The prognosis of aggressive adult T-cell leukemia-lymphoma (ATL) remains poor because of frequent infections and drug resistance. Dose-intensified chemotherapy followed by autologous stem cell ...transplantation failed to improve the prognosis of patients with ATL; however, we first revealed that allogeneic hematopoietic cell transplantation (allo-HCT) might improve their prognosis. We showed that reduced-intensity stem cell transplantation using peripheral blood was feasible for elderly patients. Further, the prognosis of patients in remission, who receive cord blood transplantation, has been recently improved and is equivalent to that of patients who receive transplants from other stem cell sources. As for the timing of HCT, the patients who underwent transplantation early showed better outcomes than those who underwent transplantation late. Based on the analysis of patients with aggressive ATL, including those who received transplants, we identified five prognostic factors for poor outcomes: acute-type ATL, poor performance status, high soluble interleukin-2 receptor levels, hypercalcemia, and high C-reactive protein level. Next, we developed a new prognostic index: the modified ATL-PI. The overall survival (OS) rates were significantly higher in patients who underwent allo-HCT than those who did not in the intermediate and high-risk groups stratified using the modified ATL-PI. Two new anti-cancer agents, mogamulizumab and lenalidomide, were recently approved for ATL patients in Japan. They are expected to induce longer survival in ATL patients when administered along with transplantation. However, a retrospective analysis that the risk of severe, acute, and corticosteroid-refractory graft-versus-host disease was higher in patients who received mogamulizumab before allo-HCT, and that mogamulizumab might increase the transplant-related mortality (TRM) rates and decrease the OS rates compared to those of patients who did not receive mogamulizumab. However, our recent study showed that administration of mogamulizumab before allo-HCT tended to improve the survival of patients with ATL. In conclusion, allo-HCT procedures for patients with aggressive ATL have considerably progressed and have helped improve the prognosis of these patients; however, many concerns still remain to be resolved. Further development of allo-HCT by using new molecular targeting agents is required for the improvement of cure rates in patients with ATL.
Recent advances in treatment for adult T‐cell leukemia‐lymphoma (ATL) are reviewed herein. It is currently possible to select a therapeutic strategy for ATL and predict prognosis by classification of ...patients by clinical subtypes and clinicopathological factors. Although the overall survival (OS) of patients with ATL has increased marginally because of advances in chemotherapy, further prolongation of survival might be difficult with conventional chemotherapy alone. Promising results have been reported for antiviral therapy using zidovudine and interferon‐α, and, indeed, antiviral therapy is currently the standard treatment for patients with ATL in western countries. Remarkably, the 5‐year OS rates are 100% for both the smoldering‐type and chronic‐type ATL. Recently, treatments for ATL have included allogeneic hematopoietic stem cell transplantation and molecular targeted therapies. Furthermore, the anti‐CCR4 monoclonal antibody mogamulizumab has been shown to have marked cytotoxic effects on ATL cells, especially in the leukemic type of ATL. In the lymphoma type of ATL, the response rate may be improved by combining mogamulizumab with chemotherapy. It should be recognized that prevention of infection from carriers of human T‐cell leukemia virus type‐I and transfer of the virus from mother to infant are crucial issues for the eradication of ATL.
The prognosis of ATL is very poor by conventional chemotherapies. On the other hands, antiviral therapy of zidovudine and interferon‐α is currently the gold standard for patients with leukemic type ATL in Western countries although it is not confirmed yet in Japan. By various attempts including allogeneic hematopoietic stem cell transplantation and molecular target therapies, around one‐third of aggressive type ATL cases can be now cured.
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes adult T-cell leukemia/lymphoma (ATL), a cancer of infected CD4
T-cells. There is both sense and antisense transcription from ...the integrated provirus. Sense transcription tends to be suppressed, but antisense transcription is constitutively active. Various efforts have been made to elucidate the regulatory mechanism of HTLV-1 provirus for several decades; however, it remains unknown how HTLV-1 antisense transcription is maintained. Here, using proviral DNA-capture sequencing, we found a previously unidentified viral enhancer in the middle of the HTLV-1 provirus. The transcription factors, SRF and ELK-1, play a pivotal role in the activity of this enhancer. Aberrant transcription of genes in the proximity of integration sites was observed in freshly isolated ATL cells. This finding resolves certain long-standing questions concerning HTLV-1 persistence and pathogenesis. We anticipate that the DNA-capture-seq approach can be applied to analyze the regulatory mechanisms of other oncogenic viruses integrated into the host cellular genome.
Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells ...from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL.
A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg.
Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases.
KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.
Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and ...transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome.
Display omitted
•Lymphoma transcriptome is under control of global H3K27me3 accumulation•EZH1 and EZH2 are druggable targets in EZH2WT/WT and EZH2WT/Mu malignancies•Inactivation of chromatin-associated genes triggers EZH1/2 perturbation•Targeting epigenome for pre-cancerous states is achieved by EZH1/2 inhibition
A mechanism-based, effective strategy for controlling oncogenic H3K27me3 remains an open question. Yamagishi et al. provide the scientific rationale for dual targeting of EZH1+EZH2 in malignancies overexpressing EZH2, such as ATL, PTCL, and DLBCL, or harboring mutations in histone-modifying genes, as well as in pre-cancerous cells epigenomically perturbed by oncovirus infection.
Wnt5a is a ligand of the non-canonical Wnt signaling pathway involved in cell differentiation, motility, and inflammatory response. Adult T-cell leukemia/lymphoma (ATL) is one of the most aggressive ...T-cell malignancies caused by infection of human T-cell leukemia virus type1 (HTLV-1). Among subtypes of ATL, acute-type ATL cells are particularly resistant to current multidrug chemotherapies and show remarkably high cell-proliferative and invasive phenotypes. Here we show a dramatic increase of WNT5A gene expression in acute-type ATL cells compared with those of indolent-type ATL cells. Treatment with IWP-2 or Wnt5a-specific knockdown significantly suppressed cell growth of ATL-derived T-cell lines. We demonstrated that the overexpression of c-Myb and FoxM1 was responsible for the synergistic activation of the WNT5A promoter. Also, a WNT5A transcript variant without the exon4 (the ΔE4-WNT5A mRNA), encoding ΔC-Wnt5 (1-136aa of 380aa), is overexpressed in acute-type ATL cells. The ΔC-Wnt5a is secreted extracellularly and enhances cellular migration/invasion to a greater extent compared with wildtype (WT)-Wnt5a. Moreover, the ΔC-Wnt5a secretion was not suppressed by IWP-2, indicating that this mutant Wnt5a is secreted via a different pathway from the WT-Wnt5a. Taken together, synergistic overexpression of the ΔC-Wnt5a by c-Myb and FoxM1 may be responsible for the malignant phenotype of acute-type ATL cells.
KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, ...pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL).
Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design.
Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses.
KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.
The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody. Progression‐free survival ...(PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T‐cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1‐year PFS was 26%, whereas median OS was 14.4 months, and 3‐year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1‐year PFS was zero, with a median OS of 6.0 months, and 3‐year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1‐year PFS was 50%, with a median OS of 25.6 months, and 3‐year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.
Mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event.
Adult T‐cell leukemia–lymphoma (ATL) is a mature T‐cell malignancy associated with human T‐cell leukemia virus type 1 (HTLV‐1) infection. Japan is the most endemic country for HTLV‐1 and ATL in the ...world. Recent nationwide studies of Japanese blood donors reported that HTLV‐1 carriers spread from endemic areas to non‐endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital‐based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60–75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu–Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one‐third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV‐1 carrier status are needed.
A multicenter, hospital‐based survey of newly diagnosed ATL patients from 2010 to 2011 was conducted.This survey clarified that half of current patients with ATL were aged over 68 years.
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was ...undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval CI, 13.2, 52.9. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.
Tucidinostat is an oral novel benzamide HDACi of HDAC isoenzymes 1, 2, 3 and 10 selectively. 23 patients with relapsed/refractory ATLL were treated with tucidinostat 40mg orally twice a week. Out of 23 patients, 7 showed objective responses including 1 CR, and ORR was 30.4%.
PDF
