Peripheral T-Cell Lymphoma of Urinary Bladder Presenting With Just Irritative Voiding Symptoms

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Abstract 795 Background:Mogamulizumab (KW-0761) is a humanized anti-CCR4 antibody engineered to exert potent ADCC by defucosylation. In a phase I study for patients with CCR4-positive T-cell malignancies, once weekly administration for 4 weeks of mogamulizumab was well tolerated up to 1.0 mg/kg, and encouraging efficacy was observed (J Clin Oncol 2010;28:1591). In a subsequent phase II study in CCR4-positive relapsed adult T-cell leukemia-lymphoma (ATL) patients, mogamulizumab exhibited an overall response rate (ORR) of 50% (J Clin Oncol 2012;30:837), leading to its approval in Japan in 2012 for relapsed/refractory ATL. In addition, a phase I/IIa study for previously treated cutaneous T-cell lymphoma (CTCL) in the USA showed an ORR of 37% (14/38) (T-CELL LYMPHOMA FORUM 2012). Based on these findings, a phase II study of mogamulizumab for relapsed peripheral T-cell lymphoma (PTCL) and CTCL was conducted in Japan. Methods:A multicenter phase II study of mogamulizumab monotherapy for patients with relapsed CCR4-positive PTCL and CTCL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary endpoint was ORR and secondary endpoints included progression-free survival (PFS) and overall survival (OS). At least 35 patients were needed to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold, with an expected ORR for mogamulizumab of 25% with 90% statistical power. Patients received intravenous infusions of mogamulizumab once per week for 8 weeks at a dose of 1.0 mg/kg. Responses were assessed after the 4th and 8th infusions of mogamulizumab by an independent efficacy assessment committee. The histopathological subtypes of PTCL were confirmed by an independent pathology review committee according to the 2008 WHO classification. In addition, we examined blood T-cell subset distributions. Results:A total of 38 patients were enrolled, and 37 patients (male/female 23/14; median age 64 years, range 33–80) received mogamulizumab. One patient was withdrawn due to an infectious complication. Twenty-nine of the 37 assessable patients had PTCL [PTCL- not otherwise specified (NOS), n=16; angioimmunoblastic T-cell lymphoma (AITL), n=12; anaplastic large cell lymphoma (ALCL)-ALK negative, n=1] and 8 had CTCL [mycosis fungoides (MF), n=7; cutaneous ALCL, n=1]. Performance status at enrollment was 0 (n=24), 1 (n=12), and 2 (n=1). The median number of prior systemic chemotherapy regimens was 2 (range 1–6). Of the 37 patients, 25 completed the schedule of 8 planned infusions. Nine patients (24%) discontinued the treatment protocol due to progressive disease and 3 due to adverse events (AEs). The ORR in 37 patients was 35% (13/37, 95% CI, 20 to 53%) with 14% having a complete response (5/37) (Table 1). By PTCL subtype, the ORR was 34% (10/29) for PTCL (3/16 for PTCL-NOS, 6/12 for AITL, and 1/1 for ALCL-ALK negative) and 38% (3/8) for CTCL (2/7 for MF and 1/1 for cutaneous ALCL). AEs possibly, probably, or definitely related to mogamulizumab monotherapy were as follows. Lymphopenia of all grades and that of grades 3–4 were observed in 78% and 70% of the 37 patients, respectively. Leukopenia of all grades and that of grades 3–4 were observed in 43% and 14% of the 37 patients. For all grades and grades 3–4, neutropenia was observed in 35% and 16%, thrombocytopenia in 35% and 3%, ALT increases in 22% and 3%, and skin eruptions in 49% and 8% of patients, respectively. Infusion-related toxicities occurred in 22%, which were all within grade 2 or lower. Fourteen severe AEs were observed in 7 patients, including a grade 3 polymyositis in 1 and grade 2 cytomegalovirus retinitis in 2. All severe AEs were improved. No grade 5 AEs were observed. Pharmacokinetic analysis demonstrated that Cmax and trough (C168h) after the 8th infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. No anti-mogamulizumab antibody has been detected. Updated results of PFS, OS, and T-cell subset analysis are being analyzed for presentation. Conclusions:Mogamulizumab monotherapy showed promising antitumor activity with acceptable toxicity profiles in patients with relapsed PTCL and CTCL, warranting further investigation. [Display omitted] Disclosures:Ishida:Kyowa Hakko Kirin Co., Ltd,: Honoraria, Research Funding, Speakers Bureau. Ogura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Suzumiya:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Inagaki:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Tamura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Akinaga:Kyowa Hakko Kirin Co., Ltd,: Employment. Tomonaga:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Ueda:Kyowa Hakko Kirin Co., Ltd,: endowed chair Other.

A single-institution retrospective analysis of allo-HSCT for relapsed and refractory aggressive lymphomas: T-cell origin predicts better outcomes even in active disease.

Cutaneous and peripheral T-cell lymphomas in the u.S. population: A 25-year national review of epidemiological burden and racialdisparities

Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma.

A Phase II Clinical Study Exploring the Safety and Efficacy of the Oral PI3Kδ Inhibitor, Linperlisib, in Relapsed Refractory T Cell Lymphoma

Diagnostic Accuracy of a Defined Immunophenotypic and Molecular Genetic Approach for Peripheral T/NK-Cell Lymphomas: A North American PTCL Study Group Project

Background:Peripheral T cell lymphomas (PTCL) represent about 10% of non‐Hodgkin lymphomas and are associated with poor prognosis. T‐cell receptor (TCR) signaling is the major growth‐regulatory machinery of normal T cells. Although its involvement in T‐cell lymphomagenesis has not been extensively investigated, various genes coding components of the TCR signaling are found altered in human PTCL and several reports indicates a predominant role of chronic antigenic stimulation in some PTCL.Aims:This study was conducted to investigate the role of TCR chronic stimulation in T‐cell lymphomagenesis and to identify crucial survival factors for lymphoma cells.Methods:To mimic chronic TCR stimulation, we took advantage of a phenomenon called homeostatic proliferation, which is known to be driven by TCR signaling generated by self‐MHC/TCR interactions. To this end, purified mature T cells from p53‐deficient mice were transferred into CD3epsilon‐deficient mice.Peripheral T‐cell lymphomas generated were analyzed using different approaches; flow cytometry, transcriptomic analysis, kinome, western blot, immunohistochemistry and by various in vitro or in vivo functional experiments.Human PTCL cases from Grenoble, Lyon and Tenomic or CeVi collections were analyzed using flow cytometry and immunochemistry.Results:Sixty percent of mice died from PTCL originating from conventional alpha‐beta T cells with an effector‐memory (CD44hi, CD62Llo, CD122hi) and exhausted (PD1hi) phenotype. Transcriptomic analysis reveals a chronic TCR activation signature, showing the role of TCR in lymphomagenesis.To study signals involved in lymphoma survival, we performed a kinome analysis showing a constitutive activation of the Syk kinase. Syk expression and activation was confirmed by western blot and constitutive activation of downstream targets of Syk such as PLCg1&2 and the PI3K‐Akt‐mTOR pathway was demonstrated. However, using in vivo experiments, we demonstrated that TCR signaling is not required for PTCL survival, suggesting that Syk may be involved in other signaling pathways. Interestingly, transcriptomic analyses of both mouse and human PTCLs showed an upregulation of a subset of genes involved in Natural Killer (NK) cells biology, such as NK receptors (NKRs) and signaling effectors of NKR, compared to normal T‐cells. This suggests that PTCL acquire “innate‐like” features during chronic TCR stimulation that would be implicated in cell survival and we next show that activatory NKRs are functional and signalize through SYK in murine PTCL. We also demonstrate that activatory NKRs participate to murine PTCL survival as in vivo NKR blockade delays PTCL evolution as well as Syk inhibition.We studied NKRs and Syk expression in a large subset of human PTCL and confirmed their various expression by many PTCL entities.Summary/Conclusion:Using a murine model, we show that chronic TCR stimulation is crucial for T‐cell lymphomagenesis and is associated with an ”innate like“ reprogramming. We characterized potential novel mechanisms of PTCL survival involving NKR and Syk signaling in murine PTCL that could lead to new therapeutic strategy development as a large proportion of human PTCL shares some common features with this murine PTCL generated in this experimental model.

Final results from the embolden trial: pembrolizumab in combination with decitabine and pralatrexate in heavily pretreated patients with peripheral and cutaneous T-cell lymphoma

e19524 Background: T-cell lymphomas are a heterogeneous group of lymphomas, including the cutaneous T cell lymphoma (CTCL) and the peripheral T cell lymphomas (PTCL). Regarding the PTCL, it’s a heterogeneous group including approximately 23 different diseases with the peripheral T-cell lymphoma not otherwise specified (PTCL NOS), angioimmunoblastic lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) being the most frequent subtypes. In contrast with the B cell lymphomas, most of the PTCL have a worse prognosis. We aim in our study to quantify the prognosis in each of the most frequent subtypes of PTCL. Methods: We analyzed patients with either PTCL NOS, AITL, or ALCL treated at Sylvester Comprehensive Cancer Center between 2010 and 2020. We calculated overall survival (OS) using the Kaplan-Meier method with Log-Rank Test to estimate the 95% confidence interval. Results: 98 patients belonged to 1 of the 3 major T-cell lymphoma subtypes: 43 to PTCL NOS, 33 to AITL, and 20 to ALCL, being 7 ALK-positive and 13 ALK-negative. Mean age in PTCL NOS, AITL and ALCL was 56 years (ranging from 8-88), 62 (8-89), and 52 (1-79), respectively. In PTCL NOS, AITL and ALCL respectively, 21 (46%), 15 (45%) and 7 (35%) of patients were female. The three-year and five-year overall survival was 62% (95% CI 42-82) and 30% (95% CI 6-54%) in PTCL NOS, 64% (95% CI 44-84) and 42% (95% CI 4-78%) in AITL, 75 (95% CI 51-99) and 67% (95% CI 33-100) in ALK-negative ALCL. There were no reported deaths in ALK-positive ALCL. The mean survival was lowest in PTCL NOS (p = 0.02), being 3,6 years, while AITL it is 5.2 and in ALCL it is 8.4. Conclusions: Amongst the three major subtypes of PTCL, PTCL NOS have the worse prognosis. Future research is needed to develop a risk stratification tool in each subtype.

Real World Prevalence of Diagnostic Revision Among Patients with Peripheral T-Cell Lymphomas (PTCL) in the US: Results of an Administrative Claims and Electronic Medical Record Analyses

Peripheral scalp T-cell lymphoma is a very rare disease. We report a case of a 22-year-old man who presented an indolent large scalp mass in the right frontal scalp region. The patient’s physical examination demonstrated no palpable mass in the chest, abdomen, and extremities. The brain CT revealed a high-density large scalp mass of the subgaleal layer in the right frontal and a small scalp mass of the subgaleal layer in the left frontal. The brain MRI showed multifocal enhancing masses in the bilateral dura, the subgaleal layer of the scalp, and the skull. The patient underwent removal of the tumor found in the right frontal scalp. The histologic diagnosis was peripheral T-cell lymphoma. Bone marrow aspiration showed the involvement of T-cell lymphoma. The patient received chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP protocol) for 3 cycles. The patient was discharged without neurological deficit. The patient showed no evidence of recurrence 15 months after surgery. We report a rare case of peripheral T-cell lymphoma mimicking benign scalp tumors.

Most peripheral T-cell lymphomas (PTCL) express the αβ T-cell receptor (TCR) whereas rare PTCL express the γδ TCR. Most if not all γδ PTCL are extranodal lymphomas and among them, hepatosplenic γδ PTCL constitute a distinct clinicopathological entity. Besides αβ and γδ PTCL, there is a recently recognized group of extranodal, mainly nasal tumours, which display, in most instances, phenotypic and genotypic features of Natural-Killer cell non-Hodgkin's lymphomas (NK-NHL). Cytotoxic cells, including NK cells and cytotoxic αβ and γδ T lymphocytes may induce lysis of the target by using granule-associated cytotoxic proteins such as the T-cell intracellular antigen-1 (TIA-1), perforin and granzyme B. Expression of TIA-1 can be detected in all cytotoxic cells whereas granzyme B and perforin expression can be detected in high levels only in activated cytotoxic cells. Recently, several studies showed that the expression of these cytotoxic proteins in tumour cells of PTCL and NK-NHL is associated with a) extranodal site of clinicopathological presentation b) NK or Tγδ -cell phenotype c) CD30 expression in cutaneous T-cell lymphoproliferations and d) anaplastic morphology in nodal PTCL. This latter finding contrasts with the data that only rare Hodgkin lymphomas (HL) express cytotoxic proteins in Hodgkin and Reed-Sternberg cells. Altogether the data of the literature indicate that most extranodal T and NK-NHL are activated cytotoxic lymphomas with the notable exception of hepatosplenic γδ PTCL which represent tumours of non-activated cytotoxic cells. On this basis, it is suggested that the expression of cytotoxic proteins may be useful for the identification and classification of extranodal T and NK-cell lymphomas and, to some extent, for the differential diagnosis between HL and CD30+ anaplastic large cell lymphomas. Cytotoxic lymphomas are preferentially localized in extranodal sites such as skin, lung, upper respiratory and gastrointestinal tracts, which are continuously exposed to various antigens. Since cytotoxic T and NK cells are regarded as first line of defense in these sites, and some cytotoxic tumours such as nasal lymphomas and enteropathy-type intestinal lymphomas are associated with EBV and gliadin, respectively, it is likely that chronic antigen exposure may play a role in the pathogenesis of cytotoxic lymphomas occurring in mucosa and/or skin. Besides chronic antigenic stimulation, chronic immunosuppression may also have pathogenetic significance in cytotoxic lymphomas in view of their increased incidence in immunocompromised patients.

Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma: Results of a Phase II Study.

Low Serum Total Protein and Unfavorable Pathological Subtype Are Independent Unfavorable Factors in Peripheral T-Cell Lymphoma (PTCL) Treated in Prospective Clinical Tirals; Japan Clinical Oncology Group (JCOG) 0108A Study.