Refractory Peripheral T-cell Lymphoma Research Articles

289P - Safety and efficacy of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma from China

289P - Safety and efficacy of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma from China

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.

Strategy for Assessing New Drug Value in Orphan Diseases: An International Case Match Control Analysis of the PROPEL Study.

BackgroundAlthough randomized studies are designed to assess overall survival (OS) benefit, the conduct of regulatory studies in patients with orphan diseases can be timely and costly without offering the same commercial return on the investment. The peripheral T-cell lymphomas (PTCL) represent a rare group of heterogeneous lymphoid malignancies with very poor prognosis. PROPEL was a pivotal phase II study that led to the accelerated approval of pralatrexate for patients with relapsed or refractory PTCL.MethodsAn international database of 859 patients was assembled from four institutions with an interest in PTCL, of which 386 were considered eligible for matching against the PROPEL criteria. Using a rigorous propensity score matching algorithm, a unique 1:1 case match of 80 patients was performed.ResultsThe analysis demonstrated an OS benefit for the PROPEL population with a median OS of 4.07 and 15.24 months (hazard ratio = 0.432, 95% confidence interval = 0.298 to 0.626), respectively, for the control and PROPEL populations. Highly statistically significant improvements in OS were noted for the PROPEL population about the subtype of PTCL (save anaplastic large cell lymphoma) and all age groups, including the elderly (>65 years of age). For patients on PROPEL, there was a statistically significant prolongation in progression free survival compared with the line of prior therapy, including those with refractory disease.ConclusionIn the context of this case-match-control study, patients treated on PROPEL experienced an OS advantage compared with an international database of historical controls. This information can help inform critical decision-making regarding clinical studies in PTCL.

Determination of chidamide in rat plasma and cerebrospinal fluid

Chidamide is a new subtype-selective histone deacetylase inhibitor (HDACi), which has been approved for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in China. However, there are few studies about the application of chidamide in PTCL with central nervous system (CNS) involvement. It is essential to investigate the penetration of chidamide in the blood brain barrier (BBB). LC-MS methods were established firstly to determine the concentration of chidamide in rat plasma and CSF. Then five rats were anaesthetized and the plasma and CSF samples were collected at the time of 5, 15, 30, 60, 120, 180, 240, 360 and 480 min after being administered 1 mg/kg chidamide by intravenous injection, respectively. All samples were analyzed with the established LC-MS method by using the precursor/product transitions (m/z) of 391.1/265.1 for chidamide and 441.1/138.2 for internal standard (IS). The PK parameters were calculated after both of the concentrations of chidamide in plasma and CSF were determined. The penetration ratio of chidamide in BBB ranged from 0.19% to 0.67%. Result indicated chidamide could pass through the BBB, enter into the CNS and have the potential to be utilized in PTCL with CNS involvement.

The PRIMO study: A phase 2 study of duvelisib efficacy and safety in patients with relapsed or refractory peripheral t-cell lymphoma (PTCL).

TPS7590Background: Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ being developed for the treatment of hematologic malignancies. In preclinical investigations,...

Pilot trial of ibrutinib in patients with relapsed or refractory T-cell lymphoma

AbstractIbrutinib has previously been shown to inhibit Bruton's tyrosine kinase (BTK) and interleukin-2–inducible T-cell kinase (ITK), which mediate B-cell and T-cell receptor signaling, respectively. BTK inhibition with ibrutinib has demonstrated impressive clinical responses in a variety of B-cell malignancies. Whether ibrutinib inhibition of ITK can lead to clinical response in T-cell malignancies is unknown. We hypothesized that ibrutinib-mediated ITK inhibition in T-cell lymphoma would result in decreased signaling through the T-cell receptor pathway and promote antitumor immune response by driving selective cytotoxic Th1 CD4 effector T-cell differentiation. This pilot clinical trial evaluated 2 dose levels of ibrutinib: 560 and 840 mg orally daily. Fourteen patients with relapsed, refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma were enrolled. Both dose levels were safe and well tolerated, and no dose-limiting toxicities were observed. One patient achieved a partial response (overall response rate, 8% [1/13]). ITK occupancy studies demonstrated a mean occupancy of 50% (range, 15%-80%). Higher ITK occupancy of more than 50% correlated with higher serum levels of tumor necrosis factor-α and interferon-γ and favored a Th1 phenotype. Our data suggest that ibrutinib inhibition of ITK has limited clinical activity in T-cell lymphoma. This study is registered at www.clinicaltrials.gov as #NCT02309580.

A New Types of Polymorphic Form of 10-Propargyl-10-Deazaaminopterin, from SL: As a Refractory Peripheral T-cell Lymphoma Drug

A new crystal form of 10-Propargyl-10-Deazaaminopterin, form SL, was discovered which is thermodynamically stable, shows long term stability and is applicable for using in final dosage forms. Form SL was characterized by several analytical methods such as thermal analysis by DSC, IR, X-ray powder diffraction, SEM (Scanning Electron Microscopy), Digital optical microscopy and solubility/dissolution measurements. Active pharmaceutical ingredients should be stable during technological processes for the preparation of a final dosage form and must also remain stable during storage. The morphology of long needle and plate shaped crystals was investigated by scanning electron microscopy (SEM) and optical microscopy. Form SL was compared to other forms of 10-Propargyl-10-Deazaaminopterin such as form A, B, C and to the amorphous form. The thermodynamic stability of form SL is supported by its long-term stability. Form SL is a pharmaceutically applicable crystal form.

The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project.

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P<0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively (P<0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, P=0.001), whereas late relapse (>12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation.

Potential Application of 5-Aryl-Substituted 2-Aminobenzamide Type of HDAC1/2- Selective Inhibitors to Pharmaceuticals.

Diverse histone deacetylase (HDAC) inhibitors have been developed to date. They control not only histone modification but also gene expression of diverse proteins and thus are expected to provide useful therapeutic effects on various diseases, including cancers, psychiatric and cognitive disorders and neurodegenerative diseases, as well as cardiovascular and diabetic diseases. Some isoform-nonselective HDAC inhibitors have been successfully used for clinical treatments of the haematological malignancies, including advanced forms of cutaneous T-cell lymphoma, refractory peripheral T-cell lymphoma and multiple myeloma. However, the nonselective HDAC inhibitors threaten to cause adverse effects, such as thrombocytopenia, nausea, fatigue and cardiotoxicity, and their influence on the health care of patients is of concern. It is therefore anticipated that the development of isoform-selective HDAC inhibitors may offer more efficacy and less toxicity. Recently, a number of 5- aryl-substituted 2-aminobenzamide series of HDAC1/2-selective inhibitors have been synthesized, and their useful biological activities have been reported. In this review, we introduce the recent development of synthetic and biological studies on 5-aryl-substituted 2-aminobenzamide-type HDAC1/2 inhibitors, together with the latest research findings on biology of broad-spectrum HDAC inhibitors. In addition, we refer to the possibility of their application in clinical therapies.

Bendamustine in peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. Three main studies described bendamustine in these patients: one prospective phase II study, Bently and two retrospectives Italian and French studies. Patients were mainly angioimmunoblastic, PTCL-not otherwise specified (PTCL-NOS) and anaplastic large cell lymphoma. The majority of patients had disseminated disease and extranodal localizations refractory or in relapsed with over one previous line therapy. Overall response rate (ORR) was 32% to 55% with complete response (CR) rate of 10% to 28%. Median progression free survival and overall survival (OS) were 3.1 to 3.6 and 4.4 to 6.2 months in different studies. Bendamustine as single agent could be considered as an accessible therapeutic option for relapsed or refractory PTCL (R/R PTCL). It can be a way to bring the eligible patients to transplant. In another way, this treatment could be administered for elderly patients. Combinations of bendamustine with other drugs warrant further evaluation.

Romidepsin (Istodax® for intravenous injection 10 mg): pharmacokinetics, pharmacodynamics and clinical study outcome

Romidepsin (Brand name: ISTODAX® for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T-cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U.S. and other countries. Thereafter, domestic phase I/II studies were planned. The phase I study was designed to evaluate the tolerability of romidepsin in Japanese patients with relapsed or refractory PTCL/CTCL and thereby determine the recommended dose, as patients were administered romidepsin by intravenous infusion at a dose of 9 or 14 mg/m2 over 4 hours on days 1, 8 and 15 of each 28-day cycle, and 14 mg/m2 was determined as the recommended dose for phase II. While the phase II study was designed to include 40 Japanese patients with relapsed or refractory PTCL to evaluate the efficacy and safety of romidepsin. Treatment response was 42.5% and the most common AEs of Grade ≥ 3 were lymphopenia (74.0%), neutropenia (54.0%), leukocytopenia (46.0%) and thrombocytopenia (38.0%). The overall safety profile was considered to be within the acceptable range. On the basis of these result, romidepsin was approved in July 2017 for the treatment of relapsed or refractory PTCL in Japan.

Survival following salvage therapy for primary refractory peripheral T-cell lymphomas (PTCL).

Optimal salvage therapy for primary refractory peripheral T-cell lymphomas (PTCL) and the role of hematopoietic stem cell transplant (SCT) remain poorly defined. We conducted a retrospective review of clinical outcomes and prognostic factors in a single-center cohort of 93 patients with primary refractory PTCL, defined as progression during first-line therapy or relapse within 6 months of its completion. Clinical outcomes were poor in this population, with median event-free survival (EFS) of 3.5 months, median overall survival (OS) of 9.1 months, and 34% 3-year survival. Outcomes were comparable in patients who progressed through first-line therapy and patients who achieved CR/PR and subsequently relapsed within 6 months. A majority exhibited high-risk features and had intermediate to high risk IPI, which correlated with inferior outcomes. There was no difference in outcomes between patients who received single-agent salvage regimens and patients who underwent traditional, multi-agent salvage regimens. Thus, participation in well-designed clinical trials should be encouraged in this population. Additionally, there may be a trend toward improved EFS and OS in patients who underwent autologous or allogeneic SCT compared to patients who achieved CR or PR but were not transplanted.

Pralatrexate in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Phase 1 Dose-Escalation Study

Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O'Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naïve PTCL patients.Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of pralatrexate in combination with CHOP (Fol-CHOP).Methods: In Part 1 of this 3+3 dose-escalation study, pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and “leucovorin rescue” throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count < 25 X 109/L at any time, or ANC < 0.5 X 109/L for >7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade >3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse >28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively.Conclusions: The combination of pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. DisclosuresShustov:Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat:Spectrum Pharmaceuticals: Employment. Reddy:Spectrum Pharmaceuticals: Employment.

THE EFFICACY AND TOLERANCE OF CHIDAMIDE, PREDNISONE, CYCLOPHOSPHAMIDE AND THALIDOMIDE (C‐PCT) IN RELAPSED OR REFRACTORY PERIPHERAL T‐CELL LYMPHOMA: A PILOT STUDY

Introduction: The aim of this study was to evaluate the clinical efficacy and safety of chidamide, prednisone, cyclophosphamide and thalidomide (C-PCT) in relapsed or refractory (R/R) Peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR). Methods: Between June 2015 and September 2016, 12 Chinese patients with R/R PTCL were enrolled in this study. The median age was 52 years (range 28−69). Four patients were males, and 8 were females. Four (33.3%) patients were diagnosed as subtypes of PTCL not otherwise specified (PTCL, NOS), 4 (33.3%) were angioimmunoblastic T-cell lymphoma (AITL), 2 (16.7%) were type II enteropathy-associated T-cell lymphoma (EATL-II), 1 (8.3%) was ALK negative anaplastic large-cell lymphoma (ALK- ALCL) and 1 (8.3%) was cutaneous T-cell lymphoma (CTCL). Majority (11/12, 91.7%) of patients had an Ann Arbor stage III or IV, the only patient with CTCL had a TNMB stage IIB; 75% (9/12) patients had poor performance status, with ECOG 2 or more. The median IPI score was 2 (range 1−5) and 50% of patients had IPI between 3 and 5. The median number of prior systemic chemotherapies was 2 (range 1−4), 10 (83.3%) patients presented with PD to last line of prior systemic chemotherapy at enrollment, 1 was in SD, only 1 achieved PR but failed to autologous stem cell mobilization. C-PCT regimen was administered orally until disease progression or unacceptable toxicity. Results: The median time on treatment was 12 months (range 3–18 months). The ORR was 83.3% (10/12), 5 (41.7%) and 4 (33.3%) patients achieved CR and PR, respectively, 1(8.3%) patients obtained SD and 2 (16.7%) patients presented with PD. The median time to response was 3 months (range 3−6 months). All (100%, 4/4) the AITL patients responded to C-PCT regimen, including 2 CR and 2 PR; Notably, the patient relapsed after autologous stem transplantation (ASCT) achieved PR at 3 months and experienced further CR at 9 months. Approximately 75% (3/4) of PTCL-NOS patients achieved CR and 2 patients of EATL-II achieved PR and SD, respectively. The patient with CTCL progressed to the previous systemic chemotherapies and achieved PR at 3 months. With a median follow-up of 13 (3–18) months, 2 patients relapsed and 3 patients died of PD. The median overall survival (OS) and progression-free survival (PFS) have not been reached. The most common grade 3/4 adverse events were neutropenia (22%), thrombocytopenia (16%) and anemia (20%). Moreover, one patient experienced epstein-barr virus reactivation. Conclusions: C-PCT as salvage therapy was effective with manageable toxicity for patients with R/R PTCL. Further prospective trials are warranted to validate the efficacy of C-PCT in a large cohort of patients. Keywords: Chemotherapy; peripheral T-cell lymphomas (PTCL).

Pilot trial of chidamide, an oral histone deacetylase (HDAC) inhibitor, in combination with exemestane in hormone receptor-positive advanced breast cancer.

e12543 Background: Chidamide (CHI) is a novel benzamide type of subtype-selective histone deacetylase inhibitor approved in China for refractory and relapsed peripheral T-cell lymphoma with a dosage of 30 mg PO twice a week. A randomized, double blind and placebo-controlled phase 3 clinical trial of CHI plus exemestane (EXE) is currently ongoing in patients (pts) with hormone receptor-positive (HR+) advanced breast cancer (ABC). This abstract reports the results from the pilot study preceded the phase 3 trial. Methods: Eligible pts were postmenopausal women recurrent or progressed to at least one endocrine therapy. In the run-in period for pharmacokinetic (PK) analysis, pts received EXE 25 mg on day (D) 1 and CHI 30 mg on D 2. From D 5 pts started combination treatment having EXE 25 mg daily and CHI 30 mg twice a week until progression of disease (PD) or intolerable toxicities. A treatment cycle was defined as 28 days. Safety, PK parameters and preliminary efficacy were assessed. Results: 20 pts with HR+ and HER-2 negative were enrolled between Jul and Dec, 2015. Median duration of treatment was 5 cycles (range 0-16), with 4 pts still on treatment. 3 pts discontinued due to adverse events (AE). Drug-related AEs ≥ grade 3 in 2 or more pts were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). Similar plasma exposure of EXE was observed in the absence and presence of CHI ( 73 ± 27 vs. 80 ± 29 ng·hr/mL). A potential increased plasma exposure of CHI was noted in the presence of EXE compared with CHI alone ( 2232 ± 973 vs 1787 ± 946 ng·hr/mL), apparently related to the inter-patient variations in CHI plasma concentrations. Best response in 18 pts was assessed by RECIST, including 3 pts with partial response, 12 pts with stable disease and 3 pts with PD. Median progression free survival was 7.6 months. Conclusions: The combination of CHI and EXE was generally well tolerated. Most AEs were related to the CHI single-agent treatment that are generally manageable. Encouraging antitumor activity was observed. The overall results from this pilot trial enabled the next-stage clinical development of this combination regimen in HR+ ABC pts. Clinical trial information: NCT02482753.

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.

Chidamide tablets: HDAC inhibition to treat lymphoma.

Chidamide is the first oral subtype-selective histone deacetylase inhibitor (HDACI) approved in China as well as the first HDACI of the benzamide class approved for the treatment of relapsed and refractory peripheral T-cell lymphoma (PTCL). This review addresses detailed information regarding chidamide, including the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, clinical studies and application, safety, drug interactions and ongoing clinical trials. Although twice-weekly chidamide monotherapy has been recommended based on the evidence from preclinical and clinical studies with tolerable toxicities, its clinical efficacy could be further increased by combination with multidrug chemotherapy or chemo-free regimens. Further investigations into the mechanism of chidamide will facilitate the identification of optimal combined therapy approaches and suitable treatment populations. This review will contribute to a comprehensive understanding and better use of chidamide in clinical practice.

A Phase II Trial of Bendamustine, Carboplatin and Dexamethasone (BCD) for Refractory or Relapsed Peripheral T-Cell Lymphoma (BENCART): A Consortium for Improving Survival of Lymphoma (CISL) Trial

BackgroundThere is no standard salvage chemotherapy for relapsed or refractory peripheral T-cell lymphomas (PTCLs). In BETLY trial, which is sole prospective trial for bendamustine in refractory or relapsed T-cell lymphoma, bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed PTCLs. We planned this trial to investigate the efficacy and toxicity of bendamustine, carboplatin and dexamethasone (BCD) for relapsed or refractory PTCLs, which would be expected to show more promising clinical outcomes than that of bendamustine single therapy.Patients and MethodsPatients with relapsed or refractory PTCLs with more than one previous regimen regardless stem cell transplantation are eligible and totally 30 patients are needed. BCD treatment, which consist of bendamustine 80mg/m2 intravenously (i.v.) on Days 1 and 2, carboplatin AUC 5.0 i.v. on Day 1, and dexamethasone 40 mg orally on Days 1-4, was planned up to six treatment cycles without progressive disease and Peg-GCSF was supported at every cycle. Autologous stem cell transplantation (ASCT) after 3 cycles of BCD could be proceeded for eligible patients.ResultsTwenty-eight eligible patients were evaluated for toxicity and response. The diagnoses of participants included 15 cases of PTCL-NOS (54%), five cases of angioimmunoblastic T-cell lymphoma (18%) and four cases of ALK-negative anaplastic large cell lymphoma (14%) among others. The median age of the patients was 59 years (range, 23-75 years). After treatments with BCD, which delivered a median of three BCD cycles, there were 8 patients with complete responses (CR; 30%) and seven with partial responses (PR; 25%). The overall response rate (RR) was 55%. Five patients preceded to ASCT and three patients finally achieved CR. The median progression free survival was 4.8 months with a median follow-up duration of 4.5 months. In a total of 85 cycles of BCD, grade 3 or 4 neutropenia, thrombocytopenia and anemia occurred in 17.6%, 38.8% and 16.5% of cycles, respectively. Only one patients experienced febrile neutropenia.ConclusionsBCD is an effective salvage regimen for relapsed or refractory PTCLs and can be administered with acceptable toxicity. 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.

Analysis of Drugs for Hematological Malignancy That Were Granted Accelerated Approval and Feasibility of Randomized Phase 3 Clinical Trials for Relapsed and Refractory Hematological Malignancy

Background: Accelerated approval regulation was instituted in 1992 in the US. Principally, accelerated approval is granted based on a surrogate endpoint that is reasonably likely to predict clinical benefit and postmarketing confirmatory clinical trials are required to verify clinical benefit and convert accelerated approval to regular approval. However, it is a big challenge in terms of feasibility to conduct randomized phase 3 trials for relapsed or refractory hematological malignancy. Methods: We examined indications of accelerated approval and target population and development status of postmarketing confirmatory clinical trials regarding all drugs for hematological malignancy that were granted accelerated approval during December, 1992 and July, 2016. In addition, we searched Pubmed for results of randomized phase 3 trials that were published after the year of 2000 and Clinicaltrials.gov database for information on ongoing or terminated randomized phase 3 trials for adult patients with relapsed or refractory lymphoid malignancies other than chronic lymphocytic leukemia and multiple myeloma. Results: As of July 31, 2016, 37 indications of 31 drugs for hematological malignancy were granted accelerated approval. Of these, 31 indications were relapsed or refractory hematological malignancy. Although postmarketing clinical trials for verifying clinical efficacy were completed regarding the other 6 indications, accelerated approval regarding only 13 of the 31 indications for relapsed or refractory hematological malignancy was converted to regular approval and this conversion took median 1155 (166-3220) days. Moreover, 5 of the 13 indications were granted regular approval based on clinical data in different population from (earlier treatment line than) the indications granted accelerated approval as follows: ibritumomab tiuxetan for follicular lymphoma, alemtuzumab for chronic lymphocytic leukemia, imatinib for pediatric chronic myeloid leukemia, ofatumumab for chronic lymphocytic leukemia and brentuximab vedotin for Hodgkin lymphoma. The other 8 of 13 indications were grated regular approval for very similar population to the indications granted accelerated approval as follows: relapsed or refractory cutaneous T-cell lymphoma (denileukin), relapsed or refractory chronic myeloid leukemia (dasatinib, nilotinib and omacetaxin), relapsed or refractory multiple myeloma (bortezomib, carfilzomib and pomalidomide) and relapsed or refractory chronic lymphocytic leukemia (ibrutinib). Therefore, accelerated approval of any drugs has never been converted to regular approval based on clinical trials for relapsed or refractory B-cell lymphoma, relapsed or refractory peripheral T-cell lymphoma and relapsed or refractory acute lymphoblastic leukemia. In fact, regarding phase 3 trials for adult patients with relapsed or refractory lymphoid malignancies other than multiple myeloma and chronic lymphocytic leukemia, we found 20 trials published in international journals and 32 trials in clinicaltrials.gov. The details are 23 trials for indolent B-cell non-Hodgkin's lymphoma including follicular lymphoma, 13 for autologous stem cell transplantation (ASCT)-eligible aggressive non-Hodgkin's lymphoma, 4 for ASCT-ineligible aggressive non-Hodgkin's lymphoma, 4 for mantle cell lymphoma, 4 for Hodgkin's lymphoma, 2 for acute lymphoblastic leukemia, 1 for peripheral T-cell lymphoma and 1 for cutaneous T-cell lymphoma. In total, 11 trials were stopped due to low accrual. The median (Min, Max) number of actual or anticipated enrolled patients in the other 41 trials was 317 (143, 800). Negative results were reported regarding 9 trials including 7 trials for ASCT-eligible aggressive non-Hodgkin's lymphoma. There were no trials in which result of overall survival as single primary endpoint was positive. Conclusions: Our analysis indicates that drug approval based on phase 3 trials for patients with relapsed or refractory lymphoid malignancies other than multiple myeloma and chronic lymphocytic leukemia remains a big challenge. Therefore, how to evaluate results of single-arm trials for these patients and how to enroll these patients to clinical trials efficiently are important. Disclosures Nagai: Takara Bio Inc.: Consultancy. Ozawa:Celgene Japan: Consultancy; Takara Bio Inc: Research Funding; Sumitomo Dainippon Pharma Co. Ltd: Research Funding; JCR Pharmaceutical Inc: Consultancy.