scholarly journals PEG10 amplification at 7q21.3 potentiates large-cell transformation in cutaneous T-cell lymphoma

Blood ◽  
2021 ◽  
Author(s):  
Fengjie Liu ◽  
Yumei Gao ◽  
Bufang Xu ◽  
Shan Xiong ◽  
Shengguo Yi ◽  
...  
Keyword(s):  
T Cell ◽  
Late Stage ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Treatment Resistance ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
In Vivo Models ◽  
Large Cell Transformation

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergoes large-cell transformation (LCT) in the late stage, manifesting aggressive behavior, resistance to treatments, and poor prognosis, but the mechanisms involved remain unclear. To identify the molecular driver of LCT, we collected tumor samples from 133 MF patients and performed whole-transcriptome sequencing on 49 advanced-stage MF patients, followed by integrated copy number inference and genomic hybridization. Tumors with LCT showed unique transcriptional programs and enriched expressions of genes at chr7q. Paternally expressed gene 10 (PEG10), an imprinted gene at 7q21.3, was ectopically expressed in malignant T cells from LCT, driven by 7q21.3 amplification. Mechanistically, aberrant PEG10 expression increased cell size, promoted cell proliferation, and conferred treatment resistance by a PEG10/KLF2/NF-κB axis in in vitro and in vivo models. Pharmacologically targeting PEG10 reversed the phenotypes of proliferation and treatment resistance in LCT. Our findings reveal new molecular mechanisms underlying LCT and suggest that PEG10 inhibition may serve as a promising therapeutic approach in late-stage aggressive T-cell lymphoma.

Induction and Maintenance Therapy for Patients with Mycosis Fungoidus (MF) and Sezary Syndrome (SS) in Large Cell Transformation Phase.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4758-4758
Author(s):  
Yulia E Vinogradova ◽  
Irina Lucenko ◽  
Irina Kaplansky ◽  
Lyuba Varticovski ◽  
Nikita E Shklovskiy-Kordi ◽  
...  
Keyword(s):  
T Cell ◽  
Maintenance Therapy ◽  
Tumor Cells ◽  
Partial Remission ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Sézary Syndrome ◽  
Large Cell Transformation

Abstract Abstract 4758 Aim To determine the frequency of transformation of cutaneous T-cell tumors (CTCL) and effect of different therapies. Materials and methods Retrospective analysis of treatment results for 68 patients with two types of CTCL, MF and SS, selected from 263 patients T-cell lymphoma/leukemia treated at NCH during 9 years. All 68 patients have CD 3 +, CD 4+, CD 7-, CD 8-, CD 30- immunophenotype and T-cell clonality (rearranged genes for T-cell receptor). MF was diagnosed in 48 patients (24 men, 24 women) with median age 52 years (26 - 77), SS in 20 patients (12 men, 8 women), median age 61 years (23 -87). Half of the MF patients started surveillance at III - IV stages, 15 of 20 patients with SS - at stage IV. Treatment of CTCL in the indolent phase was conducted in accordance with their stage: monochemotherapy (leukeran or methotrexate) and biologically active agents (interferons, retinoids, monoclonal antibody) were used. Appearance of transformation to large cell lymphoma was consistent with tumor progression as determined by presence of two or more of the following: 1. rapid growth of tumors in MF or leukemization in SS; 2. presence of large anaplastic cells in blood or tumor biopsy; 3. increase in expression of Ki-67 (10-70%); 4. appearance of activation markers (CD30, CD25) in tumor cells, and 5. loss of certain linear T-cell markers. For treatment of patients in large cell transformation phase Promace-Cytabom or FNC protocols were used in 7 patients. Five patients received A-CHOP-14 (with alemtuzumab) and subsequent maintenance therapy (methotrexate 20 mg per week, 6-mercaptopurine 50-100 mg/day in combination with alpha interferon 3 million daily). Results and Discussion The overall median time of observation (before and during treatment) in 48 patients with MF was 96 months (8-264). For 13 patients who died it was 76 months (8-264), mortality rate was 27%. The overall median observation (before and during treatment) in 20 patients with SS was 60 months (6-123), for 8 who died, it was 62 months (6-94), mortality 40%. The median observation for treatment of MF was 30 months (from 3-122) for the SS, it was 18 months (1 - 85). Restraining aggressive therapy for an indolent process resulted in complete or partial remission, while maintaining a good quality of life. Large cell transformation phase was observed in 12 patients (7 of 48 patients with MF (14.5%) and 5 of 20 patients with SS (25%). Seven of the 12 patients died within 2-4 months due to septic complications during Promace-Cytabom or FNC protocols. The remaining 5 patients received A-CHOP-14 (6-7 courses) which reduced tumor formation and /or leukemization. However, the persistence of patches, plaque or erythrodermia was the reason for maintenance therapy. This combination led to further regression of skin manifestations and full or partial remission within 4-12 months. Conclusion Because of the lack of a generally accepted treatment for GM and SS in Large Cell Transformation phase, even small successes should be discussed. The effectiveness of combining of polychemotherapy with maintenance therapy may be effective due to the presence of several distinct clones of tumor cells with different properties. Keywords: treatment of cutaneous T-cell lymphoma, Mycosis Fungoidus, Sezary Syndrome, Large Cell Transformation Phase, immunohistochemical markers of T-cell lymphomas. Disclosures: No relevant conflicts of interest to declare.

Pralatrexate Is An Effective Treatment for Heavily Pretreated Patients with Relapsed/Refractory Transformed Mycosis Fungoides (tMF)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1762-1762 ◽  
Author(s):  
Francine M Foss ◽  
Steven M Horwitz ◽  
Lauren Pinter-Brown ◽  
Andre Goy ◽  
Barbara Pro ◽  
...  
Keyword(s):  
T Cell ◽  
Mycosis Fungoides ◽  
Research Funding ◽  
Response Rate ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Large Cell ◽  
The United States ◽  
T Cell Lymphoma ◽  
Large Cell Transformation

Abstract Abstract 1762 Background: Cutaneous T-cell lymphoma, which includes mycosis fungoides (MF) and the Sézary Syndrome, is an indolent T-cell lymphoma. Large-cell transformation (tMF) is a well-defined histopathological disease that is distinguished from primarily cutaneous MF by the presence of large cells that exceed 25% of total lymphoid infiltrate (Barberio et al. Br J Dermatol 2007; 157:284-9) and occurs in 11% to 23% of cases. tMF represents a significantly poorer prognostic subset of MF patients with median overall survival of 12 to 22 months from the time of diagnosis of large-cell transformation (Arulogun et al. Blood 2008; 112:3082-7). There is no standard therapy for tMF and most patients are treated with multiagent systemic chemotherapy regimens. Because of its poor outcome similar to that of aggressive peripheral T-cell lymphomas (PTCLs), tMF patients were included in PROPEL, the pivotal study that led to the accelerated approval of pralatrexate (FOLOTYN®) in the United States for the treatment of relapsed or refractory PTCL. Methods: Of 109 evaluable patients in the PROPEL trial, 12 patients had histologically confirmed tMF. All patients received pralatrexate at a dose of 30 mg/m2 weekly for 6 weeks in a 7 week cycle. Results: Of the 12 patients with tMF, the median age was 56.5 years. The median number of prior therapies was 6.5 (range 1 to 12), and 5 patients (42%) received ≥5 prior systemic regimens. The majority of patients had received prior multiagent chemotherapy, including cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or CHOP-based therapy in 67% of patients and other multiagent regimens in 17% of patients. Only 1 of 12 patients had a response to their most recent prior chemotherapy regimen. The objective response rate (ORR) to pralatrexate in this group of refractory tMF using International Workshop Criteria based on investigator assessment, was 58%. Consistent with the overall study population, the ORR by independent central review was 25%. The difference in ORR between independent central review and investigator assessment for tMF is mainly due to challenges with photodocumentation of response assessment of cutaneous lesions. The 12 patients with tMF received a median of 10 doses of pralatrexate and remained on treatment for a median of 89 days. The median response duration was 4.4 months and median PFS was 5.3 months, per investigator assessment. The median survival in this group of patients was 13 months. Mucosal inflammation was reported in 7 patients (58%) including 1 patient with grade 3. Grade 4 adverse events (AEs) were fatigue (1 patient) and thrombocytopenia (1 patient). Overall, patients with tMF were able to tolerate full-dose pralatrexate treatment, with no patients discontinuing due to an AE. Conclusions: Pralatrexate demonstrated significant activity in the 12 refractory tMF patients enrolled in the PROPEL trial with an investigator assessed response rate of 58%. Pralatrexate should be considered as a treatment option for patients with tMF. Disclosures: Foss: Allos Therapeutics, Inc.: Consultancy, Speaker. Horwitz:Allos Therapeutics, Inc.: Consultancy, Research Funding. Pinter-Brown:Allos Therapeutics, Inc.: Consultancy. Goy:Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc.: Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

scholarly journals Inert CD30-positive extranodal NK/T cell lymphoma with large cell transformation: a case report

2020 ◽  
Author(s):  
Hui Wang ◽  
PengYi Yu ◽  
Qing Li
Keyword(s):  
T Cell ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Lymphoid Cells ◽  
T Cell Lymphoma ◽  
Epstein Barr Virus Infection ◽  
Rare Type ◽  
Large Cell Transformation ◽  
Nk T Cell

Abstract Background Extranodal natural killer (NK)/T-Cell Lymphoma is a rare type of cytotoxic lymphoma associated with Epstein-Barr virus infection, highly invasive and relatively resistant to chemotherapy. Inert CD30-positive extranodal NK/T cell lymphoma with large cell transformation is very rare. Case presentation A married 55-year-old male was admitted to hospital in February 2017, because of “diagnosis of malignant lymphoma for about 12 years with high fever and a left neck mass present for about 3 weeks". The patient was diagnosed to NK/T Cell Lymphoma as early as 2006, repeated relapses in June 2010 and April 2013. The patient was biopsied again in February 2017, lymph node, about 2.5×2×1.3cm.The section was off-white and tender. Microscopic examinations showed a diffuse proliferation of small and atypical lymphoid cells, admixed with large lymphoid cells. Immunohistochemically, the tumor cells exhibited positivity for CD30, CD3, CD43, CD2, CD56, TIA, negativity for CD4, CD8, AE1/AE3, CD20, ALK, EMA staining. In situ hybridization for EBER was strongly positive in the specimens.Conclusions Herein, we report a case of CD30-positive extranodal NK/T Cell Lymphoma with large cell transformation, nasal type, in indolent course over a period of 12 years. The accurate diagnosis of NK/T-cell lymphoma with CD30 expression and large cell transformation is very important. The disease usually has a poor prognosis related to several factors, but the indolent behavior of the present case is more unusual. A long-term follow-up is suggested to be performed to inspect the progression for this tumor.

scholarly journals Prognostic markers of mycosis fungoides by means of two cases

2020 ◽  
Vol 96 (5) ◽  
pp. 223-229
Author(s):  
Ildikó Csányi ◽  
◽  
Henriette Ócsai ◽  
Irma Korom ◽  
Erika Varga ◽  
...  
Keyword(s):  
T Cell ◽  
Mycosis Fungoides ◽  
Prognostic Markers ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
First Case ◽  
Extracutaneous Manifestation

Cutaneous T-cell lymphoma is a heterogeneous group of malignancies including both indolent and aggressive forms, with an average 5-year disease-specific survival rate of 11-100%. Prognostic factors in cutaneous T-cell lymphoma according to the different subtypes are not clearly defined, however extracutaneous manifestation seems to predict a poor prognosis. Tonsil involvement was revealed as a cause of oropharyngeal complaints in two of our male patients, treated for histologically confirmed tumour stage of mycosis fungoides. In the first case urgent tracheostomy followed by radiotherapy, while in the other case systemic treatment resulted in complete remission of the tonsil involvement. Both patients were subsequently lost due to the progression of mycosis fungoides. Factors predicting an unfavourable prognosis included extracutaneous manifestation, late stage disease, age over 60 years, elevated lactate-dehydrogenase levels, and large cell transformation. With our cases we would like to shed light to the prognostic markers of mycosis fungoides, and to the rare tonsil involvement, which is potentially life-threatening and requires urgent intervention.

Cytologic transformation in cutaneous T cell lymphoma: a clinicopathologic entity associated with poor prognosis.

1987 ◽  
Vol 5 (2) ◽  
pp. 208-215 ◽  
Author(s):  
E Dmitrovsky ◽  
M J Matthews ◽  
P A Bunn ◽  
G P Schechter ◽  
R W Makuch ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Blood Smears ◽  
Large Cell Lymphoma ◽  
Aggressive Clinical Course ◽  
Peripheral Blood Smears

The clinical course of cutaneous T cell lymphoma (mycosis fungoides and Sezary syndrome) is generally indolent, but in occasional patients becomes fulminant. We found that biopsies from patients with accelerating disease can reveal cytologic transformation from previously observed small, convoluted lymphocytes to large cells that are similar to cells seen in large-cell lymphoma. The cerebriform nuclei characteristic of malignant T cells can only rarely be identified. Of 150 cutaneous T cell lymphoma patients we treated from 1976 to 1984, cytologic transformation was identified in 12 after review of peripheral blood smears and biopsies from skin, lymph nodes, and visceral sites. Patients who developed cytologic transformation were initially characterized by advanced stage (11 of 12), with lymph node effacement (seven of 11) and erythroderma (five of 12). The tumor cell DNA content after transformation was aneuploid (four of four), and the ability to form rosettes with sheep erythrocytes was retained in transformed cells (three of three). The median time from diagnosis of cutaneous T cell lymphoma to cytologic transformation was 21.5 months (range, 4 to 64), and the median survival from transformation was only 2 months (range, 0 to 19+). We conclude that cytologic transformation in cutaneous T cell lymphoma represents a distinct clinicopathologic entity, characterized by an aggressive clinical course.

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