Adult T-cell Leukemia Research Articles

Anti-tumor activity of 5-aminoimidazole-4-carboxamide riboside with AMPK-independent cell death in human adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell leukemia/lymphoma caused by human T-cell lymphotropic virus type I (HTLV-1). Acadesine or 5-aminoimidazole-4-carboxamide riboside (AICAR) is an AMP-activated protein kinase (AMPK) activator that was recently shown to have tumor suppressive effects on B cell chronic lymphocytic leukemia, but not ATL. This study evaluated the cytotoxic effects of AICAR on ATL-related cell lines and its anti-tumor activity. Here, we demonstrated that AICAR induced cell death via apoptosis and the mitochondrial membrane depolarization of ATL-related cell lines (S1T, MT-1, and MT-2) but not non-HTLV-1-infected Jurkat cells. However, AICAR did not increase the phosphorylation levels of AMPKα. In addition, AICAR increased the expression of the death receptors (DR) DR4 and DR5, and necroptosis-related proteins including phosphorylated receptor-interacting protein family members and the mixed lineage kinase domain-like protein. Interestingly, HTLV-1 Tax, an HTLV-1-encoded oncogenic factor, did not affect AICAR-induced apoptosis. Furthermore, AICAR inhibited the growth of human ATL tumor xenografts in NOD/SCID/gamma mice in vivo. Together, these results suggest that AICAR induces AMPK-independent cell death in ATL-related cell lines and has anti-tumor activity, indicating that it might be a therapeutic agent for ATL.

Anti-HTLV-1 immunity combined with proviral load as predictive biomarkers for adult T-cell leukemia-lymphoma.

Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV-1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV-1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV-1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV-1-infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti-Gag proteins to predict high risk group in HTLV-1 carriers. Consistent with this finding, anti-Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti-Gag CTLs for disease control. Our findings suggest that our strategy that combines anti-HTLV-1 antibodies and proviral load may be useful for prediction of the development of HTLV-1-associated diseases.

Abstract 17431: A Rare Cause of Constrictive Pericarditis in a Case of Adult T-cell Lymphoma

Introduction: Adult T-cell lymphoma (ATCL) is a rare T cell lymphoproliferative malignancy that typically presents with lymphadenopathy, hepatosplenomegaly, lytic lesions, hypercalcemia or skin lesions. Cardiac involvement is rare. Case presentation: A 66-year-old male with a history of chronic kidney disease and hypertension presented with dyspnea. Transthoracic echocardiography revealed a moderate pericardial effusion and a left ventricular ejection fraction of 45%. Further workup with MRI and transesophageal echocardiography found extensive circumferential pericardial thickening with enhancement and extensive mediastinal and hilar lymphadenopathy along with a mass along the course of the superior vena cava with extension of disease into the right atrium along the right atrial wall (Figure 1). Endobronchial biopsy of the mediastinal lymph nodes was positive for T-cell lymphoma. Chemotherapy was initiated; however, the patient decided to focus on comfort measures only. Discussion: Cardiac involvement in ATCL is rare and usually detected in postmortem autopsies. Incidence is unknown, and experience is limited to case reports. The largest case series to date found 16 patients who had antemortem diagnosis of symptomatic cardiac involvement of ATCL. The characteristic features included infiltration of the myocardium, pericardial effusion, valvular lesions, and masses in the atrium, similar to what was seen in our patient. To our knowledge, there have been no reported cases of ATCL causing constriction. Prognosis is poor, with median survival of 5 months after development of symptoms (n = 15, range 0-120 months). Conclusion: The incidence of cardiac ATCL is unknown, but it is an extremely rare occurrence. It can present with a wide variety of cardiac involvement, including constriction. The prognosis of cardiac ATCL remains poor.

Clinical Course of Adult T-Cell Leukemia-Lymphoma with Central Nervous System Involvement

Background: Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell lymphoma with a highly diverse clinical presentation. Although central nervous system (CNS) involvement is common, the detailed clinical presentation of CNS-ATL needs to be clarified. Objective: This study aims to clarify the clinical course of ATL with CNS involvement. CNS involvement was classified according to the criteria of JALSG202 for acute lymphocytic leukemia as follows: Grade I: no symptoms and cerebrospinal fluid (CSF)cell count less than 5/μl and presence of abnormal lymphocytes; Grade II: asymptomatic and CSF cell count 5-50/μl and presence of abnormal lymphocytes; Grade III: symptomatic or CSF cell counts > 50 cells/μl and presence of abnormal lymphocytes. Results: The analysis included 213 cases of ATL treated at Kagoshima University Hospital from 2002 to 2021. Of these aggressive ATL cases, the clinical subtypes at initial presentation were as follows: acute type 109, lymphoma type 54, chronic type 30, smoldering type 18, and 2 cases were unclassifiable. The median age of the patients was 63 years, and 96 cases (45.1%) were women. Sixty patients had received allogeneic hematopoietic stem cell transplants. During the clinical course, 28 patients (13.1%) with a median age of 61 years and 13 women（46.4%）had CNS involvement. Two cases were classified as Grade I, six as Grade II, and 20 as Grade III. Among them, nine patients (4.2%) showed neurological symptoms at the initial ATL diagnosis, and 1 patient presented with neurological findings at the time of chronic to acute transformation. Of the remaining 203 patients, prophylactic intrathecal chemotherapy was administered in 101 cases, at which time CNS involvement was diagnosed in 9 cases (8.9%). Three patients developed symptomatic involvement while responding to chemotherapy. One patient developed symptomatic involvement when refractory to chemotherapy. Four cases were CNS recurrence with systemic disease progression after remission. Two cases were identified as primary CNS-ATL. The simplified ATL-PI (Prognostic Index) at initial ATL diagnosis for the 28 patients with CNS involvement revealed four cases with high-risk, thirteen with intermediate-risk, two with low-risk, six not eligible due to indolent ATL subtypes, and three cases with unknown risk. The incidence of CNS involvement by ATL subtype was 17.8% (19/107) for acute type, 1.8% (1/54) for lymphoma type, 16.7% (5/30) for chronic type, and 0% for smoldering type (excluding 1 case of unknown subtype and 2 cases of primary CNS-ATL) at ATL diagnosis. At the diagnosis of CNS involvement, 15 (53.6％) patients showed at least 5% of ATL cells in the peripheral blood. During a median observation period of 429 days, the 1-year cumulative incidence of CNS involvement was 12.3% (95% CI 8.3-17.1%). High-dose methotrexate-based therapy was administered to 5 patients with CNS involvement, which had a certain effect on CNS lesions but had limited efficacy for other lesions. All of these cases were treated with concomitant intrathecal chemotherapy. The 2-year overall survival rate after diagnosis of CNS involvement was 16.9% (95% CI 4.9-35.2%). The CNS-IPI (International Prognostic Index) did not predict CNS involvement in ATL. Conclusions: This is the largest study to examine the clinical course of CNS involvement of ATL. The 1-year cumulative incidence of CNS involvement was 12.3%, indicating that CNS involvement is an early complication after diagnosis of aggressive ATL, especially in leukemic subtypes. The prognosis after the diagnosis of CNS involvement was also clarified. The high frequency of CNS involvement during prophylactic intrathecal chemotherapy in patients with ATL without neurological symptoms suggests that it is an important clinical question that needs to be addressed.

Extracellular CD30 and ADAM10/17 Regulate Brentuximab Vedotin-Induced Cell Death in an Adult T-Cell Leukemia Cell Line

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus 1 (HTLV-1)-induced malignancy of mature T lymphocytes with poor outcomes. Brentuximab vedotin (BV), which is an anti-CD30 antibody conjugated with monomethyl auristatin E, is included in the treatment of CD30-positive ATL, but there is no useful therapeutic marker for BV. Soluble CD30 (sCD30) in serum is increased in aggressive-type ATL at diagnosis, but the effects of extracellular CD30 on BV-induced cell death in ATL remain unclear. Similarly, a disintegrin and metalloproteinase (ADAM) 10 and 17 have CD30 sheddase activity in anaplastic large cell lymphoma, but this activity is unknown in ATL. The present study showed that sCD30 concentrations were related to BV activity in ATL-related cell lines. Extracellular vesicles (EVs) such as exosomes containing CD30 also inhibited BV activity. Additionally, the knockdown of ADAM10/17 significantly reduced sCD30 concentrations with increased cell death by BV. Our results suggest that ADAM10/17 are involved in sCD30 production in ATL. Moreover, endogenous extracellular CD30, such as sCD30 shed by ADAM10/17, and CD30-positive EVs may be responsible for the BV-induced cell death. Correctively, extracellular CD30 concentrations, including EV, may be useful as biomarkers for BV therapy in ATL.

Clinical Outcomes of Tucidinostat Therapy for Relapsed/Refractory Adult T-Cell Leukemia-Lymphoma (ATL) in Clinical Practice

【Objective】 Tucidinostat, approved for relapsed/refractory adult T-cell leukemia-lymphoma (ATL) treatment in June 2021 in Japan, demonstrated an objective response rate (ORR) of 30.4%, progression-free survival (PFS) of 1.7 months (95% CI: 0.8-7.4), and overall survival (OS) of 7.9 months (95% CI: 2.3-18.0) in a phase IIb trial for 23 cases of relapsed/refractory adult T-cell leukemia-lymphoma (ATL) in Japan. We report the treatment results of this agent in Miyazaki Prefecture. 【Methods】 We retrospectively analyzed the treatment results of relapsed/refractory ATL patients who received Tucidinostat at 6 facilities within the Miyazaki prefecture, and HTLV-1 endemic area in southwest Japan, after its approval. All clinical procedures for patients were part of routine care, and the requirement for written patient consent was waived by the committee in view of the retrospective nature of this study. Approved study protocols were presented on the web site in an opt-out format, ensuring patients had the right to refuse participation in the study. In accordance with these protocols, clinical information was then collected. 【Results】 From October 2021 to July 2023, Tucidinostat was administered to 24 cases of relapsed/refractory ATL. The median age at the start of administration was 72.5 (41-85), with 13 cases of the acute type, 7 cases of the lymphoma type, and 4 cases of poor-prognosis chronic type. The median number of prior treatment regimens was 2 (1-4), with 19 cases of multi-drug combination chemotherapy, 18 cases of mogamulizumab, and 5 cases of oral chemotherapy. There were no cases of transplantation. The period from prior treatment to Tucidinostat administration was 3.2 months (0-27.5 months), and the disease stage at the start of Tucidinostat administration was relapse in 7 cases and refractory in 17 cases. The starting dose was 40mg/day (twice a week) in 19 cases and 20mg/day (twice a week) in 4 cases, with a median number of total treatment courses of 3 (1-20). Of the 24 cases,19 had their dose reduced or treatment suspended because of myelosuppression. The best treatment response was complete response(CR) in 5 cases, parcial response (PR) in 8 cases, Stable Disease(SD) in 8 cases, with an efficacy rate (CR/PR) of 54.2%. The PFS after the start of treatment was 3.7 months (1.8-7.8), and the OS after the start of treatment was 8.6 months. The reason for discontinuation of administration were progression disease in 15 cases, intolerance in 1 case (skin rash in 1 case), and severe complications in 1 case (cryptococcal meningitis). In the Cox proportional hazards model analysis, considering the clinical characteristics at the initiation of Tucidinostat, the initial sIL-2R level negatively impacted PFS. PFS was then stratified using an sIL-2R cutoff of 5000 U/mL, showing a Median Survival Time (MST) of PFS: 0.65 months for those below the cutoff versus 0.15 months for those above it, p=0.006 (log-rank).“A similar trend was observed for OS (Median OS: not reached vs. 0.53 months, p=0.032 (log-rank)). 【Conclusion】 In relapsed/refractory ATL, Tucidinostat achieved treatment results similar to those in the phase IIb trial in clinical practice. In particular, for cases with an sIL2-R value of less than 5000, it was suggested that Tucidinostat may be a meaningful treatment option.

Examining Adult T-Cell Leukemia/Lymphoma in the United States: A Hospital Based Study of Demographics and Survival Outcomes Focused on Hispanics

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive neoplasm of mature CD4(+) T-cells caused by infection by Human T-lymphotropic virus type1 (HTLV-1) ( Arch Pathol Lab Med PMID: 24476526). ATLL affects 5% of those infected by HTLV-1, mainly in Africa, the Caribbean, Japan, and South America ( Rev Assoc Med Bras (1992) PMID: 27925051). In the United States (US) it is usually seen in immigrants from these regions ( Arch Pathol Lab Med PMID: 24476526). While there are treatment options for ATLL, it is often refractory to conventional chemotherapy and in general has a poor prognosis ( Actas Dermosifiliogr (Engl Ed) PMID: 29685460, Cancer Treat Res PMID: 30596217). Considering its poor outcomes and unique epidemiology, more information is needed regarding its effect in Hispanics (HI) vs Non-hispanics (NH) in the US. METHODS: Data were analyzed on ATLL patients in the US reported to the National Cancer Database (NCDB) between 2004 and 2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare overall survival (OS) between HI and NH populations. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, comorbidity score, and insurance status, type of facility and great circle distance. RESULTS Of the 3073 ATLL patients studied between 2004 and 2019, 9% were HI, and 87% NH. In both groups, most here male with 65% of HI and 66% of NH. At diagnosis, HI patients were younger with a median age of 35 years vs. 42 years in NH (p<0.001). HI patients were more likely to be <65 at diagnosis 89% vs 83% (p=0.044). Most HI and NH patients identified as white (86% vs 68%), followed by black (4% vs 25%). Private insurance was the most common type in both groups (50% vs 57%), followed by government sponsored insurance (33% vs 36%). HI had a higher rate of being uninsured 12% vs 6% (p<0.001). Regarding Census Median Income (2008-2012), the most prevalent bracket for HI was $48,000 - $62,000 (28%), compared to NH $63,000+ (33%). HI were more likely to have an income of less than $38,000 (21% vs 18%) (p=0.512). HI also tended to live closer to their hospital (Great Circle Distance), with a median of 8.0 miles, vs NH at median of 11.6 miles (p=0.001). On survival analysis; the survival probability at 2, 5 and 10 years of HI vs NH were (64% vs 58%), (53% vs 48%), and (51% vs 43%), respectively. The median survival (MS) time was 3.7 years for NH and not reached for HI. The overall survival (OS) difference favoring HI was marginal and non-statistically significant (p=0.067). Independently, on multivariate analysis, NH ethnicity was not associated with worse OS (HR 1.25, CI 0.9-1.74, p=0.18). Interestingly, the propensity matched analysis demonstrated significant MS difference between HI vs NH (median 1.84 vs. 1.53 years). CONCLUSION Although the difference in OS in this study between HI and NH was not significant, there is a trend in the data showing increased survivability among HI despite patients in this group being more likely to be uninsured or in a lower income bracket. One possible explanation is that HI tended to present at an earlier age when compared to NH. It is evident that more data is needed to increase the power of these findings. Therefore, further study into the disease differences between these two groups, early detection, tumor markers, and targeted treatments will be necessary to improve the overall poor prognosis of this aggressive disease.

IPSC-Derived CD4 T Cell Generation and Investigation of CD4/CD8 T Cell Lineage Choice

iPSC-derived functionally rejuvenated antigen-specific cytotoxic T lymphocytes generated from exhausted CTLs show promising antitumor effect towards refractory tumors. Currently, we are preparing for clinical trials using iPSC-derived CTLs for EBV-associated lymphomas. These iPSC-derived T cells (iPSC-Ts) all generated into CD8 T cells, and stable generation of CD4 single positive (SP) T cells from iPSCs has never been accomplished without enforced CD4 gene transduction even though many research groups have challenged to do so. Even when an iPSC is established from a CD4 T cell clone, differentiating this iPSC does not generate into CD4 T cells, but in fact it generates into CD8 T cells. Therefore, we aimed to investigate why iPSC-Ts only differentiate into CD8T cells, and not into CD4T cells. We focused on adult T cell leukemia (ATL), because HTLV-1 infected CD4 T cells clonally expand. We reprogrammed CD4T cells obtained from acute-type ATL patients into iPSCs (ATL-iPSCs), then differentiated them into T cells using our established method. Interestingly, ATL-iPSCs from different donors all successfully differentiated into CD4 SP T cells (ATL-iPSC-Ts). Upon characterization of ATL-iPSC-Ts we confirmed that they showed FOXP3 positive naive regulatory T cell (Treg) phenotype. To investigate the function of these cells, we performed 51Cr-release assay. The cytotoxicity of HTLV-1 Tax-specific CTLs (Tax-CTLs) with or without ATL-iPSC-Ts against primary ATL cells was measured. The percentages of ATL cells lysed by Tax-CTLs was 34 ± 3.2%, whereas by the addition of ATL-iPSC-Ts, the cytotoxicity decreased to 23.4 ± 1.0% revealing the functionally suppressive effect of ATL-iPSC-Ts. In order to further understand the mechanism of CD4/CD8 T cell lineage choice, and discover the key regulators needed for generation of CD4 SP T cells from iPSCs, we performed single cell RNA-sequencing (scRNA-seq) on ATL-iPSC-Ts. As a control we used healthy donor (HD) CD4 SP T cell clone-derived iPSCs (HD-iPSCs), which differentiated into CD8 T cells (HD-iPSC-Ts [CD8 +]). We identified several genes expressed at a significantly higher level on HD-iPSC-Ts (CD8 +) than on ATL-iPSC-Ts (CD4 +). We presumed these genes to be essential for CD8 T cell differentiation. Therefore, we used CRISPR/Cas9 technology to knock out the respective gene in HD-iPSCs and confirmed if these iPSCs could differentiate into CD4 SP T cells, instead of CD8 T cells. This resulted in successful generation of CD4 SP T cells. We confirmed that these CD4 SP T cells were FOXP3 negative and were not Tregs. On the other hand, overexpression of this gene on ATL-iPSCs differentiated into CD8 SP T cells, instead of CD4 T cells. In conclusion, our work represents the first successful generation of natural CD4 SP T cells from iPSCs. The gene we identified appears to be a pivotal regulator of CD4/CD8 T cell lineage choice in our iPSC-T differentiation system. While more investigation is required, our method shows promise towards facilitating stable generation of CD4 T cells for T cell therapy.

Predictors of Outcome for Allogeneic Stem Cell Transplantation with a Reduced Intensity Pentostatin/TBI Conditioning Regimen in T-Cell Lymphomas: A Single Center Experience

Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative option for patients with relapsed/refractory T-cell lymphoma (TCL).A reduced intensity conditioning (RIC) regimen of infusional pentostatin and 6 Gy of total body irradiation (TBI) has been shown to be well-tolerated and to have favorable engraftment kinetics 1. We utilized this regimen for patients with aggressive TCL undergoing alloSCT due to the demonstrated activity of pentostatin as a single agent in TCL and its potential impact, along with TBI, on eradicating residual TCL. Methods: This retrospective review includes adult patients with Nodal TCL (PTCL , AITL, ALCL), rare aggressive TCL [(T-ALL, natural killer/T-cell lymphoma (NKTL), adult T-cell leukemia/lymphoma (ATLL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL)], and T-Prolymphocytic leukemia (TPLL) who underwent alloSCT between 2006 and 2021. The primary objective was to determine transplant related outcomes including grade 3-4 acute graft-versus-host disease (aGVHD), extensive chronic GVHD (cGVHD), relapse, non-relapse mortality (NRM), and overall (OS), relapse-free (RFS), and GVHD-free, relapse-free survival (GRFS) following transplant. A subgroup analysis was conducted to evaluate the impact of disease status at the time of transplant and other factors, including age and subtype of TCL. Results: We report results for 40 patients (Nodal TCL: 21, Rare aggressive TCL: 10, T-PLL: 10) with a median age of 56.6 years ( range 24-71). Seventy-five percent were in clinical CR at the time of transplant. The 1-y cumulative incidence rate (CIN) of aGVHD was 42.5%. The 3-y CIN for cGVHD was 22.9. The median OS was 3.18 years with a 3-y OS rate of 51.9%. The median RFS was 1.24 years, with a 3-year RFS rate of 41.4%. OS and RFS were significantly higher in patients <65 compared to ≥65 (p-value 0.050 and 0.010 respectively), with no difference between the complete response (CR) and non-CR groups or different subtypes of TCL. The median GRFS was 0.52 years, with a 3-year GRFS rate of 20%. There was no statistically significant difference in GRFS or the incidence of GVHD between groups. Renal toxicity was noted in 10 patients. No cases of pulmonary or central nervous system (CNS) toxicities were observed. By day 100, 15 patients had an infection, including 8 bacterial infections and 5 viral infections. A total of 12 patients had reactivation of cytomegalovirus. Twelve patients died within the first year: 4 from relapse, 3 from aGVHD, 3 from infection, 1 from a subdural hematoma after a fall, and 1 from bladder perforation in the setting of hemorrhagic cystitis. Of 13 patients who relapsed, all received salvage therapy and 3 received DLI. Four are alive and in remission. Conclusions: In patients with TCL, RIC for alloSCT was well tolerated and compared favorably with retrospective data from larger groups of patients from CIBMTR and EBMT who were transplanted with different regimens 2. Interestingly, transplant-related outcomes were similar for patients with CR vs partial response (PR) at the time of transplant, and outcomes were better in patients younger than 65. Relapsed patients had a poor outcome despite salvage therapy with only a 30% OS at 3 years. 1. Foss et al, Transfusion 2020 2. Hamadani et al, Blood Advances 2022

Acetyl Transferase EP300 Deficiency Leads to Chronic Replication Stress in Adult T-Cell Leukemia/Lymphoma

Mutations in the epigenetic regulator and global transcriptional activator, E1A binding protein (EP300), is being increasingly reported in aggressive hematological malignancies including adult T-cell leukemia/lymphoma (ATLL). However, the mechanistic contribution of EP300 dysregulation to cancer initiation and progression are currently unknown. Independent inhibition of EP300 in human cells results in the differential expression of genes involved in regulating the cell cycle, DNA replication and DNA damage response. Nevertheless, specific function played by EP300 in DNA replication initiation, progression and replication fork integrity has not been studied. Here, using ATLL cells as a disease model to study EP300 deficiency and an EP300-selective PROTAC degrader, as a pharmacologic tool, we reveal that EP300-mutated cells display prolonged cell cycle kinetics, due to pronounced dysregulations in DNA replication dynamics leading to persistent genomic instability. Aberrant DNA replication in EP300-mutated cells is characterized by elevated replication origin firing due to increased replisome pausing genome-wide. We demonstrate that EP300 deficiency results in nucleolytic degradation of nascently synthesized DNA at stalled forks due to a prominent defect in fork stabilization and protection. This in turn results in the accumulation of single stranded DNA gaps at collapsed replication forks, in EP300-deficient cells. Inhibition of Mre11 nuclease rescues the ssDNA accumulation indicating a dysregulation in downstream mechanisms that restrain nuclease activity at stalled forks. Importantly, we find that the absence of EP300 results in decreased expression of BRCA2 protein expression and a dependency on POLD3-mediated error-prone replication restart mechanisms. The overall S-phase abnormalities observed lead to under-replicated DNA in G2/M that instigates mitotic DNA synthesis. This in turn is associated with mitotic segregation defects characterized by elevated micronuclei formation, transmission of unrepaired inherited DNA lesions in the subsequent G1-phase and accumulation of cytosolic DNA in EP300-deficient cells. However, EP300 deficient cells show a significant defect in innate immune system activation. Altogether these results suggest that mutations in EP300 cause chronic DNA replication stress, persistent genomic instability and innate immune system evasion underlie aggressive chemo-resistant tumorigenesis in humans.

Efficacy and Safety of Valemetostat Monotherapy in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results of the Phase 2 VALENTINE-PTCL01 Study

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin lymphoma (NHL), with limited available treatment options for patients (pts) with relapsed or refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for pts with R/R PTCL treated with valemetostat in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (DS3201-A-U202; NCT04703192). Methods: Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Pts received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review of PTCL following computed tomography (CT)-based response assessment according to Lugano 2014 criteria. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Positron emission tomography (PET)-CT-based response assessment by Lugano 2014 criteria was an exploratory endpoint. Efficacy analyses included all pts who received ≥ 1 dose of valemetostat and had an eligible PTCL subtype confirmed by central hematopathology review; safety analyses included all pts who received ≥ 1 dose of valemetostat. Results: A total of 133 pts with R/R PTCL were enrolled and received ≥ 1 dose of valemetostat. Pts had a median age of 69 years (range 22-85) and 91 pts (68.4%) were male. Pts had received a median of 2 prior lines of therapy (range 1-12) and 35 pts (26.3%) received prior hematopoietic cell transplant (HCT; autologous, n = 32; allogeneic, n = 5). PTCL subtype eligibility was confirmed in 119 pts: 42 pts (31.6%) had angioimmunoblastic T-cell lymphoma (AITL), 41 (30.8%) had PTCL, not otherwise specified (PTCL, NOS), 9 (6.8%) had ALCL (7 [5.3%] ALK-negative and 2 [1.5%] ALK-positive), 8 (6.0%) had nodal PTCL with T follicular helper cell phenotype, and 19 (14.3%) had other PTCL subtypes. As of data cutoff (May 5, 2023), 32 pts (24.1%) were still receiving treatment; reasons for treatment discontinuation included progressive or relapsed disease in 46 pts (34.6%), clinical progression in 19 pts (14.3%), adverse event in 13 pts (9.8%), and 12 pts (9.0%) discontinued study drug to proceed with allogeneic HCT. Median treatment duration was 18 weeks (range 0.3-93.4) and median duration of follow-up was 10.5 months (range 0.2-21.5). Among 119 efficacy-evaluable pts, the CT-based ORR was 43.7% (n = 52) (95% confidence interval [CI], 34.6-53.1), including 17 pts (14.3%) achieving CR and 35 pts (29.4%) achieving PR as best overall response. Median DOR was 11.9 months (95% CI, 7.8-not evaluable [NE]) and median time to response was 8.1 weeks (range 5-37). ORR by PTCL subtype ranged from 31.7% for PTCL, NOS to 54.8% for AITL (Table 1). Using PET-CT-based response assessment, ORR was 52.1% (n = 62) (95% CI, 42.8-61.3), including 32 pts (26.9%) with a complete metabolic response. Median CT-based PFS was 5.5 months (95% CI, 3.5-8.3) and median OS was 17.0 months (95% CI, 13.5-NE). Of 133 pts in the safety analysis set, 128 pts (96.2%) experienced ≥ 1 treatment-emergent adverse event (TEAE) of any grade, 77 pts (57.9%) experienced grade ≥ 3 TEAEs, and 53 pts (39.8%) experienced serious adverse events. The most common all grade and grade ≥ 3 TEAE was thrombocytopenia (Table 2). Overall, 13 pts (9.8%) experienced a TEAE that led to treatment discontinuation, 21 pts (15.8%) had a TEAE that led to dose reduction, and 66 pts (49.6%) had a TEAE that led to dose interruption. Conclusions: Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL.

MO48-5 Progression of disease within 5 months of adult T-cell leukemia-lymphoma (ATL5) as a clinical endpoint for high-risk mortality outcomes

MO48-5 Progression of disease within 5 months of adult T-cell leukemia-lymphoma (ATL5) as a clinical endpoint for high-risk mortality outcomes

A case of acute kidney injury due to native kidney BK polyomavirus-associated nephropathy in a human T-lymphotropic virus type 1 carrier

BackgroundBK polyomavirus-associated nephropathy (BKPyVAN) has become a major cause of kidney dysfunction and graft loss in kidney transplant recipients. On rare occasion, polyomavirus has also been known to affect native kidneys of immunocompromised individuals. Only a small number of opportunistic infections have been reported in the carrier phase of human T-lymphotropic virus type 1 (HTLV-1). This is the first reported case of BKPyVAN in native kidneys of an HTLV-1 carrier.Case presentationA 61-year-old man was referred to our hospital from a primary care physician for work-up and treatment of pneumonia. He was diagnosed with Pneumocystis pneumonia and identified as a HTLV-1 carrier who had not yet developed adult T-cell leukemia (ATL). The pneumonia was successfully treated with sulfamethoxazole-trimethoprim. He had never been diagnosed with any kind of kidney dysfunction. Laboratory investigations showed a serum creatinine of 5.3 mg/dL, and urinary sediment showed cells with nuclear enlargement and inclusion bodies suggesting viral infection. The urinary Papanicolaou stain showed inclusions in swollen, ground-glass nuclei, typical of “decoy cells”. Renal biopsy showed degeneration of tubules with epithelial enlargement, vacuolar degeneration, nuclear inclusion bodies, and detachment from the tubular basement membrane. Tubular nuclei showed positive staining positive for simian virus 40 large-T antigen. Polymerase chain reaction tests for BK polyomavirus DNA of both urine and plasma were positive. These findings confirmed a diagnosis of BKPyVAN. Intravenous immunoglobulin therapy did not improve renal function, necessitating maintenance hemodialysis therapy.ConclusionsBKPyVAN should be considered when acute kidney injury occurs with opportunistic infection. HTLV-1 carriers can develop opportunistic infections even before the onset of ATL.

Seroprevalence of Human T-Cell Lymphotropic Virus-1 in a Jamaican Antenatal Population and Assessment of Pooled Testing as a Cost Reduction Strategy for Implementation of Routine Antenatal Screening.

Mother to child transmission (MTCT) of human T-cell lymphotropic virus (HTLV)-1 is associated with increased risk of adult T-cell leukemia and can be unrecognized without routine antenatal screening. We assessed the seroprevalence of HTLV-1/2 among pregnant women attending The University Hospital of the West Indies Antenatal Clinic, 2019, and validated a cost-effective strategy to screen antenatal clinic attendees for HTLV-1/2. Residual antenatal samples from 370 women were tested for HTLV-1/2 by chemiluminescence microparticle immunoassay (CMIA). Six samples were confirmed HTLV-1 positive by Western blot (none for HTLV-2) for a prevalence of 1.62%. Four mother-child pairs were able to be recruited for HTLV testing of children, with two children testing HTLV-1/2 positive. Medical records of HTLV-1-infected women revealed that all women breastfed, indicating an unrecognized risk for HTLV MTCT. To assess whether pooling of samples as a cost-reduction strategy could be introduced, we pooled all antenatal samples received between November and December 2021 into 12 pools of eight samples/pool. Two pools were CMIA positive, and de-pooling of samples identified two CMIA-positive samples (one per pool), both confirmed as HTLV-1 by Western blot. These results indicate that HTLV-1 remains prevalent in pregnant Jamaican women and that sample pooling can be a cost-effective strategy to limit MTCT in Jamaica.

Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review.

Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5-10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient's immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL.

Poor Outcome of Adult T-Cell Leukemia/Lymphoma with Current Available Therapy: An Experience of Two Centers

Introduction: Adult T-cell leukemia lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection. Despite its poor prognosis, there is no standard therapy for ATLL due to its low incidence and the disease affecting only endemic geographical clusters. Methods: A retrospective evaluation of patients with the diagnosis of ATLL at Moffitt Cancer Center and Memorial Healthcare System was done to identify patients and disease characteristics along with the progression-free survival (PFS) and overall survival (OS) for the different therapies used. Results: The 61 patients analyzed showed a median age of 58 with 82.5% of them being of African American descent. The acute variant contributed to the majority of cases (43.9%), followed by 36.8% presenting as a lymphoma variant. There was no statistical difference in the PFS (6.4 m, 3.1 m, 2.1 m; p = 0.23) or OS (14 m, 8.9 m, 18.5 m; p = 0.14) between cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), intensive chemotherapy regimens, and other modalities, respectively. However, the patients who had complete or partial remission with first-line therapy had better OS (15.9 m vs. 7.2 m; p = 0.004). Conclusions: The study highlighted the poor outcome of the current regimens and the lack of a unifying protocol for this vicious disease. The acute variants were treated with more intensive regimens, but there was no difference in the OS between the three major options of CHOP, intensified chemotherapy, and others. This underscores the need for more clinical trials to develop better outcomes.

Adult T-cell Leukemia/Lymphoma (ATL) in the Nasal and Paranasal Cavity: Four Cases Report.

Adult T-cell leukemia/lymphoma (ATL) is a form of leukemia caused by the human T-cell leukemia virus type I (HTLV-1). Otolaryngologists often diagnose ATL based on cervical lymphadenopathy or Waldeyer ring lesions. However, there are few reports of ATL occurring in the nasal and paranasal cavity. Here, we report four such cases of ATL. Case 1: An 82-year-old man diagnosed with acute-type ATL with a tumor in the nasal cavity underwent 5 courses of THP-COP, but died after 36 months due to ATL. Case 2: A 62-year-old woman diagnosed with lymphoma-type ATL with a tumor in the frontal sinus was treated with 5 courses of VCAP-AMP-VECP, and has survived for more than 10 years. Case 3: A 64-year-old man diagnosed with lymphoma-type ATL with a tumor in the maxillary sinus underwent 8 courses of VCAP-AMP-VECP and 2 courses of mogamulizumab, but died after 34 months due to ATL. Case 4: A 52-year-old woman diagnosed with lymphoma-type ATL with tumors in both ethmoid sinuses received 2 courses of CHOP, 2 courses of DeVIC, radiotherapy (32Gy) and 2 courses of mogamulizumab, but died after 9 months due to ATL.

Clinicopathologic characterization of cutaneous adult T-cell leukemia/lymphoma: A single tertiary care center experience in the United States.

Adult T-cell leukemia/lymphoma (ATLL) is a rare aggressive T-cell leukemia/lymphoma associated with human T lymphotropic virus type 1 infection. The patients might present with skin rash before, at, or after the diagnosis. The dermatopathologic finding might be diagnostically very challenging. We retrospectively identified 110 patients with ATLL at a single institution in a 19-year period, with 19 patients having skin biopsies. Clinical, dermatopathologic, immunophenotypic, and molecular findings were studied. The cohort included 13 skin-first (5 acute, 5 lymphomatous, 2 chronic, 1 smoldering), 6 skin-second (4 acute, 1 lymphomatous, 1 smoldering), and 91 patients without skin biopsy. Some nonphotoprotected areas of body such as the forearm and lower lip were also seen. Skin manifestations included papular (5), erythroderma (1), nodulotumoral (3), plaques (1), patches (1), and a combination of skin rashes (2). Histopathologic findings included large pleomorphic cells, angiocentrism, epidermal infiltration with large Pautrier-like microabscesses, and folliculotropism. Fifteen (78.9%) cases showed CD4+/CD7-/CD25+. Next-generation sequencing study was conducted on 5 patients using either blood or bone marrow samples, revealing multiple genetic mutations across multiple signaling pathways. Pleomorphic large, atypical cells with CD4+/CD25+/CD7- immunophenotype from a non-"bathing trunk" location, especially in a patient from endemic regions, raise suspicion for ATLL. T-cell receptor gene rearrangement is almost always positive, and the neoplasm usually demonstrates multiple mutations by next-generation sequencing study.

SAT258 Successful Treatment Of Adult T-cell Leukemia-lymphoma Induced Hypercalcemia With Denosumab

Abstract Disclosure: S. Yuksel: None. R. Lopez Fanas: None. D. Schwartz: None. V. Tabatabaie: None. S. Sachdev: None. Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive lymphoproliferative disorder associated with human T-cell leukemia virus type 1 (HTLV-1), often presenting with severe refractory hypercalcemia. Here, we present a rare case of bisphosphonate-resistant ATLL-associated hypercalcemia successfully treated with denosumab (Dmab). Clinical Case: A 47-year-old woman from Jamaica presented with pruritic rash of left forearm and bilateral lower extremity (LE) pain for 6 weeks. Laboratory evaluation noted serum Ca of 16.2 mg/dL (n 9-11), PTH 12.5 pg/mL (n 16-65), PTHrP 24 pg/mL (n 11-20) and 25(OH)D 16 ng/mL (n 30-60). 1,25(OH)2D level was normal. Cr was 1.5 mg/dL (n 0.7-1.2). X-rays demonstrated punctate lytic lesions throughout LEs. The patient received IV fluids, calcitonin, pamidronate 60 mg IV, and ergocalciferol 50,000 IU. Corrected Ca (cCa) improved to 9.3 mg/dL. However, hypercalcemia recurred after 2 days. HTLV-1 serology was positive. Flow cytometry and bone marrow biopsy were consistent with ATLL. When Ca rose to 14.3 mg/dL, Dmab 60 mg SC was administered. Within 1 week, she developed asymptomatic hypocalcemia with cCa of 7.1 mg/dL requiring oral calcium citrate and calcitriol. Stable normocalcemia was achieved after 10 days. Hospital course was complicated by pathologic right wrist fracture. Palliative radiation to LE was initiated. She was discharged on calcium citrate 2850 mg TID, calcitriol 0.25 mcg BID and ergocalciferol 50,000 IU weekly. The patient was treated with 6 cycles of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab, as well as intrathecal methotrexate for CNS prophylaxis. She received 120 mg of Dmab 6 months after the first dose. Ca remained stable. Conclusion: ATLL-associated hypercalcemia is mediated by increased secretion of PTHrP, and RANK ligand and proinflammatory cytokines that promote RANK expression. Dmab is an effective treatment for ATLL-associated hypercalcemia as it specifically targets RANK ligand. A dose of 120 mg Dmab is recommended for patients with bisphosphonate-resistant hypercalcemia of malignancy and GFR greater than 30 mL/min. In another published case report on the use of Dmab in ATLL-associated hypercalcemia, treatment with Dmab 120 mg SC resulted in protracted hypocalcemia lasting 5 months despite calcium carbonate and Vitamin D supplements (1). Our patient had a significantly shorter hypocalcemia course likely due to reduced Dmab dose and more aggressive proactive treatment with ergocalciferol, calcium citrate and calcitriol. This case supports the successful use of Dmab in bisphosphonate-resistant ATLL-associated hypercalcemia. Protracted Dmab-induced hypocalcemia may be mitigated by Dmab dose reduction even in the presence of normal GFR and early aggressive treatment with calcium citrate and calcitriol. Reference: (1) Japp et al. AACE Clin Case Rep.2019;5:e210-213 Presentation: Saturday, June 17, 2023

Decoding dysregulated angiogenesis in HTLV-1 asymptomatic carriers compared to healthy individuals.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the first identified human retrovirus responsible for two significant diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although the majority of infected individuals remain asymptomatic carriers, a small percentage may develop ATLL or HAM/TSP. In tumorigenesis, a crucial process is angiogenesis, which involves the formation of new blood vessels. However, the precise mechanism of HTLV-1 associated angiogenesis remains unclear. This study aims to investigate the gene regulation involved in the angiogenesis signaling pathway associated with HTLV-1 infection. The research enrolled 20 male participants, including asymptomatic carriers and healthy individuals. Blood samples were collected and screened using ELISA for HTLV-1 confirmation, and PCR was performed for both Tax and HBZ for validation. RNA extraction and cDNA synthesis were carried out, followed by RT-qPCR analysis targeting cellular genes involved in angiogenesis. Our findings indicate that gene expression related to angiogenesis was elevated in HTLV-1 ACs patients. However, the differences in gene expression of the analyzed genes, including HSP27, Paxillin, PDK1, PTEN, RAF1, SOS1, and VEGFR2 between ACs and healthy individuals were not statistically significant. This suggests that although angiogenesis-related genes may show increased expression in HTLV-1 infection, they might not be robust indicators of ATLL progression in asymptomatic carriers. The results of our study demonstrate that angiogenesis gene expression is altered in ACs of HTLV-1, indicating potential involvement of angiogenesis in the early stages before ATLL development. While we observed elevated angiogenesis gene expression in ACs, the lack of statistical significance between ACs and healthy individuals suggests that these gene markers may not be sufficient on their own to predict the development of ATLL in asymptomatic carriers.