Aggressive Adult T-cell Leukemia/lymphoma Research Articles

Improved survival among elderly patients with aggressive adult T-cell leukemia/lymphoma: Impact of mogamulizumab-containing chemotherapy.

Due to the poor prognosis of adult T-cell leukemia/lymphoma (ATL), new treatments are urgently needed, especially for elderly patients with aggressive ATL. The anti-CCR4 antibody drug mogamulizumab (MOG) has been approved for the treatment of untreated ATL. To analyze the impact of MOG on elderly patients, we conducted a retrospective analysis of patients aged 70years and older with aggressive ATL diagnosed at our institution between 2015 and 2021. Among 32 patients, including those who received best supportive care, the median survival time (MST) and 2-year overall survival (OS) rate were 14.6months (range, 0.0-83.7), and 34.7% [95% confidence interval (CI), 18.2-51.9], respectively, which were better than outcomes in our previous study. The MST and 2-year OS for patients treated with MOG-containing chemotherapy were 18.1months (range, 4.0-83.7) and 45.0% (95%CI, 23.1-64.7), respectively, demonstrating clear improvement. Adverse events observed with MOG-containing treatment, such as myelosuppression and skin rash, were similar to those reported previously. Univariate analysis identified comorbidity as a predictor of poor outcomes, but not intensity of MOG-containing treatment, suggesting a different mechanism of action than that of classical chemotherapy. Our study suggests that MOG-containing treatments are an option for elderly patients with ATL.

Chemotherapy and allo-HSCT for young patients with aggressive ATL

Adult T-cell leukemia-lymphoma (ATL) is an aggressive malignancy with a poor prognosis, especially for patients with the aggressive subtype. While conventional chemotherapy offers short-term disease control, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most promising curative approach for young, transplant-eligible patients. This review focuses on current treatment strategies for aggressive ATL in this specific population. We discuss the rationale for early upfront allo-HSCT following induction chemotherapy. The advent of allo-HSCT using alternative donors, particularly haploidentical HCT, has broadened the applicability of early upfront allo-HSCT in patients with aggressive ATL worldwide. Finally, we address emerging therapies that may improve outcomes in the context of allo-HSCT, paving the way for further advancements in the treatment of aggressive ATL.

Clinical characteristics, genetic alterations, and prognosis of adult T-cell leukemia/lymphoma: an 11-year multicenter retrospective study in China.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis, and there is little data available from the Chinese population. This retrospective study included 115 patients diagnosed with ATLL who were treated across five hospitals in China from June 2011 to December 2022. The median age at diagnosis was 53 years. Several genes involved in T-cell receptor-induced nuclear factor κB (TCR-NF-κB) signaling were commonly mutated, including PLCG1, CIC, PRKCB, CARD11, and IRF4. Eighty-seven patients received chemotherapy. Of these, 13 received a hematopoietic stem cell transplant (HSCT) (allogeneic-HSCT, n=9; autologous-HSCT, n=4) after chemotherapy. Following initial multiagent chemotherapy using EPOCH/CHOEP and other regimens, the overall response rates were 80.6% (complete response [CR], 44.4%) and 42.8% (CR, 14.2%), respectively. The 4-year survival rates (median survival time in days) for EPOCH/CHOEP (n=43), HSCT (n=13), and CHOP-based regimens (n=31) were 12.7% (138), 30.8% (333), and 0% (66), respectively. Lymphadenopathy, EPOCH/CHOEP, and hematopoietic stem cell transplantation were independent prognostic protective factors in patients with aggressive ATLL. Chinese patients exhibit a higher incidence of aggressive-type ATLL, sharing similar genetic alterations with Japanese patients. Etoposide-based chemotherapy (EPOCH or CHOEP) remains the preferred choice for aggressive ATLL, and upfront allogeneic HSCT should be considered in all eligible patients.

Final 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: Aggressive adult T-cell leukemia/lymphoma (ATLL) is a type of non-Hodgkin lymphoma that is often fatal. ATLL is exceedingly rare in the United States (US), with most cases occurring in emigrants from human T-lymphotropic virus type 1 (HTLV-1) endemic regions. Studies focusing on ATLL in the US are sparse, and have shown poor response rates; because of this, there is no standard of care treatment approach. Brentuximab vedotin (BV) is a CD30 targeting antibody-drug conjugate that is effective in treating many types of lymphoma, including CD30+ peripheral T-cell lymphomas. Studies have shown efficacy even in lymphomas with very low CD30 expression. 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 final safety and efficacy analysis below. Methods: Adult patients (pts) from 5 centers were enrolled from October 2017 through June 2022. Newly diagnosed ATLL pts were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Pts did not have to express CD30 to be enrolled; pts were considered CD30+ if there was >1% expression. Frontline consolidation with allogeneic stem cell transplant (alloSCT) was permitted at any time after 2 cycles of BV-CHEP. Transplant-ineligible pts completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance. Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Pts 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 pts received GCSF support. The primary endpoint was CR by PET-CT (and peripheral blood for leukemic types) 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: 16 pts were enrolled and evaluable for the safety and efficacy analysis. All pts were HTLV-1 positive. Seven of 16 were the acute type, 8 were lymphomatous, and 1 was chronic unfavorable. Seven of 16 (43.75%) expressed CD30. The median age was 56 (range 34 to 69) and 12 of 16 (75%) were female. 14 of 16 pts identified as Black, 1 identified as Asian, and 1 was other. Countries of origin included: Antigua and Barbuda N=1, Colombia N=1, Haiti N=7, Jamaica N=2, Japan N=1, Liberia N=1, and the US N=3. All pts were advanced stage (12 of 16 stage IV; 4 stage III). Four had positive cerebrospinal fluid at baseline, which cleared with intrathecal (IT) treatments, and 10 were given IT prophylaxis. Nine pts had an ATL-PI score >3 (56.25%) with a median score of 3 (range 2-4). No subjects received prior antiretroviral therapy. 12 of 16 pts completed at least 4 cycles of treatment (median 4.5 cycles; range 2 to 6). Ten of 16 pts achieved a CR (62.5%) and 4 pts achieved a PR (ORR of 87.5%) after >2 cycles of BV-CHEP. The median duration of follow-up was 47.2 mo. The median PFS (mPFS) was 7.11 mo (3.93 to NR) and the median OS (mOS) was 12.2 mo (9.29 to NR) (Fig.1). Of pts who achieved a CR, the mPFS was 11.07 mo and the mOS was 15.7 mo. There was no significant difference in PFS or OS by CD30 status or by ATLL subtype. One pt received 3 cycles of maintenance BV. 5 pts received alloSCT consolidation and there was an OS benefit for this group ( p=0.007; Fig.2). Grade 3 or higher toxicities included neutropenia (N=13), anemia (N=11), thrombocytopenia (N=9), febrile neutropenia (N=7), mucositis (N=6), colitis (N=3), infections (N=3; COVID19, thrush, clostridium difficile), hyponatremia (N=3), and vomiting (N=2). Nine of 16 patients had peripheral neuropathy (all grade 1/2). There were 11 pt deaths, 9 of which were disease-related and 2 were due to shock (hypovolemic and septic) off-treatment. No patients had to come off study due to toxicity and there were no treatment-related deaths. Conclusions: In this final analysis, BV-CHEP was safe and effective for the treatment of aggressive ATLL. High ORR and CR rates were achieved regardless of CD30 status, and compare favorably to prior clinical trials. AlloSCT had an OS benefit with 4 of 5 pts achieving long-term remission. Toxicity was manageable and cytopenias were expected. Peripheral neuropathy was common, but low-grade.

Single-Cell RNA Sequencing Revealed the YY1/EZH2/MLH1 Axis As a Possible Therapeutic Target of Intractable Adult T-Cell Leukemia

Background: Due to clinical heterogeneity of adult T-cell leukemia/lymphoma (ATL) and its diverse genetic abnormality, common therapeutic targets of ATL remains unclear. Whereas the YY1/EZH2 axis regulates global epigenetic modification of genes in ATL, its downstream target genes have not been fully elucidated. Meanwhile, DNA mismatch repair proteins may be targeted in ATL. Here we explored underlying molecular axes for ATL progression through comprehensive single-cell RNA-sequencing (sc-RNA-seq). Methods: Peripheral blood of 42 ATL patients and asymptomatic HTLV-1 carriers in addition to two cell lines of ATL43T and ED+ were subjected to the following analyses. Molecular markers associated with their clinical phenotypes were extracted through sc-RNA-seq analysis. Expression levels of DNA mismatch repair proteins (MLH1, MSH2) and target molecules were validated by flow cytometry. Finally, their function was verified through lentiviral shRNA-dependent knockdown and molecular-targeting reagents. Results: While the frequencies of CADM1+ cells among CD4+ T cells were generally correlated with HTLV-1 proviral loads (R = 0.76, p < 0.001), substantial CADM1+ cells were detected but did not increase in some long-remitted cases; thus, CADM1+ cells are biologically heterogeneous. sc-RNA-seq of CADM1+ cells of four ATL cases identified a cluster of CD48-deficient cells. in silico promoter analysis of the cluster extracted a transcription factor YY1 as a candidate for common master regulators. EZH2 and the putative driver genes (CELF2, PTPRC, CBLB, ATXN1, IKZF2) were identified as differentially expressed genes (DEGs) in the cluster. The EZH2-overexpressed cluster was increased in acute-type ATL compared with remitted ATL and smoldering-type ATL. Interestingly, the cluster increased moderately in the other smoldering-type ATL, which required UVB irradiation due to intractable skin lesion. Given that YY1 and EZH2 were up-regulated in acute-type ATL, the cluster may represent tumor aggressiveness. Furthermore, biphasic expression of YY1/EZH2 was observed in 2 acute-type ATL, which indicates that the EZH2 high ATL cells confer malignant signature. In-house analysis on microarray dataset GSE55851 specified the MLH1 associated with YY1/EZH2. MLH1 within CADM1+ fraction was down-regulated in ATL patients with remission (n = 7) but maintained in progressive ATL (n = 6) (p < 0.05). Lentiviral shYY1 knockdown resulted in down-regulation of MLH1 in both ATL43T and ED+ (p < 0.01). The EZH1/2 inhibitor valemetostat down-regulated EZH2 (p = 0.018) and MLH1 (p = 0.014) in primary ATL cells. Finally, knockdown of either YY1 or MLH1 suppressed proliferation of ATL43T and ED+ (p < 0.0001). Conclusions: Our findings indicate that down-regulation of MLH1 through YY1/EZH2 inhibition plays a key role in the treatment of aggressive ATL.

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.

An update on the developments in the treatment of adult T-cell leukemia-lymphoma: current knowledge and future perspective.

Adult T-cell leukemia-lymphoma is defined as peripheral T-cell lymphoma caused by the human T-cell leukemia virus type I. Adult T-cell leukemia-lymphoma is classified into indolent (favorable chronic or smoldering) or aggressive (acute, lymphoma or unfavorable chronic) types. This review discusses the therapeutic developments for patients with adult T-cell leukemia-lymphoma and unmet issues in treating adult T-cell leukemia-lymphoma. For indolent adult T-cell leukemia-lymphoma, a watchful waiting strategy is recommended until the disease progresses to aggressive adult T-cell leukemia-lymphoma. For aggressive adult T-cell leukemia-lymphoma, multi-agent chemotherapy with or without allogeneic hematopoietic stem cell transplantation has been recommended. However, many patients with adult T-cell leukemia-lymphoma relapse, and their prognosis is poor. Recently, novel agents, including mogamulizumab, lenalidomide, brentuximab vedotin, tucidinostat and valemetostat, have been approved for patients with relapsed or refractory aggressive adult T-cell leukemia-lymphoma, and the combination of mogamulizumab with multi-agent chemotherapy or brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone has been approved for patients with untreated aggressive adult T-cell leukemia-lymphoma in Japan. Importantly, the aging of patients with adult T-cell leukemia-lymphoma has recently been reported, and no standard of care for elderly patients with adult T-cell leukemia-lymphoma has been established. New evidence must be obtained from prospective clinical trials to improve the prognosis of patients with adult T-cell leukemia-lymphoma.

A PHASE 2 TRIAL OF CHOP WITH ANTI‐CCR4 ANTIBODY MOGAMULIZUMAB FOR ELDERLY PATIENTS WITH CCR4‐POSITIVE ADULT T‐CELL LEUKEMIA/LYMPHOMA

Background: No standard of care for elderly patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established yet. We assessed the efficacy of an anti-CCR4 antibody, mogamulizumab (Moga)combined with biweekly cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisone (PSL) (Moga-CHOP-14) for untreated elderly patients with aggressive ATL. Methods: In this phase 2 trial conducted at 21 centers in Japan, untreated CCR4-positive aggressive ATL patients aged 66 years or older and 56–65 years who were not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) received six cycles of Moga-CHOP-14, followed by two cycles of Moga monotherapy. The primary endpoint was 1-year progression-free survival (PFS), defined as the time from enrollment to the progression/relapse of ATL or death due to any cause, whichever occurred first. Secondary endpoints were complete response rate (CR), overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and the incidence of adverse events. The necessary number of patients calculated by setting the threshold 1-yearPFS at 16% and the expected 1-year PFS at 31% using the exact method based on binomial distribution under the conditions of one-sided level of significance of 5% (α = 0.05) and power of 70% was 43. Results: A total of 50 patients were enrolled from October 2015, until September 2020. Among the 48 evaluable patients, the median age was74 years (interquartile range [IQR], 70–78). ATL subtypes included 31, 9, and 8 patients for the acute, lymphoma, and unfavorable chronic type, respectively. ATL-PI included 9, 31, and 8 patients for high, intermediate, and low risk, respectively. With a median follow-up of 1.6years (IQR, 0.7–2.4), 1-year PFS was 36.2% (90% confidence interval (CI), 24.9–47.6), and a median PFS was 0.7 years (95% CI, 0.5–1.0).CR and ORR were noted in 64.6% (95% CI, 49.5–77.8), and 91.7%(95% CI, 80.0–97.7), respectively. One-year OS was 66.0% (95% CI, 50.6–77.6) and median OS was 1.6 years (95% CI, 1.1–2.8). One-year EFS was 29.9% (95% CI, 17.6–43.2) and median EFS was 0.5 years (95% CI, 0.4–0.7). The most frequent adverse events grades 3/4, which occurred in >10% of patients were lymphocytopenia (97.9%), leukopenia (93.8%), neutropenia (89.6%), febrile neutropenia (64.8%), anemia (58.3%), thrombocytopenia (45.8%), infection (27.1%), skin rash (20.8%), and hyperglycemia (20.8%). Relative dose intensity (RDI) was calculated for each drug: the mean RDI for Moga was 82.1%, for CPA 71.7%, for DXR 72.7%, for VCR 72.0%, and for PSL 77.3%. Conclusions: This study demonstrated that Moga-CHOP-14 significantly improved PFS in elderly patients with aggressive CCR4-positive ATL who were ineligible for allo-HSCT. Moga-CHOP-14 is now considered for the preferred first-line treatment in those patients. Clinical trial ID:jRCTs041180130. Encore Abstract—previously submitted to ASCO 2023 The research was funded by: Kyowa Kirin and Japan Agency for Medical Research and Development Keyword: combination therapies Conflicts of interests pertinent to the abstract A. Utsunomiya Consultant or advisory role: JIMRO, Otsuka Medical Devices Honoraria: Bristol-Myers Squibb Japan, Meiji Seika Kaisha S. Kusumoto Honoraria: Chugai Pharma, Kyowa Kirin, Daiichi Sankyo Research funding: Chugai Pharma, Kyowa Kirin, Daiichi Sankyo M. Yoshimitsu Consultant or advisory role: Takeda Honoraria: Takeda, Sanofi, Novartis, Daiichi Sankyo K. Nosaka Consultant or advisory role: Kyowa Kirin Honoraria: Meiji Seika, Janssen, Kyowa Kirin, Abbvie, Daiichi Sankyo, Eisai, Bristol-Myers Squibb Japan Research funding: Chugai Pharma, Kyowa Kirin S. Rai Honoraria: Chugai Pharma, Janssen, Ono Pharmaceutical D. Nakamura Honoraria: Sanofi, Takeda, Nippon Shinyaku, Chugai Pharma, Janssen, Abbvie, Meiji Seika K. Ishitsuka Consultant or advisory role: Daiichi Sankyo, Meiji Seika Honoraria: Celgene, Bristol-Myers Squibb Japan, Eisai, Pfizer, Daiichi Sankyo, Takeda, Chugai Pharma, CSL Behring, Nippon Shinyaku, Janssen, Sanofi, Meiji Seika, Kyowa Kirin, Abbvie, Yakult Honsha, Ono Pharmaceutical, Otsuka, Astellas Pharma Research funding: Ono Pharmaceutical, Japan Blood Products Organization, Eisai, Taiho Pharmaceutical, MSD, Chugai Pharma, Sumitomo Dainippon Pharma, Mochida Pharmaceutical, Takeda, Kyowa Kirin

A phase 2 trial of CHOP with anti-CCR4 antibody mogamulizumab for elderly patients with CCR4-positive adult T-cell leukemia/lymphoma.

7504 Background: No standard of care for elderly patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established yet. We assessed the efficacy of an anti-CCR4 antibody, mogamulizumab (Moga) combined with biweekly cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisone (PSL) (Moga-CHOP-14) for untreated elderly patients with aggressive ATL. Methods: In this phase 2 trial conducted at 21 centers in Japan, untreated CCR4-positive aggressive ATL patients aged 66 years or older and 56-65 years who were not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) received six cycles of Moga-CHOP-14, followed by two cycles of Moga monotherapy. The primary endpoint was 1-year progression-free survival (PFS), defined as the time from enrollment to the progression/relapse of ATL or death due to any cause, whichever occurred first. Secondary endpoints were complete response rate (CR), overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and the incidence of adverse events. The necessary number of patients calculated by setting the threshold 1-year PFS at 16% and the expected 1-year PFS at 31% using the exact method based on binomial distribution under the conditions of one-sided level of significance of 5% (α = 0.05) and power of 70% was 43. Results: A total of 50 patients were enrolled from October 2015, until September 2020. Among the 48 evaluable patients, the median age was 74 years (interquartile range [IQR], 70-78). ATL subtypes included 31, 9, and 8 patients for the acute, lymphoma, and unfavorable chronic type, respectively. ATL-PI included 9, 31, and 8 patients for high, intermediate, and low risk, respectively. With a median follow-up of 1.6 years (IQR, 0.7-2.4), 1-year PFS was 36.2% (90% confidence interval (CI), 24.9-47.6), and a median PFS was 0.7 years (95% CI, 0.5-1.0). CR and ORR were noted in 64.6% (95%CI, 49.5-77.8), and 91.7% (95% CI, 80.0-97.7), respectively. One-year OS was 66.0% (95% CI, 50.6-77.6) and median OS was 1.6 years (95%CI, 1.1-2.8). One-year EFS was 29.9% (95% CI, 17.6-43.2) and median EFS was 0.5 years (95%CI, 0.4-0.7). The most frequent adverse events grades 3/4, which occurred in > 10% of patients were lymphocytopenia (97.9%), leukopenia (93.8%), neutropenia (89.6%), febrile neutropenia (64.8%), anemia (58.3%), thrombocytopenia (45.8%), infection (27.1%), skin rash (20.8%), and hyperglycemia (20.8%). Relative dose intensity (RDI) was calculated for each drug: the mean RDI for Moga was 82.1%, for CPA 71.7%, for DXR 72.7%, for VCR 72.0%, and for PSL 77.3%. Conclusions: This study demonstrated that Moga-CHOP-14 significantly improved PFS in elderly patients with aggressive CCR4-positive ATL who were ineligible for allo-HSCT. Moga-CHOP-14 is now considered for the preferred first-line treatment in those patients. Clinical trial information: jRCTs041180130 .

HTLV-1 cell-free DNA in plasma as a potential biomarker in HTLV-1 carriers and adult T-cell leukemia-lymphoma.

Viral cell-free DNA (cfDNA) in plasma has been widely evaluated for detecting cancer and monitoring disease in virus-associated tumors. We investigated whether the amount of cfDNA of human T-cell leukemia virus type 1 (HTLV-1) correlates with disease state in adult T-cell leukemia-lymphoma (ATL). HTLV-1 cfDNA in aggressive ATL was significantly higher than that in indolent ATL and asymptomatic carriers. Notably, patients with lymphoma type represented higher HTLV-1 cfDNA amount than chronic and smoldering subtypes, though they had no abnormal lymphocytes in the peripheral blood. HTLV-1 cfDNA can be a universal biomarker that reflects the expansion of ATL clones.

Abstract 4409: Survival determinants of aggressive adult T-cell leukemia/lymphoma (ATLL): analysis of a pooled database

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare Peripheral T-cell Lymphoma subtype caused by Human T-Lymphotropic Virus 1 (HTLV-1). The disease encompasses a vast phenotype ranging from the smoldering and chronic indolent subtypes to the lymphoma and acute aggressive subtypes. Aggressive ATLL which comprise acute/leukemic, lymphoma, and other indolent subtypes with aggressive transformation tend to have poor outcome with conventional chemotherapy rarely achieving durable lasting remission. We conducted this pooled database analysis to identify key factors that affect the clinical outcomes of aggressive ATLL subtypes. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 462 ATLL cases. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on the overall survival (OS). Results: Three hundred and forty-seven aggressive ATLL patients with survival data were included in this analysis. The median OS of the whole group was 14 months, with a median OS of 12.8, 16, and 12 months for acute, lymphoma, and transformed subtypes. The median age was 54 years, with a M:F ratio of 1.1. SCT demonstrated superior OS compared to chemotherapy (28 vs. 10 months, p<0.0001). Similarly, LSG15 regimens were superior to no chemotherapy and other combinations (29 vs. 1 vs. 15 months, p<0.0001). Asians and Afro-Caribbeans lived longer than Whites, Indians, and Hispanics (15.7, 15, 10, 3, 1 months, p<0.0001, respectively). The presence of hypercalcemia (Ca>11 mg/dl, Anemia (Hgb<12 g/dl), elevated LDH (>1000 U/L), and effusions adversely effected OS. Moreover, visceral involvement generally and specifically GI, kidney, lung, and heart were significantly detrimental to OS. However, age, sex and the presence of constitutional symptoms or HAM/TSP did not impact the OS. Conclusions: This study explored a wide array of clinical factors and their impact on the OS of aggressive ATLL. It identified race, types of treatment, the presence of hypercalcemia, anemia, elevated LDH, effusion and visceral metastases as significant determinants of OS in aggressive ATLL. Citation Format: Supriya Gupta, Christopher Graham, Philip A. Haddad. Survival determinants of aggressive adult T-cell leukemia/lymphoma (ATLL): analysis of a pooled database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4409.

Current and emerging therapeutic strategies in adult T-cell leukemia-lymphoma.

Adult T-cell leukemia-lymphoma (ATL) is classified into four clinical subtypes: acute, lymphoma, chronic, and smoldering. Chronic ATL is further divided into unfavorable and favorable chronic types according to serum lactate dehydrogenase, blood urea nitrogen, and serum albumin values. Acute, lymphoma, and unfavorable chronic types are categorized as aggressive ATL, whereas favorable chronic and smoldering types are categorized as indolent ATL. Intensive chemotherapy alone is not sufficient to prevent relapse of aggressive ATL. Allogeneic hematopoietic stem cell transplantation is a potential therapeutic option to cure aggressive ATL in younger patients. Reduced-intensity conditioning regimens have decreased transplantation-related mortality, and increased donor availability has dramatically improved transplant access. New agents, including mogamulizumab, brentuximab vedotin, tucidinostat, and valemetostat, have recently become available for patients with aggressive ATL in Japan. Here, I provide an overview of recent advances in therapeutic strategies for ATL.

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma.

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).

Adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an extremely refractory peripheral T-cell lymphoma that develops after persistent human T-lymphotropic virus type 1 (HTLV-1) infection. In recent years, the number of HTLV-1 carriers has decreased due to lifestyle changes and different measures. Rapid progression in comprehensive genetic analysis techniques has revealed the molecular basis of ATL. Therefore, in addition to conventional prognostic indices based on clinical parameters, prognostic indices incorporating genetic mutations have been proposed. The standard treatment for untreated aggressive ATL is combination chemotherapy such as VCAP-AMP-VECP or CHOP, followed by allogeneic hematopoietic stem cell transplantation, as appropriate. Combined mogamulizumab and chemotherapy is a promising first-line treatment option for patients not eligible for transplantation. Salvage treatment with lenalidomide, brentuximab vedotin, tucidinostat, and valemetostat, in addition to mogamulizumab, has been introduced over the last decade. Advancements in allogeneic transplantation therapy, including early induction and transplantation with post-transplant cyclophosphamide for GVHD prophylaxis, have also improved patient outcomes. This article highlights recent developments in the field of ATL.

Valemetostat: First approval as a dual inhibitor of EZH1/2 to treat adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell lymphoma with a poor prognosis. Accumulating trimethylation of histone H3 lysine 27 (H3K27me3) caused by upregulated function of either enhancer of zeste homologue 2 (EZH2) or its homolog EZH1 plays an essential role in the maintenance of transcriptional repression in ATL. Selective inhibition of EZH2 may complementarily induce EZH1 activation, so dual targeting EZH1/2 is a rational strategy in developing potent antitumor agents. Valemetostat is the first dual EZH1/2 inhibitor approved for treatment of aggressive ATL in Japan in September 2022. Several other dual EZH1/2 inhibitors such as HH2853, HM97594, and HM97662 have also demonstrated potential in treating malignant tumors. Dual targeting EZH1/2 may have promising antitumor action in hematological malignancies and solid tumors.

Highly Sensitive Detection Method Reveals Significant Anti-Tumor Activity of Valemetostat in Patients with Relapsed/Refractory Adult T Cell Leukemia

Background: Enhancer of zeste homolog 2 (EZH2) and its close homolog, EZH1, catalyze the attachment of 3 methyl groups to histone H3 at lysine 27 (H3K27me3). H3K27me3 is an epigenetic mark involved in downregulating gene expression associated with tumor suppression and cell differentiation. Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma (NHL) subtype that arises from CD4 positive T cells associated with human T-lymphotropic virus type 1 (HTLV-1) infection. During asymptomatic period, genetic and epigenetic abnormalities in the HTLV-1 infected cells accumulates and finally leads to ATL development. Current therapy for aggressive type ATL is still unsatisfactory and prognosis of relapsed and refractory (r/r) ATL after lenalidomide or mogamulizumab treatment is poor. Dysregulation of EZH2/PRC2-mediated epigenome status has been reported to be highly involved in tumorigenesis in ATL as well as other tumors such as B cell lymphoma. Valemetostat is a potent dual inhibitor of EZH1 and 2 which are key catalytic subunits of PRC2. The safety and efficacy of valemetostat in patients with r/r ATL were evaluated in a multicenter, single-arm, open-label phase 2 study (NCT04102150) and the results were presented at ASH 2021. Here we show clinical biomarker data using peripheral blood obtained over time, accompanying clinical outcomes. Also we discuss relevance of the measured data in blood to clinical outcomes among assay formats. Method: In the Ph2 study, valemetostat 200mg was orally administrated once daily in continuous 28-day cycles until disease progression or intolerance. Nine of 25 patients in the Ph2 study had abnormal lymphocytes in their peripheral blood. Peripheral blood from these 9 patients (7 acute and 2 unfavorable chronic) was drawn at pre-dosing and every 4-weeks for the analysis of this study. Abnormal lymphocytes (Ably) and soluble IL-2R (sIL-2R) are indicator of ATL prognosis. For HTLV-1 proviral load (PVL) detection, genomic DNA was extracted from PBMC from each patient. Droplet Digital PCR (ddPCR) was performed using probes specific for HTLV-1 provirus and RNase 5’ pyrophospgohydrolase (RPPH) gene. % PVL was determined from the copy number ratio of HTLV-1 to RPPH1 genes. For HTLV-1 Analysis System (HAS)-flow cytometry, frozen cell suspensions were thawed and stained with anti- CD3/4/7/14/CADM1 Abs. The data from live T cells was analyzed by CD7 versus CADM1 plot. CADM1+CD7- population ratio was denoted as %N. We analyzed changes of each measured parameter in every patient in comparison with clinical outcome. Result: In the 9 patients who met criteria in blood collection for blood biomarker evaluation at screening, 1 CR, 6 PRs and 1 SD were observed as the best response by blood assessment (not evaluable in one patient, who failed to meet criteria for blood assessment at pre-treatment evaluation). Significant decrease in Ably number and blood sIL-2R concentration was observed after 4-week valemetostat treatment in all 9 patients and this decrease was maintained during the treatment until PD. Valemetostat also decreased the %PVL and %N in HAS-flow. The reduction trends were weaker in comparison with Ably and sIL-2R. As for %PVL, most of the patients experienced modest reduction and sustained around 50%. Especially HAS-flow results exhibited two patient groups with either lower (<25%) or higher %N at pre-dosing. Two patients in the lower %N group showed CR or PR, and in overall response the remaining 7 patients with higher %N showed SD or PR. Conclusion: Valemetostat significantly reduced markers of ATL progression. Ably and sIL-2R to very low levels in all patients. In contrast, PVL assay did not exhibit complete %PVL reduction. HAS-flow showed variable %N at pre-dosing and the patients with higher %N exhibited SD or PR throughout the treatment in overall response and blood assessment. These data suggest that PVL assay and HAS-flow can detect ATL cells with a high resolution, which cannot be detected by Ably and sIL-2R, when valemetostat has significant therapeutic efficacy in ATL patients. Further analyses, such as gene mutation, transcription, chromatin state and histone methylation, using the collected blood samples will be performed next.

Beneficial impact of first‐line mogamulizumab‐containing chemotherapy in adult T‐cell leukaemia‐lymphoma

Chemotherapy in combination with mogamulizumab (Mog) was approved in Japan in 2014 for untreated aggressive adult T-cell leukaemia-lymphoma (ATL), but the survival benefit remains unclear. Therefore, we retrospectively analysed clinical outcomes in 39 transplant-ineligible patients with untreated aggressive ATL at Kumamoto University Hospital between 2010 and 2021. The probability of four-year overall survival was 46.3% in the first-line Mog-containing treatment group compared to 20.6% in the chemotherapy-alone group (p= 0.033). Furthermore, this survival benefit was observed even in the elderly. In conclusion, first-line Mog-containing treatment can be a promising strategy for transplant-ineligible patients with ATL, especially in the elderly.

Prognostic implication of CTLA-4, PD-1, and PD-L1 expression in aggressive adult T-cell leukemia–lymphoma

The prognosis of patients with aggressive adult T cell leukemia-lymphoma (ATLL) is dismal even with intensive chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a promising option for patients with aggressive ATLL, but the posttransplant outcome remains unsatisfactory. Hence, to further improve clinical outcomes, novel therapeutic approaches are needed. The clinical significance of immune checkpoint protein expression has not been well-established in aggressive ATLL. This study aims to identify the association between the expression profile of immune checkpoint proteins on ATLL cells and clinical outcomes. This retrospective study cohort included 65 patients with aggressive ATLL diagnosed between 2001 and 2015 at the National Cancer Center Hospital, Tokyo, Japan. Formalin-fixed paraffin-embedded tissue was used to immunohistochemically determine the expression of immune checkpoint proteins and assess the impact of expression profile on the probability of overall survival from diagnosis or HSCT. The current analysis shows that cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) expressions were adverse prognostic factors in patients with aggressive ATLL. Experiments that assess the efficacy of immune checkpoint inhibitors are warranted to alleviate the adverse impacts associated with negative immune checkpoints.

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.

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.