Angioimmunoblastic T-cell Lymphoma Research Articles

Psychosis Prompts Detection of Early Stage Angioimmunoblastic T-Cell Lymphoma

AimsAngioimmunoblastic T-cell lymphoma (AITL) is a rare (2%) and aggressive form of Non-Hodgkin lymphoma, with poor prognosis and median overall survival under 3 years. Most patients with AITL present at an advanced stage (3 or 4). Neuropsychiatric manifestations of lymphoma, though rare, have been reported as associated symptoms. We present a case of successfully treated Stage 2 AITL, whose rare presentation, of florid affective and atypical psychotic phenomena without neurological deficit, eluded clinical detection of AITL for months.MethodsA 58 year-old gentleman with a history of Major Depressive Disorder, presented to hospital with a second episode of generalised tonic clonic seizure, following 4 months of manic disorganised behaviour and multimodal hallucinations.Atypical psychotic features (preserved insight, multimodal hallucinations resistant to high dose anti-psychotics) and new systemic symptoms prompted suspicion of underlying organic pathology. CT Thorax Abdomen and Pelvis uncovered enlarged bilateral common iliac and external iliac lymph nodes, and small sub-centimetre retroperitoneal nodes. Eventually, Stage 2 Angioimmunoblastic T-cell lymphoma (Pattern 1 & 2), with concomitant psychosis with atypical features, was diagnosed.Olanzapine 10mg ON and 2.5mg OD PRN, Sodium Valproate EPILIM CHRONO 300mg BD and Diazepam 10mg ON were continued over 6 rounds of chemotherapy and autologous stem cell transplant. The patient remains in remission.ResultsNeuropsychiatric manifestations of lymphoma are rare and usually associated with Central Nervous system (CNS) lymphoma. Here, we observe Stage 2 AITL (without CNS involvement), can present with neuropsychiatric symptoms in the absence of neurological deficits.We found the combination of Olanzapine, Sodium Valproate and Diazepam to be effective in managing secondary neuropsychiatric symptoms.Limbic Encephalitis is an important consideration for similar cases despite this patient not meeting the qualifying criteria (unremarkable neuroimaging and EEG).This case highlights the importance of a thorough history, documenting and understanding the patient's psychopathology (both reported and observed), and differentiating atypical psychotic features which raise suspicions for underlying organic pathology.ConclusionThis case is an an eye-opener for psychiatric and non-psychiatric clinicians. It reminds us to remain vigilant in such florid psychiatric presentations and highlights the importance of thorough organic workup and psychiatric medications that may be used to successfully address psychosis secondary to lymphoma.We hope to contribute to the increasing awareness and broadening literature of psychiatric disturbance as initial manifestations of malignant illnesses, and the association between psychiatric manifestations and the rare form of lymphoma, AITL.

Multicenter phase 2 study of romidepsin plus lenalidomide for previously untreated peripheral T-cell lymphoma

AbstractPeripheral T-cell lymphomas (PTCLs) are associated with poor prognosis when treated with cytotoxic chemotherapy. We report the findings of a phase 2 study evaluating a chemotherapy-free combination of romidepsin plus lenalidomide as initial treatment for patients with PTCL who were aged >60 years or noncandidates for chemotherapy. Treatment was initiated with romidepsin 10 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg taken orally from days 1 to 21 of 28-day cycle for up to 1 year. The primary objective was overall response rate (ORR). Secondary objectives included safety and survival. The study enrolled 29 patients with a median age of 75 years, including 16 (55%) angioimmunoblastic T-cell lymphoma (AITL), 10 (34%) PTCL– not otherwise specified, 2 ATLL, and 1 EATL. Grade 3 to 4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%), and anemia (28%). Grade 3 to 4 nonhematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), and infection (10%). At median follow-up of 15.7 months, 23 patients were evaluable and received a median treatment of 6 cycles. The ORR was 65.2% with complete response (CR) at 26.1%, including 78.6% ORR and 35.7% CR for AITL. Median duration of response was 10.7 months, with 27.1 months for patients achieving CR. The estimated 2-year progression-free survival was 31.5%, and 2-year overall survival was 49.5%. This study provides the first demonstration that the biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as #NCT02232516.

A preliminary investigation of the relationship between 18F-FDG PET/CT metabolic parameters and prognosis in angioimmunoblastic T-cell lymphoma.

The goal of the study was to determine the prognostic significance of metabolic parameters in baseline 18F-FDG PET/CT images obtained from patients with angioimmunoblastic T-cell lymphoma (AITL). Forty patients with pathologically diagnosed AITL who had baseline 18F-FDG PET/CT between May 2014 and May 2021 were assessed as part of this study. Maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV) were obtained and analyzed. In addition, many relevant features were evaluated, including sex, age, staging, International Prognostic Index (IPI), prediction index for T-cell lymphoma (PIT), Ki-67, and so on. Estimates of progression-free survival (PFS) and overall survival (OS) were determined using the log-rank test and Kaplan-Meier. The median follow-up was 30.2 months (interquartile range 9.82-43.03). Throughout the follow-up period, 29 (72.5%) deaths occurred and 22 (55.0%) patients made progress. The rates for 2- and 3-year PFS were 43.6% and 26.4%, respectively. The 3- and 5-year OS were 42.6% and 21.5%. For TMTV, TLG, and SUVmax, the cut-off values were 87.0 cm3, 711.1, and 15.8, respectively. Poorer PFS and OS were substantially correlated with high SUVmax and TLG. An increased TMTV suggested a shorter OS. TLG performed independently as OS predictors in multivariate analysis. The risk score for predicting the prognosis of AITL includes the TMTV, TLG, SUVmax, and IPI scores, with 4.5 for TMTV, 2 for TLG, 1.5 for IPI scores, and 1 for SUVmax. Three risk categories of patients with AITL had 3-year OS rates of 100.0%, 43.3%, and 25.0%, respectively. Baseline TLG was a strong predictor of OS. Here a new prognostic scoring system for AITL based on the clinical indicators and PET/CT metabolic parameters was constructed, which might make stratification of prognosis easy and also help to individualize treatment.

Treating relapsed/refractory mature T- and NK-cell neoplasms with tislelizumab: a multicenter open-label phase 2 study

AbstractPatients with relapsed/refractory (R/R) mature T- and natural killer (NK)–cell neoplasms lack effective treatments after failure of standard therapies. This phase 2 study evaluated the efficacy and safety of the programmed cell death protein 1 inhibitor tislelizumab in these patients. Seventy-seven patients were treated with 200 mg tislelizumab every 3 weeks. Twenty-two patients with extranodal NK-/T-cell lymphomas were enrolled in cohort 1; 44 patients with peripheral T-cell lymphoma (PTCL) were enrolled in cohort 2 (21 patients had PTCL not otherwise specified, 11 patients had angioimmunoblastic T-cell lymphoma, and 12 patients had anaplastic large-cell lymphoma). Cohort 3 comprised 11 patients with cutaneous T-cell lymphoma, of which 8 patients had mycosis fungoides (MF) and 3 had Sézary syndrome. Of the 77 patients, 76.6% had advanced-stage disease, 51.9% had refractory disease, and 49.4% received ≥3 prior systemic regimens. Promising efficacy was observed in cohort 3 (median follow-up [FU], 16.6 months; overall response rate [ORR], 45.5%; complete response [CR], 9.1%; median duration of response [DOR], 11.3 months; median progression-free survival, 16.8 months; median overall survival, not reached). Modest efficacy was observed in cohort 1 (median FU, 8.4 months; ORR, 31.8%; CR, 18.2%; median DOR, not reached) and cohort 2 (median FU, 9.3 months; ORR, 20.5%; CR, 9.1%; median DOR, 8.2 months). Most treatment-related adverse events were grade 1 or 2, and the safety profile was consistent with the known safety profile of tislelizumab. In conclusion, tislelizumab was well tolerated, achieving modest efficacy in R/R mature T- and NK-cell neoplasms, with some long-lasting remissions. This trial was registered at www.clinicaltrials.gov as #NCT03493451.

Peripheral T-cell lymphoma-not otherwise specified, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma: Are the outcomes any different in Hispanics?

e18773 Background: Peripheral T cell lymphoma – not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) are unusual non-Hodgkin lymphomas with miscellaneous clinical characteristics which share the same treatment regimen (Blood PMID28115372 Cancer Treat ResPMID30596215 Blood PMID28115369). Gene expression profiling has facilitated their diagnosis; but much remains to be learned about risk factors, biological and clinical implications (Oncologist PMID16880242). This is the first national population-based analysis evaluating ethnic differences for Hispanics (HI) diagnosed with PTCL-NOS, AITL and ALCLin the US. Methods: Data were analyzed on PTCL-NOS, AITL and ALCL patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) database between 2000-2018. Demographic, clinical and survival patterns were analyzed. Kaplan-Meier and Cox regression analyses were used when appropriate. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. Results: 12,749 patients were diagnosed with PTCL-NOS, AITL and ALCL (1,666 cases were HI = 798 PTCL-NOS, 316 AITL and 552 ALCL). Male predominated for HI and Non-HI (NH) in the 3 malignancies. HI were diagnosed at a younger median age than NH, PTCL-NOS 60 years(y) vs 65y, AITL 65y vs 69y, and ALCL 45y vs 55y, respectively [p <0.001]. White race predominated for both. When diagnosed with PTCL-NOS or AITL, HI were more likely diagnosed from 2015-2018 but those with ALCL were identified from 2000-2004. For the 3 malignancies limited information regarding B symptoms was available. Most of the cases of HI and NH were diagnosed at advanced stages in all subtypes. Overall, for both the tendency was towards not receiving radiation. HI vs NH diagnosed with PTLC-NOS had median survival of 1.2 vs 1.3y; AITL was 2.2 vs 1.7y and ALCL 6.0 vs 9.3y. Survival probability for 2, 5 and 10y were comparable among HI and NH for all malignancies and no difference in OS was noted. On multivariate analysis, patients who were older than 80y and between 60-80 y, had worse OS compared to those <60y. For all subtypes, those who were diagnosed at stage III/IV had worse OS than those at early stage I/II. Conclusions: Similar OS for HI and NH diagnosed with PTCL-NOS, AITL and ALCL. Nonetheless, diagnosis at younger age and early stage play a significant role to better survival. Although HI were more subjected to early age at diagnosis and less likely to be at a stage I/II, no impact in survival was evidenced, which suggests that unique responses may counteract within this race. It is captivating that no gradual increase in diagnosis was noted despite the continuous development of genetic testing and improved diagnostic tools, which highlights that socioeconomical variables may have been influencing its access.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Angioimmunoblastic T cell Lymphoma (AITL) is a subtype of peripheral T cell lymphoma and prognosis is generally felt to be poor. Molecular characteristics differentiating good or poor risk AITL has not been identified. In our Asian multicentre study, we investigate the clinical prognostic factors affecting the outcomes of our AITL patients. We also interrogate the gene expression profiles in our patients to identify if there may be different immune and cell signalling signatures in different risk groups. Methods: Patients who were diagnosed with AITL and seen at National Cancer Centre Singapore, Singapore General Hospital and National University Cancer Institute, Singapore between June 1999 and December 2019 were retrospectively analysed. Relevant demographical and clinical characteristics were collected. Outcomes of interest were that of 5-year overall survival (OS) and 5-year progression free survival (PFS). Kaplan-Meier curves were plotted to estimate survival for each individual clinical parameter. Parameters found to be significant on univariate analysis were subsequently used in the generation of multivariate cox regression models. NanoString PanCancer IO360 panel (NanoString Technologies, Seattle, WA, USA) was used to interrogate gene expression on AITL FFPE tissue, following manufacturer’s protocol using the nCounter platform. Results: A total of 174 patients were identified. Median duration of follow up was 20.4 months. Median PFS and OS was 1.8 years and 5.6 years respectively. In multivariate analyses, Age >60, bone marrow Involvement, Total white cell count and serum Lactate dehydrogenase were associated with poorer PFS and OS. A prognostic index (AITL-PI) differentiated patients into low (0–1 factors, n = 64), moderate (2 factors, n = 59) and high-risk (3–4 factors, n = 49) subgroups with 5-year OS of 84.0%, 44.0% and 28.0% respectively (p < 0.0001). Gene expression studies performed in 23 patients found disparate immune cell type profiles and oncogenic signalling pathway signatures in the low risk as compared to the intermediate and high-risk groups. In the low risk group, neutrophilic, T-regulatory and Th-1 cell profiles were predominant whereas cytotoxic cell profile was predominant in the intermediate and high-risk groups. The low risk group was more active in the myeloid compartment, WNT, cytokine and chemokine, TGF-β and hedgehog signalling pathways whereas cytotoxicity, interferon and lymphoid compartment signalling signatures returned higher in the intermediate and high-risk groups. The research was funded by: NCCS Cancer Fund (Research) (NCCSCF-R-YR2021-JUN-SSD1), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Research Transition Awards (TA21jun-0005 and TA20nov-0020), Large Collaborative Grant (OFLCG18May-0028), and Collaborative centre grant (TETRAD II). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with a poor prognosis for relapsed/refractory disease. The WHO classification of NK and T-cell lymphomas includes 39 entries; the 3 most common subtypes in the US are PTCL-NOS (not otherwise specified), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL). Except for brentuximab vedotin in CD30-positive disease, agents were generally approved based on overall response rates (ORR) of less than 30%. The PRIMO Trial (NCT03372057; sponsored by Secura Bio, Inc.) evaluated duvelisib (DUV), an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms in PTCL. Anti-tumor activity of single agents may not be uniform across different PTCL subtypes. Here we present data on 3 specific subtypes of some of the patients (pts) included in the PRIMO trial (fully enrolled as of January 2022). Methods: Eligibility criteria included adults with pathologically confirmed PTCL after ≥2 cycles of at least 1 prior standard regimen. A criterion for CD4 lymphocyte count ≥50/mm3 was added for the Expansion Phase (EP). Based on dose optimization results, the EP dose was DUV 75 mg BID for 2 cycles, to maximize disease control, followed by 25 mg BID, to mitigate late toxicities, until progressive disease/unacceptable toxicity. Pneumocystis jirovecii prophylaxis was required; herpes simplex and varicella zoster virus prophylaxis were indicated as needed. The primary endpoint was ORR by IRC assessment (Lugano 2014 criteria); efficacy is or will be assessed in all pts who received ≥1 dose of DUV. Secondary objectives included additional outcome measures, safety, and pharmacokinetics. Exploratory endpoints included pharmacodynamics and biomarkers. Results: The PRIMO study included 101 pts from the EP (data cutoff October 1, 2021), with a median follow-up of 8.7 months (mo) from time of first response. In the overall PRIMO study (N = 101), pts had a median age of 67.0 (21–92) years, a median of 3 (1–9) prior lines of therapy, an ORR (by IRC) of 49%, a CR rate of 34%, and a median PFS of 3.6 mo. Pts with the 3 most common histology subtypes from the PRIMO study are included in the current analysis (n = 97); these are PTCL-NOS (n = 52), AITL (n = 30), and ALCL (n = 15). Median PFS stratified by baseline histology was 3.5 mo (PTCL-NOS), 9.1 mo (AITL), and 1.5 mo (ALCL). Table 1 shows additional outcomes by histology. Adverse events seen were consistent with those observed previously in the PRIMO trial with no additional unexpected treatment-related toxicities. Conclusions: The ORR (by IRC) of DUV was higher in pts with PTCL-NOS (48%) and AITL (67%), compared with ALCL (13%). This corresponded to a longer median PFS of 3.5 mo in PTCL-NOS and 9.1 mo in AITL compared with 1.5 mo in ALCL. Although not powered for subset analyses, this analysis suggests activity of DUV may not be uniform across different types of lymphomas. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Secura Bio, Inc. Keywords: molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract. N. Mehta-Shah Consultant or advisory role: AstraZeneca, Celgene/BMS, C4 Therapeutics, Celgene, Corvus, Daiichi Sankyo, Genentech/Roche, Innate Pharmaceuticals, Karyopharm, Kyowa Kirin, ONO Pharmaceuticals, Secura Bio, Verastem ​ E. D. Jacobsen Consultant or advisory role: Ascerta, Astra-Zeneca, Merck; Pharmacyclics, F. Hoffman-LaRoche, Novartis, Takeda P. L. Zinzani Consultant or advisory role: Celltrion, Gilead, Janssen-cilag, BMS, Servier, Sandoz, MSD, TG therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, Novartis, ADC Therapeutics, Incyte, Beigene, Secura Bio​ J. Zain Consultant or advisory role: Kyowa Kirin, Mundi, Seattle Genetics​ G. Gritti Consultant or advisory role: Beigene, Clinigen, Genmab, Ideogen, Incyte, IQVIA, Italfarmaco, Kite-Gilead, Roche, Sandoz, Takeda K. Izutsu Consultant or advisory role: Celgene/BMS, MSD, AstraZeneca, AbbVie, Eisai, Incyte, Solasia, Novartis, Bayer, Pfizer, Janssen, Yakult, Kyowa Kirin, ONO Pharmaceuticals, Daiichi Sankyo, Chugai, Takeda, Beigene, Genmab, Otsuka, Loxo Oncology, FUJIFILM Toyamachemical, Symbio​ S. Waters Employment or leadership position: Secura Bio, Inc. J. E. Brammer Consultant or advisory role: BMS, Verastem Consultancy: Kymera, Seattle Genetics B. Pro Consultant or advisory role: Takeda, Seattle Genetics, Celgene, Verastem, Astex pharmaceuticals S. M. Horwitz Consultant or advisory role: ADC Therapeutics, Affimed, Celgene, Crispr Therapeutics, Daiichi Sankyo, Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Verastem/SecuraBio, Acrotech Biopharma, C4 Therapeutics, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, SecuraBio, Shoreline Biosciences, Inc., Takeda, Trillium Therapeutics, Tubulis, Cimieo Therapeutics

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Purpose: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas, and their prognoses are still poor because of frequent relapses and the absence of optimal standard therapy. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the backbone of frontline chemotherapy for PTCL for many years. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL. Thus, we conducted a randomized phase II study to compare the efficacy of CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED). Patients and Methods: This study was a phase II, multicenter, open-label randomized trial at 21 hospitals that belonged to the Consortium for Improving Survival of Lymphoma (CISL) in Korea (CISL-1504/ROSE study). Eligible participants were patients aged 20–65 years with previously untreated histologically confirmed PTCLs based on the World Health Organization classification 2008 including PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large-cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), and hepatosplenic T-cell lymphoma (HSTL). Patients with ALK-positive ALCL, extranodal NK/T-cell lymphoma, and mycosis fungoides/sezary syndrome were not included in the study. Patients were randomized at a 1:1 ratio to receive either CHOP or ICED every 3 weeks for 6 cycles. Upfront autologous stem cell transplantation (ASCT) was done for patients achieving complete or partial response and the primary end point was progression-free survival (PFS). Results: Between September 2015 and March 2021, 145 patients were screened, and 138 patients were enrolled. The characteristics were not different between CHOP (n = 69) and ICED (n = 66), and PTCL-NOS (n = 60) and AITL (n = 53) were dominant. The objective response rate was not different between CHOP (41/69, 59.4%) and ICED (37/66, 56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%, P = 0.709). Around 80% of patients who completed either CHOP or ICED followed by upfront ASCT showed 3-year overall survival (Figure 1). There was no statistically significant difference in PFS between the CHOP and ICED arms for any subgroup analyzed except AITL. CHOP was favored over ICED in AITL patients, whereas ICED was favored over CHOP in EATL/HSTL patients. ICED was associated with more anemia, neutropenia, and thrombocytopenia of all grades and grade 3 or worse, and the frequency of febrile neutropenia was higher in the ICED arm. Keywords: aggressive T-cell non-Hodgkin lymphoma, chemotherapy, stem cell transplant No conflicts of interests pertinent to the abstract.

ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR SHR2554 IN RELAPSED OR REFRACTORY (R/R) PERIPHERAL T‐CELL LYMPHOMA (PTCL): UPDATED OUTCOMES FROM THE FIRST‐IN‐HUMAN PHASE 1 STUDY

Introduction: Inhibition of histone methyltransferase EZH2 represents a rational therapeutic strategy for lymphomas. SHR2554 is an oral small-molecule inhibitor exhibiting potent selectivity for EZH2. The multicenter, 2-part, phase 1 study was initiated to assess SHR2554 in patients (pts) with r/r lymphomas (NCT03603951). In part I, 350 mg BID was established as the recommended phase 2 dose (RP2D) based on the findings in the dose-escalation and expansion phases; subsequently, pts with selected lymphoma subtypes were recruited in the clinical expansion phase to receive SHR2554 at RP2D (Y Song et al. Lancet Haematol, 2022). Here we report the updated results of part I focusing on PTCL pts at RP2D. The prognosis of PTCL is extremely poor due to low response to chemotherapy regimens and limited treatment options thereafter, highlighting an urgent, unmet medical need. Methods: Pts with histologically confirmed PTCL that had relapsed or were refractory to ≥1 line of prior systemic therapy were eligible for inclusion in part I of this study. Efficacy and safety were assessed in PTCL pts who received at least one dose of SHR2554 at 350 mg BID. Results: Totally, 28 pts were included in this analysis: median age, 56 y (range 30–70); ECOG PS 1, 64.3% (18/28); median lines of prior systemic therapies, 2 (range 1–14). At data cutoff on 31 August 2022, the median follow-up duration was 11.9 mo (range 0.9–23.9). 17 pts achieved complete or partial response, resulting in a confirmed objective response rate (ORR) of 60.7% (95% CI 40.6–78.5). Responses were still ongoing in 58.8% (10/17) of the responders; estimated median duration of response (DoR) was 12.3 mo (95% CI 7.4–NR). 16 (57.1%) pts had disease progression or died; median progression-free survival (PFS) was 11.1 mo (95% CI 5.3–22.0). 4 (14.3%) deaths occurred; 1-y overall survival rate was 92.2% (95% CI 72.1–98.0). Of the 28 pts, 17 were diagnosed with angioimmunoblastic T-cell lymphoma (AITL), and 11 had PTCL not otherwise specified (PTCL-NOS). AITL pts showed better outcomes than PTCL-NOS pts: ORR, 76.5% versus 36.4%; median DoR, 20.3 versus 3.3 mo; median PFS, 22.1 versus 5.0 mo (Table). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 14 of the 28 pts (50.0%), with the most common being decreased platelet count (32.1%), decreased white blood cell count (14.3%), decreased neutrophil count (14.3%), and anemia (14.3%). One (3.6%) pt discontinued treatment due to TRAE (interstitial lung disease). No treatment-related deaths were reported. Conclusions: This extended follow-up analysis further provides evidence of potent anti-tumor activity, durable response, and acceptable safety of SHR2554 in pts with r/r PTCL. The research was funded by: The study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. Keywords: aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract Y. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals J. Shen Employment or leadership position: Jiangsu Hengrui Pharmaceuticals Z. Xiao Employment or leadership position: Jiangsu Hengrui Pharmaceuticals

A multi-institutional prospective cohort study of minimal residual disease in peripheral T-cell lymphoma: Impact of autologous stem cell transplant.

7563 Background: Roughly 80% of pts with peripheral T-cell lymphomas (PTCL) respond to CHOP-based therapy but 5-yr survival ranges between 20-40%. The high relapse rate after complete response (CR) suggests more sensitive response assessment, such as minimal residual disease (MRD) testing, could have prognostic or predictive value. Next generation sequencing (NGS) of the T-cell receptor (TCR) can detect a known TCR clonotype at 10-5. In a prospective study, we evaluated the utility of MRD testing via TCR NGS in PTCL (NCT03297697). Here we report results for pts pre- and post-autologous stem cell transplant (ASCT). Methods: This investigator-initiated, multi-institutional, prospective cohort study assessed MRD testing by TCR NGS in PTCL. Pts with previously untreated PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), PTCL with T-follicular helper (TFH) phenotype, or monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) treated with anthracycline-based curative-intent therapy were eligible. Baseline TCR (TRG or TRB) clonotypes were established from diagnostic tissue or peripheral blood if tissue was not available. TCR clonality was determined positive via the LymphoTrack TRG/TRB Assays – MiSeq (Invivoscribe, San Diego, CA) when top % reads were ≥2.5% and ≥2x above background. Samples were obtained at diagnosis (pre-treatment), following induction therapy (EOT/pre-ASCT), and serially post-ASCT. Results: Of 43 enrolled pts, 19 underwent consolidative ASCT, of which 10 had post-ASCT samples available for MRD testing (Table). Median age at ASCT was 62 years (range: 38-77). Baseline TCR clonotypes were identified in 10/10 pts. At pre-ASCT evaluation, 7/10 pts had detectable TCR MRD (‘pos’) and 3/10 pts had TCR MRD below the level of detection (‘neg‘). Of the 3 MRD neg pts pre-ASCT, 2 had CR and 1 had PR by PET-CT. All 7 TCR MRD pos pts pre-ASCT had CR by PET-CT. Of 7 MRD pos pts pre-ASCT, 6 remained MRD pos and 1 became MRD neg post-ASCT. Of the 4 MRD neg pts post-ASCT, none have relapsed at 52, 31, 34, and 31 mo post-ASCT. Of 7 MRD pos pts pre-ASCT, 3 have relapsed following ASCT (at 3, 9, and 29 mo post-ASCT). Conclusions: In this cohort of patients with PTCL receiving consolidative ASCT in CR1, all 4 pts with negative TCR MRD post-ASCT remain in remission at median follow up of 32.5 mo post-ASCT. The negative predictive value of TCR NGS MRD post-ASCT should be further evaluated. Clinical trial information: NCT03297697 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Relapsed/refractory (r/r) peripheral T cell lymphomas (PTCL) are highly aggressive tumors associated with very poor prognosis. We recently described a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2) (Maciocia, PM. et al. Nat Med, 2017) which can spare a proportion of the normal T cell compartment. Here we describe first in human clinical findings of AUTO4, a TRBC1 directed autologous CAR T cell therapy for patients with TRBC1-positive PTCL. Methods: NCT03590574 is an ongoing, multi-centre, single-arm phase 1/2 study of AUTO4 in r/r TRBC1-positive PTCL. Here we report the findings of the dose escalation. Four dose levels were explored: 25 × 106, 75 × 106, 225 × 106, and 450 × 106 CAR T cells were administered as a single dose. CAR T-cell products were generated using a semi-automated closed process. The initial AUTO4 manufacturing process A was optimized and is now being used in process B to define the recommended phase 2 dose. Primary endpoints in phase 1 are incidence of ≥Grade 3 toxicity occurring within 60 days of AUTO4 infusion and the frequency of dose limiting toxicities (DLT) within 28 days of AUTO4 infusion. Overall response (CR + PR) rate by Lugano PET-CT criteria is a secondary endpoint. Results: As of 8 February 2023, 12 patients (10 process A, 2 process B) have been treated with AUTO4. The median age was 57 years (range 34–72) with a median prior lines of 2 (range 1–5). 7 patients were diagnosed with PTCL-NOS, 4 with AITL (Angioimmunoblastic T-cell lymphoma) and 1 with ALCL (Anaplastic large cell lymphoma). Chemotherapy bridging was given to 70% of patients and 4/8 CD30+ patients recieved brentuximab as bridging or as prior line therapy. 3/12 patients had prior autoSCT. The most common treatment adverse events were transient Grade1–4 neutropenia, thrombocytopenia. Lymphopenia was observed with CD3+ lymphocytes recovering to baseline levels after pre-conditioning. No ≥Grade 3 infections were observed. Any grade CRS was observed in 6/12 patients (5 at 450 × 106, 1 at 250 × 106) and one patient developed Grade 3 CRS which resolved within 3 days. No ICANS or DLTs were observed. Response at month 1 was evaluable in 9/10 patients using process A. Five patients were in complete metabolic response (CMR) (1/5 was in CMR at the time of lymphodepletion), 1 patient achieved a partial response (PR) and 3 patients had no response. At the 450x106 dose level, 3/4 patients achieved CMR at month 1, and 2 of them are in ongoing remission at 12 and 15 months, respectively. The efficacy non-evaluable patient at month 1, due to COVID19 infection, showed no response at month 3 but achieved a delayed PR by month 9 without any further treatment. Conclusions: AUTO4 was well tolerated with no DLT. Ongoing CMR at months 12 and 15 are encouraging. Updated data and longer follow up using the improved manufacturing process B will be presented. The research was funded by: Autolus Ltd Keywords: aggressive T-cell non-Hodgkin lymphoma, cellular therapies, ongoing trials Conflicts of interests pertinent to the abstract J. Shang Employment or leadership position: Autolus Therapeutics E. Xue Employment or leadership position: Autolus Therapeutics M. Zhang Employment or leadership position: Autolus Therapeutics S. Basilico Employment or leadership position: Autolus Therapeutics M. Raymond Employment or leadership position: Autolus Therapeutics P. Lao-Sirieix Employment or leadership position: Autolus Therapeutics K. Lilova Employment or leadership position: Autolus Therapeutics W. Brugger Employment or leadership position: Autolus Therapeutics M. Pule Employment or leadership position: Autolus Therapeutics

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. Standard CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy is still the most widely used regimen for front-line management. To explore new targeted drugs in PTCL, we conducted a phase 2, multi-center, non-randomized clinical trial, comparing the efficacy and safety of targeted agents combined with CHOP (CHOPX) with CHOP in newly diagnosed patients with PTCL. Methods: The primary outcome was complete response rate (CRR) at the end of treatment (EOT). Patients with newly diagnosed PTCL had enough tumor tissue for next generation sequencing (NGS) and were assigned to CHOPX and CHOP group based on investigators’ discretion. Patients in CHOPX group received intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (up to a maximum of 2 mg) on day 1, and oral prednisone 60 mg/m2 (up to a maximum of 100 mg) on day 1–5 every 21 days at the first cycle. X (i.e., targeted agent) was added from the second to sixth cycles as following, intravenous decitabine 10 mg/m2 on day -5 to -1 if with TP53 mutation. Subcutaneous azacytidine 100 mg on day −7 to −1 if with TET2/KMT2D mutation. Oral chidamide 20 mg on day1, 4, 8, 11 if with CREBBP/EP300 mutation. Oral lenalidomide 25 mg on day 1–10 if without above mutations. Patients in control group received standard CHOP regimen for 6 cycles. Analysis of efficacy and safety was of the intent-to-treat population. The study was registered with ClinicalTrials.gov, number NCT04480099. Results: Between 20 June 2020 and 22 September 2022, 108 patients were assessed for eligibility in the study. Ten patients met exclusion criteria and 2 patients withdrew informed consent before treatment. Forty-eight patients in the CHOPX group and 48 patients in the CHOP group were included into intent-to-treatment population. Baseline patient characteristics like age, gender, Ann Arbor stage, performance status, prognostic risk group was comparable between CHOPX and CHOP groups. The most common pathological subtypes were angioimmunoblastic T-cell lymphoma (67% vs. 60%), PTCL-not otherwise specified (17% vs. 21%), anaplastic T-cell lymphoma (6% vs. 8%) in the CHOPX and CHOP groups. As of 1 February 2023, 91 patients completed response evaluation at EOT. CRR in the CHOPX group was higher than the CHOP group (58% [25/43] vs. 33% [16/48]). The most common grade 3–4 hematological adverse events in CHOPX group were neutropenia (61%) and febrile neutropenia (27%). Conclusions: Preliminary analysis showed targeted agents combined with CHOP was effective and safe compared with standard CHOP in PTCL. Therapeutic strategy specifically towards molecular features may change current PTCL management in front-line setting. Keywords: combination therapies, molecular targeted therapies No conflicts of interests pertinent to the abstract.

A REAL‐WORLD STUDY OF CHIDAMIDE FOR PATIENTS WITH PERIPHERAL T‐CELL LYMPHOMA IN CHINA

Background: Peripheral T-cell lymphoma (PTCL) is featured with a poor survival outcome. Targeting histone deacetylases (HDACs) has become a novel treatment option for PTCL. Chidamide is the first oral selective HDAC inhibitor. Objective: This observational study aimed to investigate the efficacy and safety of Chidamide in patients with PTCL. Methods: From June 2015 to April 2022, 49 PTCL patients treated with Chidamide were included in this study. Objective responses, progression-free survival (PFS), overall survival (OS), and safety were analyzed. Results: The median age was 59 years (range, 30–85 years). Angioimmunoblastic T-cell lymphoma (AITL, 57.1%) was the main pathological subtype, followed by PTCL-not otherwise specified (PTCL-NOS, 14.3%), NK/T-cell lymphoma (NKTCL, 8.2%), anaplastic large cell lymphoma (ALCL, 6.1%) and other subtypes (14.3%). 77.6% of patients were previously untreated. 91.8% of patients had stage Ⅲ/Ⅳ disease. Thirty-three patients achieved objective responses with an overall response rate (ORR) of 67.4%, including 21 patients with complete response (CR). The 2-year PFS rate and 2-year OS rate were 51.5% and 68.5%, respectively. Among the 27 previously untreated patients who received Chidamide combined with chemotherapy, the ORR of all various PTCL subtypes, AITL and PTCL-NOS were 85.2%, 68.8% and 75.0%, respectively. The most common adverse events (AEs) were hematological toxicities. 24.5% of patients reduced the dosage or stopped using Chidamide due to AEs. No treatment-related death occurred. Conclusion: The favorable efficacy and safety profiles indicate that Chidamide would be a new therapeutic option in patients with PTCL. Encore Abstract - previously submitted to EHA 2023 Keyword: Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Emerging evidence suggests the prognostic impact of the tumor microenvironment (TME) in peripheral T-cell lymphomas (PTCLs). To better understand PTCL pathobiology, we performed an integrative multi-omics study to explore the genetic subtypes and the TME signatures of PTCLs, especially nodal T-follicular helper T-cell lymphomas (nTFHLs) and PTCL, not otherwise specified (PTCL-NOS). Method: We performed whole-exome sequencing of 92 nTFHLs and 37 PTCL-NOSs, a total of 129 cases. Ninety-two nTFHLs included 85 angioimmunoblastic T-cell lymphomas (AITLs), four nPTCL with TFH phenotypes, two follicular T-cell lymphomas, and one unclassifiable nTFHL. Genetic drivers were integrated using non-negative matrix factorization consensus clustering (NMF). We estimated the proportion of immune cell fractions from bulk RNA sequencing data (n = 57) using CIBERSORTx and classified the TME signatures using hierarchical clustering. Results: NMF clustering analysis revealed three genetic subtypes within our cohort, except for 10 cases lacking recurrent genetic abnormalities (denoted as cluster 0). C2 was characterized by TP53 mutation, CDKN2A loss, PTEN loss, and chromosomal instability, corresponding to the previously described GATA3-PTCL subtype. C1 and C3 shared TFH-related genomic alterations, but C3 had significantly higher frequencies of chromosome (Chr) 5 gain, Chr 21 gain, RHOA, IDH2, and CD28 mutations. A higher frequency of rash and higher C-reactive protein levels than the other AITLs characterized C3-AITL. Pairwise association analysis of genomic alterations revealed that multiple TET2 mutations, rather than a single TET2 mutation, significantly co-occurred with IDH2 and RHOA mutations. A Bradley-Terry model estimated that the first TET2 and DNMT3A mutations occurred earlier, and the second or later TET2, RHOA, and IDH2 mutations occurred later. Compared to C1, significantly inferior survival was observed in C2 (hazard ratio (HR), 2.52; 95% CI, 1.37–4.63) and C3(HR, 2.14; 95% CI, 1.17–3.89; Figure A). The TME signatures were divided into TME1 (B-cells and follicular helper T-cells), TME2 (activated memory CD4 T-cells, M2 macrophages, and CD8 T-cells), and TME3 (naïve CD4 T-cells and activated mast cells). mTORC1 signaling was enriched in the TME2 signature compared to TME1 and TME3 signatures. The TME2 signature was significantly associated with shorter survival than the TME3 signature (HR: 3.4, 95% CI 1.6–7.5; Figure B). C2 had significantly more TME2 signature than C1 (64.3% vs. 7.7%), while C1 had significantly more TME3 signature than C2 (80.8% vs. 28.6%, p = 0.006; Figure C). Keywords: genomics, epigenomics, and other -omics, microenvironment Encore Abstract—previously submitted to EHA 2023 The research was funded by: Japan Society for the Promotion of Science KAKENHI grants (grant numbers: 19K23879, 22K19451, and 21H02945) and Japan Agency for Medical Research and Development (AMED) grants (20ck0106544 and 21ck0106644)

Involvement of spleen is associated with shorter survival in patients with angioimmunoblastic T cell lymphoma.

The prognosis of patients with angioimmunoblastic T cell lymphoma (AITL) remains dismal, with their 5-year overall survival (OS) and progression-free survival (PFS) rates of 32-41% and 18-38%, respectively. Spleen involvement occurs in a proportion of patients with AITL. But still, it is unclear whether spleen involvement impacts the prognosis of AITL patients. In this study, we aim to establish new prognostic indicators for the identification of high-risk patients to draft optimal treatment regimens. We collected and counted the clinical data of 54 patients with AITL treated with CHOP-based first-line chemotherapy regimen between 2010 and 2021 at Hubei Cancer Hospital and Hunan Cancer Hospital. In addition, all patients received PET-CT scan prior to receiving treatment. We performed univariate and multivariate analyses to assess the predictive role of tumor characteristics, laboratory, and radiographic data for the prognosis of AITL. We observed that PFS and OS are worse in patients with high ECOG scores, spleen involvement, and low serum albumin levels in patients with AITL. In univariate analysis, stage (HR 3.515 [1.142-10.822], p = 0.028) and spleen involvement (HR 8.378 [1.085-64.696, p = 0.042) were correlated with PFS in patients with AITL. Besides, stage (HR 3.439 [1.108-10.674], p = 0.033) and spleen involvement (HR 11.002 [1.420-85.254], p = 0.022) were significantly correlated with OS. Consistently, spleen involvement was correlated with OS (HR 16.571 [1.350-203.446], p = 0.028) and PFS (HR 10.905 [1.037-114.690], p = 0.047) in AITL patients in a multivariate analysis. This study demonstrates that spleen involvement might be used as a prognostic indicator for AITL patients.

All-oral low-dose chemotherapy TEPIP is effective and well-tolerated in patients with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogenous hematologic malignancy with poor prognosis especially in elderly and frail patients who are not eligible for intensive treatment. The resulting palliative setting necessitates tolerable but effective schedules for outpatient treatment. TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. In this observational retrospective, single-center study, the safety and efficacy of TEPIP was evaluated in 12 patients (pts.) with PTCL treated at the University Medical Center Regensburg between 2010 and 2022. The endpoints were overall response rate (ORR) and overall survival (OS), and adverse events were individually reported according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. The enrolled cohort was characterized by advanced age (median 70 years), extensive disease (100% Ann Arbor ≥stage 3), and poor prognosis (75% high/high-intermediate international prognostic index). The most common subtype was angioimmunoblastic T-cell lymphoma (8/12), and 11/12 patients had relapsed or refractory disease at TEPIP onset with a median of 1.5 prior treatment regimens. After a median of 2.5 TEPIP cycles (total of 83 cycles), the ORR was 42% (complete remission 25%), and the OS reached a median of 185 days. Any grade of adverse event (AE) occurred in 8/12 patients, with four patients showing AE ≥CTCAE grade 3 (33%), and the AEs were mainly non-hematological. TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.

Bazex Syndrome Associated with Angioimmunoblastic T-cell Lymphoma

Bazex syndrome, also known as Acrokeratosis paraneoplastica, is a paraneoplastic disorder characterized by erythematous psoriasiform plaques involving the nose, ears, and acral sites. Although classically associated with squamous cell carcinomas of the upper aerodigestive tract, it has also been reported in association with adenocarcinoma, genitourinary tumors, multiple myeloma, and rarely, peripheral T-cell lymphoma and follicular lymphoma in-situ. Herein, we present a patient with Bazex syndrome associated with angioimmunoblastic T-cell lymphoma (AITL), a rare association not previously reported in the literature.

Transdifferentiation, phenotypic infidelity, progression, and transformation in T/NK-cell neoplasms: Report from the 2021 SH/EAHP Workshop.

Sessions 8 and 9 of the 2021 Society for Hematopathology and the European Association for Haematopathology Workshop aimed to collect examples of transdifferentiation, lineage infidelity, progression, and transformation in precursor and mature T/natural killer (NK)-cell neoplasms. Twenty-eight cases were submitted and analyzed, with whole-exome sequencing and genome-wide RNA expression analysis performed in a subset of the cases. In session 8, 7 T-lymphoblastic lymphoma/leukemia cases were received that showed transdifferentiation to clonally related mature myeloid hematopoietic neoplasms, including 6 histiocytic/dendritic cell lineage neoplasms and a mast cell sarcoma. Session 9 included 21 mature T-cell neoplasms that were grouped into 3 themes. The first one addressed phenotypic infidelity in mature T-cell lymphomas (TCLs) and included 8 TCLs expressing aberrant antigens, mimicking classic Hodgkin and non-Hodgkin B-cell lymphomas. The second theme addressed disease progression in TCL and included 5 cutaneous T-cell lymphoproliferative disorders and 2 T-cell large granular lymphocyte proliferations with subsequent progression to systemic TCL. The third theme included 6 patients with TCL with T-follicular helper phenotype, mainly angioimmunoblastic T-cell lymphoma, with concurrent/subsequent clonal hematopoiesis or myeloid neoplasms and/or subsequent/concomitant diffuse large B-cell lymphoma. This cohort of cases allowed us to illustrate, discuss, and review current concepts of transdifferentiation, aberrant antigen expression, and progression in various T/NK-cell neoplasms.

DNMT3AR882H accelerates angioimmunoblastic T-cell lymphoma in mice.

DNA methylation-related genes, including TET2, IDH2, and DNMT3A are highly frequently mutated in angioimmunoblastic T-cell lymphoma (AITL), an aggressive malignancy of T follicular helper (Tfh) cells associated with aberrant immune features. It has been shown that TET2 loss cooperates with RHOAG17V to promote AITL in mice but the functional role of DNMT3A mutations in AITL remains unclear. Here, we report that DNMT3AR882H, the most common mutation of DNMT3A in AITL, accelerates the development of Tet2-/-; RHOAG17V AITL in mice, indicated by the expansion of malignant Tfh cells and aberrant B cells, skin rash, and significantly shortened disease-free survival. To understand the underlying cellular and molecular mechanisms, we performed single-cell transcriptome analyses of lymph nodes of mice transplanted with Tet2-/-, Tet2-/-; RHOAG17V or DNMT3AR882H; Tet2-/-; RHOAG17V hematopoietic stem and progenitor cells. These single-cell landscapes reveal that DNMT3A mutation further activates Tfh cells and leads to rapid and terminal differentiation of B cells, probably through enhancing the interacting PD1/PD-L1, ICOS/ICOSL, CD28/CD86, and ICAM1/ITGAL pairs. Our study establishes the functional roles of DNMT3A mutation in AITL and sheds light on the molecular mechanisms of this disease.

Frontline Management of Nodal Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) represent only 10%-15% of all non-Hodgkin lymphoma but encompass a diverse group of diseases with over 30 different subtypes. As a result of both disease heterogeneity and rarity, therapeutic progress of PTCLs has lagged behind B-cell lymphomas with very few randomized controlled studies to guide management. The most common subtypes are the so-called nodal PTCLs: PTCL-not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL), and nodal T follicular helper cell lymphoma (TFHL) lymphoma, the latter of which includes angioimmunoblastic T-cell lymphoma. Anthracycline-based primary chemotherapy is still the mainstay of treatment for these common PTCL subtypes, but in recent years, we have moved into an era where more personalized therapy can be applied in some settings. Cyclophosphamide, doxorubicin, prednisone, and brentuximab vedotin CHP-BV is the first therapy in PTCL to show an overall survival benefit and represents a new standard for ALCL; however, there is less therapeutic certainty in other CD30-positive PTCLs. Recurrent mutations of epigenetic modifier genes typify TFHLs lymphomas, and collective studies demonstrate a heightened sensitivity to epigenetic therapies, leading to trials integrating these agents in the frontline setting. Molecular studies of PTCL-NOS have defined at least two subtypes, GATA3 and TBX21, the former having a poorer prognosis, but how this guides therapeutics remains unknown. Outside of ALCL, there is a growing debate as to whether trials should focus on adding a novel agent to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or whether combination novel therapies should be explored in the frontline therapy setting. Finally, the role of consolidative autologous stem-cell transplant in first remission remains an area of active debate.