Anaplastic T-cell Lymphoma Research Articles

Primary anaplastic T-cell lymphoma of the omentum presenting as small bowel obstruction and complicated with Massilia timonae infection: a case report

BackgroundAnaplastic large-cell lymphoma primarily involving the omentum is an extremely rare entity with variable clinical presentation. Owing to its rarity and nonspecific clinical manifestation, omental T-cell lymphoma is often diagnosed at a later stage, riddled with complications. While imaging modalities such as computed tomography scan can help a physician reach a diagnosis, cases that present with complications may require a multidisciplinary approach that combines surgical exploration along with consultation from Oncology.Case presentationWe hereby report a rare case of a 66-year-old African American male patient who presented to the emergency department with complaints of acute gastrointestinal obstruction. A computed tomography scan of the abdomen and pelvis revealed evidence of an internal hernia and surgical exploration revealed a hemorrhagic and infarcted omentum. Biopsies along with immunophenotypic studies confirmed the diagnosis of anaplastic T-cell lymphoma of the omentum complicated by Massilia timonae infection.ConclusionThe case highlights the significance of considering lymphoma, although rare, as a differential in a patient who presents with small bowel obstruction and the importance of investigating for malignancy for early diagnosis and treatment of primary omental lymphomas, before complications develop.

Primary Central Nervous System ALK-Negative Anaplastic T-Cell Lymphoma is a Challenging and Uncommon Diagnosis

Abstract Introduction/Objective Primary central nervous system lymphoma (PCNSL) accounts for only 1% of all lymphomas and 6% of all tumors in the central nervous system. Most of these lymphomas are B-cell types, while T-cell types are less common. Anaplastic T-cell lymphoma with ALK-negative is the least common form of anaplastic T-cell lymphoma. It has a similar morphology but is more aggressive than ALK-positive variant. Smaller numbers of ALK-negative PCNSL have been reported. Herein, we report a case of cerebellar ALK-negative anaplastic T-cell lymphoma (ATCL) not only because of the unique location but also to highlight this entity to be considered in future diagnosis to avoid delay or misdiagnosis. Methods/Case Report A 58-year-old woman with no significant past medical history presented with headaches, aphasia, confusion, short memory loss, and loss of control over her body. She had had similar episodes more than three months before. MRI demonstrated extensive enhancement of the leptomeningeal, pial, and pachymeningeal surfaces. Moreover, there are nodular mass-like areas along the cerebellar folia. Left suboccipital craniotomy with biopsy of left cerebellar lesion was performed. Histopathological examination revealed numerous large, atypical lymphocytes characterized by large-size, ovoid to irregular to lobated nuclei, vesicular chromatin, and vacuolated cytoplasm. These cells react positive to CD3, CD30, CD43, CD2, CD7CD56, and negative to ALK1, CD8, CD20, PAX5, CD5, CD10, CD15, CD34, CD138, EMA, p63, TdT, GFAP, CAM5.3, synaptophysin, SOX10, and EBER in situ hybridization. No ALK separation is observed by FISH; however, three copies of the ALK gene are found on chromosome 2p23. ALK-negative ATCL was diagnosed based on all these findings. Results (if a Case Study enter NA) N/A Conclusion Primary central nervous system lymphoma (PCNSL) is extremely rare, and most lymphomas are B-cell types. Anaplastic T-cell lymphomas, ALK-negative lymphoma is a rare and most aggressive variant of T-cell lymphoma. Reporting this tumor is crucial to avoid delay or misdiagnosis.

Chimeric kinase ALK induces expression of NAMPT and selectively depends on this metabolic enzyme to sustain its own oncogenic function.

As we show in this study, NAMPT, the key rate-limiting enzyme in the salvage pathway, one of the three known pathways involved in NAD synthesis, is selectively over-expressed in anaplastic T-cell lymphoma carrying oncogenic kinase NPM1::ALK (ALK + ALCL). NPM1::ALK induces expression of the NAMPT-encoding gene with STAT3 acting as transcriptional activator of the gene. Inhibition of NAMPT affects ALK + ALCL cells expression of numerous genes, many from the cell-signaling, metabolic, and apoptotic pathways. NAMPT inhibition also functionally impairs the key metabolic and signaling pathways, strikingly including enzymatic activity and, hence, oncogenic function of NPM1::ALK itself. Consequently, NAMPT inhibition induces cell death in vitro and suppresses ALK + ALCL tumor growth in vivo. These results indicate that NAMPT is a novel therapeutic target in ALK + ALCL and, possibly, other similar malignancies. Targeting metabolic pathways selectively activated by oncogenic kinases to which malignant cells become "addicted" may become a novel therapeutic approach to cancer, alternative or, more likely, complementary to direct inhibition of the kinase enzymatic domain. This potential therapy to simultaneously inhibit and metabolically "starve" oncogenic kinases may not only lead to higher response rates but also delay, or even prevent, development of drug resistance, frequently seen when kinase inhibitors are used as single agents.

Photogallery. Rare dermatoses. Part II

In continuation of orphan dermatosis, I would also like to say about diseases such as lichen planus ― which is an autoimmune disease in which the expression of an antigen that has not yet been identified by keratinocytes of the basal layer leads to the activation and migration of T-lymphocytes into the skin with the formation of an immune response and an inflammatory reaction.
 BournevillePringle syndrome (tuberous sclerosis complex) is a rare genetic disease that is part of the group of phakomatoses, characterized by a polysystemic lesion involving the skin, central nervous system, organs of vision, etc. in the pathological process.
 Bullous scleroderma is a rare type of localized scleroderma with a predominant skin lesion in the form of foci of induration and sclerosis, subepidermal blisters with serous contents.
 Trichoadenoma is a rare skin tumor belonging to the group of benign follicular tumors. Consists of numerous, relatively large, round or oval funnel-shaped structures separated by an underdeveloped fibrous stroma.
 Pseudolymphoma is a reactive polyclonal T- or B-cell lymphoproliferative process that can manifest as both localized and disseminated skin lesions.
 Giant flaming nevus of the skin of the face is usually a benign disease, but in some cases malignancy is possible.
 T-cell anaplastic lymphoma associated with sarcoidosis is characterized by lymphadenopathy, lesions, circulating abnormal lymphocytes, and hypercalcemia leading to the sarcoidosis-lymphoma syndrome.
 Devergy's disease is caused by a violation of keratinization and the appearance of follicular hyperkeratotic papules, palmoplantar hyperkeratosis and erythematous scaly plaques with an orange tint.
 FavreShay ocher yellow dermatitis occurs in patients with varicose ulcers on the inner surface of the lower third of the legs, which it either precedes or accompanies.
 Sweet's febrile neutrophilic dermatosis manifests itself in three clinical cases: classical (the disease is preceded by an infectious disease), malignant (occurs as a paraneoplastic syndrome), medicinal (most often occurs in patients treated with G-CSF).
 Lipodermatosclerosis is manifested by induration and hyperpigmentation of the skin, affecting one or both legs, in a characteristic "upside down champagne bottle" appearance.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. Standard CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy is still the most widely used regimen for front-line management. To explore new targeted drugs in PTCL, we conducted a phase 2, multi-center, non-randomized clinical trial, comparing the efficacy and safety of targeted agents combined with CHOP (CHOPX) with CHOP in newly diagnosed patients with PTCL. Methods: The primary outcome was complete response rate (CRR) at the end of treatment (EOT). Patients with newly diagnosed PTCL had enough tumor tissue for next generation sequencing (NGS) and were assigned to CHOPX and CHOP group based on investigators’ discretion. Patients in CHOPX group received intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (up to a maximum of 2 mg) on day 1, and oral prednisone 60 mg/m2 (up to a maximum of 100 mg) on day 1–5 every 21 days at the first cycle. X (i.e., targeted agent) was added from the second to sixth cycles as following, intravenous decitabine 10 mg/m2 on day -5 to -1 if with TP53 mutation. Subcutaneous azacytidine 100 mg on day −7 to −1 if with TET2/KMT2D mutation. Oral chidamide 20 mg on day1, 4, 8, 11 if with CREBBP/EP300 mutation. Oral lenalidomide 25 mg on day 1–10 if without above mutations. Patients in control group received standard CHOP regimen for 6 cycles. Analysis of efficacy and safety was of the intent-to-treat population. The study was registered with ClinicalTrials.gov, number NCT04480099. Results: Between 20 June 2020 and 22 September 2022, 108 patients were assessed for eligibility in the study. Ten patients met exclusion criteria and 2 patients withdrew informed consent before treatment. Forty-eight patients in the CHOPX group and 48 patients in the CHOP group were included into intent-to-treatment population. Baseline patient characteristics like age, gender, Ann Arbor stage, performance status, prognostic risk group was comparable between CHOPX and CHOP groups. The most common pathological subtypes were angioimmunoblastic T-cell lymphoma (67% vs. 60%), PTCL-not otherwise specified (17% vs. 21%), anaplastic T-cell lymphoma (6% vs. 8%) in the CHOPX and CHOP groups. As of 1 February 2023, 91 patients completed response evaluation at EOT. CRR in the CHOPX group was higher than the CHOP group (58% [25/43] vs. 33% [16/48]). The most common grade 3–4 hematological adverse events in CHOPX group were neutropenia (61%) and febrile neutropenia (27%). Conclusions: Preliminary analysis showed targeted agents combined with CHOP was effective and safe compared with standard CHOP in PTCL. Therapeutic strategy specifically towards molecular features may change current PTCL management in front-line setting. Keywords: combination therapies, molecular targeted therapies No conflicts of interests pertinent to the abstract.

Lymphoproliferation- a clue towards an underlying monogenic disorder of immune dysregulation- a retrospective analysis from a single center in India

BackgroundLymphoproliferation is the persistent proliferation of lymphoid cells and it’s incidence in inborn errors of immunity varies from 0.7 to 18%. Materials and MethodsThis is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. ResultsA total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin’s lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. ConclusionAll children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.

Имплант-ассоциированная анапластическая Т-клеточная лимфома. Актуальное состояние проблемы, собственный клинический опыт

Анапластическая Т-клеточная лимфома, ассоциированная с имплантами молочных желез, или имплант-ассоциированная Т-клеточная лимфома (ИА-ТКЛ), является редкой формой неходжкинскихT-клеточных лимфом (CD30+/ALK-), развивающейся в фиброзной капсуле (или за ее пределами), возникающей вследствие длительного контакта импланта с тканями реципиента. Заболеваемость данным видом лимфом неуклонно увеличивается – по данным на конец 2021 г. в мире зарегистрировано 733 случая ИА-ТКЛ и 36 летальных исходов, связанных с ИА-ТКЛ, большая часть в США – 363, Австралии – 112, Франции – 86. В России зарегистрировано только 4 случая без летальных исходов. В статье описаны современный подход к диагностике и лечению ИА-ТКЛ и собственный клинический опыт. Breast implant-associated anaplastic T-cell lymphoma or implant-associated T-cell lymphoma (BIA-TCL) is a rare type of non-Hodgkin T-cell lymphoma (CD30+/ALK-) which evolves from fibrous cap or outside due to long-term contact between the implant and the recipient tissue. The incidence of this type lymphoma is increasing – 733 cases of BIA- TCL and 36 deaths in the end of 2021 worldwide. Most cases in the United States – 363, Australia – 112, France – 86, in Russia only 4 cases are registered without fatalities. The article describes the current approach to the diagnosis and treatment of BIA-TCL and own clinical experience.

Microenvironment Immune Cells in Bone Marrow and Lymph Node Measured By Flow Cytometry Have Prognostic Impact on Survival in Nodal Non-Hodgkin T-Cell Lymphoma

INTRODUCTION Outcomes in nodal peripheral T-cell lymphomas (PTCL) remain poor. Baseline clinical risk indexes have shown to be prognostic but do not imply a change in therapeutic strategies. Many publications have addressed the role of tumor microenvironment (TME) in lymphomagenesis and disease progression. Particularly in PTCL, TME was shown to be profoundly immunosuppressive. Therefore, TME variables that may aid to improve risk stratification and treatment management are urgently needed. AIMS To determine the prognostic impact on survival in PTCL of: -Conventional clinical risk parameters. -The percentage (%) of immune cells (IC) in the bone marrow (BM) and lymph node (LN) measured by flow cytometry (FC). METHODS We retrospectively collected information of patients (pts) with PTCL and available BM aspiration and/or LN FC data at diagnosis, treated at our center between 2012-2021. FC analysis was performed with 8-color panels according to Euroflow protocols. % of BM and LN IC by FC were compared to normal values determined by Matarraz et al. (Cytometry part B 2010) and Battaglia et al. (Immunology 2003), and analyzed in 3 categories: low, normal and high. Survival analysis was performed with Kaplan-Meier (variables compared with log-rank) and multivariate analysis with Cox regression. RESULTS We included 34 pts, with a median age of 59 years. LN and BM FC data were available in 26 and 28 pts, respectively. Table 1 shows baseline patient characteristics. 85.4% received induction with CHOP or CHOP-like regimens (with etoposide or brentuximab). Complete remission (CR) rate: 52.9%. 14 pts received treatment with new drugs (brentuximab, belinostat, romidepsin or lenalidomide) in the relapsed/refractory setting. Only 10/34 pts underwent consolidation with autologous stem cell transplant (ASCT). Chemorefractory disease was the reason to forgo ASCT in 50% (12/24) of the non- transplanted pts and 3/12 underwent consolidation with allogeneic stem cell transplant in 1st CR. Median progression-free (PFS) and overall survival (OS) for the whole cohort were 15 and 72 months (m) respectively, with a median follow up time of 41.2 m. Pts with ALK+ anaplastic T-cell lymphoma had improved PFS (median of 67 vs 8, 9 and 5.6 m for ALK- anaplastic, PTCL NOS and angioimmunoblastic lymphoma, respectively). Regarding prognostic indexes, PIT score was able to discriminate subgroups with different PFS (median of 15.3 m for pts with at least 1 risk factor vs not reached and PFS rate of 100% in those without, p: 0.012). Other clinical parameters such as BM and CNS compromise were associated with inferior PFS (median of 49.7 in BM not involved vs 6.7 m, p: 0.006; and median of 19.2 in pts without CNS compromise vs 3.45 m, p<0.001, respectively). The only TME variable with prognostic impact on PFS was LN CD4/CD8 ratio (median of 30.8, 5.7 and 2.7 m for the low, normal and high subgroups, respectively, p: 0.045). On multivariate analysis, absence of CNS involvement was the only independent predictor of PFS (HR: 0.009, CI95%: 0-0.235, p: 0.005). The only clinical parameter with prognostic impact on OS was performance status (PS) (median of 72.2 vs 0.2 m in pts with PS≤2 and ≥3, respectively). Regarding TME variables, low BM neutrophil % was associated with improved OS with median not reached vs 27.8 m in pts with normal and high values, p: 0.039). BM neutrophil % did not statistically differ in involved vs not involved BM. Interestingly, only 1/9 pts with normal-high BM neutrophil % with relapse disease could achieve CR with 2nd line treatment vs 6/10 in the low % subgroup (likelihood ratio 5.26, p: 0.022). In contrast, no association was found between peripheral blood neutrophil counts and survival in our cohort. On multivariate analysis, only low BM neutrophil % remained as an independent predictor of OS with a HR of 0.12 (CI95%: 0.015-0.96), p: 0.046. CONCLUSIONS Both clinical risk factors and TME variables showed prognostic impact in our cohort of PTCL pts. A high LN CD4/CD8 ratio and a normal-high BM neutrophil % were associated with decreased PFS and OS, respectively. These TME variables are widely accessible and could help refine prediction of prognosis in pts with nodal PTCL. Manipulating TME with therapeutic strategies that promote effector T-cell function and/or suppress the pro-malignant cell effects of myeloid derived cells may improve patient outcomes in this poor risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathological Spectrum of Hodgkin's and Non-Hodgkin's Lymphoma: A Tertiary Care Cancer Hospital Study in Pakistan.

IntroductionLymphomas are a heterogeneous group of disorders that arise primarily from lymphoid tissue and are categorized based on histological features and immunophenotypes. The distribution and frequency of different types of lymphoma vary in different parts of the world. This study aimed to document the frequency and clinicopathological characteristics of various types of lymphoma in our population to understand the ever-increasing burden of disease and formulate the optimal management and prevention plans.Materials and methodsThis study was conducted at Nuclear Medicine, Oncology and Radiotherapy Institute (NORI) from August 2015 to March 2022. A total of 300 cases of lymphoma that were diagnosed and treated at NORI were included in the study. We measured the frequency of different lymphomas and patient age, sex, and stage IV presentation at the time of diagnosis. IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY: IBM Corp.) was used to analyze the data.ResultsThree hundred patients with lymphoma were included in the study. There were more non-Hodgkin’s lymphoma (NHL) cases (n=224; 74.6%) than Hodgkin’s lymphoma (HL) cases (n=76; 25.3%). T-cell NHL was seen in 11 cases (4.8%), while B-cell NHL was found in 214 cases (95%). Diffuse large B-cell lymphoma was the predominant type (n=156; 69.3%). Among T-cell lymphomas, anaplastic T-cell lymphoma was the most common subtype (n=6; 2.6%) followed by angioimmunoblastic T-cell lymphoma (n=2; 0.8%) and T-cell lymphoblastic lymphoma (n=1; 0.4%). For classical HL, mixed cellularity was the predominant type (n=38; 50%) followed by nodular sclerosis (n=31; 40.8%), lymphocyte depleted (n=5; 6.6%), and lymphocyte rich (n=2; 2.6%). Stage IV was present in 21 HL cases (27.6%), and stage IV was seen in 67 NHL cases (29.7%) at the time of diagnosis. Most HL and NHL patients were male. Most HL cases presented in the younger age group (aged 15 to 35 years), while the largest group of NHL patients were aged 56 to 75 years.ConclusionOur population has a broad spectrum of lymphoma and its subtypes. NHL is more common than HL, and the frequency of B-cell NHL is higher than that of T-cell NHL. Approximately one-third of the patients presented in stage IV at the time of diagnosis. An awareness of clinicopathological characteristics of lymphoma in our setup would aid in diagnosis, formulating standard management plans, and prevention strategies for optimal patient outcomes.

A First-in-Class STAT3 Degrader KT-333 in Development for Treatment of Hematologic Cancers

Signal Transducer and Activator of Transcription 3 (STAT3) plays important roles in the transduction of signals from growth factors and cytokines in both normal and malignant cells. Upon activation, STAT3 controls expression of genes that regulate cell growth, survival, differentiation, stemness and cell-cell interactions. Aberrant activation of STAT3 has been observed in many cancers including lymphoma and leukemias through activating mutations, hyper-signaling through upstream regulators or loss of negative feedback regulation. Additionally, STAT3-mediated cross-talk in the tumor microenvironment results in suppression of immune surveillance compromising anti-tumor immunity.STAT3 has been historically considered “undruggable”. Heterobifunctional degraders that recruit endogenous E3 ligases to ubiquitinate substrate proteins leading to their degradation by the proteosome have emerged as a novel therapeutic modality with great potentials to drug undrugged protein targets. Here we introduce a first-in-class, potent and selective STAT3 degrader KT-333 that is being developed for the treatment of hematologic malignancies and solid tumors.KT-333 is a small molecule targeted protein degrader of STAT3 and was discovered by an iterative medicinal chemistry SAR campaign improving parameters such as potency, selectivity and ADME profile. It has high solubility in PBS buffer (103 mg/mL, pH7.4). low to moderate clearance in rat, dog and monkey, and moderate plasma half lives across pre-clinical species.KT-333 exhibits potent and selective degradation of STAT3 with DC 50 of 2.5 -11.8 nM in four anaplastic T cell lymphoma (ALCL) lines. Selective degradation of STAT3 over nearly 9000 proteins, including other STAT family members, was demonstrated by mass spectrometry in human PBMCs . Tumor cells expressing NPM-ALK fusion oncoproteins have activated STAT3 and dependency on STAT3 signaling for survival KT-333 treatment led to rapid apoptosis of these ALK+ALCL cells. To better understand the cellular responses to STAT3 degradation, time-course transcriptomic and proteomic analyses were performed using SU-DHL-1 cells treated with KT-333. Time-dependent changes in both mRNA and protein levels of STAT3-regulated genes and pathways were observed: at 8 h only STAT3 showed significant depletion, at 24 h canonical STAT3 downstream genes including SOCS3, IL-2RA and GRZMB showed modulation and at 48 h, pathways including interferon response and cell cycle were significantly enriched. A comparison of the transcriptomic and proteomic data sets showed high correlation. Furthermore, changes in mRNA and protein levels of bona fide STAT3 regulated targets showed a high degree of concordance between SU-DHL-1 cells and SU-DHL-1 xenograft tumors.Preclinical in vitro experiments have demonstrated that approximately 90% degradation of STAT3 for 48 h was sufficient to drive ALK+ ALCL lines into irreversible cell growth inhibition and death. In vivo xenograft studies of SU-DHL-1 and SUP-M2 ALCL models demonstrated dose-dependent tumor growth suppression. An indirect response model that linked exposure to target degradation was established to describe the relationship between exposure and target degradation in the tumor. Consistent with the in vitro data, PK-PD-efficacy analysis in the SU-DHL-1 xenograft model showed that tumor regression could be achieved with intermittent dosing schedules that achieved ~90% degradation of STAT3 for about 48 h over a weekly or bi-weekly dosing interval. . Based on preclinical ADME and PK/PD/efficacy relationship, KT-333 is predicted to drive tumor regression using weekly doses.In conclusion, we have identified a potent STAT3 degrader as development candidate that can be administered parenterally in the clinic on an intermittent dosing regimen that is predicted to be both efficacious and tolerated in STAT3-dependent hematologic malignancies. DisclosuresLiu: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dixit: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayo: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yuan: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Walther: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shi: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rong: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yang: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollerkeri: BEAM Therapeutics: Current Employment, Current equity holder in publicly-traded company; Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. DeSavi: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Spinal Manifestation of Malignant Primary (PLB) and Secondary Bone Lymphoma (SLB).

Manifestation of malignant lymphoma in the spine is rare; there have only been a few cases reported in the literature. Due to its rarity, there is no gold standard for the management of patients suffering from spinal lymphoma manifestations. Methods: We retrospectively reviewed the data for 37 patients (14 female, 23 male) with malignant lymphoma in the spine receiving intervention in our center from March 2006 until June 2020. Neurological impairment, pain, diagnostics, and/or surgical instability were the criteria for surgery in this patient cohort. Otherwise, only CT-guided biopsies were conducted. Analysis of the patient cohort was based on the Karnofsky performance status scale (KPSS), location of the lesion, spinal levels involved, spinal instability neoplastic score (SINS), surgical treatment, histopathological workup, adjuvant therapy, and overall survival. The following surgical procedures were performed: posterior stabilization and decompression in nine patients; decompression and/or tumor debulking in 18 patients; a two-staged procedure with dorsal stabilization and vertebral body replacement in four patients; decompression and biopsy in one patient; a two-stage procedure with kyphoplasty and posterior stabilization for one patient; posterior stabilization without decompression for one patient; a vertebroplasty and cement-augmented posterior stabilization for one patient; and a CT-guided biopsy alone for two patients. Twenty-one patients (56.78%) had ≥1 lesion in the thoracic spine, 10 patients (27.03%) had lesions in the lumbar spine, two patients had lesions in the cervicothoracic junction, two patients had lesions in the thoracolumbar junction, one patient had a lesion in the lumbosacral junction, and one patient had a lesion in the sacrum. The diagnoses of the histopathological workup were diffuse large B-cell lymphoma in 23 (62.16%) cases, indolent lymphoma in 11 (29.74%) cases, anaplastic T-cell lymphoma in one case (2.70%), T-cell lymphoma in one case (2.70%), and Burkitt lymphoma in one (2.70%) case. The median overall survival was 7.2 months (range 0.1–266.7 months). Pre- and postoperative KPSS scores were 70% (IQR 60–80%). Manifestation of malignant lymphomas in the spine is rare. Similar to the approach taken for spine metastases, a surgical intervention in cases of neurological impairment or manifest or potential instability is indicated, followed by chemoimmunotherapy and radiotherapy.

Limbic Encephalitis with HU-Antibodies in T-cell Anaplastic Lymphoma. A Case Report

Limbic encephalitis is a rare paraneoplastic neurological syndrome usually associated with small cell lung cancers, testicular and breast cancers or B-cell lymphomas. We herein report the first patients with paraneoplastic limbic encephalitis associated with HU antibodies and anaplastic T-cell lymphoma.

Targeting CD30 Expression in Adult T-Cell Leukemia-Lymphoma (ATLL)

▪Introduction:Adult T-cell leukemia-lymphoma (ATLL) is caused by HTLV-1, and carries a dismal prognosis urging the development of new therapies. CD30 expression has been reported at variable frequencies in ATLL. The anti-CD30 monomethyl-auristatin-E conjugate brentuximab vedotin (BV), can be an effective treatment option for Hodgkin lymphoma, anaplastic T-cell lymphomas, and various peripheral T-cell lymphoma types. However, the impact role of BV in ATLL has not been established, which warrants an in-depth characterization of CD30 expression and clinical investigation of BV in this disease.Methods:ATLL specimens from 107 patients (pts) were classified according to Shimoyama criteria (A=acute, C=chronic, L=lymphomatous, and S=smoldering) and analyzed for CD30 expression. Unfavorable chronic (UC) had elevated LDH level < twice the normal value. Cases were confirmed or analyzed by immunohistochemistry at our institution using anti-human CD30 antibody (Dako) on formalin-fixed paraffin-embedded tissue or cellblock sections prepared from cytospun CD4+-enriched leukemic cells. The cutoff positive value was 20%. Outcomes were compared according to prior treatment. Soluble(s) CD30 levels were measured in sera of 21 pts by ELISA. Low-passage ATLL cell lines (ATLL-84c and ATLL-97c established from pts with A-type) were treated with BV, and apoptosis was measured by annexin V and FACS analysis. Five pts with relapsed CD30+ ATLL (L-type=3, A-type=2) were treated with BV.Results:ATLL specimens obtained from 95 (L=51, A=37, UC=6, and S=1) untreated pts, and 13 (L=7, and A=6) pre-treated patients were analyzed. The percent frequencies of CD30+ cases within untreated subtypes were L=41%, A=30%, UC=17%, and S=0%, as compared to L=14% and A=17% in the pre-treated group (Figure 1). There was a trend towards a higher frequency of CD30 expression in L-type vs. A-type (p=0.37, two-sided Fisher's test). Sera analyzed from 21 pts revealed positive CD30 levels regardless of CD30tumor status, suggesting ATLL cells may shed the receptor (Figure 2). The overall response (OR) and complete response (CR) rates in A/UC-type pts (n=31) treated with AZT (zidovudine) plus interferon-α (AI) were 59% (13/22) and 32% (7/22) in the CD30- group (n=22), compared to 33% (3/9) and 0% in CD30+ group (n=9) respectively (Figure 3). BV had no significant clinical significant impact in 4 out of 5 (80%) CD30+ treated pts (2 L and 2 A). A transient hematologic response was observed in one CD30+ A-type patient, followed by leukemic progression with CD30- cells (Figure 4). By contrast, BV induced a sustained CR lasting 2 years in an L-type patient with diffuse homogenously CD30+ expression (Figure 5). In vitro treatment of patient-derived ATLL cell lines confirmed BV induced more apoptosis in cells expressing higher CD30 (ATLL-84c) as compared to cells low in CD30 expression (ATLL97c).Conclusions:CD30 expression in ATLL is heterogeneous and occurs at variable frequencies, and tends to be higher in L-type, and lower in A/UC-types that respond to AZT-interferon therapy. Our data suggest CD30 may represent an elusive target in A-type ATLL, thus warranting further optimization of BV in leukemic subtypes. The analysis of additional cases is still ongoing and the final results will be presented at the meeting.This project has been accomplished with the support of “ASH HONORS award” achieved in 2016. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The diagnostic value of flow cytometry in patients with lymphoma associated hemophagocytic syndrome

Objective: To evaluate the reliability of flow cytometry (FCM) for diagnosing lymphoma associated hemophagocytic syndrome (LAHS). Method: The clinical data in 57 patients with hemophagocytic lymphohistiocytosis (HLH)were retrospective analyzed at Peking University Shenzhen Hospital from July 2010 to July 2019. All patients were performed bone marrow FCM and bone marrow pathological examination before final diagnoses were made. The golden diagnosis criterion was based on clinical, biochemical and histopathological evidence, which was regarded as the standard to evaluate the sensitivity and specificity of FCM analysis in diagnosing LAHS. Results: Among 57 cases, 36 cases were eventually diagnosed with LAHS, including 15 B-cell lymphoma(14 diffuse large B-cell lymphoma, 1 B-cell lymphoma with reactive T-cell hyperplasia), 13 aggressive NK/T cell lymphoma/leukemia, 2 cases of gamma-delta T-cell lymphoma, 4 angioimmunoblastic T-cell lymphoma, 1 enteropathy-associated peripheral T-cell lymphoma and 1 anaplastic T-cell lymphoma. Lymphoma cells in bone marrow were detected in all patients by FCM except one ENTCL patient. The sensitivity and the specificity of FCM in LASH compared to bone marrow biopsy were 97.2%(P=0.014)and 90.5%(P=0.488) respectively. In the other 21 non-LAHS patients, T cell receptor Vβ (TCRVβ) rearrangement was detected in 2 patients with Epstein-Barr virus (EBV) associated primary HLH. Conclusions: FCM effectively detects lymphoma cells in bone marrow of lymphoma patients with LHL, suggesting that FCM could be an important indicator for the diagnosis of LAHS. FCM also has the advantage in differentiating LAHS from other HLH.

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous group of mature T-cell neoplasms that comprise 10–15% of non-Hodgkin lymphoma cases in the United States. All subtypes of PTCL, except for ALK+ anaplastic T-cell lymphoma, are associated with poor prognosis, with median overall survival (OS) rates of 1–3 years. The diagnosis of PTCL is mainly based on clinical presentation, morphologic features, and immunophenotypes. Recent advances in genome sequencing and gene expression profiling have given new insights into the pathogenesis and molecular biology of PTCL. An enhanced understanding of its genomic landscape holds the promise of refining the diagnosis, prognosis, and management of PTCL. In this review, we examine recently discovered genetic abnormalities identified by molecular profiling in 3 of the most common types of PTCL: RHOAG17V and epigenetic regulator mutations in angioimmunoblastic T-cell lymphoma, ALK expression and JAK/STAT3 pathway mutations in anaplastic T-cell lymphoma, and T-follicular helper phenotype and GATA3/TBX21 expression in PTCL-not otherwise specified. We also discuss the implications of these abnormalities for clinical practice, new/potential targeted therapies, and the role of personalized medicine in the management of PTCL.

Acquired icthyosis underlying anaplastic T-cell lymphoma

Acquired icthyosis underlying anaplastic T-cell lymphoma

Anaplastic T-cell lymphoma of the urinary bladder with unspecific clinical and radiological characteristics - a unique case report

Anaplastic T-cell lymphoma of the urinary bladder with unspecific clinical and radiological characteristics - a unique case report

Long-Term Outcomes of Allogeneic Stem Cell Transplant in Peripheral T-Cell Lymphoma

Abstract Introduction: Peripheral T-cell Lymphoma represents a heterogeneous group of lymphoid malignancies characterized by poor prognosis with 5-year overall survival (OS) about 25% with conventional chemotherapy. Autologous stem cell transplant (Auto-SCT), as consolidation, is often considered in first complete remission (CR), providing between 30 to 40% long term disease-free survival. However, patients receiving Auto-SCT in second CR or with refractory disease have poor outcomes with progression-free survival ranging from 15-20% to 0%, respectively. In such cases, allogeneic stem cell transplant (Allo-SCT) may provide long term disease control. We intended to study outcomes of Allo-SCT in peripheral T-cell lymphoma patients. Methods: We have retrospectively evaluated long-term outcomes of adult peripheral T-cell lymphoma patients at Karmanos Cancer Institute. The objectives were to determine GVHD rate, overall survival (OS), relapse rate, progression-free survival (PFS) and non-relapse mortality (NRM) following Allo-SCT. Results: Between January 2005 and December 2017, 39 patients underwent Allo-SCT. The different diagnoses included peripheral T-cell lymphoma, not-otherwise-specified (n=16), angioimmunoblastic T-cell lymphoma (n=8), anaplastic T-cell lymphoma (n=8), hepatosplenic T-cell lymphoma (n=2), cutaneous T-cell (n=3) and NK cell lymphoma (n=2). The median age at transplant was 50 years (range, 21-67). The median number of prior therapies was 2 (range, 1-5) and 12 patients (31%) had failed prior Auto-SCT. Sixteen patients (41%) were in CR and 2 (5%) were in partial remission at the time of Allo-SCT, whereas 12 (31%) patients had relapsed disease and 9 (23%) had refractory disease. Twenty-one patients (54%) received matched related and 18 patients (46%) had unrelated Allo-SCT. Myeloablative conditioning regimen was used in 22 patients (56%), whereas reduced intensity regimen was used in 17 (44%) patients. Grade III-IV acute GVHD occurred in 25.6% (95% CI, 13.2-40.1%) and chronic GVHD occurred in 41% (95% CI, 25.1-56.3%). After a median follow-up of 3.08 years (95% CI, 2.49-7.28) among surviving patients, the estimated probabilities of 3-year OS and PFS were 35.9% (95% CI, 22.4-57.6%) and 32.5% (95% CI, 19.9-53%), respectively. The 3-year relapse rate was 23.9% (95% CI, 11.5-38.7%), whereas NRM was 35.9% (95% CI, 21.1-50.9%). No difference in OS and PFS was noticed in patients receiving Allo-SCT in first CR compared with patients receiving Allo-SCT beyond first CR (p=0.81; p=0.94). Similarly, no difference in OS and PFS was noted in patients with Allo-SCT followed by failed prior Auto-SCT compared with patients with upfront Allo-SCT (p=0.31; p=0.47). Seventeen of 39 patients were alive and 22 were deceased (n=7 disease relapse; n=15 NRM). Out of 39 patients, 13 (33%) alive patients are free of relapse and GVHD as of data analysis. Conclusion: Our study suggests that Allo-SCT is a viable treatment option for peripheral T-cell lymphoma and appears to provide cure in these highly selected patients. The survival advantage was noted in patients beyond first remission; therefore, it should be considered in all transplant eligible patients. In addition, certain proportion of patients who failed prior Auto-SCT benefited from Allo-SCT, which points towards potential role of graft-versus-lymphoma effect. Disclosures Deol: Novartis: Consultancy; Kite Pharmaceuticals: Consultancy.

A Phase I Study of Molibresib (GSK525762), a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of a Phase I/II Open Label Single Agent Study in Subjects with Non-Hodgkin's Lymphoma (NHL)

A Phase I Study of Molibresib (GSK525762), a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of a Phase I/II Open Label Single Agent Study in Subjects with Non-Hodgkin's Lymphoma (NHL)

Durable Responses with Ipilimumab Plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies

Background: Prevention or treatment of relapsed lymphoid malignancies after SCT requires novel strategies. We previously reported on safety and early responses of ipilimumab combined with lenalidomide in 16 treated patients (pts.) (Khouri et al. Clin Cancer Res, 2018). Here, we update the published data on a larger cohort of pts. with a longer follow-up. In addition, we define immune phenotpyes that correlated with response. Patients andMethods: Pts. with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autologous SCT were included within 6 mos post-SCT if they were still in CR, but had high risk features for relapse. Treatment consisted of 4 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1 and 3) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2 and 4). Considering the favorable safety profile in the initial patients treated, number of cycles was amended to 8 cycles in 6/2017. PBMC's from 20 pts (12 responders and 8 non-responders) were analyzed by flow cytometry. Results: Twenty-two pts. were enrolled. Autologous group (n=11): Median age was 57 yrs (range, 33-68). Histologies included diffuse-large-B-cell lymphoma (DLBCL) [n=6; including 3 with double-hit lymphoma (DHL)], mantle cell lymphoma (MCL) (n=2; one with CNS involvement), Hodgkin's disease (n=2; with persistent PET+ post-SCT), and follicular lymphoma (n=1, PIF with response to 4th line of therapy). Median time to enrollment after SCT was 3.8 months (range, 1.4-5.5). With a median follow-up duration of 23.4 months (range, 10.1- 48), median OS was not reached. Three pts. relapsed at a median of 6.7 months; 1 pt. died after developing T-cell lymph proliferative disorder 2 years after finishing treatment and ten pts. remain alive. The most common other AEs were 19 events of neutropenia (n=5, gr 4; n=2 gr 3, n=12 gr 2), two patients had thrombocytopenia gr 2, and one developed pulmonary embolism. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. AEs were similar in pts. who received 4 or 8 cycles (n=5). Allogeneic group (n=11): Median age was 55 yrs (range, 44- 66). Histologies included [Follicular (n=2), CLL (n=3), MCL (n=2), DLBCL (n=3; 2 of whom were DHL), and T-cell anaplastic lymphoma (n=1)]. Median number of therapies excluding the alloSCT was 3 (range 2-7). Two failed a prior autoSCT, one had 2 prior alloSCT, and three failed prior donor lymphocyte infusions, and one CLL pt. failed prior FCR, lenalidomide/ofatumumab, ibrutinib, idelalisib, CAR-T cell and venetoclax. Two pts. relapsed within 3 mos of their alloSCT prior to enrollment on study. One pt. was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed liver and skin GVHD, which responded to steroids. Another pt. developed chronic GVHD after cycle 4 which precluded treatment with the pre-planned 8 cycles. No other cases of GVHD were noted. ORR rate was 73%. Five (45%) pts. had CRs (four of which were durable at 14+, 32+, 33+ and 34+ months; including the CLL pt. who failed small molecule inhibitors and CAR-T), and 3 (27%) had PR. With a median follow-up time of 30.8 mos (range, 3-45.1), 9 (82%) pts. remain alive. One PR pt. died secondary to cardiac complications after a hip replacement; and 1 died of progression. AEs included eight episodes of neutropenia (n=2, gr 4; n=2, gr 3; n =4, gr 2), anemia gr 2 (n=1), thrombocytopenia gr 2 (n=1), diarrhea (gr 2; n=1), nausea (gr 2, n=1), headache (gr 2; n=1), hypertension (gr 2; n=1), hypoalbuminemia (gr 2; n=1). All AEs resolved. Immune monitoring of 20 transplant pts showed a Th1 type anti-tumor immune response in responding pts. In the responders, there was a higher frequency of CD4+ICOS+PD-1+ and CD8+PD+1 T effector cells at baseline when compared to non-responding pts. In contrast, the non-responders had a Th2 type response with a higher frequency of CD4+GATA3+ T effector memory cells at baseline when compared to responders (Figure). Conclusions: Follow-up results demonstrate better than expected response rates that are durable in pts. with lymphoid malignancies who relapsed after alloSCT. Continuous remission duration was also observed after autologous SCT. Immune monitoring analysis suggests that CD4+GATA3+ T cells could be a potentially valuable biomarker for stratification of pts. for lenalodimide+ipilimumab combination therapy. DisclosuresJabbour:novartis: Research Funding.