Peripheral T cell lymphoma.

Thirty-one Chinese patients with peripheral T cell lymphoma (PTCL) were reviewed. Using the modified Japanese Lymphoma Group classification, there were nine (29%) of the pleomorphic type, 16 (52%) immunoblastic lymphadenopathy (IBL)-like, two (7%) T-zone lymphoma, and one (3%) Lennert's lymphoepithelioid type. Three (9%) were not classifiable. All were positive for T11 (E rosette receptor antigen). Fifty-four percent (15 of 28) were positive predominantly for T4 (helper T cell) and 46% (13/28) for T8 (suppressor T cell). The median age of the patients was 57 years. They usually presented with advanced disease, and while extranodal involvement was common, CNS disease was not seen. The IBL-like type was associated with a positive Coombs' test and polyclonal hypergammaglobulinemia. Five of the nine pleomorphic type were checked for antibody to HTLV-I virus and all were negative. PTCL was associated with poor prognosis, which was not influenced by the histologic subtypes and the T4/T8 phenotypes. The complete response rate of 13 consecutive patients who received the BACOP (bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone) L17M regimen was significantly better than the 16 historic controls who received other less-intensive regiments, 84% v 19% (P less than .01). The relapse rate was also significantly lower, 9% v 100% (P less than .001). There appeared to be an improvement in the disease-free survival (DFS) (80% v 0% at 18 months), as well as the overall survival (60% v 36% at 18 months), but the differences did not reach statistical significance due to small sample sizes.

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Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2011.37.4223 ◽

2012 ◽

Vol 30 (6) ◽

pp. 631-636 ◽

Cited By ~ 362

Author(s):

Bertrand Coiffier ◽

Barbara Pro ◽

H. Miles Prince ◽

Francine Foss ◽

Lubomir Sokol ◽

...

Keyword(s):

T Cell ◽

Phase Ii ◽

Systemic Therapy ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

Complete Response ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Prior Systemic Therapy

Purpose Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Patients and Methods Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. Results Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Conclusion Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

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Venetoclax Shows Low Therapeutic Activity in BCL2-Positive Relapsed/Refractory Peripheral T-Cell Lymphoma: A Phase 2 Study of the Fondazione Italiana Linfomi

Frontiers in Oncology ◽

10.3389/fonc.2021.789891 ◽

2021 ◽

Vol 11 ◽

Author(s):

Laura Ballotta ◽

Pier Luigi Zinzani ◽

Stefano Pileri ◽

Riccardo Bruna ◽

Monica Tani ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

Tumor Lysis Syndrome ◽

B Cell Lymphoma ◽

Complete Response ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Clinical Trial Registration ◽

Prospective Phase ◽

Bcl2 Protein

Patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis, with an expected survival of less than 1 year using standard salvage therapies. Recent advances in our understanding of the biology of PTCL have led to identifying B-Cell Lymphoma 2 (BCL2) protein as a potential therapeutic target. BLC2 inhibitor venetoclax was investigated in a prospective phase II trial in patients with BCL2-positive R/R PTCL after at least one previous standard line of treatment (NCT03552692). Venetoclax given alone at a dosage of 800 mg/day resulted in one complete response (CR) and two stable diseases (SDs) among 17 enrolled patients. The majority of patients (88.2%) interrupted the treatment due to disease progression. No relationship with BCL2 expression was documented. At a median follow-up of 8 months, two patients are currently still on treatment (one CR and one SD). No case of tumor lysis syndrome was registered. Therefore, venetoclax monotherapy shows activity in a minority of patients whose biological characteristics have not yet been identified.Clinical Trial Registrationwww.clinicaltrials.gov (NCT03552692, EudraCT number 2017-004630-29).

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L-Asparaginase-Induced Complete Response in a Relapsed Patient with Epstein-Barr Virus and Cytotoxic Peripheral T-Cell Lymphoma Not Otherwise Specified

Internal Medicine ◽

10.2169/internalmedicine.49.4083 ◽

2010 ◽

Vol 49 (22) ◽

pp. 2505-2508 ◽

Cited By ~ 1

Author(s):

Tsutomu Takahashi ◽

Fumiyoshi Ikejiri ◽

Chie Onishi ◽

Koshi Kawakami ◽

Masaya Inoue ◽

...

Keyword(s):

T Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

Complete Response ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Barr Virus ◽

Not Otherwise Specified ◽

Epstein Barr

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Monocytosis As Prognostic Factor in Aggressive, Non-Primary Cutaneous Peripheral T-Cell Lymphoma: A Study of 251 Cases

Blood ◽

10.1182/blood.v120.21.1608.1608 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1608-1608

Author(s):

Brady E Beltran ◽

Erick Cotacallapa ◽

Jorge J Castillo

Keyword(s):

Overall Survival ◽

T Cell ◽

Who Classification ◽

Cell Lymphoma ◽

Statistical Significance ◽

Prognostic Index ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Worse Prognosis

Abstract Abstract 1608 Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous family of entities with a worse prognosis, stage by stage, than their B-cell counterparts. We have previously reported that an absolute lymphocyte count (ALC) <1000/uL is associated with a worse prognosis in Peruvian patients with PTCL (Castillo et al. 2010). The goal of this study is to investigate the prognostic value of absolute monocyte count (AMC) in the survival of patients with PTCL. Methods: A total of 251 cases of aggressive, non-primary cutaneous PTCL diagnosed at our institution between January 1997 and January 2012 were reviewed, reevaluated according to their morphological, immunological and clinical characteristics, and reclassified according to the 2008 WHO classification of lymphoid neoplasms. Characteristics will be presented descriptively. Kaplan-Meier method was used to estimate overall survival (OS) curves, which were compared using the log-rank test. The multivariate analysis was performed using the Cox proportional-hazard regression test. Results: According to the new WHO classification of lymphoid neoplasms, 104 cases (41%) were classified as adult T-cell leukemia/lymphoma (ATLL), 103 cases (41%) as PTCL, unspecified (PTCLU), 27 cases (11%) as analplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL), 11 cases (4%) as extranodal NK/T-cell lymphoma (NKTCL), nasal type, 4 cases (2%) as angioimmunoblastic lymphoma (AIL), and 2 cases (1%) were diagnosed with ALK+ ALCL. The median age at diagnosis was 57 years (range 14–92 years); 47% of patients were >60 years. The male-to-female ratio was 1:1. ECOG performance status >1 was seen in 51%, LDH was elevated in 67%, advanced stage was seen in 73%, and >1 extranodal sites were seen in 22% of the patients. Bone marrow involvement was reported in 30% and B symptoms in 64% of patients. An International Prognostic Index (IPI) score 3–5 was seen in 55%, and a Prognostic Index for PTCLU (PIT) score of 2–4 in 63%. The median overall survival (OS) for the whole group was 10 months. The IPI score, the PIT score, ALC <1000/uL and AMC >800/uL (Figure) showed statistical significance in the univariate survival analysis (p<0.001, p<0.001, p=0.001 and p=0.001, respectively). In the multivariate analysis, PIT score and AMC >800/uL showed statistical significance (p=0.006, p=0.046, respectively). Conclusions: Monocytosis, defined as AMC >800/uL, and the PIT score were independent prognostic factors for OS in patients with aggressive, non-primary cutaneous PTCL. Disclosures: No relevant conflicts of interest to declare.

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Marqibo (Vincristine Sulfate Liposomes Injection (OPTISOME™) Demonstrates Activity in Patients with Relapsed and Refractory Peripheral T-Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.4466.4466 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4466-4466

Author(s):

M. Alma Rodriguez ◽

Jane N. Winter ◽

Biao Lu ◽

Gary Huang ◽

Gavin S. Choy ◽

...

Keyword(s):

Adverse Event ◽

T Cell ◽

Cell Lymphoma ◽

International Workshop ◽

Objective Response ◽

Complete Response ◽

T Cell Lymphoma ◽

Low Grade ◽

Peripheral T Cell Lymphoma ◽

Best Response

Abstract Introduction: New and more effective agents are needed to improve treatment outcomes for patients with relapsed and refractory peripheral T-cell lymphoma (PTCL). Marqibo is a novel formulation of vincristine (VCR) encapsulated in sphingomyelin/cholesterol liposome called OPTISOME. In preclinical studies, OPTISOME technology has been shown to provide targeted, increased, and sustained delivery of VCR to tumor cells compared to non-encapsulated VCR or VCR encapsulated in conventional liposomes. Methods: PTCL patients from two multi-center phase 2 studies of Marqibo in relapsed and refractory lymphoid malignancies are integrated for safety and efficacy evaluation. In both studies, Marqibo (2.0 mg/m2 without dose capping IV over 60 minutes) was administered every 14 days for up to 12 cycles or until toxicity or progressive disease was observed. The primary efficacy endpoint of the 2 studies was the objective response rate (ORR) defined as the percentage of patients whose best response was complete response (CR), complete response unconfirmed, or partial response (PR). Best response was determined according to the International Workshop Response Criteria. Secondary endpoints included adverse event evaluation, time to progression (TTP) and overall survival (OS). Results: Six (3M/3F) patients diagnosed with PTCL received at least one dose of Marqibo. At baseline, the median age was 59 years (range, 34–86). All six patients had aggressive disease and most were heavily pretreated. The median number of prior lines of chemotherapy and immunotherapy regimens was 3 (range, 1–6) and four patients (66.7%) had received prior autologous bone marrow transplant. All patients had prior exposure to neurotoxic therapy: platinum compounds (33.3%), taxanes (16.7%) and VCR (100%). All patients had achieved a CR or PR to their frontline therapy and 50% (3/6) had achieved a CR or PR to their last line of therapy prior to receiving Marqibo. Patients received a median of 4 cycles of Marqibo (range, 1–9). Median cumulative dose of Marqibo was 7 mg/m2 (range, 2–17.4). The most commonly reported adverse event was peripheral sensory neuropathy (3 of 6 patients) and all of Grade 1 severity. Three patients had PR, 1 patient had stable disease, 1 patient experienced disease progression, and 1 patient was unevaluable. Median OS and TTP were 194 and 70 days, respectively. Conclusions: These preliminary results suggest encouraging activity and tolerability of Marqibo in heavily pre-treated relapsed and refractory PTCL patients. Given the high proportion of exposure to neurotoxic agents preceding Marqibo, the low grade neurotoxicity noted following Marqibo is a favorable finding.

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Phase II Trial of Romidepsin, FK228, in Cutaneous and Peripheral T-Cell Lymphoma: Clinical Activity and Molecular Markers.

Blood ◽

10.1182/blood.v108.11.2469.2469 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2469-2469 ◽

Cited By ~ 4

Author(s):

Richard L. Piekarz ◽

Robin Frye ◽

Maria Turner ◽

John Wright ◽

Steven Allen ◽

...

Keyword(s):

Molecular Markers ◽

T Cell ◽

Cell Lymphoma ◽

Fetal Hemoglobin ◽

Complete Response ◽

Clinical Development ◽

T Cell Lymphoma ◽

Rt Pcr ◽

Peripheral T Cell Lymphoma ◽

Mdr1 Expression

Abstract Histone deacetylase inhibitors induce changes in gene expression that lead to cellular differentiation and reversal of the transformed phenotype. Interest in clinical development of these agents has been spurred by the responses observed in patients with T-cell lymphoma to romidepsin, previously FK228 and depsipeptide. To date, 61 patients with CTCL and 34 with PTCL have been accrued to our ongoing multiinstitutional trial of romidepsin for patients with recurrent or refractory cutaneous or peripheral T-cell lymphoma. Romidepsin is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14 mg/m2. Complete and partial responses have been observed in patients with CTCL, with a complete response in a patient with Sézary syndrome ongoing for over 45 months and a partial response ongoing for over 60 months. Both complete and partial responses were observed in patients with various subtypes of PTCL, including PTCL, unspecified, ALK-/CD30+ anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma, with a complete response ongoing for over 34 months. Responses will be updated for presentation. Molecular endpoint analysis was performed in normal and malignant circulating peripheral mononuclear cells, PBMCs, and in tumor samples. Immunoblot analysis demonstrated increased histone acetylation in PBMCs of 2-fold or greater from 19 of 33 patients at 4 or 24 hrs. RT-PCR of RNA demonstrated a 2-fold or greater increased expression of MDR-1 in PBMCs from 27 of 45 patients, 11 of which were greater than 4-fold. Microarray performed on CTCL patient samples detected significant changes with treatment. In addition, changes in the 5 gene signature for CTCL previously published (Nebozhyn et al. Blood2006; 107:3189) were also detected when analyzed by QPCR. MDR1 expression was evaluated by RT-PCR in 30 patient’s tumors. MDR1 expression level was not significantly increased at the time of progression, mean 3.2 and 4.9 (s.d. 3.1 and 5.5, respectively) in MDR1 units as defined in Zhan et al. Blood 1997 89:3795. Since differentiating agents have been shown to induce expression of fetal hemoglobin in the laboratory, fetal hemoglobin levels were assayed in patients on this clinical trial. Increased circulating fetal hemoglobin of 2, 5, and 10 fold was observed in 34, 24, and 15 patients, respectively, from 44 patients evaluated. SNP analysis is being performed on the MDR1 gene for comparison with pharmacokinetics and induction of fetal hemoglobin and MDR1 itself. In conclusion, romidepsin has significant single agent activity in patients with CTCL or PTCL. Molecular effects can be assayed in patients treated with romidepsin and related agents. Further clinical development of these agents should include combination trials and the identification of molecular markers of response.

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Development of Masitinib for the Treatment of Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3993.3993 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3993-3993

Author(s):

Olivier Hermine ◽

Ambroise Marçais ◽

Thiago Maciel ◽

J Bagbor ◽

Darius Jagielski ◽

...

Keyword(s):

Central Nervous System ◽

T Cell ◽

Mast Cells ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Complete Response ◽

T Cell Lymphoma ◽

Phase 2 ◽

Peripheral T Cell Lymphoma ◽

Phase 3

Abstract Increasing resistance to chemotherapy means that approximately 30% of patients afflicted with peripheral T-cell lymphoma will develop a relapsed/refractory form and eventually succumb to the disease. To date there is no clearly established second-line therapy and investigation of new therapies is necessary to address this unmet medical need. Masitinib is an oral tyrosine kinase inhibitor that potently and selectively targets c-Kit and platelet-derived growth factor receptor (PDGFR). Studies in human T-cell lymphoma have identified aberrant expression of PDGFR-alpha and that this kinase fosters peripheral T-cell lymphoma cell proliferation via an autocrine loop. Masitinib may therefore exert an antiproliferative and pro-apoptotic action on abnormal T-cells. In addition to this direct mechanism of action, masitinib can elicit antitumor effects by acting on mast cells and macrophages. By inhibiting mast cells, masitinib reduces the release of pro-tumoral M2-polarizing cytokines as well as factors favoring metastasis and angiogenesis. Masitinib can also promote macrophage infiltration into tumors, inducing an anti-tumoral Th1 immune response. Inhibition of cell proliferation was observed following single-agent masitinib treatment in the OSW canine T-cell lymphoma line, with an IC50 of 0.005 μM, suggesting that it could be used efficiently for the treatment of T-cell lymphoma. This hypothesis was further substantiated by a case study in a companion dog with T-cell lymphoma treated with masitinib monotherapy 12 mg/kg/day, reporting a complete response following 3 weeks of treatment with increased quality of life. This preliminary observation was repeated in two separate independent studies, each comprised of 11 dogs with T-cell lymphoma. A first study reported an overall response rate (ORR) of 73%, including 3/11 dogs with complete response (CR) and 5/11 dogs with partial response (PR) after 3 months of treatment. A second study reported an ORR of 45%, including 2/11 dogs with CR and 3/11 dogs with PR after 3 months of treatment. Meta-analysis of these data (n=23) showed that masitinib treatment of canine T-cell lymphoma resulted in a CR in 6/23 dogs (26%) and in a PR 8/23 dogs (35%), resulting in an ORR of 61%. Naturally occurring tumors in dogs have more clinical and biological similarities to human cancers than any other animal cancer model, hence these data provide strong medical plausibility for masitinib in the treatment of human peripheral T-cell lymphoma. The above in vitro and in vivo data led to initiation of a multicenter, randomized, open-label, three-parallel group, phase 2 study to evaluate the combination of masitinib plus dexamethasone with or without gemcitabine in patients with relapsed or refractory peripheral T-cell lymphoma. A recent decision to accelerate to a phase 3 study was based on an observed survival benefit for masitinib treated patients when compared with the control arm, and an acceptable safety profile; passage to phase 3 was validated by the independent Data Safety Monitoring Board with data blinded to sponsor and investigator. Specifically, pooled data from all masitinib-treated patients in the phase 2 stage (n=34) estimated a median overall survival (OS) of 9.0 months, which compares favorably against the literature benchmark median OS of 5.5 months for documented chemotherapy in this indication. This phase 3 study is currently open for patient recruitment in at least 14 countries and has OS as the primary endpoint. If successful, masitinib could provide a new treatment option in relapsed or refractory peripheral T-cell lymphoma. Disclosures Off Label Use: Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique mechanism of action, masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. In oncology due to its immunotherapy effect, masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and consequently the inhibition of the activation of the inflammatory process, masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.. Marçais:AB Science: Consultancy. Dubreuil:AB Science: Consultancy. Moussy:AB Science: Other: CEO.

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Pralatrexate in Chinese Patients with Relapsed or Refractory Peripheral T-cell Lymphoma: A Single-arm, Multicenter Study

Targeted Oncology ◽

10.1007/s11523-019-00630-y ◽

2019 ◽

Vol 14 (2) ◽

pp. 149-158 ◽

Cited By ~ 6

Author(s):

Xiaonan Hong ◽

Yuqin Song ◽

Huiqiang Huang ◽

Bing Bai ◽

Huilai Zhang ◽

...

Keyword(s):

T Cell ◽

Multicenter Study ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Chinese Patients ◽

Peripheral T Cell Lymphoma

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T follicular helper phenotype predicts response to histone deacetylase inhibitors in relapsed/refractory peripheral T-cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2020002396 ◽

2020 ◽

Vol 4 (19) ◽

pp. 4640-4647 ◽

Cited By ~ 2

Author(s):

Paola Ghione ◽

Promie Faruque ◽

Neha Mehta-Shah ◽

Venkatraman Seshan ◽

Neval Ozkaya ◽

...

Keyword(s):

T Cell ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Cell Lymphoma ◽

Single Agent ◽

Complete Response ◽

T Cell Lymphoma ◽

World Health ◽

Peripheral T Cell Lymphoma ◽

Follicular Helper

Abstract Histone deacetylase inhibitors (HDACi) are active agents for peripheral T-cell lymphoma (PTCL). Anecdotally angioimmunoblastic T-cell lymphoma (AITL) appears to respond better than PTCL–not otherwise specified (NOS) to HDACi. The new World Health Organization classification shows that a subgroup of PTCL carries similarities in phenotype and gene expression profiling to AITL, comparable to T follicular helper (TFH) cells. The disease might behave similarly to AITL when treated with HDACi. We analyzed 127 patients with AITL or PTCL-NOS treated with HDACi at relapse as a single agent or in combination. We re-reviewed the pathology of all PTCL-NOS to identify the TFH phenotype. Patients received HDACi at relapse as a single agent in 97 cases (76%, 59 TFH, 38 non-TFH) or in combination in 30 cases (24%, 18 TFH, 12 non-TFH) including duvelisib, lenalidomide, lenalidomide plus carfilzomib, and pralatrexate. Seven PTCL-NOS had TFH phenotype; 2 PTCL-NOS were reclassified as AITL. Overall response rate (ORR) was 56.5% (28.9% complete response [CR]) in TFH and 29.4% (19.6% CR) in non-TFH phenotype patients (P = .0035), with TFH phenotype being an independent predictor of ORR (P = .009). Sixteen patients sufficiently responded to HDACi or HDACi in combination with another agent to proceed directly to allogeneic transplantation; 1 of 16 responded to donor lymphocyte infusion (12 TFH, 4 non-TFH). Our results, although retrospective, support that HDACi, as a single agent or in combination, may have superior activity in TFH-PTCL compared with non-TFH PTCL. This differential efficacy could help inform subtype-specific therapy and guide interpretation of HDACi trials.

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