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Review ARTICLE

Front. Microbiol., 28 May 2020 | https://doi.org/10.3389/fmicb.2020.01062

Novel Treatments of Adult T Cell Leukemia Lymphoma

  • 1Department of Experimental Pathology, Microbiology, and Immunology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
  • 2Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan
  • 3INSERM UMR 1163 and CNRS URL 8254, Imagine Institute, Paris, France
  • 4Department of Hematology, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris-Descartes University, Paris, France
  • 5Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
  • 6Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
  • 7Department of Medical Genome Sciences, The University of Tokyo, Tokyo, Japan

Adult T cell leukemia-lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with the human T cell leukemia virus type I (HTLV-I) retrovirus. ATL carries a dismal prognosis. ATL classifies into four subtypes (acute, lymphoma, chronic, and smoldering) which display different clinical features, prognosis and response to therapy, hence requiring different clinical management. Smoldering and chronic subtypes respond well to antiretroviral therapy using the combination of zidovudine (AZT) and interferon-alpha (IFN) with a significant prolongation of survival. Conversely, the watch and wait strategy or chemotherapy for these indolent subtypes allies with a poor long-term outcome. Acute ATL is associated with chemo-resistance and dismal prognosis. Lymphoma subtypes respond better to intensive chemotherapy but survival remains poor. Allogeneic hematopoietic stem cell transplantation (HSCT) results in long-term survival in roughly one third of transplanted patients but only a small percentage of patients can make it to transplant. Overall, current treatments of aggressive ATL are not satisfactory. Prognosis of refractory or relapsed patients is dismal with some encouraging results when using lenalidomide or mogamulizumab. To overcome resistance and prevent relapse, preclinical or pilot clinical studies using targeted therapies such as arsenic/IFN, monoclonal antibodies, epigenetic therapies are promising but warrant further clinical investigation. Anti-ATL vaccines including Tax peptide-pulsed dendritic cells, induced Tax-specific CTL responses in ATL patients. Finally, based on the progress in understanding the pathophysiology of ATL, and the risk-adapted treatment approaches to different ATL subtypes, treatment strategies of ATL should take into account the host immune responses and the host microenvironment including HTLV-1 infected non-malignant cells. Herein, we will provide a summary of novel treatments of ATL in vitro, in vivo, and in early clinical trials.

Introduction

Adult T Cell Leukemia: Epidemiology, Pathophysiology, Clinical Presentation and Classification

Adult T cell leukemia (ATL) was discovered in Japan in 1976 (Takatsuki et al., 1976), and was associated with the Human T cell leukemia virus type I (HTLV-I) in 1980 (Poiesz et al., 1981). ATL is an aggressive malignancy characterized by the clonal expansion of mature activated T cells generally CD3+ CD4+ CD5+ CD7 CD8 CD25+ (Uchiyama et al., 1983; Waldmann et al., 1984; Dasanu, 2011; Tian et al., 2011). It occurs in 1–5% of the infected individuals, after a very long latency period which may exceed 50 years (Gessain and Mahieux, 2000; Gessain, 2011; Ishitsuka and Tamura, 2014; Watanabe, 2017; Bangham, 2018). HTLV-I is the first oncogenic retrovirus allied with a human disease. It infects around 10–20 million people worldwide, and is endemic in several countries including Southern Japan, the Caribbean islands, Central and Latin America, Romania, the Middle East (chiefly Iran), Intertropical Africa, Melanasia, and Central Australia (Gessain and Mahieux, 2000; Laperche et al., 2009; Gessain, 2011; Bangham, 2018; Afonso et al., 2019). Alarmingly, a rising incidence of ATL was reported in non-endemic regions including the United States and the North of Japan (Chihara et al., 2012; Malpica et al., 2018).

The oligoclonal expansion of HTLV-I infected cells results from the expression of the viral transactivator Tax (Wattel et al., 1995; Mortreux et al., 2001). Tax oncoprotein plays a critical role in ATL initiation and leukemogenesis through alteration of many cellular pathways, following activation of the viral promoter, and creation of an autocrine loop involving interleukin-2 (IL-2), IL-15 and their respective receptors (Bamford et al., 1994; Wattel et al., 1995; Azimi et al., 1999; Mortreux et al., 2001). Tax activates CREB/ATF, AP-1, and NF-κB transcription factors, upregulates anti-apoptotic proteins, represses p53, DNA polymerase beta, PCNA, and MAD-1 checkpoints and interferes with several cell cycle regulators and DNA repair systems (Mulloy et al., 1998; Kfoury et al., 2005; Matsuoka and Jeang, 2011). Indeed, Tax binds to IKK-γ, the regulatory subunit of the IkappaB kinase (IKK) complex (Yamaoka et al., 1998; Harhaj and Sun, 1999; Kfoury et al., 2008; Wang et al., 2016), resulting in the activation of the NF-κB pathways and its downstream effector genes (Reviewed in Kfoury et al., 2005). This induced NF-κB activation highly depends on Tax post-translational modifications namely ubiquitylation, sumoylation, and urmylation (Nasr et al., 2006; Kfoury et al., 2008, 2011; Hleihel et al., 2018, Reviewed in Kfoury et al., 2012). Furthermore, Tax modulates the microenvironment and increases invasion and extravasation of ATL cells (El-Sabban et al., 2002; Bazarbachi et al., 2004a). Tax down-regulates the expression of various micro RNAs (mi-RNA) including mi-RNA31 known to inhibit the expression of the NF-κB non-canonical pathway components (Yamagishi and Watanabe, 2012). Tax transforms T cells in vitro, and its expression in T cells of transgenic mice, or in human CD34+ stem cells induces leukemia with striking ATL features recapitulating the human disease (Portis et al., 2001; Hasegawa et al., 2006; Banerjee et al., 2007; Ohsugi et al., 2007; Moodad et al., 2018). Tax also induced rough eye phenotype, a hallmark of malignant transformation in Drosophila models (Shirinian et al., 2015). Although Tax protein expression is very low in most ATL patients, recent in vitro data demonstrated that transient bursts of Tax expression occur sequentially in small fractions of ATL-derived cells (Billman et al., 2017). Importantly, ATL-derived cells depend on Tax expression for their long-term survival, even when Tax protein is undetectable by western blot (Dassouki et al., 2015; Mahgoub et al., 2018).

Another viral nuclear protein, HBZ, is encoded by the complementary strand of HTLV-I RNA genome (Larocca et al., 1989; Gaudray et al., 2002). HBZ is a negative regulator of Tax-mediated viral transcription (Gaudray et al., 2002), and its transcript levels positively correlate with HTLV-I proviral load in both ATL patients and asymptomatic carriers (Saito et al., 2009). Unlike Tax, HBZ is constantly expressed in ATL cells (Saito et al., 2009; Mahieux, 2015; Sugata et al., 2015). Although HBZ was shown to promote the proliferation of ATL cells in vitro, short hairpin RNA (shRNA) directed against HBZ only results in a modest inhibition of ATL cells proliferation, showing that HBZ is dispensable for the survival of ATL cells (Satou et al., 2006; Arnold et al., 2008). HBZ affects several cellular pathways implicated in cellular proliferation (Panfil et al., 2016). Unlike Tax, HBZ inhibits NF-κB, attenuating Tax effect and thus preventing ATL cells senescence (Panfil et al., 2016). One HBZ transgenic mouse model exhibited transforming features, yet without NF-κB activation, contrary to human ATL or Tax transgenics (Yoshida et al., 2008; Matsuoka and Green, 2009; Saito et al., 2009; Matsuoka and Jeang, 2011; Zhao and Matsuoka, 2012; Ma et al., 2016).

At the clinical level, ATL patients have a heterogeneous presentation from indolent slowly progressive disease to aggressive and life-threatening disease. The Shimoyama classification divides the disease into four major subtypes: smoldering, chronic, lymphoma, and acute (Shimoyama, 1991). All are characterized by a dismal long-term prognosis and a low median survival rate, ranging between 6 months for the acute subtype and 24 months for the chronic subtype (Shimoyama, 1991).

Acute ATL accounts for 55–60% of patients (Shimoyama, 1991; Pombo De Oliveira et al., 1999; Katsuya et al., 2015). It is characterized by major lymphocytosis of “flower cells” or “clover leaf” which are features typical of ATL, lymphadenopathy, hepatosplenomegaly, hypercalcemia, and its related symptoms such as renal dysfunction or neuropsychiatric disturbances (Tamura et al., 1986; Kiyokawa et al., 1987), high lactate dehydrogenase (LDH) (Yamaguchi et al., 1983) and frequent opportunistic infections due to a profound immunosuppression. These include pneumonia caused by Pneumocystis carinii, disseminated cryptosporidiosis and toxoplasmosis, cytomegalovirus, bacterial abscesses and sepsis as well as fungal infection and cytomegalovirus activation (Ueda et al., 1979; Blayney et al., 1983; Bunn et al., 1983; Verdonck et al., 2007). Skin and visceral lesions in the bone, the gastrointestinal tract and the lung may be also observed.

Lymphoma ATL accounts for around 20–25% of ATL cases (Shimoyama, 1991; Pombo De Oliveira et al., 1999; Katsuya et al., 2015). This form is characterized by the same symptoms of the acute subtype, but differs in presenting less than 1% leukemia cells in the peripheral blood, thus the absence of lymphocytosis. Smoldering ATL subtype accounts for 5–10% of cases (Shimoyama, 1991; Pombo De Oliveira et al., 1999; Katsuya et al., 2015) and is characterized by a normal leukocyte count but the presence of 1–5% flower cells. In addition, only skin and lungs may be infiltrated without the involvement of any other viscera. Finally, the chronic ATL subtype accounts for 10–20% of patients (Shimoyama, 1991; Pombo De Oliveira et al., 1999; Katsuya et al., 2015), and associates with a high leukocyte count causing lymphadenopathy and hepatosplenomegaly, absence of hypercalcemia, or visceral involvement, normal or slightly increased LDH levels. This subtype is further divided into favorable or unfavorable subgroups. The latter is defined by low serum concentration of albumin, high level of LDH, or high serum urea concentration, as well as high expression of Ki-67 antigen (Shirono et al., 1989; Yamada et al., 2001). It is worth noting that the term “indolent ATL” refers to smoldering and “favorable” chronic subtypes, while “aggressive ATL” includes the acute and lymphoma as well as the “unfavorable” chronic subtypes.

Classical Therapeutic Options of ATL: Chemotherapy, Antiviral Therapy and Stem Cell Transplantation

Adult T cell leukemia remains a challenging malignancy. The clinical management of ATL and the proposed therapeutic options largely depend on the ATL subtype. The aggressive forms of ATL associate with a dismal prognosis, an intrinsic chemo-resistance, and a profound immunosuppression, associated with secondary opportunistic infections (Shimoyama, 1991; Hermine et al., 1998; Bazarbachi et al., 2004b, 2011; Tobinai, 2009). Patients with indolent ATL have a better prognosis. In Japan, these patients were managed with the watch-and-wait policy until progression or with chemotherapy, yet the long term results remain very poor (Takasaki et al., 2010; Hermine et al., 2018).

In addition to the Shimoyama classification, several prognostic factors were identified. For instance, elevated LDH levels, four total involved areas or more, thrombocytopenia, bone marrow involvement, eosinophilia, hypercalcemia, age of 40 or above, p53 mutations, p16 deletions, high IL-15 serum levels, and C-C chemokine receptor 4 (CCR4) expression are nowadays factors that predict poor prognosis (Tsukasaki et al., 2009). An international consensus report, published in 2009, defined prognosis factors, clinical features, therapeutic strategies, and response criteria for ATL (Tsukasaki et al., 2009). A recent update was recently published (Cook et al., 2019).

Standard treatment strategies of ATL include watch and wait policy for indolent ATL, conventional chemotherapy, the combination of two antiviral agents zidovudine (AZT) and interferon-alpha (IFN), and allogeneic hematopoietic stem cell transplantation (HSCT) (Tsukasaki et al., 2009; Bazarbachi et al., 2011; Hermine et al., 2018; Cook et al., 2019). The different Japanese trials using acute lymphoblastic leukemia or Non Hodgkin lymphoma -inspired chemotherapy regimen clearly demonstrated that ATL cells are chemo-resistant and that chemotherapy had little effect on the survival of ATL patients, specifically those with acute ATL (Dearden et al., 1991; Tanabe et al., 1991; Tobinai et al., 1992; Tsuda et al., 1994; Taguchi et al., 1996; Yamada et al., 2001; Tsukasaki et al., 2003; Takasaki et al., 2010). Although a phase 3 study in Japan demonstrated that the chemo-intensive LSG15 regimen was better than CHOP in newly diagnosed acute, lymphoma, or unfavorable chronic ATL, the CR rate was less than 20% for patients with acute ATL who received the LSG15 regimen and their 4 year survival was less than 10% (Tsukasaki et al., 2007). In the United States, a meta-analysis study including 195 ATL patients treated with modern therapies between 2000 and 2016, showed that the median survival rate was 4 months for acute ATL, 10 months for ATL lymphoma, 72 months for chronic/smoldering ATL, and not reached for unfavorable chronic type, with 4-year survival rates of 10, 4, 60, and 83%, respectively (Malpica et al., 2018). Overall, chemotherapy improved response rates in lymphoma but not in acute subtypes, yet with little impact on long-term survival.

Indolent smoldering or chronic ATL subtypes have a better prognosis than the aggressive ATL subtypes (Shimoyama, 1991). These variants were classically managed in Japan by a watchful-waiting policy (Takasaki et al., 2010), until progression of the disease or with chemotherapy when poor prognostic factors were identified (Tsukasaki et al., 2009). In a study of watch and wait for indolent ATL in Brazil over 14 years, the reported overall survival rates remained less than 20% at 5 years in both types (Bittencourt et al., 2007). Longer follow ups in Japan using this policy, showed that patients with smoldering ATL had an estimated 15-year survival rate of 13% with a median survival of 3 years, whereas patients with chronic ATL had an estimated 15-year survival rate of 15% with a median survival of 5 years (Takasaki et al., 2010). Thus, watch and wait strategy or treatment of the smoldering and chronic subtypes with chemotherapy still associate with a poor long-term outcome.

Important advances in the treatment of ATL were reported with the combination of two antiviral agents: AZT and IFN, which induced a high rate of response and became a standard treatment of ATL (Gill et al., 1995; Hermine et al., 1995; Bazarbachi and Hermine, 1996; Kchour et al., 2009; Bazarbachi et al., 2010, 2011; Malpica et al., 2018). The efficacy of this combination was confirmed, with minor differences, in various clinical trials and in a worldwide meta-analysis (Matutes et al., 2001; White et al., 2001; Hermine et al., 2002; Ratner et al., 2009; Bazarbachi et al., 2010). These results have transformed the clinical management of ATL in most parts of the world (Bazarbachi et al., 2010, 2011; Kinpara et al., 2013). Indeed, AZT/IFN proved highly effective and significantly improved survival in the leukemic chronic and smoldering subtypes of ATL as well as in a subset of the acute subtype with wild type P53 (Bazarbachi et al., 2010). Patients with the lymphoma subtype benefited from induction chemotherapy, when given simultaneously or sequentially with AZT and IFN (Hodson et al., 2011). Patients with previously untreated ATL or newly diagnosed ATL achieved higher response rates (Matutes et al., 2001; Hermine et al., 2002) compared to heavily treated patients (White et al., 2001). An ongoing randomized trial in Japan is testing AZT and IFN versus watchful waiting in patients with indolent ATL. Unfortunately, many patients are either resistant or progress even after a long period of disease control. Furthermore, treatment should be continued for life as relapse always occurs upon stopping therapy, indicating that AZT/IFN is not curative. In the United States, first-line AZT/IFN resulted in a median progression-free survival (PFS) in patients with aggressive ATL who achieved CR after AZT/IFN of 48 months versus 11 months after chemotherapy (Malpica et al., 2018), suggesting that AZT/IFN can be used against aggressive ATL, as up-front option followed by chemotherapy switch in non-responders. At the molecular level, this combination inhibited the reverse transcriptase activity and modified the clonality pattern in responding ATL patients (Macchi et al., 2017). Since reverse transcriptase mediated viral replication does not occur in the malignant cells, these results highly suggest that the primary target of the AZT/IFN combination is the ATL microenvironment, specifically de novo infection of T cells by HTLV-1 which appears critical for the survival of the malignant clone.

Because of the high rate of relapse after conventional chemotherapy, allogeneic stem cell transplantation (alloSCT) is an attractive potentially curative option (Iqbal et al., 2019). However, most of the reports on alloSCT are from Japan. Large retrospective Japanese studies and a smaller European report demonstrate that alloSCT results in long-term survival in roughly one third of transplanted patients but only a small percentage of patients can make it to transplant (Hishizawa et al., 2010; Bazarbachi et al., 2014).

Overall, current treatments of aggressive ATL subtypes are not satisfactory. Indeed, patients with acute and lymphoma subtypes who do not respond to primary therapy remain a population with unmet medical need. The lack of curative therapy of ATL, and the low survival rates in ATL patients inquire exploring new targeted therapies to improve survival and achieve cure for these patients.

Innovative Therapies of Adult T Cell Leukemia

Monoclonal Antibodies

Mogamulizumab

C-C chemokine receptor 4 is a chemokine receptor known to be selectively expressed in type 2 helper T cells (Th2 cells) and regulatory T cells (T reg) (Ishida and Ueda, 2006). CCR4 is involved in leukocyte migration and is expressed on ATL cells. Mogamulizumab (KW-0761) is a humanized defucosylated monoclonal antibody targeting CCR4 (Ishii et al., 2010; Subramaniam et al., 2012; Tobinai et al., 2012). Interestingly, Mogamulizumab exhibits its antitumor activity in ATL by various mechanisms of action. Studies have shown that this drug induces a depletion of Treg leading to an increased antitumor immune response (Sugiyama et al., 2013; Ni et al., 2015). In addition, it highly increases antibody-dependent cellular cytotoxicity because of its reduced fucose (Shinkawa et al., 2003; Ishii et al., 2010). In Japan, this drug is approved for treatment of patients with different T cell malignancies such as relapsed/refractory (R/R) CCR4+ ATL and cutaneous T-cell lymphoma (CTCL) (Ishii et al., 2010). The efficacy of Mogamulizumab was tested in 28 patients with relapsed ATL (Ishida et al., 2012). The overall response rate (ORR) was 50% with 8 CR and 5 PR, and the OS was 13.7 months (Ishida et al., 2012). Similarly, Mogamulizumab showed an efficacy in Phase I study for R/R ATL and peripheral T-cell lymphoma (PTCL) in Japan with a response rate of 31% (Makita and Tobinai, 2017), and in a randomized Phase II study conducted on R/R patients in the United States and Europe (Makita and Tobinai, 2017, reviewed in Hermine et al., 2018). Mogamulizumab also improved response rate in newly diagnosed ATL patients when combined to dose-intensified chemotherapy but failed to improve progression free and overall survival (Ishida et al., 2015).

Anti-CD25 Antibodies

Adult T cell leukemia cells are known to express CD25, the alpha chain of the human IL-2. Thus, the efficacy of naked or Yttrium-90 anti-CD25 antibody was tested yielding few CR in indolent subtypes (Waldmann et al., 1993, 1995). Daclizumab is another humanized monoclonal antibody targeting CD25 (Berkowitz et al., 2014). In ATL, a phase 2 clinical trial demonstrated that Daclizumab blocks IL-2 binding to CD25 on ATL cells. Thus, an effective clinical response was acquired, especially in patients with indolent ATL (Berkowitz et al., 2014, reviewed in Hermine et al., 2018). This monoclonal was withdrawn from the market in March 2018.

Anti-transferrin Receptor Antibody

HTLV-1 infected cells were shown to constitutively express high levels of surface transferrin receptor. A24 is a monoclonal antibody directed against this receptor. Only pre-clinical studies were performed using this antibody. A24 induced apoptosis in both ATL cells and primary ATL cells from both acute and chronic ATL patients. Furthermore, A24 also inhibited (55Fe)-transferrin uptake in activated T cells and blocked T-cell proliferation in vitro and ex vivo (Moura et al., 2004).

Anti-KIR3DL2 Monoclonal Antibody

KIR3DL2 (CD158K), a killer immunoglobulin-like receptor (KIR) normally expressed by a subset of natural killer (NK) cells is aberrantly expressed in Sezary syndrome and several other CTCLs (Battistella et al., 2017). In few ATL patients, circulating tumor cells may also express KIR3DL2 (Obama et al., 2007), a simple biomarker that identifies most acute-type ATL (Cheminant et al. unpublished data). It has been suggested that HTLV-1 may play a role in KIR3DL2 expression, combined to DNA methylation of the KIR3DL2 gene promoter. Moreover, IPH4102, a monoclonal antibody directed against KIR3DL2 that has shown beneficial clinical activity in relapsed CTCL patients (Bagot et al., 2019), can selectively kill human KIR3DL2+ primary ATL cells ex-vivo (Cheminant et al. unpublished data).

Alemtuzumab

Alemtuzumab (Campath-1H) is a chimeric humanized antibody that binds to a glycoprotein (CD52), which is highly expressed on benign and malignant B and T- lymphocytes and monocytes (Buggins et al., 2002). Alemtuzumab showed an antitumor activity in various cancer types such as T-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia (Laribi et al., 2017). In ATL, a phase 2 clinical study using Alemtuzumab in acute, chronic, and lymphoma subtypes resulted in an ORR of 52%, mostly in the blood, but unfortunately with a short duration of response (Sharma et al., 2017, reviewed in Hermine et al., 2018).

Brentuximab Vedotin

Brentuximab vedotin (BV or SGN-35), is an anti-CD30 monoclonal antibody, conjugated to a microtubule poisoning agent monomethyl auristatin E. The latter is a cytotoxic agent, released by proteolytic cleavage following binding to anti-CD30 expressing cells, responsible of cell death induction (Laribi et al., 2018). Brentuximab vedotin is approved for the treatment of many tumors such as Hodgkin lymphoma (HL), CD30+ PTCL, and CD30+ CTCL. Several clinical trials are currently being conducted on patients with R/R CD30+ lymphomas, including some ATL patients under a pilot study in patients with R/R disease (NCT01703949), and a phase 2 study on patients with R/R CD30-low mature T-cell lymphomas (Hermine et al., 2018). Importantly, the ECHELON 2 randomized trial demonstrated that front-line treatment with BV and chemotherapy is superior to CHOP for patients with CD30-positive PTCL as shown by a significant improvement in PFS and OS with a manageable safety profile (Horwitz et al., 2019).

Anti-PD-1 Antibodies

Genomic analysis has shown a higher mutation rate in ATL than in other hematopoietic cancers. These changes include the T-cell receptor, nuclear factor κB, and immune surveillance pathways, including overexpression of the programmed cell death 1 ligand (PD-L1) gene. Kataoka et al. (2016) reported the genetic evidence of clonal selection of ATL cells by way of PD-L1 overexpression through disruption of its 3′ untranslated region (UTR) in 16% of their cohort. Several phase 1/2 studies of nivolumab, an anti-PD-1 antibody, are ongoing. Among them, Ratner et al. reported rapid progression of ATL in sequential three patients after the treatment (Ratner and the Authors, 2018; Ratner et al., 2018), supporting for the probable role of PD-1 functioning as a tumor suppressor reported in a mouse model (Wartewig et al., 2017). However, the other group did not experience such progression, requiring further evaluation of anti-PD-1 antibodies for especially aggressive ATL with PD-L1 overexpression (Ishitsuka et al., 2018).

Lenalidomide

Lenalidomide, a thalidomide analog, is an immunomodulatory drug with pleiotropic mechanisms of action, involving anti-inflammatory, antiangiogenic, and antitumor effects (reviewed in Kotla et al., 2009; Ito and Handa, 2016; Chamberlain and Cathers, 2019). Lenalidomide was approved by the FDA for the treatment of multiple myeloma, mantle cell lymphoma, and myelodysplastic syndrome with deletion 5q. In addition, lenalidomide exhibited clinical activity in other malignancies including acute myeloid leukemia and non-Hodgkin lymphoma. Its immunomodulatory properties include augmentation of NK cell number and cytotoxicity, activation of T cells, and alteration of cytokine production by monocytes (Kotla et al., 2009; Ito and Handa, 2016).

Clinical trials on lenalidomide monotherapy in ATL include a phase 1 dose-escalation study on Japanese patients with ATL and PTCL (Ogura et al., 2016). Lenalidomide safety, maximum tolerated dose, and efficacy were investigated in a small cohort study of 13 patients (9 ATL, 4 PTCL). A maximum tolerated dose of 25 mg daily on each day of 28-day cycle was recommended for phase 2 studies (Ogura et al., 2016). Subsequently, a multicenter phase 2 open-label study of 26 patients with relapsed/recurrent ATL (15 acute type, 7 lymphoma type, and 4 chronic type) was conducted (Ishida et al., 2016). Lenalidomide demonstrated significant anti-leukemic activity, accompanied by a tolerable toxicity profile. Briefly, the CR and response rates were 19 and 42% respectively with a median overall survival of 20 months. This study resulted in the approval of lenalidomide for clinical use in Japan for treating R/R ATL patients in March 2017 (Ishida et al., 2016).

Recently, a case report by Oka et al. (2019) described a potential for low-dose lenalidomide in maintenance therapy of ATL. Briefly, daily treatment with low-dose lenalidomide (5 mg/day) following LSG15 chemotherapy with mogamulizumab maintained complete remission in a patient with acute ATL, whose condition remained stable with no recurrence for at least 24 months. Lenalidomide triggered an increase in the numbers of CD3+ CD8+ cytotoxic T cells, CD3+ CD4+T cells and CD56+ CD16+?NK cells. This report warrants further investigations on possible promising combination of lenalidomide with monoclonal antibodies and chemotherapy in patients who are not eligible for HSCT. In fact, given that mogamulizumab antitumor activity completely depends on antibody dependent cellular cytotoxicity, mainly through NK cells, while lenalidomide augments NK cells activity and number, investigating a combination of both drugs in ATL treatment might result in favorable outcomes.

Arsenic Trioxide and Interferon-Alpha

Despite the important advances in the treatment of ATL using the combination of AZT/IFN many patients are either resistant or progress even after a long period of disease control. Overall, the lack of curative therapy of ATL, in patients as well as in preclinical or naturally infected models (Turpin et al., 2017), underlies the importance of exploring new therapies targeting ATL leukemia initiating cells (LICs), to achieve disease eradication, rather than long term disease control. In vitro, the combination of arsenic trioxide (AS) and IFN selectively induces cell cycle arrest and apoptosis of ATL cells (Bazarbachi et al., 1999). This was associated with proteasome-mediated Tax degradation (El-Sabban et al., 2000; Nasr et al., 2003). This AS/IFN combination cured Tax-driven murine ATL through LIC eradication and delayed tumor cell exhaustion (El Hajj et al., 2010). Critically, adding the proteasome inhibitor bortezomib (PS-341) essentially blocks the degradation of Tax triggered by the AS/IFN combination, and reversed the enhancement of survival in secondary and tertiary recipients in serial transplantation assays. Overall, ATL cells are addicted to continuous Tax expression for their LIC activity and long term proliferation but not for their short-term tumor growth (El Hajj et al., 2010).

A phase 2 trial involving seven patients with relapsed/refractory ATL showed that AS/IFN combination induced one complete remission and three partial remissions, with one patient who remained alive and disease free for more than 5 years (Hermine et al., 2004 and unpublished). A prospective phase 2 study tested the efficacy, and safety of the combination of AS/IFN/AZT in 10 de novo chronic ATL patients (Kchour et al., 2009). Strikingly, AS/IFN/AZT therapy led to a 100% response rate and 70% complete remission rate (7 CR, 2 CR with 5% circulating atypical lymphocytes and 1 PR). Some patients exhibited a sustained response, even after treatment withdrawal, suggesting a potential cure through ATL LICs loss (Kchour et al., 2009). Side effects were very moderate and mostly hematologic. Although these treated patients received a suboptimal 5-days-per-week treatment, 3 of 6 patients remained in continuous CR for 7–18 months after discontinuation of maintenance therapy, as compared to five patients with chronic ATL treated with AZT/IFN alone who all relapsed before 5 months (El Hajj et al., 2010). Recently, a clinical trial tested AS consolidation in nine patients with ATL (four patients with lymphoma, two patients with acute, and three patients with indolent ATL). Four patients were in CR, three patients were in PR, one patient in stable disease and the last one was in progressive disease. These patients received up to eight weeks of intravenous AS at the dose of 0.15 mg/kg/day intravenously in combination with AZT/IFN. One patient died rapidly, while the remaining eight patients showed prolonged median duration of response of 24 and 39 months from initiation of AS consolidation and from diagnosis, respectively (Marcais et al., 2020). These results suggest that consolidation with arsenic could be an option for ATL patients achieving a satisfactory response after induction therapy and who are not eligible for HSCT (Marcais et al., 2020).

Vaccines

Recent efforts suggested anti-ATL vaccines as a potential therapeutic option for ATL. These vaccines are meant to stimulate host immune response against the virus, and may provide some clinical benefits, especially for R/R ATL. A Tax peptide-pulsed dendritic cell (Tax-DC) vaccine was designed to augment Tax-specific cytotoxic T lymphocyte (CTL) response. This vaccine consists of autologous DCs pulsed with different Tax peptides known to be the Tax-inducing CTL epitopes (Suehiro et al., 2015). A pilot clinical trial was performed on three previously treated ATL patients who were classified as intermediate to high risk patients (Suehiro et al., 2015), and led to favorable clinical outcomes. Indeed, two patients survived for more than 4 years after vaccination without severe adverse effects (Kannagi et al., 2019a). This Tax-DC vaccine is currently under a phase 1 trial, with a promising clinical outcome. This vaccine can represent a safe alternative maintenance therapy for ATL. It can also be applied in case of indolent ATL or might be a prophylactic approach in HTLV-1 carriers (Kannagi et al., 2019b).

Another therapeutic vaccine candidate for treatment of ATL, called THV02, comprises two lentiviral vectors to be used in a prime/boost regimen. This vaccine encodes for a peptide deriving from the viral proteins Tax, HBZ, p12I, and p30II. THV02 proved to induce a cellular response in animal models warranting conducting clinical trials to test its efficacy (reviewed in Hermine et al., 2018).

Epigenetic Therapies Against ATL

Ezh Inhibitors

Enhancer of Zeste Homolog 1 and 2 (EZH1 and EZH2) are polycomb repressive protein components (PRC). EZH2, the catalytic subunit of PRC2, mediates transcriptional silencing through trimethylation of histone H3 lysine 27 (H3K27me3). Mutation or overexpression of EZH2 has been linked to numerous types of cancer and EZH2 inhibitors are being evaluated in clinical trials as potential anti-cancer agents (reviewed in Lund et al., 2014; Gan et al., 2018; Nakagawa and Kitabayashi, 2018). More recently, significance of EZH1 has been recognized also (Yamagishi et al., 2019). In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of polycomb proteins including EZH1/2 contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance (Yamagishi et al., 2012). EZH2 is affected by the HTLV-1 Tax protein. Likewise, the Tax-dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells (Fujikawa et al., 2016).

Pharmacologic inhibition of EZH2, in vitro, in ATL cells resulted in reversed epigenetic aberrations and selective elimination of leukemic and HTLV-1-infected cells presenting EZH2 as possible target for epigenetic therapy in ATL (Fujikawa et al., 2016).

Valemetostat (DS-3201) is a potent selective dual inhibitor of EZH1 and EZH2 with antineoplastic potential especially in lymphomas including ATL (Yamagishi et al., 2019). A multicenter, Phase 1 multiple ascending dose study of DS-3201b in Japanese patients with R/R NHL including ATL was conducted to evaluate the safety, pharmacokinetics, and recommended dose of DS-3201. Based on the promising results, a phase 2 trial of valemetostat for R/R aggressive ATL after mogamulizumab treatment is ongoing in Japan.

Histone Deacytelase Inhibitors

Histone deacetylase inhibitors (HDACI) are anti-cancer drugs that relieve histone deacetylation imposed by HDAC resulting in chromatin remodeling and reactivation of transcriptionally suppressed genes (reviewed in Li and Seto, 2016). Several HDACIs, vorinostat, romidepsin and belinostat, were FDA approved for the treatment of PTCL. These include Vorinostat (SAHA) and Romidepsin for CTCL. Vorinostat induced 30% response rates (Olsen et al., 2007), while Romidepsin induced 34% response rates (Whittaker et al., 2010). Combining valproic acid, a first generation HDACI, with AZT/IFN as a maintenance therapy was tested in 13 ATL patients (Ramos and Lossos, 2011). A decrease of clonal disease was observed by PCR, only in one patient. However, primary ATL cells from this patient showed an increased HTLV-I expression and induced apoptosis upon treatment with vorinostat. Thus, these results could be extrapolated to eliminate residual disease (Afonso et al., 2010).

In vitro, many HDAC inhibitors exhibited excellent anti-leukemic potential against HTLV-1 transformed or ATL-derived cell lines and primary ATL cells by blocking Notch pathway, decreasing NF-κB, and promoting apoptosis (Mori et al., 2004; Nishioka et al., 2008; Yu et al., 2015). These include valproic acid, vorinostat, romidepsin, panobinostat, and entinostat (Mori et al., 2004; Nishioka et al., 2008). An orally bioavailable HDACi, AR-42 reduced the proliferation of ATL cell lines by promoting apoptosis and histone hyperacetylation and enhanced the survival of NOD/SCID ATL mouse model (Zimmerman et al., 2011). Romidepsin as single agent prolonged survival in MT1 NOD/SCID mouse model (Yu et al., 2015). Combination of Romidepsin with anti CD25 depsipeptide resulted in prolonged survival of a Met-1 ATL murine model (Chen et al., 2009). Panobinostat, a HDACI, decreased in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ, and induced apoptosis in ATL cells via activation of a novel RAIDD-caspase-2 pathway (Hasegawa et al., 2011).

Clinical trials on HDAC included a phase 1 trial on combination of Alisertib (an Aurora kinase A inhibitor) and vorinostat in treating relapsed/recurrent Hodgkins lymphoma, B-cell non-Hodkin lymphoma, and PTCL (Siddiqi et al., 2019). Alisertib combined to vorinostat showed encouraging clinical activity with a manageable safety profile.

Chidamide, which is an orally bioavailable member of the benzamide class of HDACI, was approved by CFDA in China for treating relapsed/refractory PTCL as monotherapy with a recommended dose of 30 mg twice weekly (BIW) although the dose finding results were not conclusive (reviewed in Zhang et al., 2019). A phase 1 trial of chidamide in Japan for patients with R/R NHL including ATL revealed that MTD was 40 mg BIW and best overall response was noted in 40 mg BIW cohort (N = 7): 1 CR, 5 PR, 1 SD. Four of the partial responders were ATL patients (among total five patients). In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle (reviewed in Zhang et al., 2019). Based on the promising results, a phase 2 trial of chidamide for R/R aggressive ATL after mogamulizumab treatment is ongoing in Japan.

Concluding Remarks

Adult T cell leukemia remains a challenging disease with no current satisfying therapy. Indeed, about 40% of the patients after allo-HSCT, and 10–20% of those after chemotherapy could be cured without treatment for more than 5 years. Indolent forms of the disease present a long-term survival following treatment with antiviral therapies. The aggressive forms of the disease remain an unmet medical need, with only a small number of patients who can achieve long-term survival either following CR on antiviral therapy or if they make it to intensive chemotherapy +/− allo-HSCT. Pilot studies with Tax vaccination are promising. Monoclonal antibodies alone or combined to chemotherapy improved response rates, yet with little effect, if any, on overall survival. The use of epigenetic inhibitors yielded promising preclinical and phase 1 results. Arsenic trioxide combined with IFA targets Tax for degradation and cures murine ATL through elimination of LIC activity. Clinical studies suggest that addition of arsenic to antiviral therapy, or as a consolidation therapy, may achieve disease eradication and long-term survival. Based on the progress in understanding the pathophysiology of ATL, and the risk-adapted treatment approaches to different ATL subtypes, future strategies should include new targeted therapies that take into account the host immune responses and the host microenvironment including HTLV-1 infected non-malignant cells. That might lead the prevention of ATL development among high-risk HTLV-1 carriers.

Author Contributions

All authors contributed to the writing of this review, each under his/her area of expertise and approved this version before its submission.

Funding

This study was supported by the Japan Agency for Medical Research and Development under Grant No. JP18ck0106338 (KT).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Afonso, P. V., Cassar, O., and Gessain, A. (2019). Molecular epidemiology, genetic variability and evolution of HTLV-1 with special emphasis on African genotypes. Retrovirology 16:39. doi: 10.1186/s12977-019-0504-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Afonso, P. V., Mekaouche, M., Mortreux, F., Toulza, F., Moriceau, A., Wattel, E., et al. (2010). Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors. Blood 116, 3802–3808. doi: 10.1182/blood-2010-02-270751

CrossRef Full Text | Google Scholar

Arnold, J., Zimmerman, B., Li, M., Lairmore, M. D., and Green, P. L. (2008). Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood 112, 3788–3797. doi: 10.1182/blood-2008-04-154286

CrossRef Full Text | Google Scholar

Azimi, N., Jacobson, S., Leist, T., and Waldmann, T. A. (1999). Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. J. Immunol. 163, 4064–4072.

Google Scholar

Bagot, M., Porcu, P., Marie-Cardine, A., Battistella, M., William, B. M., Vermeer, M., et al. (2019). IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. Lancet Oncol. 20, 1160–1170. doi: 10.1016/S1470-2045(19)30320-1

CrossRef Full Text | Google Scholar

Bamford, R. N., Grant, A. J., Burton, J. D., Peters, C., Kurys, G., Goldman, C. K., et al. (1994). The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc. Natl. Acad. Sci. U.S.A. 91, 4940–4944. doi: 10.1073/pnas.91.11.4940

CrossRef Full Text | Google Scholar

Banerjee, P., Rochford, R., Antel, J., Canute, G., Wrzesinski, S., Sieburg, M., et al. (2007). Proinflammatory cytokine gene induction by human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 Tax in primary human glial cells. J. Virol. 81, 1690–1700. doi: 10.1128/JVI.01513-06

CrossRef Full Text | Google Scholar

Bangham, C. R. M. (2018). Human T cell leukemia virus type 1: persistence and pathogenesis. Annu. Rev. Immunol. 36, 43–71. doi: 10.1146/annurev-immunol-042617-053222

PubMed Abstract | CrossRef Full Text | Google Scholar

Battistella, M., Leboeuf, C., Ram-Wolff, C., Hurabielle, C., Bonnafous, C., Sicard, H., et al. (2017). KIR3DL2 expression in cutaneous T-cell lymphomas: expanding the spectrum for KIR3DL2 targeting. Blood 130, 2900–2902. doi: 10.1182/blood-2017-06-792382

CrossRef Full Text | Google Scholar

Bazarbachi, A., Abou Merhi, R., Gessain, A., Talhouk, R., El-Khoury, H., Nasr, R., et al. (2004a). Human T-cell lymphotropic virus type I-infected cells extravasate through the endothelial barrier by a local angiogenesis-like mechanism. Cancer Res. 64, 2039–2046. doi: 10.1158/0008-5472.can-03-2390

CrossRef Full Text | Google Scholar

Bazarbachi, A., Cwynarski, K., Boumendil, A., Finel, H., Fields, P., Raj, K., et al. (2014). Outcome of patients with HTLV-1-associated adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP. Bone Marrow Transplant. 49, 1266–1268. doi: 10.1038/bmt.2014.143

CrossRef Full Text | Google Scholar

Bazarbachi, A., El-Sabban, M. E., Nasr, R., Quignon, F., Awaraji, C., Kersual, J., et al. (1999). Arsenic trioxide and interferon-alpha synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells. Blood 93, 278–283.

PubMed Abstract | Google Scholar

Bazarbachi, A., Ghez, D., Lepelletier, Y., Nasr, R., de The, H., El-Sabban, M. E., et al. (2004b). New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol. 5, 664–672.

Google Scholar

Bazarbachi, A., and Hermine, O. (1996). Treatment with a combination of zidovudine and alpha-interferon in naive and pretreated adult T-cell leukemia/lymphoma patients. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 13(Suppl. 1), S186–S190.

Google Scholar

Bazarbachi, A., Plumelle, Y., Carlos Ramos, J., Tortevoye, P., Otrock, Z., Taylor, G., et al. (2010). Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J. Clin. Oncol. 28, 4177–4183.

Google Scholar

Bazarbachi, A., Suarez, F., Fields, P., and Hermine, O. (2011). How I treat adult T-cell leukemia/lymphoma. Blood 118, 1736–1745. doi: 10.1182/blood-2011-03-345702

CrossRef Full Text | Google Scholar

Berkowitz, J. L., Janik, J. E., Stewart, D. M., Jaffe, E. S., Stetler-Stevenson, M., Shih, J. H., et al. (2014). Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma. Clin. Immunol. 155, 176–187. doi: 10.1016/j.clim.2014.09.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Billman, M. R., Rueda, D., and Bangham, C. R. M. (2017). Single-cell heterogeneity and cell-cycle-related viral gene bursts in the human leukaemia virus HTLV-1. Wellcome Open Res. 2:87. doi: 10.12688/wellcomeopenres.12469.2

CrossRef Full Text | Google Scholar

Bittencourt, A. L., da Gracas Vieira, M., Brites, C. R., Farre, L., and Barbosa, H. S. (2007). Adult T-cell leukemia/lymphoma in Bahia, Brazil: analysis of prognostic factors in a group of 70 patients. Am. J. Clin. Pathol. 128, 875–882. doi: 10.1309/2YGD1P0QCVCWBLDX

CrossRef Full Text | Google Scholar

Blayney, D. W., Jaffe, E. S., Blattner, W. A., Cossman, J., Robert-Guroff, M., Longo, D. L., et al. (1983). The human T-cell leukemia/lymphoma virus associated with American adult T-cell leukemia/lymphoma. Blood 62, 401–405.

PubMed Abstract | Google Scholar

Buggins, A. G., Mufti, G. J., Salisbury, J., Codd, J., Westwood, N., Arno, M., et al. (2002). Peripheral blood but not tissue dendritic cells express CD52 and are depleted by treatment with alemtuzumab. Blood 100, 1715–1720.

Google Scholar

Bunn, P. A. Jr., Schechter, G. P., Jaffe, E., Blayney, D., Young, R. C., Matthews, M. J., et al. (1983). Clinical course of retrovirus-associated adult T-cell lymphoma in the United States. N. Engl. J. Med. 309, 257–264. doi: 10.1056/NEJM198308043090501

PubMed Abstract | CrossRef Full Text | Google Scholar

Chamberlain, P. P., and Cathers, B. E. (2019). Cereblon modulators: low molecular weight inducers of protein degradation. Drug Discov. Today Technol. 31, 29–34. doi: 10.1016/j.ddtec.2019.02.004

CrossRef Full Text | Google Scholar

Chen, J., Zhang, M., Ju, W., and Waldmann, T. A. (2009). Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25. Blood 113, 1287–1293. doi: 10.1182/blood-2008-04-149658

CrossRef Full Text | Google Scholar

Chihara, D., Ito, H., Katanoda, K., Shibata, A., Matsuda, T., Tajima, K., et al. (2012). Increase in incidence of adult T-cell leukemia/lymphoma in non-endemic areas of Japan and the United States. Cancer Sci. 103, 1857–1860. doi: 10.1111/j.1349-7006.2012.02373.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Cook, L. B., Fuji, S., Hermine, O., Bazarbachi, A., Ramos, J. C., Ratner, L., et al. (2019). Revised adult T-cell leukemia-lymphoma international consensus meeting report. J. Clin. Oncol. 37, 677–687. doi: 10.1200/JCO.18.00501

PubMed Abstract | CrossRef Full Text | Google Scholar

Dasanu, C. A. (2011). Newer developments in adult T-cell leukemia/lymphoma therapeutics. Expert Opin. Pharmacother. 12, 1709–1717. doi: 10.1517/14656566.2011.571207

PubMed Abstract | CrossRef Full Text | Google Scholar

Dassouki, Z., Sahin, U., El Hajj, H., Jollivet, F., Kfoury, Y., Lallemand-Breitenbach, V., et al. (2015). ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation. Blood 125, 474–482.

Google Scholar

Dearden, C., Matutes, E., and Catovsky, D. (1991). Deoxycoformycin in the treatment of mature T-cell leukaemias. Br. J. Cancer 64, 903–906. doi: 10.1038/bjc.1991.423

CrossRef Full Text | Google Scholar

El Hajj, H., El-Sabban, M., Hasegawa, H., Zaatari, G., Ablain, J., Saab, S. T., et al. (2010). Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia. J. Exp. Med. 207, 2785–2792.

Google Scholar

El-Sabban, M. E., Merhi, R. A., Haidar, H. A., Arnulf, B., Khoury, H., and Basbous, J. (2002). Human T-cell lymphotropic virus type 1-transformed cells induce angiogenesis and establish functional gap junctions with endothelial cells. Blood 99, 3383–3389.

PubMed Abstract | Google Scholar

El-Sabban, M. E., Nasr, R., Dbaibo, G., Hermine, O., Abboushi, N., Quignon, F., et al. (2000). Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation. Blood 96, 2849–2855.

PubMed Abstract | Google Scholar

Fujikawa, D., Nakagawa, S., Hori, M., Kurokawa, N., Soejima, A., Nakano, K., et al. (2016). Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood 127, 1790–1802. doi: 10.1182/blood-2015-08-662593

PubMed Abstract | CrossRef Full Text | Google Scholar

Gan, L., Yang, Y., Li, Q., Feng, Y., Liu, T., and Guo, W. (2018). Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential. Biomark Res. 6:10. doi: 10.1186/s40364-018-0122-2

CrossRef Full Text | Google Scholar

Gaudray, G., Gachon, F., Basbous, J., Biard-Piechaczyk, M., Devaux, C., and Mesnard, J. M. (2002). The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J. Virol. 76, 12813–12822. doi: 10.1128/jvi.76.24.12813-12822.2002

CrossRef Full Text | Google Scholar

Gessain, A. (2011). [Human retrovirus HTLV-1: descriptive and molecular epidemiology, origin, evolution, diagnosis and associated diseases]. Bull. Soc. Pathol. Exot. 104, 167–180. doi: 10.1007/s13149-011-0174-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Gessain, A., and Mahieux, R. (2000). [Epidemiology, origin and genetic diversity of HTLV-1 retrovirus and STLV-1 simian affiliated retrovirus]. Bull. Soc. Pathol. Exot. 93, 163–171.

Google Scholar

Gill, P. S., Harrington, W. Jr., Kaplan, M. H., Ribeiro, R. C., Bennett, J. M., Liebman, H. A., et al. (1995). Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N. Engl. J. Med. 332, 1744–1748. doi: 10.1056/NEJM199506293322603

PubMed Abstract | CrossRef Full Text | Google Scholar

Harhaj, E. W., and Sun, S. C. (1999). IKKgamma serves as a docking subunit of the IkappaB kinase (IKK) and mediates interaction of IKK with the human T-cell leukemia virus Tax protein. J. Biol. Chem. 274, 22911–22914. doi: 10.1074/jbc.274.33.22911

CrossRef Full Text | Google Scholar

Hasegawa, H., Sawa, H., Lewis, M. J., Orba, Y., Sheehy, N., Yamamoto, Y., et al. (2006). Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat. Med. 12, 466–472.

Google Scholar

Hasegawa, H., Yamada, Y., Tsukasaki, K., Mori, N., Tsuruda, K., Sasaki, D., et al. (2011). LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway. Leukemia 25, 575–587. doi: 10.1038/leu.2010.315

PubMed Abstract | CrossRef Full Text | Google Scholar

Hermine, O., Allard, I., Levy, V., Arnulf, B., Gessain, A., Bazarbachi, A., et al. (2002). A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol. J. 3, 276–282. doi: 10.1038/sj.thj.6200195

PubMed Abstract | CrossRef Full Text | Google Scholar

Hermine, O., Bouscary, D., Gessain, A., Turlure, P., Leblond, V., Franck, N., et al. (1995). Brief report: treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa. N. Engl. J. Med. 332, 1749–1751. doi: 10.1056/NEJM199506293322604

CrossRef Full Text | Google Scholar

Hermine, O., Dombret, H., Poupon, J., Arnulf, B., Lefrere, F., Rousselot, P., et al. (2004). Phase II trial of arsenic trioxide and alpha interferon in patients with relapsed/refractory adult T-cell leukemia/lymphoma. Hematol. J. 5, 130–134. doi: 10.1038/sj.thj.6200374

CrossRef Full Text | Google Scholar

Hermine, O., Ramos, J. C., and Tobinai, K. (2018). A review of new findings in adult T-cell leukemia-lymphoma: a focus on current and emerging treatment strategies. Adv. Ther. 35, 135–152. doi: 10.1007/s12325-018-0658-4

CrossRef Full Text | Google Scholar

Hermine, O., Wattel, E., Gessain, A., and Bazarbachi, A. (1998). Adult T cell leukaemia: a review of established and new treatments. Biodrugs 10, 447–462. doi: 10.2165/00063030-199810060-00003

CrossRef Full Text | Google Scholar

Hishizawa, M., Kanda, J., Utsunomiya, A., Taniguchi, S., Eto, T., Moriuchi, Y., et al. (2010). Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study. Blood 116, 1369–1376. doi: 10.1182/blood-2009-10-247510

PubMed Abstract | CrossRef Full Text | Google Scholar

Hleihel, R., Khoshnood, B., Dacklin, I., Omran, H., Mouawad, C., Dassouki, Z., et al. (2018). The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1). Retrovirology 15:33. doi: 10.1186/s12977-018-0415-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Hodson, A., Crichton, S., Montoto, S., Mir, N., Matutes, E., Cwynarski, K., et al. (2011). Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma. J. Clin. Oncol. 29, 4696–4701. doi: 10.1200/JCO.2011.35.5578

PubMed Abstract | CrossRef Full Text | Google Scholar

Horwitz, S., O’Connor, O. A., Pro, B., Illidge, T., Fanale, M., Advani, R., et al. (2019). Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393, 229–240. doi: 10.1016/S0140-6736(18)32984-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Iqbal, M., Reljic, T., Klocksieben, F., Sher, T., Ayala, E., Murthy, H., et al. (2019). Efficacy of allogeneic hematopoietic cell transplantation in human T cell lymphotropic virus type 1-associated adult T cell leukemia/lymphoma: results of a systematic review/meta-analysis. Biol. Blood Marrow Transplant. 25, 1695–1700. doi: 10.1016/j.bbmt.2019.05.027

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishida, T., Fujiwara, H., Nosaka, K., Taira, N., Abe, Y., Imaizumi, Y., et al. (2016). Multicenter phase II study of lenalidomide in relapsed or recurrent adult T-cell leukemia/lymphoma: ATLL-002. J. Clin. Oncol. 34, 4086–4093. doi: 10.1200/JCO.2016.67.7732

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishida, T., Jo, T., Takemoto, S., Suzushima, H., Uozumi, K., Yamamoto, K., et al. (2015). Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br. J. Haematol. 169, 672–682. doi: 10.1111/bjh.13338

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishida, T., Joh, T., Uike, N., Yamamoto, K., Utsunomiya, A., Yoshida, S., et al. (2012). Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J. Clin. Oncol. 30, 837–842. doi: 10.1200/JCO.2011.37.3472

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishida, T., and Ueda, R. (2006). CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci. 97, 1139–1146. doi: 10.1111/j.1349-7006.2006.00307.x

CrossRef Full Text | Google Scholar

Ishii, T., Ishida, T., Utsunomiya, A., Inagaki, A., Yano, H., Komatsu, H., et al. (2010). Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin. Cancer Res. 16, 1520–1531. doi: 10.1158/1078-0432.CCR-09-2697

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishitsuka, K., and Tamura, K. (2014). Human T-cell leukaemia virus type I and adult T-cell leukaemia-lymphoma. Lancet Oncol. 15, e517–e526. doi: 10.1016/S1470-2045(14)70202-5

CrossRef Full Text | Google Scholar

Ishitsuka, K., Utsunomiya, A., and Ishida, T. (2018). PD-1 Inhibitor Therapy in Adult T-Cell Leukemia-Lymphoma. N. Engl. J. Med. 379:695. doi: 10.1056/NEJMc1807852

CrossRef Full Text | Google Scholar

Ito, T., and Handa, H. (2016). Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. Int. J. Hematol. 104, 293–299. doi: 10.1007/s12185-016-2073-4

CrossRef Full Text | Google Scholar

Kannagi, M., Hasegawa, A., Nagano, Y., Iino, T., Okamura, J., and Suehiro, Y. (2019a). Maintenance of long remission in adult T-cell leukemia by Tax-targeted vaccine: a hope for disease-preventive therapy. Cancer Sci. 110, 849–857. doi: 10.1111/cas.13948

CrossRef Full Text | Google Scholar

Kannagi, M., Hasegawa, A., Nagano, Y., Kimpara, S., and Suehiro, Y. (2019b). Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL. Retrovirology 16:23. doi: 10.1186/s12977-019-0484-z

CrossRef Full Text | Google Scholar

Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S., et al. (2016). Aberrant PD-L1 expression through 3’-UTR disruption in multiple cancers. Nature 534, 402–406. doi: 10.1038/nature18294

PubMed Abstract | CrossRef Full Text | Google Scholar

Katsuya, H., Ishitsuka, K., Utsunomiya, A., Hanada, S., Eto, T., Moriuchi, Y., et al. (2015). Treatment and survival among 1594 patients with ATL. Blood 126, 2570–2577. doi: 10.1182/blood-2015-03-632489

PubMed Abstract | CrossRef Full Text | Google Scholar

Kchour, G., Tarhini, M., Kooshyar, M. M., El Hajj, H., Wattel, E., Mahmoudi, M., et al. (2009). Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon alpha, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL). Blood 113, 6528–6532.

Google Scholar

Kfoury, Y., Nasr, R., Favre-Bonvin, A., El-Sabban, M., Renault, N., Giron, M. L., et al. (2008). Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome. Oncogene 27, 1665–1676. doi: 10.1038/sj.onc.1210804

PubMed Abstract | CrossRef Full Text | Google Scholar

Kfoury, Y., Nasr, R., Hermine, O., de The, H., and Bazarbachi, A. (2005). Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-kappaB pathway. Cell Death Differ. 12(Suppl. 1), 871–877.

Google Scholar

Kfoury, Y., Nasr, R., Journo, C., Mahieux, R., Pique, C., and Bazarbachi, A. (2012). The multifaceted oncoprotein Tax: subcellular localization, posttranslational modifications, and NF-kappaB activation. Adv. Cancer Res. 113, 85–120. doi: 10.1016/B978-0-12-394280-7.00003-8

CrossRef Full Text | Google Scholar

Kfoury, Y., Setterblad, N., El-Sabban, M., Zamborlini, A., Dassouki, Z., El Hajj, H., et al. (2011). Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome. Blood 117, 190–199. doi: 10.1182/blood-2010-05-285742

PubMed Abstract | CrossRef Full Text | Google Scholar

Kinpara, S., Kijiyama, M., Takamori, A., Hasegawa, A., Sasada, A., Masuda, T., et al. (2013). Interferon-alpha (IFN-alpha) suppresses HTLV-1 gene expression and cell cycling, while IFN-alpha combined with zidovudine induces p53 signaling and apoptosis in HTLV-1-infected cells. Retrovirology 10:52. doi: 10.1186/1742-4690-10-52

PubMed Abstract | CrossRef Full Text | Google Scholar

Kiyokawa, T., Yamaguchi, K., Takeya, M., Takahashi, K., Watanabe, T., Matsumoto, T., et al. (1987). Hypercalcemia and osteoclast proliferation in adult T-cell leukemia. Cancer 59, 1187–1191.

Google Scholar

Kotla, V., Goel, S., Nischal, S., Heuck, C., Vivek, K., Das, B., et al. (2009). Mechanism of action of lenalidomide in hematological malignancies. J. Hematol. Oncol. 2:36. doi: 10.1186/1756-8722-2-36

CrossRef Full Text | Google Scholar

Laperche, S., Worms, B., and Pillonel, J., European Network of Transfusion Medecine Societies and Steering Committee (2009). Blood safety strategies for human T-cell lymphotropic virus in Europe. Vox Sang 96, 104–110. doi: 10.1111/j.1423-0410.2008.01136.x

CrossRef Full Text | Google Scholar

Laribi, K., Alani, M., Truong, C., and Baugier de Materre, A. (2018). Recent Advances in the Treatment of Peripheral T-Cell Lymphoma. Oncologist 23, 1039–1053. doi: 10.1634/theoncologist.2017-0524

CrossRef Full Text | Google Scholar

Laribi, K., Lemaire, P., Sandrini, J., and Baugier de Materre, A. (2017). Advances in the understanding and management of T-cell prolymphocytic leukemia. Oncotarget 8, 104664–104686. doi: 10.18632/oncotarget.22272

CrossRef Full Text | Google Scholar

Larocca, D., Chao, L. A., Seto, M. H., and Brunck, T. K. (1989). Human T-cell leukemia virus minus strand transcription in infected T-cells. Biochem. Biophys. Res. Commun. 163, 1006–1013. doi: 10.1016/0006-291x(89)92322-x

CrossRef Full Text | Google Scholar

Li, Y., and Seto, E. (2016). HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 6:a026831. doi: 10.1101/cshperspect.a026831

CrossRef Full Text | Google Scholar

Lund, K., Adams, P. D., and Copland, M. (2014). EZH2 in normal and malignant hematopoiesis. Leukemia 28, 44–49. doi: 10.1038/leu.2013.288

CrossRef Full Text | Google Scholar

Ma, G., Yasunaga, J., and Matsuoka, M. (2016). Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis. Retrovirology 13:16. doi: 10.1186/s12977-016-0249-x

CrossRef Full Text | Google Scholar

Macchi, B., Balestrieri, E., Frezza, C., Grelli, S., Valletta, E., Marcais, A., et al. (2017). Quantification of HTLV-1 reverse transcriptase activity in ATL patients treated with zidovudine and interferon-alpha. Blood Adv. 1, 748–752. doi: 10.1182/bloodadvances.2016001370

PubMed Abstract | CrossRef Full Text | Google Scholar

Mahgoub, M., Yasunaga, J. I., Iwami, S., Nakaoka, S., Koizumi, Y., Shimura, K., et al. (2018). Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. Proc. Natl. Acad. Sci. U.S.A. 115, E1269–E1278.

Google Scholar

Mahieux, R. (2015). A vaccine against HTLV-1 HBZ makes sense. Blood 126, 1052–1053. doi: 10.1182/blood-2015-06-652040

PubMed Abstract | CrossRef Full Text | Google Scholar

Makita, S., and Tobinai, K. (2017). Mogamulizumab for the treatment of T-cell lymphoma. Expert Opin. Biol. Ther. 17, 1145–1153. doi: 10.1080/14712598.2017.1347634

CrossRef Full Text | Google Scholar

Malpica, L., Pimentel, A., Reis, I. M., Gotuzzo, E., Lekakis, L., Komanduri, K., et al. (2018). Epidemiology, clinical features, and outcome of HTLV-1-related ATLL in an area of prevalence in the United States. Blood Adv. 2, 607–620.

Google Scholar

Marcais, A., Cook, L., Witkover, A., Asnafi, V., Avettand-Fenoel, V., Delarue, R., et al. (2020). Arsenic trioxide (As2O3) as a maintenance therapy for adult T cell leukemia/lymphoma. Retrovirology 17:5. doi: 10.1186/s12977-020-0513-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Matsuoka, M., and Green, P. L. (2009). The HBZ gene, a key player in HTLV-1 pathogenesis. Retrovirology 6:71. doi: 10.1186/1742-4690-6-71

CrossRef Full Text | Google Scholar

Matsuoka, M., and Jeang, K. T. (2011). Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy. Oncogene 30, 1379–1389.

Google Scholar

Matutes, E., Taylor, G. P., Cavenagh, J., Pagliuca, A., Bareford, D., Domingo, A., et al. (2001). Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. Br. J. Haematol. 113, 779–784.

Google Scholar

Moodad, S., Akkouche, A., Hleihel, R., Darwiche, N., El-Sabban, M., Bazarbachi, A., et al. (2018). Mouse models that enhanced our understanding of adult T cell leukemia. Front. Microbiol. 9:558. doi: 10.3389/fmicb.2018.00558

CrossRef Full Text | Google Scholar

Mori, N., Matsuda, T., Tadano, M., Kinjo, T., Yamada, Y., Tsukasaki, K., et al. (2004). Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. J. Virol. 78, 4582–4590. doi: 10.1128/jvi.78.9.4582-4590.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

Mortreux, F., Kazanji, M., Gabet, A. S., de Thoisy, B., and Wattel, E. (2001). Two-step nature of human T-cell leukemia virus type 1 replication in experimentally infected squirrel monkeys (Saimiri sciureus). J. Virol. 75, 1083–1089. doi: 10.1128/JVI.75.2.1083-1089.2001

CrossRef Full Text | Google Scholar

Moura, I. C., Lepelletier, Y., Arnulf, B., England, P., Baude, C., Beaumont, C., et al. (2004). A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients. Blood 103, 1838–1845. doi: 10.1182/blood-2003-07-2440

PubMed Abstract | CrossRef Full Text | Google Scholar

Mulloy, J. C., Kislyakova, T., Cereseto, A., Casareto, L., LoMonico, A., Fullen, J., et al. (1998). Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain. J. Virol. 72, 8852–8860.

PubMed Abstract | Google Scholar

Nakagawa, M., and Kitabayashi, I. (2018). Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Sci. 109, 2342–2348. doi: 10.1111/cas.13655

CrossRef Full Text | Google Scholar

Nasr, R., Chiari, E., El-Sabban, M., Mahieux, R., Kfoury, Y., Abdulhay, M., et al. (2006). Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kappaB activation. Blood 107, 4021–4029. doi: 10.1182/blood-2005-09-3572

PubMed Abstract | CrossRef Full Text | Google Scholar

Nasr, R., Rosenwald, A., El-Sabban, M. E., Arnulf, B., Zalloua, P., Lepelletier, Y., et al. (2003). Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells. Blood 101, 4576–4582. doi: 10.1182/blood-2002-09-2986

CrossRef Full Text | Google Scholar

Ni, X., Goswami, M., Challagundla, P., Decker, W. K., Kim, Y. H., and Duvic, M. A. (2015). Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sezary syndrome. Clin. Cancer Res. 21, 274–285. doi: 10.1158/1078-0432.CCR-14-0830

CrossRef Full Text | Google Scholar

Nishioka, C., Ikezoe, T., Yang, J., Komatsu, N., Bandobashi, K., Taniguchi, A., et al. (2008). Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB. Leuk. Res. 32, 287–296. doi: 10.1016/j.leukres.2007.05.026

CrossRef Full Text | Google Scholar

Obama, K., Kubota, R., Tara, M., Furukawa, Y., Osame, M., and Arimura, K. (2007). Killer cell immunoglobulin-like receptor/3DL2 expression in adult T-cell leukaemia. Br. J. Haematol. 138, 666–667. doi: 10.1111/j.1365-2141.2007.06704.x

CrossRef Full Text | Google Scholar

Ogura, M., Imaizumi, Y., Uike, N., Asou, N., Utsunomiya, A., Uchida, T., et al. (2016). Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. Lancet Haematol. 3, e107–e118. doi: 10.1016/S2352-3026(15)00284-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Ohsugi, T., Kumasaka, T., Okada, S., and Urano, T. (2007). The Tax protein of HTLV-1 promotes oncogenesis in not only immature T cells but also mature T cells. Nat. Med. 13, 527–528. doi: 10.1038/nm0507-527

CrossRef Full Text | Google Scholar

Oka, S., Ono, K., and Nohgawa, M. (2019). Effective maintenance treatment with lenalidomide for a patient with aggressive adult T cell leukemia after chemotherapy. Leuk. Res. Rep. 11, 21–23. doi: 10.1016/j.lrr.2019.04.001

CrossRef Full Text | Google Scholar

Olsen, E. A., Kim, Y. H., Kuzel, T. M., Pacheco, T. R., Foss, F. M., Parker, S., et al. (2007). Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25, 3109–3115. doi: 10.1200/JCO.2006.10.2434

PubMed Abstract | CrossRef Full Text | Google Scholar

Panfil, A. R., Dissinger, N. J., Howard, C. M., Murphy, B. M., Landes, K., Fernandez, S. A., et al. (2016). Functional comparison of HBZ and the related APH-2 protein provides insight into human T-cell leukemia virus type 1 pathogenesis. J. Virol. 90, 3760–3772. doi: 10.1128/JVI.03113-15

CrossRef Full Text | Google Scholar

Poiesz, B. J., Ruscetti, F. W., Reitz, M. S., Kalyanaraman, V. S., and Gallo, R. C. (1981). Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sezary T-cell leukaemia. Nature 294, 268–271.

Google Scholar

Pombo De Oliveira, M. S., Loureiro, P., Bittencourt, A., Chiattone, C., Borducchi, D., De Carvalho, S. M., et al. (1999). Geographic diversity of adult t-cell leukemia/lymphoma in Brazil. The Brazilian ATLL Study Group. Int. J. Cancer 83, 291–298.

Google Scholar

Portis, T., Harding, J. C., and Ratner, L. (2001). The contribution of NF-kappa B activity to spontaneous proliferation and resistance to apoptosis in human T-cell leukemia virus type 1 Tax-induced tumors. Blood 98, 1200–1208. doi: 10.1182/blood.v98.4.1200

CrossRef Full Text | Google Scholar

Ramos, J. C., and Lossos, I. S. (2011). Newly emerging therapies targeting viral-related lymphomas. Curr. Oncol. Rep. 13, 416–426. doi: 10.1007/s11912-011-0186-8

CrossRef Full Text | Google Scholar

Ratner, L., Harrington, W., Feng, X., Grant, C., Jacobson, S., Noy, A., et al. (2009). Human T cell leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma. PLoS One 4:e4420. doi: 10.1371/journal.pone.0004420

PubMed Abstract | CrossRef Full Text | Google Scholar

Ratner, L., the Authors. (2018). PD-1 inhibitor therapy in adult T-cell leukemia-lymphoma. N. Engl. J. Med. 379, 696–697.

Google Scholar

Ratner, L., Waldmann, T. A., Janakiram, M., and Brammer, J. E. (2018). Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N. Engl. J. Med. 378, 1947–1948. doi: 10.1056/NEJMc1803181

CrossRef Full Text | Google Scholar

Saito, M., Matsuzaki, T., Satou, Y., Yasunaga, J., Saito, K., Arimura, K., et al. (2009). In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Retrovirology 6:19. doi: 10.1186/1742-4690-6-19

PubMed Abstract | CrossRef Full Text | Google Scholar

Satou, Y., Yasunaga, J., Yoshida, M., and Matsuoka, M. (2006). HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc. Natl. Acad. Sci. U.S.A. 103, 720–725. doi: 10.1073/pnas.0507631103

CrossRef Full Text | Google Scholar

Sharma, K., Janik, J. E. O., Mahony, D., Stewart, D., Pittaluga, S., Stetler-Stevenson, M., et al. (2017). Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-cell Leukemia/lymphoma. Clin. Cancer Res. 23, 35–42. doi: 10.1158/1078-0432.CCR-16-1022

PubMed Abstract | CrossRef Full Text | Google Scholar

Shimoyama, M. (1991). Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br. J. Haematol. 79, 428–437. doi: 10.1111/j.1365-2141.1991.tb08051.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Shinkawa, T., Nakamura, K., Yamane, N., Shoji-Hosaka, E., Kanda, Y., Sakurada, M., et al. (2003). The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J. Biol. Chem. 278, 3466–3473. doi: 10.1074/jbc.M210665200

PubMed Abstract | CrossRef Full Text | Google Scholar

Shirinian, M., Kambris, Z., Hamadeh, L., Grabbe, C., Journo, C., Mahieux, R., et al. (2015). A transgenic drosophila melanogaster model to study human T-lymphotropic virus oncoprotein tax-1-driven transformation in vivo. J. Virol. 89, 8092–8095. doi: 10.1128/JVI.00918-15

CrossRef Full Text | Google Scholar

Shirono, K., Hattori, T., Hata, H., Nishimura, H., and Takatsuki, K. (1989). Profiles of expression of activated cell antigens on peripheral blood and lymph node cells from different clinical stages of adult T-cell leukemia. Blood 73, 1664–1671.

Google Scholar

Siddiqi, T., Frankel, P., Beumer, J. H., Kiesel, B. F., Christner, S., Ruel, C., et al. (2019). Phase 1 study of the Aurora kinase A inhibitor alisertib (MLN8237) combined with the histone deacetylase inhibitor vorinostat in lymphoid malignancies. Leuk. Lymphoma 61, 309–317. doi: 10.1080/10428194.2019.1672052

CrossRef Full Text | Google Scholar

Subramaniam, J. M., Whiteside, G., McKeage, K., and Croxtall, J. C. (2012). Mogamulizumab: first global approval. Drugs 72, 1293–1298. doi: 10.2165/11631090-000000000-00000

CrossRef Full Text | Google Scholar

Suehiro, Y., Hasegawa, A., Iino, T., Sasada, A., Watanabe, N., Matsuoka, M., et al. (2015). Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study. Br. J. Haematol. 169, 356–367. doi: 10.1111/bjh.13302

PubMed Abstract | CrossRef Full Text | Google Scholar

Sugata, K., Yasunaga, J., Mitobe, Y., Miura, M., Miyazato, P., Kohara, M., et al. (2015). Protective effect of cytotoxic T lymphocytes targeting HTLV-1 bZIP factor. Blood 126, 1095–1105. doi: 10.1182/blood-2015-04-641118

CrossRef Full Text | Google Scholar

Sugiyama, D., Nishikawa, H., Maeda, Y., Nishioka, M., Tanemura, A., Katayama, I., et al. (2013). Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl. Acad. Sci. U.S.A. 110, 17945–17950. doi: 10.1073/pnas.1316796110

PubMed Abstract | CrossRef Full Text | Google Scholar

Taguchi, H., Kinoshita, K. I., Takatsuki, K., Tomonaga, M., Araki, K., Arima, N., et al. (1996). An intensive chemotherapy of adult T-cell leukemia/lymphoma: CHOP followed by etoposide, vindesine, ranimustine, and mitoxantrone with granulocyte colony-stimulating factor support. J. Acquir Immune Defic. Syndr. Hum. Retrovirol. 12, 182–186. doi: 10.1097/00042560-199606010-00012

PubMed Abstract | CrossRef Full Text | Google Scholar

Takasaki, Y., Iwanaga, M., Imaizumi, Y., Tawara, M., Joh, T., Kohno, T., et al. (2010). Long-term study of indolent adult T-cell leukemia-lymphoma. Blood 115, 4337–4343. doi: 10.1182/blood-2009-09-242347

PubMed Abstract | CrossRef Full Text | Google Scholar

Takatsuki, K., Uchiyama, T., Sagawa, K., and Yodoi, J. (1976). [Surface markers of malignant lymphoid cells in the classification of lymphoproliferative disorders, with special reference to adult T-cell leukemia (author’s transl)]. Rinsho Ketsueki 17, 416–421.

Google Scholar

Tamura, K., Nagamine, N., Araki, Y., Seita, M., Okayama, A., Kawano, K., et al. (1986). Clinical analysis of 33 patients with adult T-cell leukemia (ATL)-diagnostic criteria and significance of high- and low-risk ATL. Int. J. Cancer 37, 335–341. doi: 10.1002/ijc.2910370303

PubMed Abstract | CrossRef Full Text | Google Scholar

Tanabe, K., Ikegami, Y., Ishida, R., and Andoh, T. (1991). Inhibition of topoisomerase II by antitumor agents bis(2,6-dioxopiperazine) derivatives. Cancer Res. 51, 4903–4908.

Google Scholar

Tian, Y., Kobayashi, S., Ohno, N., Isobe, M., Tsuda, M., Zaike, Y., et al. (2011). Leukemic T cells are specifically enriched in a unique CD3(dim) CD7(low) subpopulation of CD4(+) T cells in acute-type adult T-cell leukemia. Cancer Sci. 102, 569–577. doi: 10.1111/j.1349-7006.2010.01833.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Tobinai, K. (2009). Current management of adult T-cell leukemia/lymphoma. Oncology 23, 1250–1256.

Google Scholar

Tobinai, K., Shimoyama, M., Inoue, S., Takayasu, S., Mikuni, C., Kozuru, M., et al. (1992). Phase I study of YK-176 (2′-deoxycoformycin) in patients with adult T-cell leukemia-lymphoma. The DCF study group. Jpn. J. Clin. Oncol. 22, 164–171.

PubMed Abstract | Google Scholar

Tobinai, K., Takahashi, T., and Akinaga, S. (2012). Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T-cell lymphomas. Curr. Hematol. Malig. Rep. 7, 235–240. doi: 10.1007/s11899-012-0124-3

CrossRef Full Text | Google Scholar

Tsuda, H., Takatsuki, K., Ohno, R., Masaoka, T., Okada, K., Shirakawa, S., et al. (1994). Treatment of adult T-cell leukaemia-lymphoma with irinotecan hydrochloride (CPT-11), CPT-11 Study Group on Hematological Malignancy. Br. J. Cancer 70, 771–774. doi: 10.1038/bjc.1994.394

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsukasaki, K., Hermine, O., Bazarbachi, A., Ratner, L., Ramos, J. C., and Harrington, W. O. Jr. et al. (2009). Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J. Clin. Oncol. 27, 453–459. doi: 10.1200/JCO.2008.18.2428

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsukasaki, K., Tobinai, K., Shimoyama, M., Kozuru, M., Uike, N., Yamada, Y., et al. (2003). Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109). Int. J. Hematol. 77, 164–170. doi: 10.1007/bf02983215

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsukasaki, K., Utsunomiya, A., Fukuda, H., Shibata, T., Fukushima, T., Takatsuka, Y., et al. (2007). VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J. Clin. Oncol. 25, 5458–5464. doi: 10.1200/JCO.2007.11.9958

PubMed Abstract | CrossRef Full Text | Google Scholar

Turpin, J., Alais, S., Marcais, A., Bruneau, J., Melamed, A., Gadot, N., et al. (2017). Whole body clonality analysis in an aggressive STLV-1 associated leukemia (ATLL) reveals an unexpected clonal complexity. Cancer Lett. 389, 78–85.

Google Scholar

Uchiyama, T., Hattori, T., Wano, Y., Tsudo, M., Takatsuki, K., and Uchino, H. (1983). Cell surface phenotype and in vitro function of adult T-cell leukemia cells. Diagn. Immunol. 1, 150–154.

Google Scholar

Ueda, N., Iwata, K., Tokuoka, H., Akagi, T., Ito, J., and Mizushima, M. (1979). Adult T-cell leukemia with generalized cytomegalic inclusion disease and pneumocystis carinii pneumonia. Acta Pathol. Jpn. 29, 221–232. doi: 10.1111/j.1440-1827.1979.tb03176.x

CrossRef Full Text | Google Scholar

Verdonck, K., Gonzalez, E., Van Dooren, S., Vandamme, A. M., Vanham, G., and Gotuzzo, E. (2007). Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect. Dis. 7, 266–281. doi: 10.1016/S1473-3099(07)70081-6

CrossRef Full Text | Google Scholar

Waldmann, T. A., Greene, W. C., Sarin, P. S., Saxinger, C., Blayney, D. W., Blattner, W. A., et al. (1984). Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sezary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. J. Clin. Invest. 73, 1711–1718. doi: 10.1172/JCI111379

PubMed Abstract | CrossRef Full Text | Google Scholar

Waldmann, T. A., White, J. D., Carrasquillo, J. A., Reynolds, J. C., Paik, C. H., Gansow, O. A., et al. (1995). Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac. Blood 86, 4063–4075.

PubMed Abstract | Google Scholar

Waldmann, T. A., White, J. D., Goldman, C. K., Top, L., Grant, A., Bamford, R., et al. (1993). The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood 82, 1701–1712.

PubMed Abstract | Google Scholar

Wang, C., Long, W., Peng, C., Hu, L., Zhang, Q., Wu, A., et al. (2016). HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains. PLoS Pathog. 12:e1005584. doi: 10.1371/journal.ppat.1005584

PubMed Abstract | CrossRef Full Text | Google Scholar

Wartewig, T., Kurgyis, Z., Keppler, S., Pechloff, K., Hameister, E., Ollinger, R., et al. (2017). PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121–125. doi: 10.1038/nature24649

PubMed Abstract | CrossRef Full Text | Google Scholar

Watanabe, T. (2017). Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood 129, 1071–1081. doi: 10.1182/blood-2016-09-692574

PubMed Abstract | CrossRef Full Text | Google Scholar

Wattel, E., Vartanian, J. P., Pannetier, C., and Wain-Hobson, S. (1995). Clonal expansion of human T-cell leukemia virus type I-infected cells in asymptomatic and symptomatic carriers without malignancy. J. Virol. 69, 2863–2868.

Google Scholar

White, J. D., Wharfe, G., Stewart, D. M., Maher, V. E., Eicher, D., Herring, B., et al. (2001). The combination of zidovudine and interferon alpha-2B in the treatment of adult T-cell leukemia/lymphoma. Leuk. Lymphoma 40, 287–294. doi: 10.3109/10428190109057927

PubMed Abstract | CrossRef Full Text | Google Scholar

Whittaker, S. J., Demierre, M. F., Kim, E. J., Rook, A. H., Lerner, A., Duvic, M., et al. (2010). Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 28, 4485–4491. doi: 10.1200/JCO.2010.28.9066

PubMed Abstract | CrossRef Full Text | Google Scholar

Yamada, Y., Tomonaga, M., Fukuda, H., Hanada, S., Utsunomiya, A., Tara, M., et al. (2001). A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br. J. Haematol. 113, 375–382. doi: 10.1046/j.1365-2141.2001.02737.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Yamagishi, M., Hori, M., Fujikawa, D., Ohsugi, T., Honma, D., Adachi, N., et al. (2019). Targeting excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas. Cell Rep. 29, 2321–2337.e7. doi: 10.1016/j.celrep.2019.10.083

PubMed Abstract | CrossRef Full Text | Google Scholar

Yamagishi, M., Nakano, K., Miyake, A., Yamochi, T., Kagami, Y., Tsutsumi, A., et al. (2012). Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kappaB pathway in adult T cell leukemia and other cancers. Cancer Cell 21, 121–135. doi: 10.1016/j.ccr.2011.12.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Yamagishi, M., and Watanabe, T. (2012). [miRNA in HTLV-1 related disease]. Uirusu 62, 9–18. doi: 10.2222/jsv.62.9

CrossRef Full Text | Google Scholar

Yamaguchi, K., Nishimura, H., Kohrogi, H., Jono, M., Miyamoto, Y., and Takatsuki, K. (1983). A proposal for smoldering adult T-cell leukemia: a clinicopathologic study of five cases. Blood 62, 758–766.

Google Scholar

Yamaoka, S., Courtois, G., Bessia, C., Whiteside, S. T., Weil, R., Agou, F., et al. (1998). Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93, 1231–1240. doi: 10.1016/s0092-8674(00)81466-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Yoshida, M., Satou, Y., Yasunaga, J., Fujisawa, J., and Matsuoka, M. (2008). Transcriptional control of spliced and unspliced human T-cell leukemia virus type 1 bZIP factor (HBZ) gene. J. Virol. 82, 9359–9368. doi: 10.1128/JVI.00242-08

CrossRef Full Text | Google Scholar

Yu, P., Petrus, M. N., Ju, W., Zhang, M., Conlon, K. C., Nakagawa, M., et al. (2015). Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model. Leukemia 29, 556–566. doi: 10.1038/leu.2014.241

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, Q., Wang, S., Chen, J., and Yu, Z. (2019). Histone Deacetylases (HDACs) Guided Novel Therapies for T-cell lymphomas. Int. J. Med. Sci. 16, 424–442. doi: 10.7150/ijms.30154

CrossRef Full Text | Google Scholar

Zhao, T., and Matsuoka, M. (2012). HBZ and its roles in HTLV-1 oncogenesis. Front. Microbiol. 3:247. doi: 10.3389/fmicb.2012.00247

CrossRef Full Text | Google Scholar

Zimmerman, B., Sargeant, A., Landes, K., Fernandez, S. A., Chen, C. S., and Lairmore, M. D. (2011). Efficacy of novel histone deacetylase inhibitor, AR42, in a mouse model of, human T-lymphotropic virus type 1 adult T cell lymphoma. Leuk. Res. 35, 1491–1497. doi: 10.1016/j.leukres.2011.07.015

CrossRef Full Text | Google Scholar

Keywords: ATL, HTLV-1, arsenic, monoclonal antibodies, targeted therapies, epigenetic therapies, vaccine

Citation: El Hajj H, Tsukasaki K, Cheminant M, Bazarbachi A, Watanabe T and Hermine O (2020) Novel Treatments of Adult T Cell Leukemia Lymphoma. Front. Microbiol. 11:1062. doi: 10.3389/fmicb.2020.01062

Received: 26 January 2020; Accepted: 29 April 2020;
Published: 28 May 2020.

Edited by:

Hirofumi Akari, Kyoto University, Japan

Reviewed by:

Hidekatsu Iha, Oita University, Japan
Makoto Yoshimitsu, Kagoshima University Hospital, Japan

Copyright © 2020 El Hajj, Tsukasaki, Cheminant, Bazarbachi, Watanabe and Hermine. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Hiba El Hajj, he21@aub.edu.lb; Olivier Hermine, ohermine@gmail.com