Acute Adult T-cell Leukemia/lymphoma Research Articles

The Oncoprotein Fra-2 Drives the Activation of Human Endogenous Retrovirus Env Expression in Adult T-Cell Leukemia/Lymphoma (ATLL) Patients

Human endogenous retroviruses (HERVs) are retroviral sequences integrated into 8% of the human genome resulting from ancient exogenous retroviral infections. Unlike endogenous retroviruses of other mammalian species, HERVs are mostly replication and retro-transposition defective, and their transcription is strictly regulated by epigenetic mechanisms in normal cells. A significant addition to the growing body of research reveals that HERVs’ aberrant activation is often associated with offsetting diseases like autoimmunity, neurodegenerative diseases, cancers, and chemoresistance. Adult T-cell leukemia/lymphoma (ATLL) is a very aggressive and chemoresistant leukemia caused by the human T-cell leukemia virus type 1 (HTLV-1). The prognosis of ATLL remains poor despite several new agents being approved in the last few years. In the present study, we compare the expression of HERV genes in CD8+-depleted PBMCs from HTLV-1 asymptomatic carriers and patients with acute ATLL. Herein, we show that HERVs are highly upregulated in acute ATLL. Our results further demonstrate that the oncoprotein Fra-2 binds the LTR region and activates the transcription of several HERV families, including HERV-H and HERV-K families. This raises the exciting possibility that upregulated HERV expression could be a key factor in ATLL development and the observed chemoresistance, potentially leading to new therapeutic strategies and significantly impacting the field of oncology and virology.

Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country.

Background and Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1). ATLL is a rare disease, found more frequently in HTLV-1-endemic areas, Romania being one of them. Despite treatment advances, the prognosis remains dismal. We aimed to describe the clinical, biological, and survival outcome features of Romanian patients with aggressive-type ATLL. Materials and Methods: We report the data of a prospective, observational, and unicentric study of all 20 patients diagnosed with lymphoma and acute types of ATLL at our center over the past 12 years. Data were collected from the patients' medical records. Results: Lymphoma-type ATLL (60%) was more common than acute-type ATLL (40%). Median age at diagnosis was 40.5 years, and most patients were female. Laboratory data revealed significant differences between acute and lymphoma-type ATLL, namely, higher leukocyte (p = 0.02) and lymphocyte counts (p = 0.02) and higher levels of corrected calcium (p = 0.001) in acute-type ATLL. All patients received chemotherapy, and only two underwent allogeneic stem cell transplantation. Only six patients obtained a complete or partial response to chemotherapy, mostly the lymphoma-type ones. The median survival for all patients was 6.37 months, with higher survival in the lymphoma-type ATLL (8.16 months) than in the acute-type (3.60 months). Normal calcium levels (p = 0.011), uric acid (p = 0.005), BUN score (p = 0.000), JCOG-PI moderate risk (p = 0.038), and obtaining complete or partial response (p = 0.037) were associated with higher survival. Conclusion: Aggressive-type ATLL among Romanian patients presents distinct characteristics, including younger age at diagnosis, female predominance, and higher incidence of lymphoma-type ATLL compared to currently reported data. Survival remains very low, with all subtypes experiencing a median survival of less than one year.

Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (VIII): six new withanolides from Physalis philadelphica.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T-lymphocytes caused by human T-cell leukemia virus type I (HTLV-I). There are an estimated 5-20 million HTLV-1-infected individuals worldwide. Conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to patients with ATL, but the therapeutic outcomes of acute and lymphoma-type ATL remain extremely poor. In the course of our screening program for novel chemotherapeutic candidate compounds from plants against two human T-cell leukemia virus I-infected T-cell lines (MT-1 and MT-2), we screened 16 extracts obtained from different parts of 7 Solanaceae plants. We identified that the extracts of Physalis pruinosa and P. philadelphica showed potent anti-proliferative activity in MT-1 and MT-2 cells. In our previous study, we have isolated withanolides from extract of aerial parts of P. pruinosa and examined their structure-activity relationships. In addition, we are also investigating further structure-activity relationships about other withanolides from Solanaceae plants (Withania somnifera, Withania coagulans, Physalis angulate, Nicandra physalodes, Petunia hybrida, and Solanum cilistum). In this study, we attempted to isolate their active compounds against MT-1 and MT-2 from extracts of P. philadelphica. We identified 13 withanolides, including six newly isolated compounds [24R, 25S-4β, 16β, 20R-trihydroxy-1-oxowitha-2-en-5β, 6 β -epoxy-22,26-olide (1), 4β, 7β,20R-trihydroxy-1-oxowitha-2-en-5β, 6β -epoxy-22,26-olide (2), 17β,20 S-dihydroxywithanone (3), 2,3-dihydro-3β-methoxy-23β-hydroxywithaphysacarpin (4), 3-O-(4-rhamnosyl)glucosyl-physalolactone B (5), and 17R, 20R, 22S, 23S, 24R, 25R-4β, 5α, 6β, 20β, 22α -tetrahydroxy-16β, 23-diepoxy-1-oxowitha-2-en-26, 23-olide (6)], from the extract and examined the structure-activity relationships. The 50% effective concentration of withaphysacarpin (compound 7) [MT-1: 0.10µM and MT-2: 0.04µM] was comparable to that of etoposide [MT-1: 0.08µM and MT-2: 0.07µM]. Therefore, withanolides might be promising candidates for the treatment of ATL.

Primary cells from patients with adult T cell leukemia/lymphoma depend on HTLV-1 Tax expression for NF-κB activation and survival

Adult T cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with human T cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax initiates T cell transformation through activation of critical cellular pathways, including NF-κB. Unexpectedly, Tax protein is not detectable in most ATL cells, in contrast to the HTLV-1 HBZ protein which antagonizes Tax effects. Here, we demonstrate that primary ATL cells from patients with acute or chronic ATL express very low levels of Tax mRNA and protein. Critically, survival of these primary ATL cells is dependent on continued Tax expression. Mechanistically, Tax extinction results in reversal of NF-κB activation, P53/PML activation and apoptosis. Tax drives interleukin-10 (IL-10) expression and recombinant IL-10 rescues the survival of tax-depleted primary ATL cells. These results demonstrate the critical role of continued Tax and IL-10 expression for the survival of primary ATL cells, highlighting their relevance as therapeutic targets.

T-Cell Receptor Amino Acid Sequence Selected By Cytotoxic T Cells Specific to HTLV-1 in HLA-A02:01-Positive ATL Patients

Purpose: Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral malignancy of T cells caused by human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains very poor. Tax is the most important regulatory protein for HTLV-1, which is associated with the proliferation of host cells. Tax has been considered as an important target antigen for CD8+cytotoxic T cells (CTLs). We aimed to reveal such a unique sequence of complementarity-determining region 3 (CDR3) of the T cell receptor (TCR)-α and-β chain of HLA-A*02:01-restricted Tax11-19-specific CTLs (Tax-CTL). Methods: We serially analyzed Tax-CTLs from ATL patients with HLA-A*02:01 who had received allogeneic hematopoietic cell transplantation (all-HCT), chemotherapies alone, or had not ever received any treatment. Tax-CTLs were defined as a living CD3+CD8+Tax-tetramer+cells. After sorting Tax-CTLs directly from an actual patient sample into a PCR tube, TCR-α and -β chains of individual CTL clones were determined by the next-generation sequence (NGS) method with SMARTer technology. In addition, we cultured and established individual Tax-CTL clones from a sorted single cell, and finally evaluated the cytotoxicity of Tax-CTLs by calcein-acetoxymethyl (AM)-based cytotoxicity assay. Results: Peripheral blood samples were obtained from 7 patients (Pt-1,-2,-3,-4,-5,-6 and -7). Pt-1 had received allo-HCT and the samples were available 270 days, 1 year, 3 years, 5 years and 7 years after allo-HCT. Samples before treatment were available in the other 5 patient (acute ATL Pt-2,-3, and -6; chronic ATL, Pt-4; HTLV-1 asymptomatic charrier, Pt-5), while the samples after treatment were available in 1 patient (acute ATL Pt-7). Tax-specific CTLs were detected in 0.03-0.58% of total peripheral blood mononuclear cells, and 144-1000 cells per sample (median; 250 cells) were sorted and analyzed for TCR determination. Of them, 2 to 30 Tax-specific CTL clones were identified for each patient. Tax-specific CTLs seemed oligoclonal, and their usage of BV and BJ genes were restricted in TCR-BV28(30.5%), -BV6-5(33.3%), and -BJ2-1(30.5%), while their usage of AV and AJ genes were restricted in TCR-AV12-2(54.5%) and -AJ24(24.2%) gene families. The length of amino acids (AA) in TCR-α and TCR-β CDR3 of all Tax-CTLs clones seemed to be symmetrically distributed, and the most frequently observed AA length was 13 in TCR-α, and 15 in TCR-β. The unique motifs of "DSWGK" in TCR-α and "LAGG" in TCR-β at CDR3 were observed in almost all ATL patients. The 'DSWGK' motif was observed in 0-81.7% (median; 55.5%), and the 'LAGG' motif was observed in 5.2%-80.3% (median; 48%). Pt-2 didn't have any clones with 'DSWGK' motif in TCR-α, whereas regarding 'LAGG' motif in TCR-β, all patients had it in this study. We established Tax11-19-specific CTL clones from a single cell of Pt-4, which showed killing activities against Tax-peptide-pulsed HLA-A2+ T2 cell lines. Conclusion: These methods and results can help us to better understand immunity against ATL, leading to future studies on the clinical application of adoptive T-cell therapies in the future.

Allogeneic but Not Autologous Stem Cell Transplantation Improves Outcome in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare mature T-cell malignancy driven by the human T-cell lymphotropic virus type I (HTLV-1) that remains challenging to treat and is associated with a dismal prognosis. While some reports have shown encouraging results with allogeneic stem-cell transplantation (allo-SCT), data remains scarce and mostly limited to Japanese patients. Patients and Methods: This is a retrospective single center analysis with 100 HTLV-1-associated North American ATLL patients. Variables collected included age, sex, ethnicity, CMV/HTLV1 serologies, karnofsky performance score (KPS), diagnosis date, disease subtype, number of prior therapy lines, transplant type, status at transplant, transplant date, prior SCT, donor sex, CMV/HTLV1 serologies, stem cell source, donor type, in-vivo T-cell depletion, engraftment, conditioning regimen, GVHD prophylaxis, maximum acute and chronic GVHD grade, relapse date when applicable, and main cause of death. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Cumulative incidence functions were used to estimate relapse incidence (RI) and non-relapse mortality (NRM) in a competing risk setting. Death and relapse were considered as competing events for acute and chronic GVHD. Univariate analyses were done using the Gray's test for cumulative incidence functions and the log rank test for OS and PFS. A Cox proportional hazards model was used for multivariate regression, results were expressed as hazard ratio (HR) with a 95% confidence interval (CI). All tests were two-sided, type-1 error was fixed at 5%. Results: One hundred patients met eligibility criteria, 18-87 years old, 69 of which were Black, 27 Hispanic, and 2 of Asian descent. Sixty-seven patients had acute ATLL and 22 lymphomatous. In total, 22 patients underwent SCT with 17 allo-SCT and 5 autologous SCT (ASCT) between 2005-2020 with a median follow-up of 62 months. Ten patients (45%) were transplanted in first complete remission (CR1), and 15 (68%) had KPS ≥90. Among patients undergoing allo-SCT, 41% had matched sibling donors (MSD), 18% matched unrelated (MUD), and 35% haploidentical. The 1-year and 3-years rates of overall survival from diagnosis of the cohort were 42% and 21%, respectively. Acute ATLL subtype was a strong predictor of worse outcome (Figure 1) with 1-year and 3-years OS of 32% vs 71% (p=0.004) and 11% vs 46% (p=0.002), respectively, compared to lymphomatous disease. To account for immortal time bias, 37 non-transplanted patients with early mortality within 4 months of diagnosis that were not able to make it to transplant were excluded from the Kaplan-Meier survival analysis. Patients undergoing transplant had improved outcomes compared to non-transplanted patients (Figure 1, Table 1), with allo-SCT reaching statistical significance in multivariate analysis compared to the non-transplant group with OS HR of 0.3 (p=0.004) compared to 0.7 (p=0.6) in ASCT vs non-transplant. In transplanted patients, the 3-year RI and NRM were 51% and 37%, respectively, and 3-year PFS and OS were 31% and 39%, respectively. Four of five patients who received ASCT rapidly relapsed with 3 dying from disease progression and one lost to follow-up, with 1-year RI of 80% vs 30% in allo-SCT (p=0.03). In exploratory multivariate analysis, patients achieving CR1 and with good baseline performance scores (KPS >90) had significantly better outcomes compared to their counterparts regardless of transplant type, and surprisingly, race was a strong and significant predictor of outcomes affecting PFS and OS with Hispanic vs Black PFS and OS HRs of 6 (p=0.04) and 10 (p=0.04), respectively. Thirteen patients died within 2 years, eight from relapse/progression including 3 ASCT patients, and 4 from transplant-related toxicities. Conclusion: Our data suggest that allo-SCT, but not ASCT, is a valid option in select ATLL patients. It also appears that patients of Hispanic descent have worse outcome post-transplant but not overall, which could be explained by lack of compatible donors or barriers to early transplant. Although this is the largest NA-ATLL transplant cohort presented to date outside of Japan and Europe, further studies are necessary to fully explain these discrepancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Progression of Disease within 5 Months of Adult T-Cell Leukemia-Lymphoma (ATL5) As a Clinical Endpoint for High-Risk Mortality Outcomes in the Real-World Setting: A Multinational Cohort Analysis

Introduction Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy associated to poor outcomes. Most of these patients experience a rapid and aggressive disease course characterized by early progression and death. Previous studies have identified clinical and laboratory factors of prognostic value. However, their incorporation in the clinical setting has not been validated due to unstandardized management practices. Risk stratification based on time to progression has not been explored in patients with ATL. Therefore, we develop a clinical endpoint to evaluate whether patients that relapse early have a higher risk of death. Methods We designed a multicenter retrospective cohort study among treated patients with a serological and pathology confirmation of ATL. Included patients with acute or lymphomatous ATL subtypes received systemic treatment (e.g., chemotherapy; zidovudine plus interferon). The training cohort consists of patients from endemic regions treated in tertiary care centers across Latin America and the United States. A validation set of 193 patients from Japan was used for reproducibility. Our exploratory analysis identified that at least 20% of relapsed patients experienced this event within 5 months after diagnosis in both training and validation cohorts. Therefore, we used a 5-month landmark for patients with ATL (ATL5) to define early progression. Median follow-up (reverse Kaplan-Meier) was 48 and 40 months in the training and validation cohorts, respectively. Overall survival was defined from date progression for early-ATL5, and from the 5-month landmark for non-early-ATL5 (reference group). Patients that died without relapse within 5 months (n=62 training, n=54 validation) or those alive with less than 5 months of follow-up time (n=13 training, n=3 validation) were excluded from the analysis. We plotted Kaplan-Meier curves and used the log-rank test to compare groups across the datasets. Univariate and multivariate Cox regression analyses were employed to model the effect of ATL5 on all-cause mortality. Missing values were added as a missing category in the adjusted models. Results Of the 253 patients in the training cohort, 38% (n=96) relapsed within 5 months after diagnosis, and 62% (n=157) did not (reference group). There were 96 (38%) with acute (early-ATL5: n=55, reference: n=41) and 157 (62%) with lymphoma (early-ATL5: n=41, reference: n=116) ATL subtype. The median age at diagnosis was similar between both groups (early relapse: 55 years, reference: 54 years; p=0.831). Patients with early-ATL5 had poor performance status (ECOG 2-4 68% vs. 49%, p=0.009), higher frequency of acute ATL (57% vs. 26%, p<0.001), B symptoms (83% vs. 63%, p=0.034), advanced stage (III-IV 97% vs. 84%, p=0.002), hypercalcemia (51% vs. 35%, p=0.023), and higher values of lactate dehydrogenase (96% vs. 77%, p<0.001). Overall survival at 3 years was poorer among patients with early-ATL5 (12% vs. 30%; p=0.0001; Figure 1A). The univariate Cox analysis identified a hazard ratio (HR) of 2.02 (95% confidence interval [CI] 1.49-2.74) for early progression. After adjusting for ATL subtype, cancer stage, skin involvement, ECOG score, extranodal involvement, and hypercalcemia, patients with early-ATL5 remained with a higher risk of death (adjusted HR: 2.02, 95% CI 1.43-2.86). In the validation cohort, the 23 (12%) patients with early progression were deceased within 18 months after the landmark basal time (Figure 1B). The risk of death was higher among individuals with early-ATL5 in the validation set (adjusted HR: 1.84, 95% CI 1.14-2.95, Figure 1B). Conclusions Patients with ATL who relapse within 5 months after diagnosis had a higher risk of death. Treatment of ATL varies between and within countries, limiting the comparison and validation of current prognostic factors. Therefore, we developed a time-based marker to evaluate the prognosis of these patients. Our findings remain robust in the validation set, suggesting that ATTL5 is a clinically relevant endpoint in the real-world setting. Future studies should validate its applicability in prospective studies and determine its relevance for risk-based treatment in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epidemiology of Adult T-Cell Leukaemia/Lymphoma in South Africa over a 10-Year Period.

Introduction Adult T-cell leukaemia/lymphoma (ATLL) is a rare and aggressive malignancy of mature T-cells. Limited epidemiological studies have shown that there is substantial variation in age at diagnosis and subtype distribution between different geographical regions. This is the first epidemiological study of ATLL in South Africa. Methods A national epidemiological study of ATLL in South Africa was performed. All new cases of ATLL from 2009 to 2019 were identified by laboratory database search in public and private health care sectors. Demographic and diagnostic data were obtained, and the cases were subtyped according to the Shimoyama classification. Results There were 31 patients with ATLL over the 10-year period, with an incidence of 0.06 per 100000 population. The male to female ratio was 1 : 1 and the median age at diagnosis was 37 years. Acute ATLL was the most commonly seen subtype in South Africa. Conclusion In this, the first epidemiological study of ATLL in South Africa, we demonstrate that ATLL is a rare disease, that acute ATLL is the most commonly diagnosed subtype, and that ATLL is likely under diagnosed. Patients present at a considerably younger age than the reported age in other nations.

Elevation of the Plasma Levels of TNF Receptor 2 in Association with Those of CD25, OX40, and IL-10 and HTLV-1 Proviral Load in Acute Adult T-Cell Leukemia.

Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be helpful for the diagnosis or prediction of the onset of acute ATL, we examined the plasma levels of sTNFR2 in a large number of specimens obtained from a cohort of ATL patients and asymptomatic human T-cell leukemia virus type 1 (HTLV-1) carriers (ACs) and compared them to those of other candidate ATL biomarkers (sCD25, sOX40, and IL-10) by enzyme-linked immunosorbent assays (ELISA) and HTLV-1 proviral loads. We observed that sTNFR2 levels were significantly elevated in acute ATL patients compared to ACs and patients with other types of ATL (chronic, smoldering, and lymphoma). Importantly, sTNFR2 levels were significantly correlated with those of sCD25, sOX40, and IL-10, as well as proviral loads. Thus, the present study confirmed that an increase in plasma sTNFR2 levels is a biomarker for the diagnosis of acute ATL. Examination of plasma sTNFR2 alone or in combination with other ATL biomarkers may be helpful for the diagnosis of acute ATL.

Interim Results of a Multicenter Pilot Study Evaluating Brentuximab Vedotin with Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (BV-CHEP) for the Treatment of Aggressive Adult T-Cell Leukemia/Lymphoma

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare type of lymphoma that is often aggressive with poor survival. The majority of cases cluster in regions with high rates of endemic human T-lymphotropic virus type 1 (HTLV-1) because chronic infection is necessary for the development of ATLL. ATLL is rare in the US, with most cases occurring in immigrants from endemic regions. Although treatment data exist from Japan, some of the agents evaluated are not available in the US. Because of limited prospective data in the US, there is no well-defined standard of care.Brentuximab vedotin (BV) is a CD30-targeting antibody-drug conjugate that has been shown to be effective even in lymphomas with very low CD30 expression (Jagadeesh, JCO, 2019). Studies have shown 36% to 50% of ATLL cases will express CD30. CD30 may be associated with worse survival in acute ATLL, making it an important therapeutic target. BV has been studied in combination with a CHP (cyclophosphamide, doxorubicin, prednisone) backbone for the treatment of CD30 expressing PTCL. ATLL patients were eligible for the study, but only 7 patients were enrolled (Horwitz, Lancet, 2019). BV-CHEP has been studied in CD30 expressing PTCL and was shown to be safe and effective (Herrera, Blood, 2019). No ATLL patients were enrolled prior to the preliminary report.We developed a prospective, multicenter pilot study evaluating BV in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for the treatment of ATLL. We report the interim safety and efficacy analysis of the first 8 patients treated on this study.Methods: Adult patients from 5 centers (UNC Chapel Hill, Boston Medical Center, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Moffitt Cancer Center at Memorial Healthcare System) were enrolled from October 2017 until present. Newly diagnosed ATLL cases were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Patients did not have to express CD30 to be enrolled on the study. Patients could go on to frontline consolidation with allogeneic stem cell transplant per provider preference at any time after 2 cycles of BV-CHEP. Transplant-ineligible patients completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance, whereas those without CD30 expression entered follow-up. Patients could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Patients were treated with standard dosing every 21 days: BV 1.8 mg/kg on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 days 1-3, and prednisone 100mg days 1-5. All patients received GCSF support. The primary endpoint was complete response (CR) by PET-CT after at least 2 cycles of therapy per adapted Lugano and ATLL criteria. Secondary endpoints were safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS).Results: 8 patients were enrolled and were evaluable for interim safety and efficacy analysis. All patients were HTLV-1 positive; 4 of 8 (50%) were acute type and 4 of 8 were the lymphomatous type. 4 of 8 patients had CD30 expression. The median age was 56 (range 38 to 68) and 7 of 8 (87.5%) were female. 6 of 8 patients identified as Black (Antigua and Barbuda N=1, Haiti N=4, US N=1), 1 identified as Asian (Japan) and 1 patient identified as Hispanic (Colombia). All patients were advanced stage (7 of 8 stage IV; 1 stage III). Five of 8 patients completed at least 4 cycles of treatment (median 4 cycles; range 2 to 6). After at least 2 cycles of BV-CHEP, 4 of 8 patients achieved a CR (50%). An additional 2 patients achieved a PR, for an ORR of 75%. The median PFS was 196 days (Fig.1) and the median OS was not reached (Fig.2). When CD30 expressing patients (N=4) were compared to non-expressing patients (N=4), there was no significant difference in median PFS or OS. The regimen was well-tolerated with grade 3 mucositis occurring in 3 patients, grade 3 hypertension in 2 patients, and grade 3 rash in 1 patient. No patients had to come off study due to toxicity. Three patients received consolidation allogeneic transplant. No patients received maintenance BV.Conclusions: In this interim analysis, BV-CHEP chemotherapy was safe and effective in the treatment of aggressive ATLL. We look forward to reporting the final results once the study completes accrual. [Display omitted] DisclosuresDittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Sloan: Stemline: Honoraria; Abbvie: Honoraria; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:Brentuximab vedotin will be used in CD30- ATLL patients.

A Simplified Novel Prognostic Score to Predict Early Mortality and Disease Progression in Patients with Aggressive Adult T-Cell Leukemia/Lymphoma

▪Background: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature peripheral T-cell neoplasm caused by HTLV-1 infection. Despite aggressive therapy, ATLL carries a very poor prognosis. Current prognostic models (i.e., the International Prognostic Index [IPI] and the Prognostic Index for T-cell lymphoma [PIT]) have shown to not completely predict survival in ATLL (Phillips, Cancer, 2010). Moreover, these models have not been validated in Latin American ATLL patients. Therefore, we aim to validate current prognostic systems (IPI, PIT) and to develop a novel model to predict early mortality in patients with ATLL.Methods: We conducted a retrospective cohort study by analyzing 12 demographic, clinical, and laboratory variables of 169 Latin American ATLL patients with acute and lymphomatous subtypes recruited by the “Grupo de Estudio Latinoamericano de Linfoproliferativos” (GELL). All patients received cancer-directed treatment. Conditional inference trees were used to construct a new prognostic model, the ATLL-GELL, by including serum lactate dehydrogenase (LDH) and the Eastern Cooperative Oncology Group (ECOG) performance status. Our primary outcome was overall survival (OS) at 15 months, while our secondary outcome was progression-free survival (PFS). The model identified a low-risk (LDH ≤2 times upper limit value [ULV] + ECOG score 0-1), and a high-risk (LDH >2 times ULV + ECOG score ≥2; or LDH >2 times ULV) group (Figure 1). The model was validated in an independent cohort of 95 North American ATLL patients with acute and lymphomatous subtypes from Miami, FL. We used the Kaplan-Meier method and the log-rank test to estimate the survival probabilities for the score. Cox regression was used to evaluate the risk of mortality and disease progression for each score. We used the C-index to determine the discriminatory power of each score.Results: Table 1 summarizes the demographic and clinical characteristics. The mean age was 57 (± 15.1) years with a male predominance (53%). Lymphomatous ATLL was the most common subtype (66%) in the training cohort, while acute ATLL (59%) in the testing cohort. Most patients had an Ann Arbor stage III-IV (88%) and received multiagent chemotherapy (76%) as first-line treatment (Table 1). With a median follow-up of 21 months, the 15-month OS and PFS rates of the training cohort were 29% and 27%, respectively. Patients with a high-risk ATLL-GELL score had a worse OS (16% vs. 61%, p<0.0001) and PFS (14% vs. 60%, p<0.0001) (Figure 2). Table 2 shows that the ATLL-GELL model had comparable prognostic discrimination than the IPI and PIT scores, according to the C-index. Similarly, the Cox regression analysis identified a better risk stratification of the new model for OS and PFS in the training and testing cohorts. In contrast, poor risk stratification for mortality and disease progression was found with the IPI and PIT scores in the training cohort. Table 2 shows that the risk for mortality and disease progression was higher in the high-intermediate (HR 7.91 and 8.07, respectively) than the high-risk (HR 7.12, and 7.85, respectively) group according to the IPI score. Moreover, the PIT score could not properly stratify patients' OS and PFS risk (Table 2). Figures 3 and 4 illustrate narrow and crossing survival curves between risk subgroups in both scores for OS and PFS estimates, respectively, suggesting poor visual discrimination of the IPI and PIT scores.Conclusion: ATLL carries a dismal prognosis, therefore we hypothesized that current prognostic systems might not yield an appropriate risk stratification since almost universally aggressive ATLL patients are at high risk for rapid disease progression and death. After considering different clinical-epidemiological and laboratory variables, our simplified prognostic model was able to predict early mortality and disease progression in patients with aggressive ATLL. Poor performance status, thus unfit for aggressive therapy, along with a high disease burden seems to reliably predict mortality in these patients. The ATLL-GELL model also showed better risk stratification and a more clear distinction of low- versus high-risk groups for aggressive ATLL than traditional models. We are currently validating our findings in a prospective cohort of Latin American ATLL patients and to improve clinical decision-making in those deemed at high risk for early mortality. [Display omitted] DisclosuresCastillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Trial in Progress: A Phase II Trial of Belinostat As Consolidation Therapy with Zidovudine for Adult T-Cell Leukemia-Lymphoma (ATLL)

Background: Adult T-cell leukemia-lymphoma (ATLL), a lymphoid malignancy associated with human T-cell leukemia virus type 1 (HTLV-1), is endemic in regions such as southwestern Japan, the Caribbean basin, and parts of South America, and central Africa where HTLV-1 is prevalent. Generally, ATLL cannot be cured with chemotherapy alone, and has dismal long-term outcomes. Previous clinical trials have only yielded modest results.Zidovudine (ZDV) is a synthetic nucleoside analog that inhibits reverse transcriptase and DNA polymerase resulting in inhibition of DNA replication and cell proliferation. Studies have demonstrated ZDV plus interferon (IFNα) therapy, as induction, followed by maintenance therapy, can be an efficacious first line treatment in leukemic forms of ATLL. A meta-analysis showed ZDV/IFNα therapy compared better to conventional chemotherapy for acute and chronic leukemic type ATLL in terms of overall survival. NCCN guidelines include ZDV/IFNα as a first-line therapy option for ATLL. While ZDV-IFNα can be effective in some ATLL patients, as with chemotherapy, molecular response rates are suboptimal, and patients usually relapse and succumb to their disease. Therefore, new therapeutic approaches and strategies are urgently needed to treat ATLL.Belinostat, a pan-HDAC inhibitor, obtained accelerated approval in 2015 for treatment of relapsed/refractory PTCL based on efficacy and duration of response. We hypothesize that belinostat will exert anti-neoplastic effects in ATLL cells through a variety of molecular mechanisms including activation of silenced key cellular genes and suppression of HBZ (only HTLV-1 protein consistently expressed in all ATLL tumors) and through HDAC inhibition, belinostat will reactivate HTLV-1 provirus in ATLL cells and infected T-cell reservoirs, thus eliciting an immune response against virus infected cells.Here, we describe a trial designed to evaluate safety and response of belinostat in combination with ZDV as consolidation therapy for treatment of ATLL. Correlative studies include measuring HTLV-1 reactivation in peripheral blood T-cells, assessing cytotoxic T-cell response in vivo, and investigating molecular effects of belinostat in ATLL cells in vivo.Study Design: This phase 2, single arm, open-label trial will evaluate the combination of belinostat and ZDV as consolidation therapy followed by standard ZDV-based maintenance therapy with optional IFNα-2b or pegylated interferon-alfa-2b (PEG-IFN-α-2b). The study will include up to 20 adult participants with histologically or cytologically documented ATLL, HTLV-1 infection, who have achieved and maintained at least a partial hematologic response to prior ZDV/IFNα therapy or chemotherapy. Residual ATLL in peripheral blood is required prior to enrollment. Patients must have measurable, clinically evaluable or molecular disease, with adequate end organ and bone marrow function (unless due to lymphomatous infiltration) and KPS ≥50% or ECOG performance status ≤3.The active study period includes a treatment period of up to 8 cycles (21 days each = ~6-months). Additional assessments will occur at the end of Cycle 8, Month 9, Month 12 and an end-of-treatment visit (≤ 30-days after the last dose of study treatment). Patients who achieve/maintain CR and complete 1 year of therapy will undergo follow-up assessments every 3 months for 1 year, and survival assessment every 6 months up to Year 5.ZDV will be administered in the outpatient setting as 300mg tablets orally, three times daily, starting at least 24-hours prior to the first dose of belinostat. Belinostat will be administered as 1,000 mg/m 2 IV infusion over 30 minutes on Days 1-5, every 21 days, on cycles 1- 8, followed by continuation of ZDV (+/- IFN-α) as maintenance therapy up to the end of Month 12. ZDV may be administered for a minimum 12 months from the beginning of the study.Primary objectives are to evaluate safety and determine complete molecular response rate after addition of belinostat as consolidation therapy for ATLL during ZDV-based maintenance treatment. Secondary outcomes will include evaluation of clinical response rates, investigation of whether belinostat disrupts HTLV-1 latency load in vivo, investigation of whether belinostat provokes immune or cytotoxic T-cell response in vivo and determine the impact of belinostat/ZDV (+/- IFNα) on HTLV-1 proviral load (measure of HTLV-1 infected reservoirs), in vivo. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma

The Effect of a Histone Deacetylase Inhibitor (AR-42) and Zoledronic Acid on Adult T-Cell Leukemia/Lymphoma Osteolytic Bone Tumors.

Simple SummaryAdult T-cell leukemia (ATL) Leukemia is an aggressive, peripheral blood (T-cell) neoplasm associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Recent studies have implicated dysregulated histone deacetylases in ATL pathogenesis. ATL modulates the bone microenvironment of patients and activates osteoclasts (bone resorbing cells) that cause severe bone loss. The objective of this study was to assess the individual and dual effects of AR-42 (HDACi) and zoledronic acid (Zol) on the growth of ATL cells in vitro and in vivo. AR-42 and Zol reduced the viability of ATL cells in vitro. Additionally, Zol and Zol/AR-42 decreased ATL tumor growth and halted osteolysis in bone tumor xenografts in immunodeficient mice in vivo. Our study suggests that dual targeting of ATL cells (using HDACi) and bone osteoclasts (using bisphosphonates) may be exploited as a valuable approach to reduce bone tumor burden and improve the life quality of ATL patients.Adult T-cell leukemia/lymphoma (ATL) is an intractable disease affecting nearly 4% of Human T-cell Leukemia Virus Type 1 (HTLV-1) carriers. Acute ATL has a unique interaction with bone characterized by aggressive bone invasion, osteolytic metastasis, and hypercalcemia. We hypothesized that dual tumor and bone-targeted therapies would decrease tumor burden in bone, the incidence of metastasis, and ATL-associated osteolysis. Our goal was to evaluate dual targeting of both ATL bone tumors and the bone microenvironment using an anti-tumor HDACi (AR-42) and an osteoclast inhibitor (zoledronic acid, Zol), alone and in combination. Our results showed that AR-42, Zol, and AR-42/Zol significantly decreased the viability of multiple ATL cancer cell lines in vitro. Zol and AR-42/Zol decreased tumor growth in vivo. Zol ± AR-42 significantly decreased ATL-associated bone resorption and promoted new bone formation. AR-42-treated ATL cells had increased mRNA levels of PTHrP, ENPP2 (autotaxin) and MIP-1α, and TAX viral gene expression. AR-42 alone had no significant effect on tumor growth or osteolysis in mice. These findings indicate that Zol adjuvant therapy has the potential to reduce growth of ATL in bone and its associated osteolysis.

Adult T-Cell Leukemia/Lymphoma: Clinical Characteristics and Outcome of Aggressive Subtypes Treated at a Tertiary Cancer Center

Introduction:Adult T-cell leukemia/lymphoma (ATLL) is a disease that develops in a small proportion of individuals who are chronically infected with human T-cell lymphotropic virus type 1 (HTLV-1). Infection is endemic in some parts of the world, Brazil included1.According to the Shimoyama classification, there are four ATLL subtypes: (1) acute, (2) lymphomatous, (3) chronic, and (4) smoldering2. The acute and lymphomatous subtypes are grouped together as aggressive subtypes and often appear with hypercalcemia, cutaneous lesions and visceral dysfunctions.To define a first line treatment for aggressive ATLL is challenging, as the disease is often refractory even to intensive chemotherapy. According to a meta-analysis, patients with the acute subtype should receive antiviral therapy with zidovudine (AZT) and interferon-alfa (INF) and patients with the lymphomatous subtype should receive chemotherapy, both followed by allogeneic stem cell transplantation (ASCT) when feasible3.The aim of this study is to describe the clinical and laboratory characteristics, as well as outcomes of patients with aggressive ATLL treated at a single center in Rio de Janeiro, Brazil.Methods: This is a retrospective study. All patients diagnosed with acute or lymphomatous ATLL (according to the Shymoiama classification) between January 2011 and January 2017 have been evaluated. Diagnosis criteria included positive serology for HTLV-1 and histologically or cytologically proven T-cell malignancy. All patients were treated and followed-up in the Hematology Department of Instituto Nacional de Cancer in Rio de Janeiro, Brazil.Statistical analyses were performed using SPSS software, version 21 (SPPS Inc., Chicago, IL, USA).Results: A total of 28 patients with aggressive ATLL were analyzed: patient characteristics are summarized in Table 1.Most patients (57%) were treated initially with chemotherapy (CT), usually CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) with 21-days intervals between cycles. Remaining patients were treated with antiviral therapy (AZT/INF). Treatment was considered adequate for the clinical subtype in 23 patients (82%). All patients received monthly intratechal chemotherapy.Complete response was achieved in 5 patients (18%) and partial response in 3 additional patients (11%), with an overall response rate of only 29%. Median survival time was 16.7 months (8 and 17 months for acute and lymphoma types, respectively, not statistically significant). The only factor associated with better survival was at least partial response to first line treatment (Fig 1). The main cause of death was progression of the primary disease.Only three patients (10%) were submitted to ASCT (two related and one unrelated). Two are alive one year after transplantation without evidence of the disease. The other patient died a few months after the transplantation of progressive disease.Discussion: Treatment of aggressive ATLL is challenging, as patients often appear with a heavy tumor burden and a disease refractory to primary treatment or quickly relapse after remission. A large recent Japanese study including 344 patients with aggressive ATLL showed survival times of 8.3 and 10.6 months for the acute and lymphomatous subtypes, respectivelly4. Despite the limitations of our study, including its retrospective nature and the small sample, our resultsprovide relevant information from cases of an endemic area with limited number of studies. At least a partial response to first line treatment is necessary for long term survival.Conclusion:Treatment of aggressive ATLL are ineffective and limited. The challenge is to develop therapeutic approaches with higher response rates and to increase the number of patients undergoing ASCT.References1 - Proietti FA, Carneiro-Proietti ABF, Catalan-Soares BC, et al. Global epidemiology of HTLV-1 infection and associated diseases. Oncogene 2005;24:6058-682 - Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma. Br J Haematol 1991;79:428-373 - Bazerbachi A, Plumelle Y, Ramos JC, et al. Meta-analysis on the use of zidovudine and interferon-alpha in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol 2010;28:4177-834 - Katsuya H, Ishitsuka K, Utsunomiya A, et al. Treatment and survival among 1594 patients with ATL. Blood 2015;126:2570-2577. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Histone Deacetylase Inhibitors Abolish HBZ Protein Expression and Induce Cell Death in HTLV-1 Related Adult T-Cell Leukemia-Lymphoma

Background:Adult T-cell leukemia-lymphoma (ATL) is a malignancy with dismal prognosis caused by HTLV-1. ATL is incurable by conventional drugs. Histone deacetylase (HDAC) inhibitors (HDIs) are broadly active anti-neoplastic agents that can be cautiously exploited in the treatment of viral related lymphomas. HTLV-1 usually establishes lifelong latency in human CD4+ T-cells, which in turn propagate and persist as result of the multifaceted functions of HTLV-1 basic zipper factor (HBZ) through various signaling pathways that promote growth and proliferation, and block apoptosis and cell senescence. All ATL cells harbor at least one copy of latent intact HTLV-1 provirus in most cases, and unlike Tax, all tumors express HBZ from the negative 3‘ proviral strand via SP-1 activity. The HTLV-1 promoter is negatively regulated by HDACs at the 5‘ long terminal repeat (LTR), and by HBZ, which disrupts Tax positive interaction with the transcriptional activator p300/CBP, thus blocking viral transcription. Therefore, treatment of HTLV-1 infected cells with HDIs can induce expression of Tax protein, which is highly immunogenic, and which could promote immune-mediated clearance of ATL cells in vivo.Methods:Low-passage IL-2 dependent ATL cell lines established from patients with acute type ATL and freshly isolated ATL cells were treated with several HDIs (VPA, sodium butyrate, vorinostat, belinostat, panabinostat, and mocetinostat) at various doses and time points. Apoptosis was measured by annexin V and FACS analysis. Expression of HBZ protein, Tax, acetyl and total histone 3 subunits (H3), BIM, caspase 3, caspase 9, Jun B, c-Jun, Jun D, and Sp-1 were measured by Western blots before and after HDI treatment. HBZ and Tax mRNA expression was measured by quantitative RT-PCR. SP-1 binding to HTLV-1 specific oligonucleotide consensus sequence was measured by gel shift assay using nuclear protein extracts before and after HDI treatment.Results:HDIs sequentially increased acetylated H3 levels, blocked HBZ protein, upregulated Tax expression, stabilized BIM, and induced cleavage of pro-caspases 9 and 3 (intrinsic apoptotic pathway), resulting in apoptosis of ATL cells. HDIs tested (VPA and belinostat) blocked expression of Jun-B, which is known to be upregulated by HBZ, while no significant effects were observed on c-Jun and Jun D protein levels. HDIs tested (VPA, belinostat, and panabinostat) did not significantly alter spliced-HBZ RNA levels or affect SP-1 binding to HBZ promoter-specific oligonucleotide sequence, suggesting a post-translational mechanism may contribute to abrogation of HBZ in ATL cells.Conclusions:Our data demonstrate that HDIs target ATL cells in part by abrogating HBZ protein, which could negatively impact the longevity of ATL and HTLV-1 cells in vivo. Long-term clinical use of HDIs might be beneficial for eliminating residual ATL cells after definitive treatment. A pilot clinical trial testing belinostat-based consolidation therapy for aggressive leukemic ATL types is currently ongoing at our institution (available at Clinicaltrials.gov , NCT02737046). DisclosuresNo relevant conflicts of interest to declare.

Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases

BackgroundHuman T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation.MethodsHere, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples.ResultsWe found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation.ConclusionsThese results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

Diagnosis and management of adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1). Between 3% and 5% of HTLV-1-infected individuals develop ATL after a long latency. Confirmation of seropositivity of anti-HTLV-1 antibody, and clonal proliferation of CD4 and CD25 positive lymphocytes with nuclear pleomorphism in patients suspicious of malignant lymphoma or chronic lymphocytic leukemia is crucial for the diagnosis of ATL. The clinical course of ATL is very heterogeneous, and divided into acute, lymphoma, chronic, and smoldering types. The chronic type is further subclassified into the favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL, and favorable chronic and smoldering type ATL are defined as aggressive and indolent ATL, respectively. Recently identified prognostic indices based on clinical parameters and/or genetic predictors of outcomes need to be confirmed and incorporated for more stratified therapeutic interventions. The standard of care for aggressive ATL is multiagent chemotherapy followed by allogeneic hematopoietic stem cell transplantation if possible, while that for indolent ATL is watchful waiting until progression to aggressive ATL. The combination of interferon-α and zidovudine is also standard for leukemic type ATL. In addition, mogamulizumab, lenalidomide, and brentuximab vedotin have been incorporated into clinical practices in Japan. Furthermore, several novel drugs are currently undergoing clinical trials.

Development of future treatment for ATL

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I. The clinical course of ATL is heterogeneous, and this condition has different types, which are as follows: acute, lymphoma, chronic, and smoldering. The chronic type is further subclassified into favorable and unfavorable subtypes. Acute, lymphoma, and unfavorable chronic type ATL and favorable chronic and smoldering-type ATL are defined as aggressive and indolent ATL, respectively. Newly identified prognostic indices based on clinical parameters and/or genetic predictors should be incorporated in the stratified treatment approach. The standard of care for aggressive ATL is multiagent chemotherapy, followed by allogeneic hematopoietic stem cell transplantation if applicable. Meanwhile, that for indolent ATL is watchful waiting until progression to the aggressive type. The combination of interferon-α and zidovudine is a treatment option for indolent ATL in other countries, and a confirmatory phase 3 trial is ongoing in Japan. In addition to mogamulizumab, lenalidomide, and brentuximab vedotin, which have been recently utilized in clinical practice, the use of a novel histone deacetylase (HDAC) inhibitor has been filed for approval. Moreover, an EZH1/2 inhibitor has completed the enrollment of a phase 2 trial in Japan. The standard of care for elderly patients should be established because the median age of those with newly diagnosed ATL reaches up to 70 years old.

Adult T‐cell leukemia/lymphoma clinically confused with viral/drug skin eruptions and pathologically misinterpreted as mycosis fungoides/Sézary syndrome

Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder of mature CD4-positive T-cell lymphoid cells associated with retrovirus human T-lymphotropic virus type-1 (HTLV-1) with a wide clinical and pathologic spectrum. We report a case of a 53-year-old African man who presented with fever and skin eruptions on the trunk composed of non-itchy erythematous reticulated macules and papules initially suspected for viral exanthem or drug rash. Skin punch biopsy showed a dermal T-cell lymphoid infiltrate with epidermotropism. The patient developed generalized lymphadenopathy and his peripheral blood showed lymphocytosis with atypical lymphocytes with convoluted nuclei. Our initial diagnosis was mycosis fungoides with Sézary syndrome. However, some clinical and histopathologic features were unusual. The acute onset, lack of previous skin lesions, the histomorphologic features of the dermal, nodal and peripheral blood lymphocytes and the geographic origin of the patient raised the suspicion of other T-cell lymphomas, particularly ATLL. This was confirmed by a positive anti-HTLV-1 serology. Our final diagnosis was acute variant ATLL. Different T-cell lymphomas can involve the skin with overlapping clinical, histomorphologic and immunohistochemical features. Some clinical and pathologic features should alarm dermatologists and pathologists to the possibility of ATLL particularly in patients from HTLV-1 endemic geographic areas.