Common Peripheral T-cell Lymphoma Research Articles

Valemetostat for Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: Treatment (Tx) options for T-cell non-Hodgkin lymphomas (T-NHLs) are limited and prognosis is too often poor for patients (pts) with relapsed or refractory (R/R) disease. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional profile is broadly associated with gene silencing. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that prevents H3K27me3 and increases expression of genes involved in immune function ( SLA, PAG1) that can be silenced by H3K27me3. Valemetostat was approved in Japan for the Tx of R/R adult T-cell leukemia/lymphoma (ATLL) in 2022. The clinical activity of valemetostat in pts with R/R NHLs was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary outcomes for pts in J101 with R/R T-NHLs treated with valemetostat. Methods: This open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were ≥ 18 (US) or ≥ 20 (Japan) years (y) of age and relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation phase (Japan only) followed by a dose-expansion phase (Japan & US). Enrollment in the expansion phase was limited to pts with R/R peripheral T-cell lymphoma (PTCL) or ATLL. Pts received valemetostat once daily in continuous 28-day (d) Tx cycles at 150-300 mg/d in the escalation phase and 200 mg/d in the expansion phase until disease progression or intolerance. Key endpoints for the dose-escalation and dose-expansion cohorts were safety and PK parameters. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). DOR and PFS were estimated using Kaplan-Meier methods. Results for PTCL and ATLL are reported separately. Results: At the primary data cutoff (Dec 31, 2022), 71 pts were included in the efficacy and safety analyses; 57 with PTCL and 14 with ATLL. Median age at baseline was 68.0 (range 26-83) y in the PTCL group and 66.5 (37-78) y in the ATLL group, and median prior therapies were 2.0 (1-8) and 2.5 (1-8), respectively; 16 (28%; 14 autologous, 2 allogeneic) pts with PTCL and 2 (14%, both allogeneic) with ATLL had previously undergone transplant. The most common PTCL subtypes were PTCL, not otherwise specified (PTCL, NOS; n = 26, 46%) and angioimmunoblastic T-cell lymphoma (AITL; n = 23, 40%). Tx was ongoing for 8 (11%) pts at data cutoff. All 71 pts included at data cutoff experienced ≥ 1 Tx-emergent adverse event; 59 (83%) pts had a Tx-related adverse event (TRAE). The most common all-grade TRAEs were cytopenias, dysgeusia, and alopecia; the most frequent grade ≥ 3 TRAEs were decreased neutrophil (17%), lymphocyte (11%), and platelet (14%) counts ( Table 1). TRAEs led to Tx discontinuation for 4 (6%) pts (1 each: acute myeloid leukemia, myelodysplastic syndrome, colitis, and acute kidney injury), dose reduction for 5 (7%) pts, and Tx interruption for 18 (25%) pts. The ORR was 55% (30/55) in the PTCL group and 64% (9/14) in the ATLL group, with CR rates of 31% (17/55) and 29% (4/14), respectively; within the PTCL group, the ORR among evaluable pts was 50% (13/26) for PTCL, NOS and 64% (14/22) for AITL ( Table 2). Median times to response were 1.8 (range 1.0-5.6) months (mo) in the PTCL group and 1.9 (1.7-19.4) mo in the ATLL group. Median DOR was 21.9 mo (95% confidence interval [CI], 10.2 mo to not reached [NR]) in the PTCL group (median follow-up 16.4 mo) and 21.2 (95% CI, 1.4 to 38.7) mo in the ATLL group (median follow-up 23.0 mo). Median PFS was 7.7 and 4.1 mo, respectively (median follow-up 18.2 mo and NR). Conclusions: Valemetostat was well tolerated and showed encouraging clinical activity in pts with R/R T-NHLs. Cytopenias were common but could usually be managed without Tx discontinuation. Valemetostat induced durable responses, with median DOR of > 1.5 y in both the PTCL and ATLL groups. Results for pts in this trial with R/R B-NHLs (Izutsu et al) and from a phase 2 trial in R/R T-NHLs (Horwitz et al) are reported separately.

Outcomes of Contemporary Novel Agent and Stem Cell Transplantation in Relapsed/Refractory PTCL

Background Outcomes in relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) continue to be suboptimal. In the last decade, several novel agents have been approved; however, their impact on survival remains to be defined. In this multi-center retrospective analysis, we assessed survival following initial progression with respect to novel agent exposure with and without the use of stem cell transplant (SCT). Methods Patients with PTCL diagnosed between 1998-2021 at New York Presbyterian Hospitals, Columbia and Cornell, were included after IRB approval. Medical records were reviewed for baseline characteristics and treatment parameters. In the second line setting, each patient fell into one of four categories: 1. novel agent containing regimen only ( novel-containing only), 2. novel agent containing regimen with SCT at end of second line ( novel + SCT), 3. chemotherapy alone ( chemo-only), and 4. chemotherapy with SCT at end of second line ( chemo + SCT). Event-free survival (EFS) was calculated as time from 1 st progression to 2 nd progression, re-treatment, or death. Subsequent OS (sOS) was calculated from date of first progression to death or last follow-up. Kaplan-Meier method was used to estimate survival probability. Survival difference was tested by log-rank and Cox regression analysis. Results A total of 348 patients with PTCL were identified, of which 189 had R/R disease and 184 had sufficient data for analysis. The median follow-up was 62.5m. Baseline characteristics are shown in Table 1. Most common PTCL subtypes were AITL (N=52, 28.3%), PTCL-NOS (N=39, 21.2%), ATLL (N=34, 18.5%), and ALCL (ALK- = 13, ALK+ = 11, n=24, 13%). Median age at diagnosis was 58 years. Median EFS and sOS from date of initial progression for the entire cohort was 5.0m and 25.1m, respectively. In the second-line setting, 92 (50%) received a novel-containing only, 62 (34%) patients received chemo-only, 17 (9%) received chemo + SCT, and 13 (7%) received novel + SCT. Median EFS from first progression among patients who received second-line novel + SCT was 16.0m (95% CI 6.0 - NR), chemo + SCT 15.0m (95% CI 6.2 - 24.5), novel-containing only 3.9m (95% CI 3.5 - 5.3), and chemo-only 4.1m (95% CI 2.9 - 5.1) as shown in Figure 1. Two-year EFS favored novel + SCT at 38.5m (95% CI 12.0 - 64.9) and chemo + SCT 34.0m (95% CI 10.8 - 57.1), compared to novel-containing only at 18.3m (95% CI 10.1 - 26.6) and chemo-only 11.3m (95% CI 3.0 - 19.6), with p < 0.001 across all groups. Median sOS among patients who received second-line novel + SCT was 70.7m (95% CI 16.0 - NR), chemo + SCT not reached (95% CI 15.0 - NR), novel-containing only 23.3m (95% CI 10.5 - NR), and chemo-only 16.7m (95% CI 11.7 - 27.0). Two-year sOS favored novel + SCT at 74.6m (95% CI 49.7 - 99.5) and chemo + SCT 70.4m (95% CI 48.5 - 92.2) compared to novel-containing only at 49.4m (95% CI 37.9 -61.0) and chemo-only 43.4m (95% CI 30.0 - 56.9), with p =0.014 across all groups. Conclusion This multi-center study represents one of the largest retrospective R/R PTCL cohorts in the modern era with sOS of 25.1m, which compares favorably to historical data collected a decade ago reporting a sOS of 5.5m in R/R patients receiving chemo-only (Mak 2013), however, compares similarly to more recent data from the COMPLETE study (Lansigan 2019). This improvement in sOS may reflect availability of more effective therapies for sequencing in the novel agent era. Our data suggests that SCT in second-line setting is associated with improved EFS and sOS for both those treated with novel agent containing regimens and chemotherapy. Differences are more prominent for two-year EFS and sOS, favoring SCT arms and novel agents. However, the retrospective nature of our data limits definitive conclusion of benefit derived from SCT in the second-line setting, which underscores the need for prospective studies in this area. *This work has been funded ASH RTAF

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5months for PTCL with a TP53 mutation (n= 21) vs 10.5months for PTCL without a TP53 mutation (n= 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n= 9), CDKN2A-deleted PTCL correlated with inferior OS, witha median of 17.6months vs 56.7months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

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.

PTCL, NOS: An update on classification, risk-stratification, and treatment.

The peripheral T-cell lymphomas (PTCL) are relatively rare, heterogeneous, and therapeutically challenging. While significant therapeutic gains and improved understanding of disease pathogenesis have been realized for selected PTCL subtypes, the most common PTCL in North America remains "not otherwise specified (NOS)" and is an unmet need. However, improved understanding of the genetic landscape and ontogeny for the PTCL subtypes currently classified as PTCL, NOS have been realized, and have significant therapeutic implications, which will be reviewed here.

Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice.

Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis. We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays. In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners. We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.

Clinical Characteristic and Survival Outcome of Peripheral T Cell Lymphoma in a Chinese Population

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group comprising about 10-15% of non-Hodgkin lymphomas in Western populations. Only a minority (~30%) of patients with the most common PTCL subtypes achieve a durable remission and long-term survival. Data on the clinical features of PTCL in a Chinese population are limited. Methods: We retrospectively reviewed 342 patients with pathologically diagnosed T cell lymphoma at Guangdong Provincial People's Hospital from June 2007 through March 2019. We evaluated the incidence of PTCL subtypes, clinical characteristics and survival status. Results: Of the 342 patients, 17.3% (n=59) had PTCL-not otherwise specified(NOS), 9.4% (n=32) had angioimmunoblastic T-cell lymphoma(AITL), 19.6% (n=67) had anaplastic large cell lymphoma(ALCL) (anaplastic lymphoma kinase positive ALCL:12.0%, n=41; anaplastic lymphoma kinase negative ALCL: 9.6%, n=26), 36.2%(N=124) had NK/T cell lymphoma, 12.9% (n=44)had lymphoblastic lymphoma(LBL), and 4.6%(n=16) had other subtypes. For next data analysis, NK/T cell lymphoma and LBL were excluded. Finally, a total of 164 patients with integrally follow-up information were analyzed. The median age was 49.5 years (range 15-87) old and the median follow-up time was 15.8 months (range 0.5-124.3). Most patients were males (62.0%) with advanced stage disease (III/IV, 74.5%), and 51.0% of patients presented with B symptoms and 83.0% with no bulky disease. For the total population, the median progression-free survival(PFS) and overall survival(OS) was 6.5 months and 13.5 months, respectively. ALCL patients had better PFS and OS than PTCL-NOS and AITL (PFS: 51.2 vs. 5.8 vs.4.7 months, P = 0. 000; OS: not reached vs. 13.4 vs. 8.8 months, P = 0.000). There were no difference of PFS and OS between PTCL-NOS and AITL(P = 0. 550 and P = 0. 333, respectively). Conclusions: ALCL has better outcome than other PTCL subtypes. However, no efficacy therapy has emerged for patients with relapsed/refractory PTCL and outcomes in this setting are still poor. Novel potential targets for PTCL, with particular focus on identifying markers of response and resistance need further investigation. Disclosures Li: Guangdong Province Hospital: Employment.

Lenalidomide in Combination with CHOP in Patients with Angioimmunoblastic T-Cell Lymphoma (AITL): Final Analysis of Clinical and Molecular Data of a Phase 2 Lysa Study

Lenalidomide in Combination with CHOP in Patients with Angioimmunoblastic T-Cell Lymphoma (AITL): Final Analysis of Clinical and Molecular Data of a Phase 2 Lysa Study

Molecular Subgroups of Peripheral T-Cell Lymphoma Evolve By Distinct Genetic Pathways

Peripheral T-cell lymphoma (PTCL) is a group of clinically and pathologically heterogeneous non-Hodgkin lymphomas (NHL). Using gene expression profiling (GEP), we have defined molecular classifiers for PTCL subtypes reflecting their pathobiology and oncogenic pathways (Iqbal et al. 2014). We have also shown associations of specific mutations with the molecular subgroups (Wang et al. 2015). Although genomic information is increasing, the pathogenetic mechanisms of PTCLs remain largely unknown. Therefore, we analyzed copy number variation (CNV) and GEP to identify unique genetic abnormalities in the defined PTCL molecular subgroups.CNV data were generated on fresh frozen or formalin-fixed paraffin-embedded genomic DNA (n=114) on 3 Affymetrix platforms (SNP 6.0, 250K SNP, and OncoScan). Two published cohorts (PTCL-NOS, Hartmann et al. 2010; ALCL, Boi et al. 2013) were included for validation. The gene expression analysis, morphological review and clinical characteristics of these cases have been included in previous studies (Iqbal et al. 2010, 2014).Angioimmunoblastic T-cell lymphoma (AITL) represents 20% of all PTCL cases. The most recurrent CNV in AITL was chromosome (chr) 5 gain (39%), followed by chr 21 gain (21%). Interestingly, chr 21 gain co-occurred with chr 5 gain (p=0.003). No recurrent losses (≥20%) were identified among these cases. Molecularly re-classified AITL cases from morphologically classified PTCL-NOS cases showed concordant results with bonafide AITL cases. Of the commonly mutated genes, DNMT3A, IDH2, RHOA and TET2, only IDH2R172Kshowed a significant association (p=0.012) with chr 5 gain. GEP showed enrichment of gene signatures associated with oxidative phosphorylation (PGC-1α target genes) in cases with chr 5 gain.PTCL, not otherwise specified (PTCL-NOS) is the most common PTCL subtype and cannot be further sub-classified using conventional approaches; however, we have identified 2 molecular subgroups within PTCL-NOS, the GATA3 and TBX21 subgroups which are related to 2 distinct T-helper subsets (Iqbal et al. 2014), by employing GEP. Consistent with earlier observations (Hartmann et al. 2010), PTCL-NOS showed remarkably varied CNVs with nearly 50% of cases showing high CNV frequencies. When correlated with molecular subgroups, distinctive CNVs were observed in the molecular GATA3 and TBX21 subgroups. The GATA3 subgroup displayed a large assortment of CNVs. Complete or partial gain of chr 7 (57%) was the most recurrent gain in these cases. Losses affecting 17p, 10q and 9p21, encompassing tumor suppressors such as TP53 (57%), PTEN (43%) and CDKN2A (43%), were frequent in the GATA3 subgroup. The TBX21 subgroup had significantly fewer CNVs, as none were recurring (≥20%); but gains of 5p or 11p were observed in 14%. Additionally, PTCL-NOS cases with ≥10% abnormal genome had significantly poorer overall survival (p=0.012) compared to those with fewer abnormalities. This finding validates the GEP molecularly defined subgroups, as the GATA3 subgroup displayed more CNVs and has been associated with a worse prognosis compared to the TBX21 subgroup (Iqbal et al. 2014).We were able to distinguish CNVs characteristic of the different entities, including the co-occurrence of chr 5 and 21 gains specific in AITL. Gain of 1q (complete or partial) was identified in the GATA3 subgroup of PTCL-NOS and anaplastic lymphoma kinase (ALK) (-) ALCL with equal frequencies (~ 36%), but only 16% in ALK(+) ALCL. Complete or partial gain of chr 7 was also observed in ALCL, but at a considerably lower frequency than in the GATA3 subgroup. Additionally, gain of chr 18 or regions of 17q, and loss of 5q or regions on both arms of chr 9, were more frequent in the GATA3 subgroup compared to other entities. The TBX21 subgroup was primarily differentiated from the GATA3 subgroup by presence of fewer CNVs.Our analysis provides a framework for future investigations into the molecular pathogenesis of PTCL, and highlights potential candidate oncogenes and tumor suppressors deregulated by copy number aberrations. Comparative analysis revealed that certain chromosomal abnormalities are entity-specific. AITL cases with IDH2R172K also had trisomy 5 suggesting that these oncogenic events cooperate in malignant transformation. Thus, the complexity of PTCL is finally becoming clearer with the integration of high resolution molecular techniques for global genomic analysis. DisclosuresNo relevant conflicts of interest to declare.

Phase I/II Multicenter Study of Romidepsin in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma associated with poor prognosis. There is no consensus on standard therapy, and options are limited for patients with relapsed/refractory (R/R) disease. Romidepsin, a potent histone deacetylase inhibitor, has US FDA approval for patients with >=1 prior treatment for PTCL based on 25%-38% overall response rates (ORR) and durable responses (Piekarz et al, Blood. 2011;117:5827; Coiffier et al, J Clin Oncol. 2012;30:631). Here we report results from the phase I/II, multicenter, open-label study of romidepsin in Japanese patients with R/R PTCL or cutaneous T-cell lymphoma (CTCL) (TCL-001; NCT01456039). Methods: Patients aged >=20 years with R/R PTCL or CTCL received romidepsin via a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle until progressive disease or unacceptable toxicity. The phase I portion of the study used a 3+3 design to identify any dose-limiting toxicity (DLT; phase I primary endpoint) with romidepsin 9 mg/m2 (cohort 1) and 14 mg/m2 (cohort 2). The phase II dose was based on the highest dose where =1 day. Assessments of the intent-to-treat (ITT) population included all patients receiving at least 1 dose of romidepsin. Results: The ITT population comprised 48 patients with PTCL and 2 with CTCL (1 each in the 9 and 14 mg/m2 cohorts). The common PTCL subtypes were angioimmunoblastic T-cell lymphoma (AITL, n=21, 44%), PTCL not otherwise specified (PTCL-NOS, n=20, 42%), and anaplastic large-cell lymphoma (ALCL ALK-1 negative, n=3, 6%). Most patients had a favorable ECOG performance status (86% 0-1) and 72% were >=65 years of age. Patients had received a median of 2 prior therapies (range, 1-9). Of 9 patients assessable in phase I (n=3 at 9 mg/m2 and n=6 at 14 mg/m2), none experienced a DLT. The recommended phase II dose was 14 mg/m2 in 40 subsequently treated patients. The overall population received a median of 10 doses (range, 1-135) for a median treatment duration of 12.9 weeks (range, 0.1-184.3; 8 patients were treated for >=36 weeks). The common all-grade adverse events (AEs) were thrombocytopenia (n=49, 98%), lymphopenia (n=44, 88%), leukopenia (n=42, 84%), neutropenia (n=40, 80%), pyrexia (n=33, 66%), dysgeusia (n=31, 62%), decreased appetite (n=28, 56%), and nausea (n=27, 54%). The common grade >=3 AEs were lymphopenia (n=37, 74%), neutropenia (n=27, 54%), leukopenia (n=23, 46%), and thrombocytopenia (n=19, 38%). Of the 39 patients whose CD4+ T-cell counts were monitored, while decreased CD4+ T-cell counts ( Among the 40 patients with PTCL (phase II), the ORR was 43% (95% CI, 27%-58%), including 10 patients (25%) with complete response (CR) or CR unconfirmed (CRu) and 7 (17%) with partial responses (PR) (Table 1). The obtained ORR was significantly higher compared with the threshold ORR of 10% (P Conclusions: Results from this phase I/II study identified a tolerable dose of romidepsin and indicated that romidepsin has an acceptable toxicity profile with clinically meaningful, efficacy in Japanese patients with R/R PTCL. The efficacy and safety data were comparable with results from other romidepsin phase II studies. Disclosures Ogura:Celltrion, Inc.: Consultancy, Honoraria; SymBio Pharmaceuticals: Consultancy, Honoraria. Maruyama:Janssen: Honoraria; Takeda: Honoraria. Tobinai:Chugai Pharma: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Celgene: Research Funding; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Ishizawa:SymBio Pharmaceuticals: Research Funding. Laille:Celgene: Employment, Equity Ownership. Ro:Celgene: Employment, Equity Ownership. Tamakoshi:Celgene: Employment, Equity Ownership. Sakurai:Celgene: Employment. Ohtsu:Celgene: Employment, Equity Ownership.

Peripheral T-cell lymphomas of follicular helper T-cell type frequently display an aberrant CD3−/dimCD4+ population by flow cytometry: an important clue to the diagnosis of a Hodgkin lymphoma mimic

AbstractNodal follicular helper T-cell-derived lymphoproliferations (specifically the less common peripheral T-cell lymphomas of follicular type) exhibit a spectrum of histologic features that may mimic reactive hyperplasia or Hodgkin lymphoma. Even though angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma of follicular type share a common biologic origin from follicular helper T-cells and their morphology has been well characterized, flow cytometry of peripheral T-cell lymphomas of follicular type has not been widely discussed as a tool for identifying this reactive hyperplasia/Hodgkin lymphoma mimic. We identified 10 peripheral T-cell lymphomas of follicular type with available flow cytometry data from five different institutions, including two cases with peripheral blood evaluation. For comparison, we examined flow cytometry data for 8 classical Hodgkin lymphomas (including 1 lymphocyte-rich classical Hodgkin lymphoma), 15 nodular lymphocyte predominant Hodgkin lymphomas, 15 angioimmunoblastic T-cell lymphomas, and 26 reactive nodes. Lymph node histology and flow cytometry data were reviewed, specifically for the presence of a CD3−/dimCD4+ aberrant T-cell population (described in angioimmunoblastic T-cell lymphomas), besides other T-cell aberrancies. Nine of 10 (90%) peripheral T-cell lymphomas of follicular type showed a CD3−/dimCD4+ T-cell population constituting 29.3% (range 7.9–62%) of all lymphocytes. Five of 10 (50%) had nodular lymphocyte predominant Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma-like morphology with scattered Hodgkin-like cells that expressed CD20, CD30, CD15, and MUM1. Three cases had a nodular growth pattern and three others exhibited a perifollicular growth pattern without Hodgkin-like cells. Epstein–Barr virus was positive in 1 of 10 cases (10%). PCR analysis showed clonal T-cell receptor gamma gene rearrangement in all 10 peripheral T-cell lymphomas of follicular type. By flow cytometry, 11 of 15 (73.3%) angioimmunoblastic T-cell lymphomas showed the CD3−/dimCD4+ population (mean: 19.5%, range: 3–71.8%). Using a threshold of 3% for CD3−/dimCD4+ T cells, all 15 nodular lymphocyte predominant Hodgkin lymphoma controls and 8 classical Hodgkin lymphomas were negative (Mann–Whitney P=0.01, F-PTCL vs Hodgkin lymphomas), as were 25 of 26 reactive lymph nodes. The high frequency of CD3−/dimCD4+ aberrant T cells is similar in angioimmunoblastic T-cell lymphomas and peripheral T-cell lymphomas of follicular type, and is a useful feature in distinguishing peripheral T-cell lymphomas of follicular type from morphologic mimics such as reactive hyperplasia or Hodgkin lymphoma.

Abstract IA02: Principles of lymphoma classification.

Abstract IA02: Principles of lymphoma classification.

T-Cell Receptor Engagement Confers Resistance to Chemotherapy in T-Cell Lymphoproliferative Disorders

Background: Chemotherapy resistance and primary refractory disease are common among patients with the more common peripheral T-cell lymphomas (TCL) treated with anthracycline-based chemotherapy. Antigen-receptor signaling activates a number of proliferation and survival pathways in normal lymphocytes. When activated in lymphomas, antigen-receptor signaling might confer resistance to chemotherapy. Until recently, the role of antigen-receptor signaling in B-cell malignancies was poorly understood. It is now appreciated that B-cell receptor (BCR) signaling is an important driver of B-cell lymphoma growth and survival, and represents an attractive therapeutic target in these lymphomas. In contrast, the potential role of T-cell receptor (TCR) signaling in T-cell lymphomagenesis is poorly understood. The observation that most (≈95%) TCLs express an intact TCR suggests that malignant T cells, like their B-cell counterparts, may benefit from antigen-receptor signaling.Methods: TCL cell lines and primary patient specimens were subjected to TCR activation by CD3/CD28 beads. Gene expression profiling was performed by Affymetrix human gene 2.1 ST array at different time points (4, 8, 24 hours) following TCR engagement. Results were further validated by immunophenotyping by flow cytometry, western blot and cytokine measurement by enzyme-linked immunosorbent assay (ELISA). The proliferation and chemoresistance of the TCL cells following TCR engagement were determined by MTT assay.Results: Microarray gene expression profiling of TCLs showed differential gene expression upon TCR engagement by CD3/CD28 beads at different time points. A total of 1274 genes were differentially expressed commonly in the patient specimens. Some of the differentially expressed genes were confirmed in independent samples by immunophenotyping (CD25, CD30, CD69, CD137, CCR4, GITR) and cytokine (IL2, IL13, IL10, IFNγ) release. Gene enrichment analysis of the common differentially expressed genes showed that pro-proliferation and pro-survival signaling pathways, including TCR (FDR: 0.05%), MAPK (FDR: 2.8%), NFκB (FDR: 0.1%) and cytokines (FDR: 0.03%) were enriched in TCR-engaged TCL cells. The activation of TCR and NFκB signaling in TCR-engaged TCLs was also confirmed by western blot and flow cytometry. More importantly, the proliferation of TCLs increased by 2-4 fold when cocultured with CD3/CD28 beads for 72 hours (p<0.01). In the presence of either vincristine or romidepsin, the viability of TCLs increased by 1.5-4 fold by CD3/CD28 bead treatment (p<0.01). TCR-dependent proliferation and chemoresistance in TCLs was significantly inhibited by agents targeting TCR and NFκB signaling pathways.Conclusions: T-cell receptor dependent signaling pathways are rational therapeutic targets in the T-cell lymphomas. DisclosuresNo relevant conflicts of interest to declare.

Survival in patients with limited-stage peripheral T-cell lymphomas

The natural history of limited-stage peripheral T-cell lymphoma (PTCL) remains poorly defined. Therefore, we examined outcomes in patients with the most common PTCL subtypes (PTCL, not otherwise specified [PTCL, NOS], angioimmunoblastic T-cell lymphoma [AITL], anaplastic large cell lymphoma [ALCL]) and limited-stage disease. In this retrospective, multicenter study, 75 patients with limited-stage disease were identified. The median event-free survival (EFS) and overall survival (OS) observed were 2.1 and 6.5 years, respectively. In a landmark analysis excluding patients with primary refractory disease, no significant benefit was observed for patients undergoing consolidative radiation therapy. With the exception of patients undergoing salvage hematopoietic stem cell transplant, survival following disease relapse or progression was poor, thus highlighting the need for improved therapeutic strategies.

Past, Present and Future Treatment Strategies in Peripheral T-Cell Lymphomas

SUMMARY Nodal peripheral T-cell lymphomas (PTCLs) are very aggressive tumors characterized by poor response to conventional chemotherapy and dismal prognosis. Recent evidence has indicated that, at least for patients aged less than 60 years, frontline high-dose chemotherapy followed by autologous stem cell transplantation can be an effective strategy. Unfortunately, however, a significant fraction of patients cannot benefit from this approach, due to age, poor performance status or early relapse. In addition, a percentage of transplanted patients eventually relapse. In this article, based on their experience and on the most recent literature, the authors review the current concept on PTCL treatment, focusing on the most common PTCL nodal subtypes.

GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features

AbstractThe cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.

How I treat the peripheral T-cell lymphomas

AbstractThe peripheral T-cell lymphomas (PTCLs) encompass a heterogeneous group of diseases that have generally been associated with poor prognosis. The most common PTCLs, peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALK-negative), despite their unique presentations and histologies, are currently treated similarly. Here we discuss our general approach to the treatment of the most common PTCLs. Based on the best data currently available, which include retrospective analyses and phase 2 prospective studies, our approach has involved cyclophosphamide, doxorubicin, vincristine, prednisone-based therapy followed by consolidation in first remission with autologous stem cell transplant. This treatment strategy likely improves the outcome for patients compared with historical series; however, progression-free survival rates remain disappointing, ranging from 40% to 50%. This is currently an exciting time in the treatment of PTCL due to the advent of recently approved drugs as well as new targeted agents currently under investigation. In addition, gene expression profiling is allowing for a better understanding of underlying disease biology, improved diagnostic accuracy, and prognostication in PTCL. As a result, over the next few years, we expect a significant shift in our management of these diseases with a move toward more individualized therapy leading to improved outcomes.

Pharmacotherapy of peripheral T-cell lymphoma: review of the latest clinical data

The peripheral T-cell lymphomas (PTCL) are a disparate group of diseases with varying clinical and pathological features and heterogeneous natural histories. All of the PTCL histologies are uncommon in North America and western Europe. Even the most common PTCL histology, PTCL-not otherwise specified, accounts for only a small fraction of all cases of non-Hodgkin’s lymphoma. The relative rarity and clinical heterogeneity of these diseases has hampered basic science and clinical research and, until recently, made PTCL a neglected area of drug development. This has partly contributed to lower success rates in treating PTCL relative to the more common B-cell nonHodgkin’s lymphomas. The roles of many therapies utilized to treat PTCL, including stem cell transplantation, remain undefined. Thankfully, several therapies have been approved in recent years and large scale studies are evaluating the comparative efficacy of various therapeutic approaches. This review describes the common PTCL subtypes and delineates recent advances.

Treatment of Peripheral T-cell Lymphoma: Are We Data Driven or Driving the Data?

Peripheral T-cell lymphomas (PTCL) are a group of uncommon and heterogeneous malignancies arising from a postthymic or mature T-lymphocyte. The treatment of PTCL remains a challenging endeavor. Compared with the more common aggressive B-cell lymphomas, more patients with PTCL will be refractory to initial therapy and those who achieve responses often will have shorter progression-free survival. Despite retrospective data that suggest that anthracycline-based multiagent chemotherapy regimens may not provide a benefit compared with nonanthracycline regimens, nonanthracycline-based regimens, with the notable exception of L-asparaginase regimens for extranodal NK/T-cell lymphoma, have been disappointing so far. Based on phase II evidence and subset analyses available, we believe that the addition of etoposide to standard regimens and consolidation of first remissions with autologous stem cell transplantation (autoSCT) provides the best outcome in patients with PTCL and currently use CHOEP followed by ASCT for eligible patients with the common PTCL subtype: PTCL-NOS, AITL, and ALK negative ALCL. For those with ALK-positive ALCL standard CHOP or CHOEP is appropriate with consideration of ASCT only for those with high-risk disease. Other strategies to incorporate additional agents, such as with dose-adjusted EPOCH or sequential CHOP-ICE regimens are logical options; however, they lack the supporting literature of CHOEP. Whereas the above recommendation is our current off-protocol approach, with the possible exception of low risk ALK positive ALCL, none of these choices is supported by strong enough data to supplant a well-conceived clinical trial as the truly preferred strategy in PTCL. The novel agents, romidepsin, pralatrexate, and brentuximab vedotin, are currently approved in the relapsed/refractory setting. These agents are being studied as additions or substitutions for other agents in up-front multiagent chemotherapy regimens. In the relapsed/refractory setting, both pralatrexate and romidepsin remain well-studied choices with some patients achieving a response with durability. Clinical trials of new agents in PTCL continue to be a valuable option and an important part of routine patient management as progressive disease often is seen. Lastly, we believe patients with relapsed/refractory PTCL should be considered for allogeneic stem cell transplantation if a suitable response is demonstrated and a willing donor is available.

Gene Expression Signatures That Delineate Biologic and Prognostic Subgroups in Peripheral T-Cell Lymphoma

AbstractAbstract 679 Background:Peripheral T-cell lymphoma (PTCL) represents approximately 10–12% of all non-Hodgkin lymphoma (NHL) in the Western world, with a higher incidence in Asian populations. The World Health Organization classification recognizes a number of distinctive subtypes of PTCL including angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), extranodal NK/T-cell lymphoma of nasal type (ENKTCL), and many other rare entities that present mainly as extranodal PTCL. However, with current immunophenotypic and molecular markers, about 30–50% of PTCL cases are not classifiable and are categorized as PTCL-not otherwise specified (PTCL-NOS). With the exception of ALK(+)ALCL, the PTCLs generally have a poor outcome and, thus a better understanding of the biology of these diseases is greatly needed to improve the long-term survival of these patients. Methods:In the current study, we performed gene expression profiling analysis on a large and well- characterized series of PTCL and ENKTCL cases (n=372) from the Lymphoma Leukemia Molecular Profiling Project (LLMPP), the International Peripheral T-cell Lymphoma Project (IPTCL) and other major institutions to define robust molecular classifiers, oncogenic pathways and prognosticators for the more common PTCL entities, as well as unique molecular and prognostic subgroups within PTCL-NOS. Molecular signatures for diagnosis and prognosis were generated in training data sets and validated in separate cohorts. Results:Robust molecular classifiers for AITL, two types of systemic ALCL (ALK(+) and ALK(-)), ATLL and ENKTCL were identified (Figure 1). These classifiers reflect the pathobiology of the tumor cells, as well as their microenvironment, and represent a refinement of what we reported previously (Iqbal et.al Blood, 2010; Iqbal et.al Leukemia. 2011). Importantly, ALK(-)ALCL can be differentiated from ALK(+)ALCL and PTCL-NOS with a unique gene expression signature. Approximately 14% of PTCL-NOS were re-classified as ALK(-)ALCL and showed expression of CD30 protein, TIA-1 or granzyme B by immunohistochemistry. ENKTCL can be separated molecularly into NK-cell lymphoma and gd-PTCL, the latter of which was also identified in 9% of PTCL-NOS. The remaining PTCL-NOS cases could be separated into two major subgroups related to T-cell differentiation and characterized by either high expression of GATA3 (30%) or TBX21(T-BET) (45%) and many of the corresponding target genes (Figure 2). Cases with high expression of GATA3 had poor overall survival and showed enriched Wnt and mTOR pathways, but no prominent microenvironment signature. The high TBX21 subgroup had a remarkably good outcome for patients with a high plasma cell-like gene expression signature, but poor overall survival when expressing a high cytotoxic signature (Figure 3). The molecular prognosticator for AITL largely reflected the role of the tumor microenvironment, with the presence of a high B-cell signature correlating with favorable outcome, whereas high dendritic cell/monocyte signatures were associated with inferior survival. Conclusion:We have organized the most comprehensive molecular profiling study of PTCL, and have not only refined the molecular diagnostic and prognostic signatures for the common subtypes of PTCL, but also segregated PTCL-NOS in meaningful biological and prognostic subtypes. Molecular diagnostic and prognostic signatures of PTCL frequently include components of the tumor-host interactions, highlighting the importance of the microenvironment in PTCL biology. This study provides an important framework for additional analysis to identify novel therapeutic targets to improve the outcome of patients with PTCL. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.