Treatment Of Peripheral T-cell Lymphoma Research Articles

Alemtuzumab Added to CHOP for Treatment of Peripheral T-Cell Lymphoma (PTCL) in Previously Untreated Young and Elderly Patients: Pooled Analysis of the International ACT-1/2 Phase III Trials

Background: Standard treatment in PTCL pts is unsatisfactory due to a high rate of early progression. Alemtuzumab (A), a monoclonal anti CD52 antibody, has demonstrated efficacy in relapsed PTCL pts. The results of the final analyses of the ACT-1 phase III and the ACT-2 phase III trial, comparing standard CHOP to A-CHOP showed higher response rates, but did not yield significant differences in EFS, PFS and OS in both previously untreated young and elderly patients, but the planned sample sizes could not be reached due to low recruitment. We undertook a planned pooled analysis of both ACT trials comparing CHOP with A-CHOP to increase statistical power.Patients and Methods: Between 2007 and 2013, 252 pts from Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Norway, Poland, Portugal, Sweden and The Netherlands were randomized to receive either 6 cycles CHOP or A-CHOP at 14 day intervals. The planned pooled analysis was performed to compare patient outcome adding A to CHOP with patients treated with CHOP alone. Primary endpoint within ACT-1 and ACT-2 trial was the 3 years event free survival (EFS), secondary endpoints were progression free survival (PFS) and overall survival (OS). EFS is defined as the time from randomization to disease progression, start of salvage treatment, additional (unplanned) treatments, relapse, or death of any cause.Results: 252 pts were randomized (ACT-1: 136; ACT-2: 116). Five patients received no study treatment; therefore, 247 pts were analyzed (CHOP: 124; A-CHOP: 123). Median age was 61 years. 62% were male. Histologies were 33% AITL, 34% PTCL NOS, 33% other subtypes. In the pooled data set, the two treatment groups were comparable. Infections grade ≥3 occurred more often in patients treated with Alemtuzumab (A-CHOP: 55% [95% CI: 45% - 64%] vs. CHOP 23% [16% - 32%]; p<0.001). Complete remissions were achieved in 56% [47% - 65%] of A-CHOP and 43% [34% - 52%] of CHOP pts (p=0.036). However, EFS (A-CHOP at 3 yrs: 32% [23% - 40%] vs. CHOP 25% [17% - 33%]; p=0.159), PFS (33% [25% - 42%] vs. 27% [19% - 35%]; p=0.220) and OS (46% [37% - 55%] vs. 53% [44% - 62%]; p=0.332) showed no significant differences. Multivariate analyses, adjusted for IPI factors, bulky disease and gender, confirmed these results (hazard ratio HREFS: 0.8 ([95% CI: 0.6 - 1.1]; p=0.196), HRPFS: 0.8 ([95% CI: 0.6 - 1.1]; p=0.246), HROS: 1.2 ([95% CI: 0.8 - 1.6]; p=0.370). Male gender (HR 2.5), ECOG > 1 (HR 2.1) and bulky disease (HR 2.1) were the most prominent unfavorable risk factors for EFS. With the sample size of 247 pts the power for detecting the planned EFS difference of 15% was 74%.Conclusion: Adding Alemtuzumab to CHOP increased the rate of CR in PTCL patients, albeit at the costs of higher treatment related toxicity. Addition of Alemtuzumab did not improve EFS, PFS, or OS. Female gender is associated with a significantly better prognosis. This is the largest prospective dataset collected for PTCL.Supported by Federal Ministry of Research BMBF FKZ 01KG0705 and unrestricted research grants by Genzyme-Sanofi and AMGEN DisclosuresNo relevant conflicts of interest to declare.

Management of Mucositis with the Use of Leucovorin As Adjunct to Pralatrexate in Treatment of Peripheral T-Cell Lymphomas (PTCL) — Results from a Prospective Multicenter Phase 2 Clinical Trial

Background: A frequent complication of Pralatrexate therapy is development of oral mucositis. In a recent pivotal trial of pralatrexate (PROPEL, O'Connor et al. J Clin Onc 2011) the incidence of ≥ Grade 2 mucositis was 52%, occurring primarily in the first treatment cycle. Mucositis often leads to dose reduction or omission and possibly, diminished efficacy of pralatrexate in relapsed/refractory (R/R) PTCL. Leucovorin (d,l-folinic acid) is an approved rescue therapy for high-dose methotrexate (MTX) therapy, mitigating gastrointestinal lining, and bone marrow cell toxicity and has been used adjunctively with pralatrexate to manage mucositis. The objective of this prospective Phase 2, single-arm study was to evaluate the effect of leucovorin on the incidence of pralatrexate-induced mucositis in patients with R/R PTCL, including primary cutaneous T-cell lymphomas.Methods: Eligible patients had diagnosis of PTCL, including CTCL, confirmed by local hematopathologist or dermatopathologist and were deemed appropriate for pralatrexate therapy by investigator. Study treatment consisted of two cycles of Pralatrexate, (6 weekly doses (30 mg/m2) followed by 1 week of rest per cycle, currently approved label). All patients received vitamin B12 and folic acid supplementation; oral leucovorin, 25 mg TID was self-administered for 2 consecutive days (a total of 6 doses) beginning 24 hours after each dose of Pralatrexate. Patients underwent in-clinic oral mucositis assessment at baseline and at each visit prior to pralatrexate administration by healthcare professional. Patients also completed a daily oral mucositis questionnaire (OMDQ) from Day 1 of Cycle 1 to the end of treatment visit. Mucositis was assessed by the investigator and recorded as an AE along with grade and causality. Toxicities were assessed using Common Terminology Criteria (CTCAE V4.03). Responses were assessed by the investigator per revised Response Criteria for Malignant Lymphoma (Cheson 2007) and Modified SWAT Criteria for CTCL.The primary endpoint was the incidence of Grade 2 or higher oral mucositis in Cycle 1. Secondary endpoints included the incidence of ≥ Grade 3 mucositis, and overall response rate.Results: A total of 30 patients have been enrolled as of time of data analysis. The majority of patients were male, white, with the median age of 63 yrs (range, 31-85). To date (5 July 2018) 11 patients have completed the study treatment, 12 patients discontinued (1 AE, 9 PD, 1 death, and 1 withdrawal) and 7 patients remain in the trial. All 30 subjects reached the assessment of the primary endpoint. The primary endpoint of the study has been met. Twenty (67%) patients have reported TEAEs, of which 11 (37%) have been ≥Grade 3 AEs. Overall toxicity profile was consistent with previously reported in the PROPEL trial. Most common Pralatrexate-related AEs were fatigue in 6 (20%) patients and diarrhea that occurred in 4 (13%) patients. SAEs occurred in 9 patients (only pyrexia in >1 pt; N=2), none were treatment-related. The rate of ≥2 mucositis was 4% (95% C.I. = 0, 20%). No Grade 3 or higher mucositis occurred; Grade 1 mucositis was observed in 4 patients. Assessment of treatment response rate (secondary endpoint) is ongoing and will be reported at the meeting.Conclusions: Overall safety profile of the study treatment was consistent with pivotal trial of Pralatrexate in R/R PTCL. Leucovorin as adjunctive treatment resulted in a significant reduction in rates of both ≥Grade 2, and ≥Grade 3 mucositis and should be considered in patients treated with Pralatrexate. DisclosuresShustov:SPECTRUM PHARMACEUTICALS: Consultancy, Research Funding. Bhat:SPECTRUM PHARMACEUTICALS: Employment.

Preliminary Results of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Two Phase IIa Dose Expansion Cohorts in Relapsed/Refractory TP53 Wild-Type Peripheral T-Cell Lymphoma

Preliminary Results of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Two Phase IIa Dose Expansion Cohorts in Relapsed/Refractory TP53 Wild-Type Peripheral T-Cell Lymphoma

Pseudoprogression (PsP) in Patients with Peripheral T-Cell Lymphoma (PTCL) Treated with the Novel Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2

Background: ALRN-6924, an α-helical stapled p53 peptide, is the first-in-class and only dual inhibitor of MDMX and MDM2 currently in clinical trials for both, solid and hematologic malignancies. In tumors with wild-type (WT) TP53, ALRN-6924 can induce p53-dependent cell cycle arrest and apoptosis and separately can invoke p53-mediated immunomodulatory effects, including but not limited to lymphocyte chemotaxis and diminution of PD-L1 expression on tumor cells. This report begins to describe the biologic underpinnings of PsP in selected PTCL patients (pts) treated with ALRN-6924. Despite imaging-based progressive disease (PD), careful monitoring for clinical benefit in light of conflicting imaging (PsP) results led to the decision to treat beyond radiologic progression and the observation of subsequent, delayed radiologic responses.Methods: Pts with relapsed or refractory PTCL received either 3.1 mg/kg ALRN-6924 on days 1, 8, and 15 of a 28-day cycle (QW) or Days 1, 3, and 5 of a 21-day cycle (TIW). Responses were assessed locally using IWG 2014 criteria as well as through independent radiology assessment. Treatment continued until symptomatic PD, unacceptable toxicity, or other indication for withdrawal. Continuation beyond radiologic PD was permitted for perceived clinical benefit. RNA-based immune profiles from pre- and post-treatment tumor biopsies from pts who were treated with ALRN-6924 were evaluated by gene expression panels.Clinical findings were correlated with CT26 and MC38 murine syngeneic tumor models, where immune cell infiltration after ALRN-6924 dosing was measured by flow cytometry.Results: PsP was observed in 3 PTCL pts who eventually achieved a PR. A pattern of transient tumor flare and new lesion formation was noted in one pt (pt 13-196) while the other 2 PsP pts (pt 3-159 and 11-155) had atypical PsP patterns, including tumor shrinkage by CT, but transient new and/or increased 18Fluorodeoxyglucose (FDG)-PET uptake. In one pt, there was rapid clinical improvement of malignant hypercalcemia and B symptoms despite formal IWG 2014 progression after 2 cycles of ALRN-6924 QW treatment plus an additional transient episode of PsP due to new FDG-avid lesions at cycle 8. Another pt had a similar PsP pattern with decrease in lesion size on CT but increased FDG-avidity of target lesions following 2, 4, and 6 cycles of QW-therapy with ALRN-6924, with new FDG-avid lesions that appeared, and then resolved in different anatomical locations at each imaging assessment. Local pathology reported findings consistent with PTCL upon post-baseline biopsy of one of these lesions. Pre- and post-baseline biopsies were analyzed for differences in RNA-expression of immune-related genes, and showed changes consistent with p53-mediated immunomodulatory effects. Despite formal progression due to transient PET-avid lesions, both pts remained on therapy, subsequently achieving a confirmed PR.A pt treated with TIW ALRN-6924 (pt 13-196) exhibited worsening abdominal pain by Day 5 of ALRN-6924, with CT scans on days 6, 11, and 22 showing transient enlargement and increased number of nodes, splenomegaly, and ascites, consistent with progression. The pt continued therapy with resolution of clinical symptoms, and an efficacy assessment after 3 cycles showed dramatic reduction in lesion sizes and FDG-avidity, assessed as a PR (unconfirmed).Preclinically, in mice treated with ALRN-6924, a significant increase in tumor-infiltrating CD8+ T cells and M1-polarized macrophages was found in murine TRP53-WT CT26 tumors as well as in TRP53-mutant MC38 tumors.Conclusion: Treatment of PTCL with ALRN-6924 can be associated with PsP. Pts have benefitted from treatment beyond radiologic progression, with new FDG-avid lesions resolving over time. Murine tumor models plus changes in immune-related gene expression in pre- and post-baseline tumor samples from pts suggest that p53-mediated immune-activation may account for these findings. Transient tumor flare observed in pts, was consistent with increased immune cell infiltration that was detected after p53-activation in the tumor microenvironment of TRP53-mutant syngeneic models. ALRN-6924 is a promising anticancer agent that warrants further investigation and consideration should be given to possible pseudoprogression prior to discontinuing pts from treatment with ALRN-6924. DisclosuresShustov:Seattle Genetics: Research Funding. Mehta:Spectrum: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite: Consultancy, Speakers Bureau; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Research Funding; Merck: Research Funding; Epizyme: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Carvajal:Aileron Therapeutics Inc.: Employment, Equity Ownership. Guerlavais:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Samant:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Narasimhan:Aileron Therapeutics Inc.: Employment, Equity Ownership. Sutton:Aileron Therapeutics Inc.: Consultancy. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Korn:Aileron Therapeutics Inc.: Other: Client; Imaging Endpoints: Employment, Equity Ownership.

Role of Single Agent and Combination Chemotherapy Strategies in Relapsed/Refractory Peripheral T-Cell Lymphoma: Results from the Complete Registry

Introduction:Patients with aggressive peripheral T-cell lymphoma (PTCL) often undergo induction with anthracycline-based chemotherapy followed by autologous stem cell transplantation in fit patients. Up to 40% of patients have primary refractory disease, and even for those who respond to induction, 5-year overall survival (OS) is 32% with the exception of ALCL. This results in a significant number of patients who need treatment in the relapsed and refractory (R/R) setting. While there is no standard approach for this group, multiagent chemotherapy regimens are often used, particularly in those who may be transplant candidates. Several novel single agents have shown activity in R/R PTCL and can often be given in a more continuous fashion than combination chemotherapy. In order to explore the potential benefits of single agents in comparison to combination chemotherapy in R/R PTCL, we examined treatment outcomes in a prospectively enrolled cohort of PTCL patients.Methods:Patients were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE), a multinational prospective cohort of 500 newly diagnosed PTCL patients. Demographics, treatments, and outcomes were recorded until death or for at least 5 years. Analysis was restricted to 6 subtypes of PTCL: PTCL-NOS, AITL, ALCL, EATL, NKT, HSTCL. Primary refractory was defined as lack of a complete response (CR) to initial treatment. Relapsed was defined as a CR to initial treatment with progression at a later date. Patients in whom initial treatment was ≤4 days, unreported, or began >30 days before or after informed consent were excluded. Single agents were pralatrexate, romidepsin, brentuximab vedotin (BV), bendamustine, alisertib, denileukin diftitox, and lenalidomide. Combinations were any multiagent chemotherapy regimen excluding the above agents.Results:Of 462 patients with locked records, 57 met the above eligibility criteria and had treatment and followup data available for analysis. As first treatment in R/R disease, 26 patients received combination therapy (by subtype: PTCL-NOS [10], AITL [6], ALCL [3], EATL [1], NKT [5], HSTCL [1]) and 31 received single agents (by subtype: PTCL-NOS [13], AITL [5], ALCL [7], EATL [2], NKT [2], HSTCL [2]). The most common combination regimens had an ifosfamide-, gemcitabine-, or platinum-based backbone. Single agents used were: BV (12), romidepsin (8), pralatrexate (5), alisertib (3), bendamustine (1), denileukin diftitox (1), and lenalidomide (1). The objective response rate (ORR) for single agents was higher than for combination therapy (59% [17/29] vs. 46% [12/26], P=0.36), as was the CR rate (41% [12/29] vs. 19% [5/26], P=0.02). In those with R/R ALCL who received BV, ORR was 83% (5/6) and CR was 67% (4/6). Given these expected high response rates of BV in R/R ALCL, a subtype analysis excluding ALCL patients who received BV (ALCL-BV) was conducted and showed similar ORR between single and combination therapy (52% [12/23] vs. 46% [12/26], P=0.26), though CR still favored single agents (35% [8/23] vs. 19% [5/26], P=0.07). Excluding the ALCL-BV group, CRs were observed with BV (3/6), romidepsin (2/8), pralatrexate (1/5), bendamustine (1/1), and alisertib (1/3). Median progression-free survival (PFS) favored single over combination therapy (11.2 vs. 6.7 months, P=0.02). PFS in the ALCL-BV group was comparable at 11 months. Stem-cell transplantation occurred more frequently after single agent use than combination therapy (25% [8/31] vs. 7% [2/26]).Conclusion:Our analysis confirms the unmet need for better therapies in R/R PTCL. This data shows a trend towards increased CR and PFS with single agents in comparison to combination therapy, while maintaining the potential to bridge to transplantation. It is unclear whether the differences were driven by reduced toxicity and longer treatment duration with single agents, increased efficacy from BV in CD30-expressing cancers, or patient factors that led to therapy selection. However, despite the small size and exploratory nature of this analysis, single agents do not appear inferior to combination therapy with respect to disease control or ability to bridge to transplant with intent to cure. Our data can serve as a foundation for larger datasets or randomized trials which are needed to identify the truly superior strategy. In the meantime, the optimal approach for R/R PTCL remains unclear. DisclosuresSchwartz:MS Biostatistics, LLC: Employment. Acosta:Spectrum: Employment. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; kiowa: Honoraria; portola: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses. Shustov:Seattle Genetics: Research Funding. Horwitz:Aileron Therapeutics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Trillium: Consultancy; Corvus: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding. Foss:Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Mallinkrodt: Consultancy; Spectrum: Consultancy.

FDA approves first-line treatment for peripheral T-cell lymphoma under new review pilot

FDA approves first-line treatment for peripheral T-cell lymphoma under new review pilot

Orphan designation: Mogamulizumab, Treatment of peripheral T-cell lymphoma (nodal, other extranodal and leukaemic/disseminated)

Orphan designation: Mogamulizumab, Treatment of peripheral T-cell lymphoma (nodal, other extranodal and leukaemic/disseminated)

Successful implementation of genomically based treatment of chemotherapy refractory peripheral T-cell lymphoma (PTCL)

ABSTRACT Background: The treatment of peripheral T-cell lymphoma (PTCL) after failure of standard therapy represents a significant clinical challenge as the best approach has not been defined. The outcomes of patients with peripheral T-cell lymphoma (PTCL) after relapse, in the absence of hematopoietic stem-cell transplantation, are poor with median overall survival is less than six months. Thus, relapsed/refractory PTCL presents an area of unmet medical need. Case presentation: Herein, we report an 84-year old woman with stage IV PTCL with extensive involvement of the bowel and abdominal pain. She was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy which was complicated by prolonged pancytopenia, without response. Disease progression was manifested by small bowel obstruction, for which she received palliative radiation therapy, further complicated by cardiac arrhythmia and sepsis. In the meantime, clinical-grade next generation sequencing of a lymph node (406 gene panel) showed six genomic alterations: NRAS Q61R, PTEN Q17*, CREBBP R768*, EP300 R1529*, SETD2 loss exons 19–21, along with an intermediate tumor mutational burden. Tissue PD-L1 staining was low positive by immunohistochemistry. The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration) and the checkpoint inhibitor nivolumab for the elevated mutational burden and PD-L1 positivity. Her abdominal pain resolved and she achieved a complete remission ongoing at 5+ months. Side effects at five months included only low-grade rash and peripheral edema. Conclusions: Our observations suggest that matching patients with hematologic malignancies with customized combinations based on genomic sequencing warrants further study as a way to achieve and/or deepen responses, including in patients who are elderly and/or have refractory disease and significant disease-related complications.

Optimising initial treatment for peripheral T-cell lymphoma: a tough nut to CHOP

Optimising initial treatment for peripheral T-cell lymphoma: a tough nut to CHOP

Recent Advances in the Treatment of Peripheral T-Cell Lymphoma.

Recent progress in understanding of the biology and pathogenesis of peripheral T-cell lymphoma has led to the emergence of new drugs. Unfortunately, this has not been met with similar advances in outcome improvement. Anthracycline-containing regimens, mostly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), are considered the standard of care, although the best first-line approach remains to be defined. In the relapsed and refractory settings, several new agents achieved response rates between 10% and 30%, although these drugs do not significantly affect survival rates. Therapeutic options based on better molecular characterization of various histological types and combinations with the CHOP regimen or synergic combinations of new drugs may lead to better outcomes.

Forodesine in the treatment of relapsed/refractory peripheral T-cell lymphoma: an evidence-based review.

T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL) generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor), brentuximab vedotin (antibody–drug conjugate targeting CD30), chidamide (histone deacetylase inhibitor), and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody), have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients), which included four patients with complete response. In general, the toxicity of forodesine is manageable. As the study met the primary end point, forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of forodesine in the world. As forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL. However, it is necessary to appropriately manage opportunistic infections and secondary lymphomas possibly associated with long-lasting lymphocytopenia caused by forodesine. In this manuscript, we have summarized the currently available evidence for forodesine and discussed the clinical implications for PTCL treatment.

Recent advances in understanding and managing T-cell lymphoma.

Owing to the rarity of peripheral T-cell lymphoma (PTCL) and the heterogeneity of subtypes, there are no compelling data to guide the therapeutic approaches for such patients. Over the years, there have been remarkable advances in molecular subtyping and treatment of PTCL, although there are still many areas to be explored. In this review, we summarize recent updates on the evolution of understanding and treatment for PTCL.

Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells.

Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin's lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen. Because PTCLs develop from mature T-cells, these NHLs are commonly CD4+, and CD4 is highly and uniformly expressed. Therefore, CD4 is an ideal target for PTCL CAR immunotherapy. To that effect, we created a robust third-generation anti-CD4 CAR construct (CD4CAR) and introduced it into clonal NK cells (NK-92). CD4CAR NK-92 cells specifically and robustly eliminated diverse CD4+ human T-cell leukemia and lymphoma cell lines (KARPAS-299, CCRF-CEM, and HL60) and patient samples ex vivo. Furthermore, CD4CAR NK-92 cells effectively targeted KARPAS-299 cells in vivo that modeled difficult-to-access lymphoma nodules, significantly prolonging survival. In our study, we present novel targeting of CD4 using CAR-modified NK cells, and demonstrate efficacy. Combined, our data support CD4CAR NK cell immunotherapy as a potential new avenue for the treatment of PTCLs and CD4+ T-cell malignancies.

Redefining the role of etoposide in first-line treatment of peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) have an aggressive biological course and poor clinical outcomes. Despite producing somewhat less-than-satisfactory results, the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the de facto standard in PTCL treatment. Addition of etoposide to CHOP backbone to overcome such unsatisfactory results has yielded contradictory information. We aimed to thoroughly analyze the impact of incorporating etoposide into first-line treatment. Using merged data from the Korean National Health Insurance Service and National Cancer Registry, a total of 1933 patients (median age, 58 years) were evaluated for clinical characteristics and treatment outcomes. Thirty-eight percent (n = 748) of the 1933 patients received CHOP or CHOP-like regimen, 35.1% (n = 678) received CHOP-like regimen plus etoposide, 5.9% (n = 113) received other backbone chemotherapy plus etoposide, and 20.3% (394) received other treatments in the first-line setting. When we divided the patients into 3 groups according to regimen (group 1, CHOP or CHOP-like regimen; group 2, CHOP or CHOP-like regimen plus etoposide; group 3, all others), group 1 was associated with longest progression-free survival (PFS; P < .001) and overall survival (OS; P < .001). This lack of benefit with etoposide addition was observed across different PTCL subtypes and age groups. Adding etoposide led to longer hospitalizations and cytopenias requiring more transfusion. Upfront hematopoietic stem-cell transplantation led to better OS. Addition of etoposide to CHOP-like regimens does not result in better PFS or OS for patients with PTCL. Overall, Asian patients with PTCL do not benefit from chemotherapy intensification of first-line treatment. We hereby provide crucial information on establishing standardized PTCL treatment.

Advances in therapeutic options for peripheral T-cell lymphomas

Peripheral T-cell lymphoma (PTCL) is a highly specific and invasive non-Hodgkin’s lymphoma derived from mature T-cells that leave the thymus. At present, the clinical progress in PTCLs is behind that in B-cell lymphomas, and the current treatments for PTCLs have low efficacy and poor overall prognosis. Therefore, there is currently still no standard treatment for PTCL. The efficacy of the conventional CHOP chemotherapy regimen is poor, and the value of radiotherapy in early-stage PTLC patients remains to be determined. Autologous hematopoietic stem cell transplantation is the top choice for consolidation treatment for high-risk patients, but the efficacy of novel drugs for PTCLs needs to be further confirmed. In addition, PET/CT plays a more important role in predicting the prognosis of PTCLs. Key words: T-cell lymphomas; Treatment; Prognosis

Treatment of Peripheral T-Cell Lymphoma in Community Settings.

Peripheral T-cell lymphomas (PTCLs) represent a rare and heterogeneous group of malignancies that do not have consensus treatment recommendations. Strategies extrapolated from B-cell lymphoma have met with limited efficacy, although T-cell-specific salvage therapies have been recently developed. To determine treatment patterns and associated outcomes in PTCL not otherwise specified (PTCL-NOS), anaplastic large T-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL), a retrospective analysis was undertaken at a large US community oncology network among patients treated between January 2010 and April2015. Among 93 patients (44 PTCL-NOS, 30 ALCL, 19 AITL), 23 unique treatments were used in 66 first-line patients and 12 unique second-line treatments were used in 24 relapsed/refractory patients. First-line CHOP and CHOP-like regimens were used in 74% of patients, providing 4-year overall survival (OS) outcomes of 34% (95% confidence interval [CI], 14%-83%) in patients without transplant consolidation (82% in ALCL, 37% in PTCL-NOS, and 0% in AITL). Upfront stem cell transplantation trended toward improved 4-year progression-free survival 77% (95% CI, 54%-100%) versus 34% (95% CI, 14%-80%); (P= .08; hazard ratio [HR] 0.29) with 4-year OS 77% (95% CI, 54%-100%) versus 34% (P= .22; HR 0.41). Brentuximab was the most common second-line therapy, with multiple additional regimens used in sequence (up to 5 salvage regimens) in many. The significant variability in treatments used for PTCL emphasizes the lack of consensus therapy in this rarer lymphoma and calls for additional organized prospective and registry studies to evaluate comparative effectiveness.

Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States.

With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTSAND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States. A total of 499 patients were enrolled from 40 academic and 15 community-based centers. Baseline assessment forms were collected for 493 patients, of which 435 (88%) were available for analysis. The most common diagnoses were PTCL, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, and angioimmunoblastic T-cell lymphoma (AITL). A mean of 10 markers (range, 0-21) was assessed per patient. CD30 was assessed frequently but not uniformly in cases that were not anaplastic large cell lymphoma. Only 17% of PTCL-NOS cases were assessed for PD1. CXCL13 was a relatively sensitive marker in AITL, expressed in 84% of tested cases; however, only 3% of PTCL-NOS cases were tested. T follicular helper cell marker assessment differed between academic and community practices, with PD1 more often evaluated by academic centers in cases of AITL (62% vs. 12%; P= .01). The diagnostic workup for PTCL in the United States varies widely and often lacks important phenotypic information to fully characterize the lymphoma. Gaps in testing of selected markers should be filled, given the impending revision to the World Health Organizationclassification. The accuracy of diagnosis will become increasingly important as we enter the era of targeted treatment for PTCL.

Chidamide in the treatment of peripheral T-cell lymphoma.

Mature T-cell lymphomas are aggressive malignancies. Treatment outcome is poor with conventional chemotherapy. They are about twice as common in Asia as compared with other non-Asian countries. Histone proteins form the basic structure of chromatin, and their acetylation at lysine residues relaxes chromatin structure, facilitating gene transcription. Conversely, histone deacetylation, catalyzed by histone deacetylases, compacts chromatin and represses gene transcription. Histone deacetylase inhibitors are an important class of antineoplastic agents. Chidamide is a novel orally active benzamide-type histone deacetylase inhibitor that has shown in vitro activities against a wide array of neoplasms. In Phase I trials, chidamide showed preferential efficacy in mature T-cell lymphomas. In a pivotal Phase II trial of chidamide in 79 patients with relapsed or refractory mature T-cell lymphomas, an overall response rate of 28% (complete remission/complete remission unconfirmed: 14%) was achieved, with most responses occurring within the first 6 weeks of treatment. The median duration of response (DOR) was 9.9 (1.1–40.8) months. Of 22 responders, 19 patients (86%) had a DOR of ≥3 months and eight patients (36%) had a DOR of >12 months. Angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma (anaplastic lymphoma kinase-negative) showed better response rates, with the most durable responses observed in angioimmunoblastic T-cell lymphoma patients. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. Chidamide is approved by the China Food and Drug Administration for the treatment of relapsed and refractory peripheral T-cell lymphomas.

A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.

Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]). To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

VAV1 Activating Mutations and Translocations in Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCL) are malignant and highly aggressive hematologic tumors arising from mature post thymic T-cells. The diagnosis of PTCL includes diverse lymphoma subgroups, altogether accounting for about 15% of all non-Hodgkin lymphomas. Despite much effort in developing reliable diagnostic markers, the diagnosis of PTCLs is challenging and 20-30% of cases are diagnosed as PTCL-NOS (not otherwise specified). This heterogeneous and poorly defined group of lymphomas is frequently characterized by chemotherapy resistance and a very poor prognosis. Here we report the presence of recurrent driver activating genetic alterations in the VAV1 gene in PTCL, NOS. RNA-seq analysis of a comprehensive series of 154 PTCLs and targeted sequencing identified VAV1 gene fusions with different partners including VAV1-THAP4, VAV1-MYO1F and VAV1-S100A7. In all cases the resulting oncoproteins lack the C-terminal SH3 domain of VAV1, a motif implicated in the negative regulation of VAV1 signaling, leading to increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (NFAT) VAV1 effector pathways. In addition, and most notably, we also identified focal microdeletions at the VAV1 intron 25-exon 26 boundary, which result in the activation of an alternative intraexonic splice acceptor site and the consequent expression of mis-splicing-driven mutant transcripts harboring a recurrent VAV1 Δ778-786 in-frame deletion. Mechanistically, the VAV1 Δ778-786 mutation removes 9 amino acids proximal to the C-terminal VAV1 SH3 domain and induces in increased VAV1 activation and signaling in biochemical assays. In all, these results support a driver role for oncogenic VAV1 signaling in T-cell transformation of major importance for the design of targeted therapies for the treatment of PTCL, NOS. DisclosuresNo relevant conflicts of interest to declare.