**

## **T- and NK/T-Cell Leukemia in East Asia**

Tsung-Hsien Lin, Yen-Chuan Hsieh, Sheng-Tsung Chang and Shih-Sung Chuang

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53743

#### **1. Introduction**

[73] Kluin-nelemans, HC, van Marwijk Kooy, M, Lugtenburg, PJ, van Putten, WL, Luten, M, Oudejans, J, & van Imhoff, GW. Intensified alemtuzumab-CHOP therapy for pe‐

[74] Ravandi, F, Aribi, A, O'Brien, S, Faderl, S, Jones, D, Ferrajoli, A, Huang, X, York, S, Pierce, S, Wierda, W, Kontoyiannis, D, Verstovsek, S, Pro, B, Fayad, L, Keating, M, & Kantarjian, H. Phase II study of alemtuzumab in combination with pentostatin in pa‐

[75] Kobayashi, H, Dubois, S, Sato, N, Sabzevari, H, Sakai, Y, Waldmann, TA, & Tagaya, Y. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated kill‐ ing, which leads to enhanced tumor immunosurveillance. Blood. (2005). , 105, 721-7.

[76] Morris, JC, Janik, JE, White, JD, Fleisher, TA, Brown, M, Tsudo, M, Goldman, CK, Bryant, B, Petrus, M, Top, L, Lee, CC, Gao, W, & Waldmann, TA. Preclinical and phase I clinical trial of blockade of IL-15 using Mikbeta1 monoclonal antibody in T cell large granular lymphocyte leukemia. Proc Natl Acad Sci USA. (2006). , 103,

[77] Yoshie, O, Fujisawa, R, Nakayama, T, Harasawa, H, Tago, H, Izawa, D, Hieshima, K, Tatsumi, Y, Matsushima, K, Hasegawa, H, Kanamaru, A, Kamihira, S, & Yamada, Y. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia vi‐

[78] Ito, A, Ishida, T, Yano, H, Inagaki, A, Suzuki, S, Sato, F, Takino, H, Mori, F, Ri, M, Kusumoto, S, Komatsu, H, Iida, S, Inagaki, H, & Ueda, R. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer

[79] Yamamoto, K, Utsunomiya, A, Tobinai, K, Tsukasaki, K, Uike, N, Uozumi, K, Yama‐ guchi, K, Yamada, Y, Hanada, S, Tamura, K, Nakamura, S, Inagaki, H, Ohshima, K, Kiyoi, H, Ishida, T, Matsushima, K, Akinaga, S, Ogura, M, Tomonaga, M, & Ueda, R. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in re‐ lapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lympho‐

[80] Ishida, T, Joh, T, Uike, N, Yamamoto, K, Utsunomiya, A, Yoshida, S, Saburi, Y, Miya‐ moto, T, Takemoto, S, Suzushima, H, Tsukasaki, K, Nosaka, K, Fujiwara, H, Ishitsu‐ ka, K, Inagaki, H, Ogura, M, Akinaga, S, Tomonaga, M, Tobinai, K, & Ueda, R. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. (2012). , 30, 837-42.

ripheral T-cell lymphoma. Ann Oncol. (2011). , 22, 1595-600.

52 T-Cell Leukemia - Characteristics, Treatment and Prevention

tients with T-cell neoplasms. J Clin Oncol. (2009). , 27, 5425-5430.

rus type 1-transformed T cells. Blood. (2002). , 99, 1505-1511.

Immunol Immunother. (2009). , 58, 1195-1206.

ma. J Clin Oncol. (2010). , 28, 1591-1598.

401-6.

The relative frequency of lymphoma types varies in different geographic region. Human Tcell lymphotropic virus type I (HTLV-I) infection is endemic in south-western Japan which leads to a high frequency of adult T-cell leukemia/lymphoma (ATLL). As compared to the West, East Asian countries have higher relative frequencies of T- and natural killer (NK)-cell lymphomas, which account for about 15-20% of non-Hodgkin lymphoma after excluding ATLL in some Japanese series [1-5]. Accordingly, a higher frequency of T- and NK/T-cell leukemia would be expected in East Asia. As compared to B-cell lymphomas, T- and NK/Tcell neoplasms more frequently occur at extranodal locations, and may occasionally present as leukemia, either with or without concomitant lymphoma.

There are around 20 entities and variants of T- and NK/T-cell neoplasms in the 4th edition of World Health Organization (WHO) classification of lymphoid neoplasms [6]. Table 1 lists the T- and NK/T-cell neoplasms which may have leukemic presentation. The first category comprises entities that are predominantly leukemic including T-cell prolymphocytic leuke‐ mia (T-PLL), T-cell large granular lymphocytic leukemia (T-LGLL) and aggressive NK-cell leukemia (ANKL). The second category includes neoplasms that frequently present with concurrent lymphoma and leukemia such as T lymphoblastic leukemia/lymphoma (T-LBL), ATLL and Sézary syndrome. The third category includes T-cell lymphoma with secondary peripheral blood involvement such as unspecified peripheral T-cell lymphoma (PTCL-NOS) progressing to a leukemic phase and very rarely extranodal NK/T-cell lymphoma (ENKTL) with peripheral blood involvement, which might overlap with ANKL [7]. In the East Asian region other than Japan, ATLL is extremely rare and the discussion on this entity is covered in the other chapters. Sézary syndrome is extremely rare in this region as well. Accordingly we will not discuss these two entities in this chapter.

© 2013 Lin et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


cytometric TCR-Vβ repertoire analysis) [10]. While in other pathology laboratories, such cas‐ es might either be unrecognized or diagnosed solely by hematologists without marrow tre‐ phine biopsy and thus not being enrolled in the pathology files for lymphoma analysis. In

**Taiwan [9] Japan-1A [1] Japan-1B [1] Japan-2 [5] Korea [4]**

T-LBL 2.92% (n=4) 6.91% (n=55) 9.86% (n=55) 6.62% (n=19) 23.77% (n=208)

T-PLL 0.73% (n=1) 0.25% (n=2) 0.36% (n=2) 0.35% (n=1) 0.57% (n=5)

ANKL 0.73% (n=1) 0.38% (n=3) 0.54% (n=3) 0.70% (n=2) 3.31% (n=29)

ATLL 2.92% (n=4) 29.90% (n=238) Excluded 14.29% (n=41) 0.11% (n=1)

\*Data of various T- and NK-cell neoplasms are presented as percentage (case number) among the total number of T-

**Table 2.** Relative frequency of various T- and NK/T-cell leukemia among T-cell neoplasms in representative East Asian

T-LBL is a rare neoplasm occurring more commonly in adolescents, accounting for 1-4% among malignant lymphomas in East Asia [1,2,4,5,9]. Patients with T-LBL usually present with a very high leukemic cell count (frequently over 150,000/μL), and often with a large mediastinal mass [9]. The diagnosis is often straightforward with typical clinical features and numerous blasts in the peripheral blood with a fine chromatin pattern and irregular nu‐ clear contours (Fig. 1A). Phenotypically, the neoplastic cells express cytoplasmic but not sur‐ face CD3; and they frequently co-express CD4 and CD8. The most important and reliable immature cell marker is terminal deoxynucleotidyl transferase (TdT), which could be used either in immunohistochemistry or flow cytometry [11]. The other immature markers are CD1a, CD34 and CD99 [12,13]. Immunohistochemically, occasional cases of T-LBL may not express TdT, but instead, express CD34 and/or CD99 [14]. The immunophenotype of T-LBL and T-cell acute lymphoblastic leukemia are identical but differ in frequency, with a higher rate of later phases of development (cortical or mature immunophenotype) in T-LBL, which

Columns Japan-1A and -1B are from the same reference with exclusion of ATLL cases in the column of Japan-1B.

**2. T Lymphoblastic Leukemia/Lymphoma (T-LBL)**

is probably reflecting the higher rate (> 90%) of mediastinal tumors [15].

T-LGL leukemia 5.10% (n=7) 0.25% (n=2) 0.36% (n=2) - 0.23% (n=2)

(24.92%) 558/2,956 (18.88%) 287/1,552

(18.49%)

T- and NK/T-Cell Leukemia in East Asia http://dx.doi.org/10.5772/53743

> 875/5,318 (16.45%)

55

the following sections, we will discuss each specific T- and NK/T-cell neoplasm.

796/3,194

T-cell/total neoplasms (%)

countries.

and NK-cell neoplasms in each country.

137/718 (19.08%)

**Table 1.** T- and NK/T-cell neoplasms with leukemic presentation.

There are very few reports systemically reviewing the whole spectrum of T- and NK/T-cell neoplasms with leukemic presentation in the East Asia. In a prospective study of chronic lymphoproliferative disorders in Hong Kong in an 18-month period from January 1995 to June 1996, there were a total of 34 cases of chronic lymphoproliferative disorder, estimated at 0.54 case per million populations per year, as compared to 245 new cases of acute myeloid leukemia in the same study period [8]. Of these 34 cases, the majority were B-cell neoplasms with the remaining 3 (9%) cases being T-cell leukemias including one case each of T-PLL, Sézary syndrome and T-LGLL [8]. In our recent retrospective study of 718 consecutive pa‐ tients with lymphoid neoplasms in a single institution in Taiwan, the frequency of T- and NK/T-cell neoplasms with leukemic presentation was 13.1% (18 of 137 patients) [9]. Our study showed that cases with concurrent lymphoma, higher absolute leukemic cell counts, and elevated lactate dehydrogenase level carried a poorer prognosis. The survival of pa‐ tients with leukemic presentation was dichotomous, with a very poor prognosis for patients with T-LBL, T-PLL, ANKL, ATLL in acute phase, and PTCL-NOS; while those with T-LGLL and ATLL in chronic phase had a favorable outcome.

Table 2 summarizes the relative frequency of various T- and NK/T-cell leukemia in different countries in the East Asia [1,4,9]. As mentioned previously, T- and NK/T-cell neoplasms ac‐ count for 15-20% of lymphomas in this region. The relative frequency of T-LBL among T-cell neoplasms is low in Taiwan and Japan at less than 10%, but it is high at 23.77% (208 of 875 cases) in Korea, which is partly due to the inclusion of all lymphoid neoplasms including Tcell acute lymphoblastic leukemia in that Korean study [4]. T-PLL is very rare in all 3 coun‐ tries with a relative frequency of less than 1% among T-cell neoplasms. T-LGLL and ANKL are also rare with a frequency of less than 1% except for a higher frequency of the former in Taiwan and the latter in Korea, respectively. The higher relative frequency of T-LGLL in our series in Taiwan is probably due to a higher interest of this entity in our laboratory with con‐ firmation of suspicious cases by T-cell receptor (TCR) gene rearrangement and/or flow cy‐ tometry immunophenotyping (aberrancy in T-cell antigen expression or clonal by flow cytometric TCR-Vβ repertoire analysis) [10]. While in other pathology laboratories, such cas‐ es might either be unrecognized or diagnosed solely by hematologists without marrow tre‐ phine biopsy and thus not being enrolled in the pathology files for lymphoma analysis. In the following sections, we will discuss each specific T- and NK/T-cell neoplasm.

**A. Predominantly leukemic**

54 T-Cell Leukemia - Characteristics, Treatment and Prevention

3. Sézary syndrome

**Table 1.** T- and NK/T-cell neoplasms with leukemic presentation.

and ATLL in chronic phase had a favorable outcome.

1. T-cell prolymphocytic leukemia (T-PLL)

3. Aggressive NK-cell leukemia (ANKL) **B. Concurrent lymphoma/leukemia**

2. T-cell large granular lymphocytic leukemia (T-LGLL)

**C. Lymphoma with secondary peripheral blood involvement** 1. Peripheral T-cell lymphoma with peripheral blood involvement 2. Extranodal NK/T-cell lymphoma with peripheral blood involvement

There are very few reports systemically reviewing the whole spectrum of T- and NK/T-cell neoplasms with leukemic presentation in the East Asia. In a prospective study of chronic lymphoproliferative disorders in Hong Kong in an 18-month period from January 1995 to June 1996, there were a total of 34 cases of chronic lymphoproliferative disorder, estimated at 0.54 case per million populations per year, as compared to 245 new cases of acute myeloid leukemia in the same study period [8]. Of these 34 cases, the majority were B-cell neoplasms with the remaining 3 (9%) cases being T-cell leukemias including one case each of T-PLL, Sézary syndrome and T-LGLL [8]. In our recent retrospective study of 718 consecutive pa‐ tients with lymphoid neoplasms in a single institution in Taiwan, the frequency of T- and NK/T-cell neoplasms with leukemic presentation was 13.1% (18 of 137 patients) [9]. Our study showed that cases with concurrent lymphoma, higher absolute leukemic cell counts, and elevated lactate dehydrogenase level carried a poorer prognosis. The survival of pa‐ tients with leukemic presentation was dichotomous, with a very poor prognosis for patients with T-LBL, T-PLL, ANKL, ATLL in acute phase, and PTCL-NOS; while those with T-LGLL

Table 2 summarizes the relative frequency of various T- and NK/T-cell leukemia in different countries in the East Asia [1,4,9]. As mentioned previously, T- and NK/T-cell neoplasms ac‐ count for 15-20% of lymphomas in this region. The relative frequency of T-LBL among T-cell neoplasms is low in Taiwan and Japan at less than 10%, but it is high at 23.77% (208 of 875 cases) in Korea, which is partly due to the inclusion of all lymphoid neoplasms including Tcell acute lymphoblastic leukemia in that Korean study [4]. T-PLL is very rare in all 3 coun‐ tries with a relative frequency of less than 1% among T-cell neoplasms. T-LGLL and ANKL are also rare with a frequency of less than 1% except for a higher frequency of the former in Taiwan and the latter in Korea, respectively. The higher relative frequency of T-LGLL in our series in Taiwan is probably due to a higher interest of this entity in our laboratory with con‐ firmation of suspicious cases by T-cell receptor (TCR) gene rearrangement and/or flow cy‐ tometry immunophenotyping (aberrancy in T-cell antigen expression or clonal by flow

1. T lymphoblastic lymphoma/leukemia (T-LBL) 2. Adult T-cell lymphoma/leukemia (ATLL)


\*Data of various T- and NK-cell neoplasms are presented as percentage (case number) among the total number of Tand NK-cell neoplasms in each country.

Columns Japan-1A and -1B are from the same reference with exclusion of ATLL cases in the column of Japan-1B.

**Table 2.** Relative frequency of various T- and NK/T-cell leukemia among T-cell neoplasms in representative East Asian countries.

#### **2. T Lymphoblastic Leukemia/Lymphoma (T-LBL)**

T-LBL is a rare neoplasm occurring more commonly in adolescents, accounting for 1-4% among malignant lymphomas in East Asia [1,2,4,5,9]. Patients with T-LBL usually present with a very high leukemic cell count (frequently over 150,000/μL), and often with a large mediastinal mass [9]. The diagnosis is often straightforward with typical clinical features and numerous blasts in the peripheral blood with a fine chromatin pattern and irregular nu‐ clear contours (Fig. 1A). Phenotypically, the neoplastic cells express cytoplasmic but not sur‐ face CD3; and they frequently co-express CD4 and CD8. The most important and reliable immature cell marker is terminal deoxynucleotidyl transferase (TdT), which could be used either in immunohistochemistry or flow cytometry [11]. The other immature markers are CD1a, CD34 and CD99 [12,13]. Immunohistochemically, occasional cases of T-LBL may not express TdT, but instead, express CD34 and/or CD99 [14]. The immunophenotype of T-LBL and T-cell acute lymphoblastic leukemia are identical but differ in frequency, with a higher rate of later phases of development (cortical or mature immunophenotype) in T-LBL, which is probably reflecting the higher rate (> 90%) of mediastinal tumors [15].

**3. T-cell Prolymphocytic Leukemia (T-PLL)**

series or as a single case report [9, 20].

x109

**4. T-cell Large Granular Lymphocytic Leukemia (T-LGLL)**

Large granular lymphocytes (LGLs) are medium to large-sized lymphocytes with azuro‐ philic cytoplasmic granules that normally comprise 10-15% of the peripheral blood mon‐ onuclear cells (PBMCs) and serve as the main effector cells of cell-mediated cytotoxicity. The majority (85%) of these LGLs are NK-cells with the remaining minority being CD8 positive cytotoxic T-cells [21]. LGL lymphoproliferation may be reactive or neoplastic; and reactive LGL lymphoproliferation occurs most commonly in patients with viral infec‐ tion such as cytomegalovirus infection and infectious mononucleosis, autoimmune dis‐ ease or an underlying malignancy [10,22]. In the 2008 WHO classification scheme, T-LGLL is defined as a heterogeneous disorder characterized by a persistent (> 6 months) increase in the number of LGL in the peripheral blood, usually between 2-20 x109

without a clearly identified cause [23]. In cases with absolute LGL count less than 2

/L, the diagnosis of T-LGLL could be established if clonal T-cell lymphoproliferation is confirmed, either by TCR gene rearrangement and/or flow cytometry immunopheno‐ typing (aberrancy in T-cell antigen expression or clonal by flow cytometric TCR-Vβ rep‐ ertoire analysis) [10,24-28]. In most instances, the morphology of the leukemic cells in T-LGLL is indistinguishable from that of the normal LGLs (Fig. 1C), with the exception of

/L,

T-PLL is rare, representing around 2% of mature lymphocytic leukemia in adults over the age of 30 in the West with a median age of 65 [16]. The main disease features are splenomegaly, lymphadenopathy, hepatomegaly, skin lesions, and a high leukocyte count comprising small to medium-sized nucleolated prolymphocytes with cytoplasmic protru‐ sions or blebs but devoid of granules (Fig. 1B). Small cell variant with small, less typical cells and an indistinct nucleolus has been recognized in 20% cases [16]. T-PLLs account for less than 1% of T- and NK-cell lymphomas in East Asia. The clinical manifestations and immunophenotype of T-PLL in Japan are similar to those of the Western cases [17-19]. However, there is a significantly higher frequency of tumor cells in Japanese cas‐ es expressing HLA-DR than that of Western cases [17]. Chromosome 14q11 abnormality and trisomy 8q, which are frequently seen in T-PLL of Western countries (70-80%), are not common in Japan [18]. Furthermore, a substantial number of T-PLL cases in Japan shows abnormal expression of TCL1A, probably due to rearrangement of *TCL1* gene, which may serve as a useful marker for diagnosing T-PLL [19]. In contrast to the aggres‐ sive clinical courses observed in Western T-PLL patients, Kameoka et al. reported that 6 out of 13 Japanese patients experienced an indolent course. Interestingly, the clinical course closely correlated with morphology; 86% cases of typical morphology were ag‐ gressive, whereas 83% of small-cell variant were indolent [17]. Studies on more cases are needed to see if Japanese T-PLL constitutes a variant of T-PLL. In East Asia countries other than Japan, there are only scanty reports on T-PLL, either included in a small case

T- and NK/T-Cell Leukemia in East Asia http://dx.doi.org/10.5772/53743 57

**Figure 1.** Photomicrographs of representative cases in the peripheral blood smear of A) T-LBL with indented nuclei, B) T-PLL of small cell variant without nucleoli, C) T-LGLL with usual LGL morphology containing azurophilic cytoplasmic granules, D) T-LGLL with atypical morphology characterized by irregular nuclear contours resembling a flower, E) reac‐ tive NK lymphocytosis and F), ANKL.

#### **3. T-cell Prolymphocytic Leukemia (T-PLL)**

T-PLL is rare, representing around 2% of mature lymphocytic leukemia in adults over the age of 30 in the West with a median age of 65 [16]. The main disease features are splenomegaly, lymphadenopathy, hepatomegaly, skin lesions, and a high leukocyte count comprising small to medium-sized nucleolated prolymphocytes with cytoplasmic protru‐ sions or blebs but devoid of granules (Fig. 1B). Small cell variant with small, less typical cells and an indistinct nucleolus has been recognized in 20% cases [16]. T-PLLs account for less than 1% of T- and NK-cell lymphomas in East Asia. The clinical manifestations and immunophenotype of T-PLL in Japan are similar to those of the Western cases [17-19]. However, there is a significantly higher frequency of tumor cells in Japanese cas‐ es expressing HLA-DR than that of Western cases [17]. Chromosome 14q11 abnormality and trisomy 8q, which are frequently seen in T-PLL of Western countries (70-80%), are not common in Japan [18]. Furthermore, a substantial number of T-PLL cases in Japan shows abnormal expression of TCL1A, probably due to rearrangement of *TCL1* gene, which may serve as a useful marker for diagnosing T-PLL [19]. In contrast to the aggres‐ sive clinical courses observed in Western T-PLL patients, Kameoka et al. reported that 6 out of 13 Japanese patients experienced an indolent course. Interestingly, the clinical course closely correlated with morphology; 86% cases of typical morphology were ag‐ gressive, whereas 83% of small-cell variant were indolent [17]. Studies on more cases are needed to see if Japanese T-PLL constitutes a variant of T-PLL. In East Asia countries other than Japan, there are only scanty reports on T-PLL, either included in a small case series or as a single case report [9, 20].

#### **4. T-cell Large Granular Lymphocytic Leukemia (T-LGLL)**

**Figure 1.** Photomicrographs of representative cases in the peripheral blood smear of A) T-LBL with indented nuclei, B) T-PLL of small cell variant without nucleoli, C) T-LGLL with usual LGL morphology containing azurophilic cytoplasmic granules, D) T-LGLL with atypical morphology characterized by irregular nuclear contours resembling a flower, E) reac‐

tive NK lymphocytosis and F), ANKL.

56 T-Cell Leukemia - Characteristics, Treatment and Prevention

Large granular lymphocytes (LGLs) are medium to large-sized lymphocytes with azuro‐ philic cytoplasmic granules that normally comprise 10-15% of the peripheral blood mon‐ onuclear cells (PBMCs) and serve as the main effector cells of cell-mediated cytotoxicity. The majority (85%) of these LGLs are NK-cells with the remaining minority being CD8 positive cytotoxic T-cells [21]. LGL lymphoproliferation may be reactive or neoplastic; and reactive LGL lymphoproliferation occurs most commonly in patients with viral infec‐ tion such as cytomegalovirus infection and infectious mononucleosis, autoimmune dis‐ ease or an underlying malignancy [10,22]. In the 2008 WHO classification scheme, T-LGLL is defined as a heterogeneous disorder characterized by a persistent (> 6 months) increase in the number of LGL in the peripheral blood, usually between 2-20 x109 /L, without a clearly identified cause [23]. In cases with absolute LGL count less than 2 x109 /L, the diagnosis of T-LGLL could be established if clonal T-cell lymphoproliferation is confirmed, either by TCR gene rearrangement and/or flow cytometry immunopheno‐ typing (aberrancy in T-cell antigen expression or clonal by flow cytometric TCR-Vβ rep‐ ertoire analysis) [10,24-28]. In most instances, the morphology of the leukemic cells in T-LGLL is indistinguishable from that of the normal LGLs (Fig. 1C), with the exception of extremely rare examples showing markedly pleomorphic nuclei indicating a neoplastic lymphoproliferation (Fig. 1D) [29].

**Taiwan (n=17) HK (n=22) West\* (n=272)** *P (Taiwan vs.*

Female 5 8 146 0.668 0.050

Low(<10 g/dL) 8 17 113 0.028 0.988

Low (<1.5x109/L) 8 8 146 0.523 0.218

High (>2x109/L) 11 14 133 0.980 0.110

Low (<150x109/L) 7 5 47 0.337 0.075

Absent 7 17 211 0.659 0.169

Absent 8 14 147 0.335 0.199

Absent 6 7 137 0.035 0.010

Absent 13 22 199 0.203 0.100

Absent 14 21 267 0.418 0.608

The statistical analyses of data were performed by student t test or chi square test where appropriate (SPSS, Chicago,

Male 12 14 125

**Age** (mean ± SE of the mean, years) 62.1 ± 4.1 52.3 ± 3.2 0.121

Mean ± SE of the mean (g/dL) 10.5 ± 0.7 8.1 ± 0.7 0.019

Mean ± SE of the mean (x109/L) 2.7 ± 0.5 3.4 ± 1.0 0.479

Mean ± SE of the mean (x109/L) 4.5 ± 1.2 4.8 ± 0.7 0.523

Mean ± SE of the mean (x109/L) 223 ± 31 204 ± 28 0.989

Present 3 5 35

Present 2 8 99

Present 2 15 6

Present 1 0 73

Present 0 1 5

Data from the Western series is based on the report by Prof. Kwong et al [30].

**Table 3.** Comparison of T-LGLL in Hong Kong, China, Taiwan and West

**Sex**

**Hemoglobin**

**Neutrophil count**

**LGL count**

**Platelet count**

**Hepatomegaly**

**Splenomegaly**

**Pure red cell aplasia**

**Rheumatoid arthritis**

**Autoimmune phenomena**

IL, USA.)

Abbreviation: HK, Hong Kong; SE, standard error.

*HK)*

T- and NK/T-Cell Leukemia in East Asia http://dx.doi.org/10.5772/53743

> *P (Taiwan vs. West)*

59

A recent study led by Prof. Kwong YL from Hong Kong characterized 22 Chinese T-LGLL patients in his institution in Hong Kong and found that the most important indication for treatment of their patients was anemia, in contrast to neutropenia in Western patients [30]. Compiling their cases with 88 Asian patients in comparison with 272 Western patients iden‐ tified from the literature, they found that Asian patients had more frequent anemia (66/110, 60% vs. 113/240, 47%; *p*=0.044), attributable to a much higher incidence of pure red cell apla‐ sia (PRCA; 52/110, 47% vs. 6/143, 4%; *p*<0.001) [30]. On the other hand, Western patients pre‐ sented more frequently with neutropenia (146/235, 62% vs. 33/110, 30%; *p*<0.001) and splenomegaly (99/246, 40% vs. 16/110, 15%; *p*<0.001) [30]. Notably, Western patients were about eight to ten times more likely than Asian patients to have rheumatoid arthritis (73/272, 27% vs. 4/106, 4%; *p*<0.001) and recurrent infections (81/272, 30% vs. 3/107, 3%; *p*<0.001) [30]. They concluded that different disease mechanisms might be involved in T-LGLL in different populations.

Table 3 summarizes the laboratory and clinical findings of T-LGLL in Taiwan, Hong Kong and the West. Our very recent study of 17 Taiwanese patients with T-LGLL showed a higher mean hemoglobin level (10.5 vs. 8.1 g/dL) and a lower rate of anemia (8/17, 47% vs. 17/22, 77%; *p*=0.028) as compared to the Chinese patients in Hong Kong; while the frequency of anemia in our patients was similar to that (113/227, 49.8%) of the Western patients (*p*= 0.988) [10]. Because anemia was not a major problem in our patients and thus bone marrow aspira‐ tion/biopsy was performed only in 8 patients. Even so, our cohort of patients showed a low‐ er rate of PRCA as compared to the Hong Kong series (2/8, 25% vs. 17/22, 68%; *p*=0.035). Interestingly, in our small series of patients, the frequency of PRCA was higher than that (6/143, 4.2%) of the Western patients (*p*= 0.010). There were no other statistically significant laboratory and clinical parameters between Taiwanese vs. Hong Kong Chinese or Taiwa‐ nese vs. Western T-LGLL patients. More studies from East Asian patients are warranted to see if there is a genuine ethnic difference in patients with T-LGLL, particularly in terms of the frequency of anemia and PRCA.

Apart from arising as *de novo* neoplasms, T-LGLL may arise after hematopoietic stem cell or solid organ transplantation [31-38]. Notably, most of the reported cases of T-LGLL af‐ ter hematopoietic stem cell transplantation are from East Asia. Prof. Kwong's group from Hong Kong recently reported the largest series of 7 such patients who did not have cyto‐ penia, autoimmune phenomenon or organ infiltration, features typical of *de novo* T-LGLL [39]. Excluding 1 patient died from cerebral relapse of the original lymphoma, the re‐ maining 6 patients had remained asymptomatic with stable LGL counts for long periods not requiring any specific treatment. T-LGLL occurring after hematopoietic stem cell transplantation seems to be distinct from *de novo* T-LGLL and may have a different pathogenesis and clinical course.


Data from the Western series is based on the report by Prof. Kwong et al [30].

Abbreviation: HK, Hong Kong; SE, standard error.

extremely rare examples showing markedly pleomorphic nuclei indicating a neoplastic

A recent study led by Prof. Kwong YL from Hong Kong characterized 22 Chinese T-LGLL patients in his institution in Hong Kong and found that the most important indication for treatment of their patients was anemia, in contrast to neutropenia in Western patients [30]. Compiling their cases with 88 Asian patients in comparison with 272 Western patients iden‐ tified from the literature, they found that Asian patients had more frequent anemia (66/110, 60% vs. 113/240, 47%; *p*=0.044), attributable to a much higher incidence of pure red cell apla‐ sia (PRCA; 52/110, 47% vs. 6/143, 4%; *p*<0.001) [30]. On the other hand, Western patients pre‐ sented more frequently with neutropenia (146/235, 62% vs. 33/110, 30%; *p*<0.001) and splenomegaly (99/246, 40% vs. 16/110, 15%; *p*<0.001) [30]. Notably, Western patients were about eight to ten times more likely than Asian patients to have rheumatoid arthritis (73/272, 27% vs. 4/106, 4%; *p*<0.001) and recurrent infections (81/272, 30% vs. 3/107, 3%; *p*<0.001) [30]. They concluded that different disease mechanisms might be involved in T-LGLL in different

Table 3 summarizes the laboratory and clinical findings of T-LGLL in Taiwan, Hong Kong and the West. Our very recent study of 17 Taiwanese patients with T-LGLL showed a higher mean hemoglobin level (10.5 vs. 8.1 g/dL) and a lower rate of anemia (8/17, 47% vs. 17/22, 77%; *p*=0.028) as compared to the Chinese patients in Hong Kong; while the frequency of anemia in our patients was similar to that (113/227, 49.8%) of the Western patients (*p*= 0.988) [10]. Because anemia was not a major problem in our patients and thus bone marrow aspira‐ tion/biopsy was performed only in 8 patients. Even so, our cohort of patients showed a low‐ er rate of PRCA as compared to the Hong Kong series (2/8, 25% vs. 17/22, 68%; *p*=0.035). Interestingly, in our small series of patients, the frequency of PRCA was higher than that (6/143, 4.2%) of the Western patients (*p*= 0.010). There were no other statistically significant laboratory and clinical parameters between Taiwanese vs. Hong Kong Chinese or Taiwa‐ nese vs. Western T-LGLL patients. More studies from East Asian patients are warranted to see if there is a genuine ethnic difference in patients with T-LGLL, particularly in terms of

Apart from arising as *de novo* neoplasms, T-LGLL may arise after hematopoietic stem cell or solid organ transplantation [31-38]. Notably, most of the reported cases of T-LGLL af‐ ter hematopoietic stem cell transplantation are from East Asia. Prof. Kwong's group from Hong Kong recently reported the largest series of 7 such patients who did not have cyto‐ penia, autoimmune phenomenon or organ infiltration, features typical of *de novo* T-LGLL [39]. Excluding 1 patient died from cerebral relapse of the original lymphoma, the re‐ maining 6 patients had remained asymptomatic with stable LGL counts for long periods not requiring any specific treatment. T-LGLL occurring after hematopoietic stem cell transplantation seems to be distinct from *de novo* T-LGLL and may have a different

lymphoproliferation (Fig. 1D) [29].

58 T-Cell Leukemia - Characteristics, Treatment and Prevention

the frequency of anemia and PRCA.

pathogenesis and clinical course.

populations.

The statistical analyses of data were performed by student t test or chi square test where appropriate (SPSS, Chicago, IL, USA.)

**Table 3.** Comparison of T-LGLL in Hong Kong, China, Taiwan and West

In patients with solid organ transplantation clonal T-LGL proliferation seems to be not un‐ common. Sabnani et al. found that 71% (10/14) cardiac and 44% (4/9) renal transplant pa‐ tients had clonal expansion of T-LGL cells but without evidence of either allograft rejection or a viral syndrome. Constitutional symptoms were present in 30% of these patients. Ane‐ mia was seen in 75% of renal transplant and 10% of cardiac transplant patients, but none of these patients had significant neutropenia. They believe that this monoclonality is not a true form of post-transplant lymphoproliferative disorder. Constant antigenic stimulus such as a cytomegalovirus reactivation may be the underlying etiology of clonal T-LGL expansion and may contribute to cytopenias and fatigue seen in transplant patients [38].

wan [45,47-49]. The EBV infection in ANKL is an episomal form, indicating a clonal inte‐ gration into leukemic cells. Prof. Ko et al. compared the clinicopathological characteristics of EBV-negative ANKL patients with those of EBV-positive ANKL pa‐ tients in Korea and reviewed the literature for reports on EBV-negative ANKL cases. They found that EBV-negative and EBV-positive ANKL patients had similar clinical and pathological characteristics, but EBV-negative patients had a longer survival than EBVpositive patients (11.5 vs. 1.5 months, respectively). EBV-negative patients achieved com‐ plete remission, but tumors often relapsed after a short interval, indicating a less

T- and NK/T-Cell Leukemia in East Asia http://dx.doi.org/10.5772/53743 61

The most common T-cell lymphoma with peripheral blood involvement is ATLL and is dis‐ cussed in the previous chapters. The other T-cell lymphoma with peripheral blood involve‐ ment is Sézary syndrome, which is characterized by the triad of erythroderma, generalized lymphadenopathy and the presence of clonally related T-cells with cerebriform nuclei (Séz‐ ary cells) in skin, lymph nodes and peripheral blood [50]. Very rarely, PTCL-NOS and ENKTL may progress to bone marrow and peripheral blood involvement, usually in the ter‐

In this chapter, we review and analyze various types of T- and NK/T-cell leukemias in the East Asia. Several of these rare neoplasms have not been reported in some East Asian coun‐ tries yet. Interestingly, there are certain features in some entities, such as T-LGLL, that are distinct from the Western population. More epidemiological, clinicopathological and genetic

The authors are grateful to Prof. Jooryung Huh at Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea and Prof. Ryo Ichinohasama at Division of Hematopathology, Tohoku University Graduate School of Medicine, Sendai, Japan for providing pertinent papers and comments. We thank Prof. Yok-Lam Kwong for

aggressive clinical course than EBV-positive ANKL [49].

**involvement**

minal stage of disease [7,9].

**Acknowledgements**

studies on these rare neoplasms are warranted.

providing the photomicrograph of ANKL for figure 1 F.

**7. Conclusion**

**6. Mature T- and NK/T-cell lymphoma with peripheral blood**

#### **5. Aggressive NK-cell Leukemia (ANKL)**

ANKL is a systemic proliferation of NK-cells, almost always associated with Epstein-Bar vi‐ rus (EBV) and an aggressive clinical course [40]. This catastrophic disease is observed almost exclusively in Asian patients who are usually very ill on presentation, with pyrexia, jaun‐ dice, pancytopenia, skin infiltration, lymphadenopathy and hepatosplenomegaly [40,41]. The most commonly involved sites are peripheral blood, bone marrow, liver and spleen. The leukemic cells may show a wide range of appearance from normal-looking LGL as seen in reactive NK lymphocytosis (Fig. 1E) to atypical (e.g. irregular nuclear foldings, very large size) or immature (e.g. open chromatin, distinct nucleoli) morphological features (Fig. 1F) even in an individual case [42]. The number of neoplastic cells in the peripheral blood and bone marrow can be limited or numerous, from less than 5% to greater than 80% of lympho‐ cytes [42]. Furthermore, there are cases with overlapping features with ENKTL [43,44]. Ac‐ cordingly, ANKL has also been called aggressive NK-cell lymphoma/leukemia; however, patients with ANKL are younger and the incidence of skin involvement is significantly low‐ er than ENKTL. It is currently unclear whether ANKL is the leukemic counterpart of ENKTL [40].

Phenotypically, the leukemic cells of ANKL in a Japanese series of 22 cases were character‐ ized by the expression of CD2, cytoplasmic CD3, CD56 and HLA-DR with frequent expres‐ sion of CD7 (14/19 cases, 74%), CD8 and CD16. They did not express surface CD3, CD4, CD5 or CD25 [45]. Interestingly, in a Korean series of 20 cases, CD7 antigen loss was detected in 10 patients (50%) [46]. The Korean investigators claimed that, in conjunction with the cyto‐ genetic findings, this characteristic immunophenotypic finding could serve as a reliable marker for the timely diagnosis in 75% of ANKL [46]. However, there were no statistically significant difference in the clinical or laboratory parameters between the CD7+ and the CD7- ANKL patients. To our knowledge, there are only 2 reports of ANKL from Taiwan, and the leukemic cells in 6 of 7 (86%) cases expressed CD7 [47,48]. No statistically significant difference on CD7 expression was identified between ANKL cases in Taiwan, Japan or Ko‐ rea (Fishers' exact test).

The great majority of ANKL is associated with EBV-- 85% (11/13) in a Japanese series, 88% (14/16) in a Korean series and 71% (5/7) compiled from the two reports from Tai‐ wan [45,47-49]. The EBV infection in ANKL is an episomal form, indicating a clonal inte‐ gration into leukemic cells. Prof. Ko et al. compared the clinicopathological characteristics of EBV-negative ANKL patients with those of EBV-positive ANKL pa‐ tients in Korea and reviewed the literature for reports on EBV-negative ANKL cases. They found that EBV-negative and EBV-positive ANKL patients had similar clinical and pathological characteristics, but EBV-negative patients had a longer survival than EBVpositive patients (11.5 vs. 1.5 months, respectively). EBV-negative patients achieved com‐ plete remission, but tumors often relapsed after a short interval, indicating a less aggressive clinical course than EBV-positive ANKL [49].

## **6. Mature T- and NK/T-cell lymphoma with peripheral blood involvement**

The most common T-cell lymphoma with peripheral blood involvement is ATLL and is dis‐ cussed in the previous chapters. The other T-cell lymphoma with peripheral blood involve‐ ment is Sézary syndrome, which is characterized by the triad of erythroderma, generalized lymphadenopathy and the presence of clonally related T-cells with cerebriform nuclei (Séz‐ ary cells) in skin, lymph nodes and peripheral blood [50]. Very rarely, PTCL-NOS and ENKTL may progress to bone marrow and peripheral blood involvement, usually in the ter‐ minal stage of disease [7,9].

#### **7. Conclusion**

In patients with solid organ transplantation clonal T-LGL proliferation seems to be not un‐ common. Sabnani et al. found that 71% (10/14) cardiac and 44% (4/9) renal transplant pa‐ tients had clonal expansion of T-LGL cells but without evidence of either allograft rejection or a viral syndrome. Constitutional symptoms were present in 30% of these patients. Ane‐ mia was seen in 75% of renal transplant and 10% of cardiac transplant patients, but none of these patients had significant neutropenia. They believe that this monoclonality is not a true form of post-transplant lymphoproliferative disorder. Constant antigenic stimulus such as a cytomegalovirus reactivation may be the underlying etiology of clonal T-LGL expansion

ANKL is a systemic proliferation of NK-cells, almost always associated with Epstein-Bar vi‐ rus (EBV) and an aggressive clinical course [40]. This catastrophic disease is observed almost exclusively in Asian patients who are usually very ill on presentation, with pyrexia, jaun‐ dice, pancytopenia, skin infiltration, lymphadenopathy and hepatosplenomegaly [40,41]. The most commonly involved sites are peripheral blood, bone marrow, liver and spleen. The leukemic cells may show a wide range of appearance from normal-looking LGL as seen in reactive NK lymphocytosis (Fig. 1E) to atypical (e.g. irregular nuclear foldings, very large size) or immature (e.g. open chromatin, distinct nucleoli) morphological features (Fig. 1F) even in an individual case [42]. The number of neoplastic cells in the peripheral blood and bone marrow can be limited or numerous, from less than 5% to greater than 80% of lympho‐ cytes [42]. Furthermore, there are cases with overlapping features with ENKTL [43,44]. Ac‐ cordingly, ANKL has also been called aggressive NK-cell lymphoma/leukemia; however, patients with ANKL are younger and the incidence of skin involvement is significantly low‐ er than ENKTL. It is currently unclear whether ANKL is the leukemic counterpart of

Phenotypically, the leukemic cells of ANKL in a Japanese series of 22 cases were character‐ ized by the expression of CD2, cytoplasmic CD3, CD56 and HLA-DR with frequent expres‐ sion of CD7 (14/19 cases, 74%), CD8 and CD16. They did not express surface CD3, CD4, CD5 or CD25 [45]. Interestingly, in a Korean series of 20 cases, CD7 antigen loss was detected in 10 patients (50%) [46]. The Korean investigators claimed that, in conjunction with the cyto‐ genetic findings, this characteristic immunophenotypic finding could serve as a reliable marker for the timely diagnosis in 75% of ANKL [46]. However, there were no statistically significant difference in the clinical or laboratory parameters between the CD7+ and the CD7- ANKL patients. To our knowledge, there are only 2 reports of ANKL from Taiwan, and the leukemic cells in 6 of 7 (86%) cases expressed CD7 [47,48]. No statistically significant difference on CD7 expression was identified between ANKL cases in Taiwan, Japan or Ko‐

The great majority of ANKL is associated with EBV-- 85% (11/13) in a Japanese series, 88% (14/16) in a Korean series and 71% (5/7) compiled from the two reports from Tai‐

and may contribute to cytopenias and fatigue seen in transplant patients [38].

**5. Aggressive NK-cell Leukemia (ANKL)**

60 T-Cell Leukemia - Characteristics, Treatment and Prevention

ENKTL [40].

rea (Fishers' exact test).

In this chapter, we review and analyze various types of T- and NK/T-cell leukemias in the East Asia. Several of these rare neoplasms have not been reported in some East Asian coun‐ tries yet. Interestingly, there are certain features in some entities, such as T-LGLL, that are distinct from the Western population. More epidemiological, clinicopathological and genetic studies on these rare neoplasms are warranted.

#### **Acknowledgements**

The authors are grateful to Prof. Jooryung Huh at Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea and Prof. Ryo Ichinohasama at Division of Hematopathology, Tohoku University Graduate School of Medicine, Sendai, Japan for providing pertinent papers and comments. We thank Prof. Yok-Lam Kwong for providing the photomicrograph of ANKL for figure 1 F.

#### **Author details**

Tsung-Hsien Lin1 , Yen-Chuan Hsieh1,2, Sheng-Tsung Chang1,3 and Shih-Sung Chuang1,4\* [9] Chang ST, Hsieh YC, Kuo SY, Lu CL, Chu JS, Chuang SS. The spectrum of T-cell and natural killer/T-cell neoplasms with leukaemic presentation in a single institution in

T- and NK/T-Cell Leukemia in East Asia http://dx.doi.org/10.5772/53743 63

[10] Hsieh YC, Chang ST, Huang WT, Kuo SY, Chiang TA, Chuang SS. A Comparative Study of Flow Cytometric T-cell Receptor Vβ Repertoire and T-cell Receptor Gene Rearrangement in the Diagnosis of Large Granular Lymphocytic Lymphoprolifera‐

[11] Suzumiya J, Ohshima K, Kikuchi M, Takeshita M, Akamatsu M, Tashiro K. Terminal deoxynucleotidyl transferase staining of malignant lymphomas in paraffin sections: a useful method for the diagnosis of lymphoblastic lymphoma. J Pathol.

[12] Pui CH, Hancock ML, Head DR, Rivera GK, Look AT, Sandlund JT, et al. Clinical sig‐ nificance of CD34 expression in childhood acute lymphoblastic leukemia. Blood.

[13] Robertson PB, Neiman RS, Worapongpaiboon S, John K, Orazi A. 013 (CD99) positiv‐ ity in hematologic proliferations correlates with TdT positivity. Mod Pathol.

[14] Terada T. TDT (-), KIT (+), CD34 (+), CD99 (+) precursor T lymphoblastic leukemia/

[15] Hoelzer D, Gokbuget N. T-cell lymphoblastic lymphoma and T-cell acute lympho‐ blastic leukemia: a separate entity? Clin Lymphoma Myeloma. 2009;9 Suppl

[16] Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, et al. Clini‐ cal and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood.

[17] Kameoka J, Takahashi N, Noji H, Murai K, Tajima K, Kameoka Y, et al. T-cell pro‐ lymphocytic leukemia in Japan: is it a variant? Int J Hematol. 2012;95:660-667.

[18] Kojima K, Kobayashi H, Imoto S, Nakagawa T, Matsui T, Kawachi Y, et al. 14q11 ab‐ normality and trisomy 8q are not common in Japanese T-cell prolymphocytic leuke‐

[19] Yokohama A, Saitoh A, Nakahashi H, Mitsui T, Koiso H, Kim Y, et al. TCL1A gene involvement in T-cell prolymphocytic leukemia in Japanese patients. Int J Hematol.

[20] Jeong KH, Lew BL, Sim WY. Generalized leukaemia cutis from a small cell variant of T-cell prolymphocytic leukaemia presenting with exfoliative dermatitis. Acta Derm

[21] Sokol L, Loughran TP, Jr. Large granular lymphocyte leukemia. Oncologist.

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\*Address all correspondence to: cmh5301@mail.chimei.org.tw

1 Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan

2 Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan

3 Department of Nursing, National Tainan Institute of Nursing, Tainan, Taiwan

4 Department of Pathology, Taipei Medical University, Taipei, Taiwan

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**Author details**

62 T-Cell Leukemia - Characteristics, Treatment and Prevention

Tsung-Hsien Lin1

**References**

Technology, Tainan, Taiwan

, Yen-Chuan Hsieh1,2, Sheng-Tsung Chang1,3 and Shih-Sung Chuang1,4\*

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**Chapter 4**

**Pleiotropic Functions of**

Kendle Pryor and Susan J. Marriott

http://dx.doi.org/10.5772/54787

to its transforming potential.

**1. Introduction**

Additional information is available at the end of the chapter

**2. HTLV-1 epidemiology and pathogenesis**

**HTLV-1 Tax Contribute to Cellular Transformation**

Human T cell leukemia virus type-1 (HTLV-1) is the only retrovirus known to be the etiologic agent of a human cancer, adult T-cell leukemia/lymphoma (ATLL), a highly aggressive cancer of mature T cells. Epidemiological reports suggest that 10 to 20 million people throughout the world are infected with HTLV-1, which is endemic in parts of sub-Saharan Africa, the Caribbean, Japan, and South America [1]. HTLV-1 encodes a regulatory protein, Tax, which is essential for virus replication and plays a significant role in the oncogenic potential of HTLV-1. This chapter will summarize the effects of Tax on cellular processes including transcription, cell cycle checkpoints, and DNA repair, and will discuss how these activities may contribute

HTLV-1 is a type C, complex, enveloped retrovirus belonging to the family *Retroviridae* and the genus deltaretrovirus. This genus includes three additional HTLV members (HTLV-2, -3, and -4), and two non-human members, bovine leukemia virus (BLV), and simian T cell leukemia virus (STLV). HTLV-1 was originally isolated from a patient diag‐ nosed with cutaneous T cell lymphoma, and was subsequently shown to be the causa‐ tive agent of ATLL [2-4]. HTLV-1 is also recognized as the etiologic agent of a neurodegenerative disease, tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), that affects the central nervous system [5,6]. The route of HTLV-1 transmis‐ sion influences its pathogenesis. Sexual transmission, which occurs most efficiently from males to females, IV drug use, and blood transfusions are typically associated with the

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