Clinicopathological significance of CD28 overexpression in adult T-cell leukemia/lymphoma.

CD28, one of the costimulatory molecules, has a pivotal role in T-cell activation, and its expression is strictly regulated in normal T cells. Gain-of-function genetic alterations involving CD28 have been frequently observed in adult T-cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non-overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86-positive non-neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non-overexpressers (P = .001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.

Clinical significance of the immunoglobulin G heavy-chain repertoire in peripheral blood mononuclear cells of adult T-cell leukaemia-lymphoma patients receiving mogamulizumab.

'Monitoring of immune responses following mogamulizumab-containing treatment in patients with adult T-cell leukaemia-lymphoma (ATL)' (MIMOGA) is a multicentre prospective clinical study (UMIN000008696). In the MIMOGA study, we found that a lower percentage of CD2- CD19+ B cells in peripheral blood mononuclear cells (PBMC) was a significant unfavourable prognostic factor for overall survival (OS). Accordingly, we then analysed the immunoglobulin G (IgG) heavy-chain repertoire in PBMC by high-throughput sequencing. Of the 101 patients enrolled in the MIMOGA study, for 81 a sufficient amount of PBMC RNA was available for repertoire sequencing analysis. Peripheral IgG B cells in patients with ATL had a restricted repertoire relative to those in healthy individuals. There was a significant positive correlation between the Shannon-Weaver diversity index (SWDI) for the IgG repertoire and proportions of B cells in the PBMC of the patients. Multivariate analysis identified two variables significantly affecting OS: a higher serum soluble interleukin-2 receptor level, and a lower SWDI for the IgG repertoire [hazard ratio, 2·124; 95% confidence interval, 1·114-4·049; n = 44]. The present study documents the importance of humoral immune responses in patients receiving mogamulizumab-containing treatment. Further investigation of strategies to enhance humoral immune responses in patients with ATL is warranted.

Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma.

Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.

Poor outcome and high prevalence of invasive fungal infections in patients with adult T-cell leukemia/lymphoma exposed to zidovudine and interferon alfa.

Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.

Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.

Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.

3D genome alterations associated with dysregulated HOXA13 expression in high-risk T-lineage acute lymphoblastic leukemia.

3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.

Karyotypic complexity, TP53 pathogenic variants, and increased number of variants on Next-Generation Sequencing are associated with disease progression in a North American Adult T-Cell Leukemia/Lymphoma cohort.

INTRODUCTION: Adult T-Cell Leukemia/Lymphoma (ATLL) is an aggressive T-cell malignancy without known characteristic cytogenetic abnormalities. Recurrent mutations in TP53, APC, and epigenetic and histone-modifying genes have been identified in North American ATLL. Their roles in disease progression are not yet fully elucidated. METHODS: We studied the cytogenetic and Next-Generation Sequencing (NGS) findings of the North American ATLL cohort at our institution and compared the findings with Japanese and other North American cohorts. We also analyzed the genetic variants in TP53, APC, and histone-modifying genes and investigated the impact of their mutations on the number of mutations via NGS in ATLL. RESULTS: Cases with more than 6 chromosomal breaks (n = 13) had significantly shorter overall survival compared to cases with fewer chromosomal breaks (n = 7) (P = .0007). Cases with breaks on chromosome 3q (n = 4) exhibited worse survival compared to the rest of the cases (n = 16) (P = .012). Chromosomal abnormalities on 3q, 14q, 1q, 1p, and 17q are likely primary changes in ATLL based on frequency and association with prognosis. The average number of mutations via NGS was significantly higher in cases with mutations in TP53 (n = 8) (P = .020) as well as APC (n = 6) (P = .024) compared to cases without mutations in these genes. All TP53 variants were pathogenic missense and truncating mutations in COSMIC database. CONCLUSION: Cytogenetic and NGS methods are useful tools to monitor disease progression in indolent ATLL and assess prognosis in aggressive ATLL.

Cord blood transplantation with a reduced-intensity conditioning regimen using fludarabine and melphalan for adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma with a poor prognosis when treated with chemotherapy alone; therefore, allogeneic stem cell transplantation is a consideration. We attempted cord blood transplantation (CBT) using a reduced-intensity conditioning regimen without total body irradiation (non-TBI-RIC) to allow for the best possible timing of transplantation and improve survival outcomes, particularly in older patients. Forty-eight patients (27 male, 21 female) underwent CBT using fludarabine (Flu) 125 mg/m2 and melphalan (Mel) 140 mg/m2 as pre-transplant conditioning. The median age was 32 years (range 44-72), and 21 patients were in complete remission (CR) at the time of CBT. The median duration to neutrophil engraftment (NE) was 19.5 days (range 15-50), with a cumulative incidence of NE of 86.7% at day 50 after CBT. The 1- and 3-year overall survival (OS) rates were 40.4% and 37.7%, respectively. The 3-year OS rate in CR patients was 60.8%, compared with 18.8% in non-CR patients. In ATLL patients, CBT with non-TBI-RIC using Flu/Mel is a promising treatment strategy.

Genetic profile of adult T-cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV-1 strains.

Genetic alterations in adult T-cell leukemia/lymphoma (ATLL), a T-cell malignancy associated with HTLV-1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next-generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV-1 tax subgroup-A (HTLV-1-taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV-1-taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF-ĸB (eg, PRKCB, PLCG1, and CARD11) and T-cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome-associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV-1-taxB, HTLV-1-taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.

Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T-cell leukemia/lymphoma.

OBJECTIVE AND METHOD: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. RESULT: As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI < 75%, n = 79) (P < .0001), with MSTs of 4.69 and 0.75 years, respectively. The occurrence of organ dysfunction and infectious complications was comparable between the two ARDI groups. CONCLUSION: Higher ARDI improves prognosis in patients with aggressive ATL in clinical practice.

Increased incidence of adult T cell leukemia-lymphoma and peripheral T cell lymphoma-not otherwise specified with limited improvement in overall survival: a retrospective analysis using data from the population-based Osaka Cancer Registry.

Peripheral T cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin lymphomas with poor outcomes. Adult T cell leukemia-lymphoma (ATL) and PTCL-not otherwise specified (PTCL-NOS)-are 2 common mature T cell lymphomas in Japan. Since it is unclear whether novel agents and treatment strategies incorporating hematopoietic cell transplantation have contributed to improved clinical outcomes in the real world, we performed a retrospective analysis using data from the population-based Osaka Cancer Registry. From 1977 to 2014, 1274 and 1143 patients were diagnosed with ATL or PTCL-NOS, respectively. Recently, the incidence of both diseases has gradually increased, and the age at diagnosis has risen. The 3-year overall survival (OS) rates in ATL patients were 12.0% in era 1 (1977-1999), 12.4% in era 2 (2000-2008), and 17.5% in era 3 (2009-2014) (P < 0.001). The 3-year OS rates in PTCL-NOS patients were 27.6% in era 1, 36.2% in era 2, and 35.0% in era 3 (P = 0.049). In conclusion, the incidences of ATL and PTCL-NOS have been increasing, particularly in elderly individuals. Clinical outcomes have improved in recent decades but are still unsatisfactory in both diseases. Thus, effective new treatment strategies incorporating novel agents are needed to further improve clinical outcomes in patients with ATL and PTCL-NOS.

Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.

Mogamulizumab Plus EPOCH Therapy for Patients With Newly Diagnosed Aggressive Adult T-cell Leukemia/lymphoma.

BACKGROUND/AIM: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy. PATIENTS AND METHODS: We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone. RESULTS: A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15. CONCLUSION: The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.

TACC3 expression as a prognostic factor in aggressive types of adult T-cell leukemia/lymphoma patients.

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a malignant peripheral T-cell neoplasm associated with human T-cell leukemia virus type-1 (HTLV-1). The acute and lymphoma subtypes are regarded as aggressive ATLLs, and the overall survival (OS) of patients remains poor. Transforming acidic coiled-coil-containing protein 3 (TACC3) regulates microtubules, which are associated with cancer-related proteins overexpressed in various cancers. Such a relationship has not been reported in hematopoietic tumors, including ATLL. METHODS: We examined tissue microarrays of histological samples from 92 cases of aggressive ATLL and assessed clinical features, including TACC3 protein expression levels. RESULTS: Compared with TACC3-low, TACC3-high ATLL patients were significantly older (P < .001), with a tendency toward pleomorphic variant over other morphological classifications (P = .019). TACC3-high patients (median survival time [MST] 10.6 months, confidence interval [CI] [6.27-15.6]) had poorer OS compared to TACC3-low patients (MST 20 months, CI [9.43-38.5]) (P = .0168). Moreover, multivariate analysis on TACC3 expression levels suggests that TACC3-high is an independent significant prognostic factor (HR, 1.700; 95% CI, 1.037-2.753; P = .0355). CONCLUSION: Certain drugs that inhibit TACC3-overexpressing neoplastic cells are used clinically. Further studies might highlight a key role for TACC3 in the oncogenesis and progression of ATLL.

Event-free survival at 24 months is a robust surrogate endpoint for long-term survival in pediatric, adolescent, and adult T cell lymphoblastic lymphoma.

T cell lymphoblastic lymphoma (T-LBL) has an aggressive clinical behavior. To date, powerful and consistent prognostic factors have not been established for T-LBL. In this study, we first evaluated the association of event-free survival (EFS) at 24 months (EFS24) with overall survival (OS) in T-LBL patients. Besides, we sought to identify clinical factors of prognostic importance in this rare entity. Between January 2006 and December 2017, ninety-one patients with newly diagnosed T-LBL were retrospectively analyzed. EFS was defined as the time from diagnosis to relapse or progression, unplanned retreatment, death from any cause, or to the last follow-up. In total, 91 patients with a median age of 24 years were enrolled. At a median follow-up of 40.4 months (range, 1.4 to 163.3 months), the 5-year OS and EFS was 47.9% and 43.2%, respectively. Of all patients, 45 (49.5%) achieved EFS24 and 46 (50.5%) did not. Patients who achieved EFS24 showed a markedly superior outcome, compared with those who failed to achieve EFS24 (5-year OS, 90.5% vs 3%, P < 0.001). Univariate analysis indicated bone marrow involvement, response to induction treatment, and stem cell transplantation (SCT) consolidation to be prognostic factors for EFS and OS. In addition, compared with the patients receiving non-Hodgkin's lymphoma (NHL)-like treatment protocols, patients treated with hyper-CVAD showed significantly improved EFS and OS. Such survival advantage in terms of EFS and OS was also observed of BMF-90 regimens over NHL-like therapy, despite that the difference in EFS did not reach statistical significance (P = 0.056). Multivariate analysis demonstrated that achievement of complete remission (CR) after induction therapy and SCT consolidation were independent prognostic indicators for both EFS and OS. We confirm that EFS24 is a strong surrogate endpoint for long-term survival in T-LBL, which is clinically useful for individualized risk reassessment, future clinical trial design, and biomarker discovery validation. Further validation in the context of directed prospective clinical trials is warranted.

Clinical and cytopathological characteristics of HTLV-1+ hodgkin lymphoma.

BACKGROUND: Human T-lymphotropic virus-1 (HTLV-1)+ Hodgkin lymphoma (HL) is difficult to differentiate from adult T-cell leukemia/lymphoma (ATLL) with HL-like histology (HL-like ATLL). METHODS: Cytological and immunohistological features, HTLV-1 proviral DNA integration, and rearrangements of the T-cell receptor (TCR) Cß1 gene were examined in 11 HTLV-1+ patients with HL-like disease. RESULTS: Six patients were classified as HTLV-1+ HL and five as HL-like ATLL in accordance with genetic findings of HTLV-1 proviral DNA integration and rearrangements of the TCR Cß1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV-1+ HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL-like ATLL specimens, small- and medium-sized atypical lymphocytes with indented and irregular-shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30+ and CD15+ Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein-Barr virus infection. The 50% overall survival period was significantly longer for the HTLV-1+ HL group (180 months) than for the HL-like ATLL group (7.8 months; P = .004). CONCLUSIONS: HTLV-1+ HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25+ and CCR4+ lymphocytes. In HTLV-1 endemic areas, distinguishing HTLV-1+ HL from HL-like ATLL is important because of their differing treatment strategies and prognoses.

Clinical efficacy of mogamulizumab for relapsed/refractory aggressive adult T-cell leukemia/lymphoma: A retrospective analysis.

OBJECTIVES: Although phase 2 studies have confirmed the efficacy of mogamulizumab for adult T-cell leukemia/lymphoma (ATL), real-world data on its benefits are limited. We assessed the benefits of mogamulizumab for relapsed/refractory ATL in clinical practice. METHODS: We retrospectively analyzed patients with acute- and lymphoma-type ATL. Among 57 patients diagnosed with ATL between January 2008 and August 2018, 42 who received salvage therapy were eligible, including 24 who received mogamulizumab. RESULTS: The overall response rate to mogamulizumab was 54.2%. Median survival time (MST) and 1-year overall survival (OS) rate from mogamulizumab initiation were 7.7 months and 42.0%, respectively. Patients with acute-type ATL showed longer MST (15.1 months) and higher 1-year OS (63.6%). MST without skin rash was 5.0 months, and 1-year OS was 34.3%; however, MST with skin rash was not reached and 1-year OS was 66.7%. Among patients who received the salvage therapy, longer MST and higher 1-year OS were observed with mogamulizumab than without mogamulizumab (P = .078; 9.2 vs. 3.9 months; 47.9% vs. 17.6%, respectively). Mogamulizumab administration improved prognosis in patients with acute-type ATL and skin rash. CONCLUSIONS: In clinical practice, mogamulizumab improved OS in patients with relapsed/refractory ATL, especially those with acute-type ATL and skin rash.

Efficacy and Safety of the Modified EPOCH Regimen (Etoposide, Vincristine, Doxorubicin, Carboplatin, and Prednisolone) for Adult T-cell Leukemia/Lymphoma: A Multicenter Retrospective Study.

BACKGROUND: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. PATIENTS AND METHODS: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m2/day), doxorubicin (10 mg/m2/day), and vincristine (0.4 mg/m2/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m2/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. RESULTS: In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation. CONCLUSION: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.

Comprehensive immunohistochemical analysis of immune checkpoint molecules in adult T cell leukemia/lymphoma.

Acute or lymphomatous type adult T cell leukemia/lymphoma (ATLL) is an aggressive hematopoietic malignancy with poor prognosis. We previously reported that programmed cell death ligand 1 (PD-L1) expression could predict ATLL outcomes. However, the roles of other immune checkpoint molecules remain largely unknown in ATLL. Our aim in this study was to explore the clinicopathological impacts of immune checkpoint molecules in ATLL. Immunohistochemistry was performed in 69 ATLL patients with antibodies against the following: PD-L1, programmed cell death ligand 2 (PD-L2), OX40, OX40 ligand (OX40L), CD137, CD137 ligand (CD137L), Galectin-9, T cell immunoglobulin mucin-3 (Tim-3), cytotoxic T lymphocyte associated protein-4 (CTLA-4), lymphocyte activating-3 (LAG-3), CD80, CD86, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), GITR ligand (GITRL), and programmed death-1 (PD-1). Immune checkpoint molecules were variably expressed on neoplastic and/or microenvironmental cells. Expression of PD-1, OX40L, Galectin-9, and PD-L1 was nearly mutually exclusive on neoplastic cells, suggesting that immune checkpoint pathways differ in patients. Microenvironmental expression of PD-L1, OX40L, and Tim-3 was significantly associated with better overall survival (log-rank test; P =0.0004, 0.0394, and 0.0279, respectively). Univariate and multivariate analyses with clinical prognostic factors identified microenvironmental expression of PD-L1 and OX40L, and age (> 70 years) as significant prognostic factors. This is the first comprehensive analysis of ATLL immune checkpoint molecules. Our results may provide information on new therapeutic strategies in ATLL.