Aggressive T-cell Lymphoma Research Articles

EPOCH Is a Safe and Effective Treatment Option for Aggressive T-Cell Lymphomas

Background: T-cell lymphomas constitute heterogeneous subtypes of non-Hodgkin lymphoma (NHL). With the exception of brentuximab (BV) with cyclophosphamide, adriamycin, prednisone (CHP) in anaplastic large cell lymphoma (ALCL) establishing a standard of care in this subtype, the choice of first-line therapy in other subtypes are based on CHOP like regimens with or without etoposide. Few studies have evaluated the efficacy of etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) in patients with aggressive T-cell lymphomas. We report our single center experience in patients receiving EPOCH in frontline or relapsed/refractory (R/R) setting for aggressive T-cell lymphomas including transformed cutaneous T-cell lymphomas (CTCL).Methods:Adult patients with aggressive T-cell lymphomas who received EPOCH from May 2015 to October 2020 at Yale-New Haven Hospital were included in this analysis. Adverse effects were graded per the CTCAE criteria. Statistical analyses were performed using STATA 14.2. The primary objective was to determine the efficacy of EPOCH in terms of response rates and survival outcome. The secondary objective was to determine toxicity rates.Results: Thirty-eight patients with aggressive T-cell lymphomas were included in the study. This included angioimmunoblastic T-cell lymphoma (AITL) (n=7), adult T-cell leukemia/lymphoma (ATLL) (n=9), ALCL (n=2), peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS) (n=7), T follicular helper (Tfh) subtype (n=1), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (n=1) and CTCL (n=11). Eighteen patients received EPOCH in the first line and 21 patients in R/R setting. The overall response rate (ORR) for the entire cohort was 77% and complete response (CR) rate was 51%. The CR rate in the frontline was 60% and in R/R setting was 45%. At a median follow up of 22.1 months (95% CI: 17.3 to 28.4), the median progression free survival (PFS) was 7.8 months (95% CI 4.3 to 9.8), and median overall survival (OS) was 19.7 months (12.1 to NR). Fifteen patients went onto allogeneic stem cell transplant after remission with EPOCH. The most common grade 3 adverse effects were anemia (63%), thrombocytopenia (34%), and neutropenia (32%). The most common grade 4 adverse effects were neutropenia (71%) and thrombocytopenia (39%).Discussion: This study reports the efficacy and safety results of EPOCH in T-cell lymphoma both in the first line in R/R setting.We found that EPOCH has excellent response rates and good tolerability in T-cell lymphomas. With CR rates of >50%, EPOCH is a promising backbone for combination trials in aggressive T-cell lymphomas targeting deep responses prior to consolidation with transplant. Our study is unique in including CTCL patients who required treatment with combination chemotherapy due to an aggressive clinical course and/or large cell transformation. DisclosuresFoss: Kura: Honoraria; Kyowa: Honoraria; Mallinckrodt: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau; Acrotech: Honoraria, Speakers Bureau; Daiichi Sankyo: Honoraria.

Outcomes of Patients with Extranodal Natural Killer/T-Cell Lymphoma: Single Institution Series

Outcomes of Patients with Extranodal Natural Killer/T-Cell Lymphoma: Single Institution Series

Long Term Outcome Patterns and Risk Factors for Early Mortality and Disease Progression in ALK-Positive Anaplastic Large Cell Lymphoma

Long Term Outcome Patterns and Risk Factors for Early Mortality and Disease Progression in ALK-Positive Anaplastic Large Cell Lymphoma

CHOP Plus Sequential Mogamulizumab As First-Line Therapy for Untreated Adult T-Cell Leukemia-Lymphoma

Introduction: Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. In younger patients, allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to improve prognosis through a graft-versus-ATL (GvATL) effect. On the other hand, elderly patients with ATL are often not amenable to HSCT, and the prognosis is extremely poor with existing chemotherapy. The most widely used chemotherapy for ATL, CHOP (combination of cyclophosphamide-doxorubicin-vincristine-prednisone) and similar chemotherapy, have shown a complete response (CR) rate of about 20% and a long-term prognosis of less than 10%. In a phase II study of mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, in concurrent combination with chemotherapy (mLSG15), the primary endpoint of CR was 52% in the mLSG15 + mogamulizumab group compared to 33% in the mLSG15 alone group. However, no improvement was observed in overall survival (OS) or progression-free survival (PFS). In addition, mLSG15 is a potent chemotherapy and not feasible in majority of elderly patients. Considering the possibility that mogamulizumab may unlock the tumor immune evasion mechanism by removing regulatory T cells and exert an immunological effect like GvATL, we investigated its usefulness as an immunological consolidation therapy following chemotherapy, with the aim of suppressing recurrence.Methods: New-onset treatment-naive ATL patients who were not eligible to HSCT received 3 courses of CHOP (combination of cyclophosphamide div 750 mg/m 2/day1, doxorubicin iv 50 mg/m 2/day1, vincristine iv 1.4 mg/m 2/day1 [max. 2.0 mg/body, and prednisone po/iv 100 mg/body/day1-5) at 21-day intervals, and then the first course of mogamulizumab (1 mg/kg for 8 doses at 2-week intervals) was initiated between the start of the third course of CHOP-21 and day 42. The primary endpoint was OS at months 12. Secondary endpoints were proportion of subjects with PFS, OS, overall response rate (ORR), organ-specific response rate, CR rate and adverse events (AEs) at month 12.Results: A total of 24 patients were enrolled and the median age was 75.5 years (range, 64-85). The median follow-up period was 11.0 (3.0-30.6) months. Five subjects discontinued study treatment before mogamulizumab administration attributable to insufficient effect (n=2), continuation deemed inappropriate (n=2), and start of the next course extended (n=1). ORR was 87.5%. Organ-specific response rates for peripheral blood, other than peripheral blood, target lesion, and skin lesion were 83.3%, 87.5%, 79.2%, and 66.7%, respectively.OS and PFS rates in the full analysis set (FAS) at months 12 were 52.6 (30.9-70.4)% and 26.6 (10.9-45.3)%, respectively. The median survival time (MST) and 80% confidence interval (CI) for OS was 12.1 (5.0 -21 .0) months (Figure 1). Since the lower limit of the 80% CI was below the threshold of 6 months, this treatment was not considered to be effective. However, the point estimate of MST was 12.1 months, which was equivalent to the expected value. One possible reason for the failure to reach statistical significance could be attributable to occurrence of events in the early stage of the protocol regimen. In other words, patients who did not respond to the preceding chemotherapy did not benefit from mogamulizumab, and only patients who managed to overcome chemotherapy benefited from the immune effects of mogamulizumab, resulting in long-term survival (Figure 1). In the long-term follow-up, the MST (95% CI) of the FAS was 12.4 (4.9-21.0) months, and the median OS (95% CI) at 24 months was 25.1 (9.6-44.1) %.AEs were observed in 16 subjects, of which serious AEs (grade 4/5) were observed in 5 subjects (acute respiratory distress syndrome, ventricular fibrillation, heart failure, hyponatremia, and pneumonia). Largely, AEs were resolved/recovered in 14 subjects including 3 subjects with serious AE; 2 subjects resulted in death, which were not considered treatment-related.Conclusions: Mogamulizumab as an immunological consolidation therapy after CHOP 21 might be one of the treatment options for transplant-ineligible elderly patients with previously-untreated ATL, despite not clearly showing improved OS. Further studies are warranted to examine the dosing timing of mogamulizumab to obtain its maximum benefit for prolonged survival. [Display omitted] DisclosuresKato: Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Suzuki: Kyowa-kirin: Honoraria, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Taiho: Research Funding; Ohtsuka: Honoraria, Research Funding; Takeda: Research Funding, Speakers Bureau; Shionogi: Research Funding; Eisai: Honoraria, Research Funding; Bristol-Meyer Squib: Honoraria; MSD: Honoraria; Janssen: Honoraria; Abbvie: Speakers Bureau; Meiji Seika: Honoraria, Speakers Bureau; Ohtsuka: Honoraria. Akashi: Sumitomo Dainippon Pharma: Consultancy; Kyowa Kirin: Consultancy, Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Shionogi: Research Funding; Asahi Kasei Pharma: Research Funding; Chugai: Research Funding; Bristol-Myers Squibb: Research Funding.

CD30+ Anaplastic Enteropathy-Associated T-cell Lymphoma Mimicking Crohn’s Disease

Abstract Introduction/Objective Enteropathy-associated T-cell lymphoma (EATL) is an aggressive peripheral T-cell lymphoma with a very poor prognosis. It is not uncommon for patients with EATL to present with intestinal obstruction or perforation, with the diagnosis made following surgical resection or autopsy. Although EATL is associated with celiac disease, this diagnosis may be made concomitant with EATL. The symptomology is often non-specific, particularly without a known history of celiac disease, and progression may be rapid. Methods/Case Report We describe the case of a 57 year old male who presented with several months of diarrhea, fatigue, night sweats, severe weight loss, and failure to thrive. Initial workup indicated positivity for Clostridium difficile and cryptosporidium, leading to antibiotic treatment. His symptoms persisted without significant improvement and a presumptive diagnosis of Crohn’s disease was made based on colonoscopy with biopsy and imaging that showed inflammatory changes with entero-enteric fistula formation. Further clinical decline necessitated exploratory laparotomy which revealed multiple enteric strictures, intra-loop abscesses, and necrotic ulceration necessitating segmental ileal resections. There was no associated lymphadenopathy. Microscopically, there was a dense, polymorphic lymphoid population within the bowel wall with associated mucosal ulceration and abundant necrosis. Striking anaplastic cytomorphology was present, with a heavy intratumoral eosinophilic infiltrate. Neoplastic lymphocytes were CD3+, CD30+ T cells with a CD7+, CD5-, CD4-, CD8-, CD56-, ALK- immunophenotype. The adjacent intestinal mucosa showed features of celiac disease (villous atrophy, intraepithelial lymphocytosis). Results (if a Case Study enter NA) NA Conclusion The prominent anaplastic morphology in combination with strong, diffuse CD30 expression prompted consideration of other T cell lymphomas, including anaplastic large cell lymphoma and peripheral T cell lymphoma, NOS, within the differential. The presence of coexisting histologic changes of celiac disease, dense eosinophilic infiltrate, and absence of lymphadenopathy were clues to the correct diagnosis. Notably, the frequency of CD30 expression in EATL is variable but common among cases manifesting large cell morphology.

Bio-O1-01 - Diagnostic performance of high throughput sequencing of the T-cell receptor beta gene for the diagnosis of cutaneous T-cell lymphoma

Bio-O1-01 - Diagnostic performance of high throughput sequencing of the T-cell receptor beta gene for the diagnosis of cutaneous T-cell lymphoma

Prec-O1-02 - Xenograft and cell culture models of Sézary syndrome reveal cell of origin diversity and subclonal heterogeneity

Sézary syndrome (SS) is a rare and aggressive epidermotropic cutaneous T-cell lymphoma (CTCL) defined by erythroderma, pruritis and a circulating atypical CD4+ T-cell clonal population. The diversity of Sézary cells (SC) phenotype and genotype possibly reflects either plasticity or heterogeneity that is difficult to assess, as SC are difficult to expand with very few cell lines available. Therefore, we developed six new defined culture conditions allowing the amplification of SC defined by their immunophenotype and monoclonality in 4 of 7 patients. The SC expansion in response to different culture conditions by addition of several cytokines and stromal cells is heterogeneous between patients. This shows the importance of tumor microenvironment for tumor SC growth. Engraftment of SC into immunodeficient NOD.Cg-Prkdc(scid)Il2rg(tm1Wjll)/SzJ (NSG) mice was achieved in 2 of 14 cases. Secondary xenograft by subcutaneous injection mimicked several clinical features of SS with dermal infiltration, epidermotropism and blood spreading. Such models permitted to assess the intra-individual heterogeneity of patient SC. Such subclones sharing the same TCR gene rearrangement evolved independently according to culture condition and/or after xenografting. This clonal selection was associated with phenotypic differences and limited genomic evolution both in vitro and in vivo. The long-term amplification of SC allowed the development of eight new SC lines derived from four different patients. They represent the cell of origin diversity of SC cells and new tools to evaluate their functional properties. Indeed, SC lines demonstrate differential responses to therapies (romidepsin, doxorubicin and vorinostat) according to the cells of origin of SC. The new in vivo model we developed mimicking both skin and blood involvement of SS represents a new preclinical model to test therapeutic agents as well as the mechanisms regulating the balance between blood and skin compartments of SC cells.

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

AbstractMycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, undergo 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.

Super-enhancer-based identification of a BATF3/IL-2R\u2212module reveals vulnerabilities in anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.

Duodenal monomorphic epitheliotropic intestinal T cell lymphoma along with unpredictable intestinal Epstein-Barr virus infection; a rare newly redefined entity in a rare site and review of literature

Introduction: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), previously known as type II enteropathy associated T-cell lymphoma (EATL), was redefined by the WHO (2016) as separate entity from the celiac disease-associated lymphoma. It is an extremely rare and highly aggressive peripheral T-cell lymphoma. It mainly involves jejunum and ileum and rarely duodenum. Case Presentation: This was a 38-year-old male patient presented by daily vomiting related to meals for 8 months along with generalized colicky abdominal pain associated with constipation and marked weight loss. Upper endoscopy showed large ulcerated mass at the third part of the duodenum. Histopathological examination showed the diffuse malignant lymphoid infiltrate with morphology and immunophenotyping consistent with MEITL associated with unpredictable Epstein-Barr virus (EBV) in intestinal epithelial cells. The patient underwent five cycles of chemotherapy (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) followed by duodenectomy. Conclusion: This case represents a rare newly redefined lymphoma entity in a rare site associated with unpredictable non-neoplastic epithelial EBV infection, which proved to be oncogenic agent involved in various hematopoietic and other neoplasms with unclear relationship to the development of this MEITL.

Transient genomic instability drives tumorigenesis through accelerated clonal evolution

Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Short-term chromosome instability (CIN) from transient Plk4 induction resulted in formation of aggressive T-cell lymphomas in mice with heterozygous inactivation of one p53 allele and accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells with a specific karyotype profile, including trisomy of chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Tumor development in mice with chronic CIN induced by an independent mechanism (through inactivation of the spindle assembly checkpoint) gradually trended toward a similar karyotypic profile, as determined by single-cell whole-genome DNA sequencing. Overall, we show how transient CIN generates cells with random aneuploidies from which ones that acquire a karyotype with specific chromosome gains are sufficient to drive cancer formation, and that distinct CIN mechanisms can lead to similar karyotypic cancer-causing outcomes.

The significance of epidermal involvement in primary cutaneous gamma/delta (γδ) T-cell lymphoma: A systematic review and meta-analysis.

Primary cutaneous gamma/delta (γδ) T-cell lymphoma (PCGDTCL) is a rare, aggressive peripheral T-cell lymphoma. There is evidence that patients with epidermotropic PCGDTCL may have an improved prognosis compared with those with only dermal and/or subcutaneous involvement. Systematic review of the literature and application of inclusion criteria yielded 48 manuscripts detailing the cases of 104 patients. Of the 104 patients, 57 were male (51.4%) and 47 were female (48.5%) Based on provided histopathologic descriptions, 57 cases (54.8%) had no epidermotropism, 47 cases (45.2%) patients demonstrated any degree of epidermotropism, and 25 cases were predominantly epidermotropic (25/104, 24%). Five-year overall survivals for patients with no epidermotropism, any epidermotropism, and predominantly epidermotropic presentation were 32.8%, 28.9%, and 40.0%, respectively (p = 0.40). The most commonly performed immunohistochemical markers were CD3, CD4, CD8, CD5, CD7, CD30, CD56, TCR beta, TCR γ, and TCR δ. There was no statistically significant difference in immunophenotype between groups. Lesion morphology was described in the majority of cases (85/104, 80.9%); most cases presented as a combination of nodules, plaques, and tumors (77.4%). Several cases had more atypical presentations, including "mycosis-fungoides-like" and ulcerated. In PCGDTCL, neither epidermotropism nor predominantly epidermotropic phenotype predict a better prognosis. In addition, the case report literature in dermatology and dermatopathology is rich and highly valuable.

Aggressive T-cell lymphomas: 2021 Updates on diagnosis, risk stratification and management.

Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 27 different subtypes of peripheral T-cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations. Gene expression profiling (GEP) can help in diagnosis and prognostication of various subtypes including PTCL-nos and anaplastic large cell lymphoma (ALCL). In addition, mutational analysis is now being incorporated in clinical trials of novel agents to evaluate various biomarkers of response to allow better therapeutic choices for patients. There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are CD25, CCR4, inhibition of PI3kinase - m TOR and JAK/STAT pathways. The ALK inhibitors are promising for ALK expressing tumors. Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial. The most promising results have been seen in cases of extranodal natural killer cell/T-cell (ENK/T) lymphomas and cutaneous T-cell lymphomas (CTCL). Bispecific antibody based treatments as well as CAR-T cell based therapies are in clinical trials.

Impact of IRF4/MUM1 Expression on Adult T-Cell Leukemia/Lymphoma and Treatment Outcome

Introduction:HTLV-1 related adult T-cell leukemia-lymphoma (ATLL) remains fatal, thus urging development of new therapies. Interferon regulatory factor 4 (IRF4), also known as MUM1, is a transcription factor expressed in various aggressive B-cell and T-cell lymphomas (1). IRF4 has been reported to be highly expressed in HTLV-1 transformed cells and in aggressive leukemic forms of ATLL, and has also been implicated in interferon resistance. However, IFR-4/MUM1 expression, and its pathogenic role in ATLL have not been fully investigated. We previously reported lack of IRF4/MUM1 in leukemic ATLL specimens from patients who responded to AZT-interferon-alpha (AI). In this study, we characterized the expression of IRF4/MUM1 in our expanded ATLL cohort.Methods:ATLL specimens from 73 chemotherapy naïve patients of all subtypes [lymphomatous (L) n=31, acute (A) n=36, unfavorable chronic (UC) n=5, and smoldering (S) n=1] were analyzed for MUM1 expression. Cases were analyzed or confirmed by immunohistochemistry at our institution using anti-human MUM1 antibody (Dako) on formalin-fixed paraffin-embedded tissue or cellblock sections prepared from cytospun CD4+-enriched leukemic samples. The cutoff positive value for MUM1 expression was 30%. MUM1 expression was correlated with treatment outcome.Results:In 73 patients the proportion of MUM1+ cases was as follows: L (28/31 =90%), A (7/36 =19%), UC (1/5 =20%), and S (0/1 =0%) (Figure 1A). MUM1 expression was analyzed in 33 chemotherapy naïve patients with A (n= 28) or UC type (n=5) treated with AI; only 3 patients (A n=2, and UC n=1) were MUM1+ and had partial response (PR) (UC n=1), stable disease (SD) (A n=1), and no response (NR) (A n=1) respectively (Figure 1B). All 9 patients who achieved a complete response (CR) (A n=7, and UC n=2) and 6 patients with PR (A n=5, UC n=1) were MUM1-. The cumulative 3-year overall survival (OS) rates in MUM1- (n=37) vs. MUM1+ (n=36) patients were 23% vs. 10% respectively (p=0.68) (Figure 2). Notably, the great majority of patients in the MUM1- group (33/37=89%) were treated with AI as first line therapy and were A-type (27/37=73%), while most patients in the MUM1+ group (26/36=70%) were treated with chemotherapy upfront and were L-type (23/36=64%). The cumulative 3-yr progression-free survival in MUM1- patients treated with AI was 28% as compared to 0% in MUM-1+ treated with chemotherapy (Figure 3).Conclusion:Our results demonstrate that MUM1 expression is highly associated with L-type ATLL. Patients with aggressive leukemic ATLL subtypes treated with AI generally lacked MUM1 and had a significant better outcome than L-type patients treated with chemotherapy. This study suggests that MUM1 expression may influence the biology at ATLL subtypes and response to interferon-based therapy. Targeting IFR-4/MUM1 function in L-type ATLL should be considered as a therapeutic strategy. The analysis of additional cases is still ongoing and the final results will be presented at the meeting. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mogamulizumab Monotherapy in the Treatment of Relapsed/Refractory Peripheral T-Cell Lymphoma or Cutaneous T-Cell Lymphoma Patients in Single-Institution Experience

Objectives; T-cell lymphomas generally have a poor outcome with shorter long-term survival compared with B-cell lymphomas. CC chemokine receptor 4 (CCR4) is highly expressed by aggressive peripheral T-cell lymphoma, not otherwise specified (PTCLs), particularly adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody that targets CCR4. In phase II study, Mogamulizumab has been shown to high clinical efficacy and low toxicity. However, its efficacy has not been well evaluated in the clinical setting. We retrospectively analyzed the efficacy and safety of Mogamulizumab of against relapsed/refractory non- ATL T-cell lymphomas.Methods; Fourteen patients with relapsed/ refractory CCR4 positive PTCLs or CTCL were treated with weekly Mogamulizumab (1.0 mg/kg) alone at Iwate Prefectural Central Hospital between January 2015 and June 2017. CCR4 expression was determined by immunohistochemistry by a central laboratory center (SRL, Tokyo, Japan). In the first line, most patients receive commonly anthracycline-containing induction chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The patients had received a median of one previous chemotherapy regime (range 1-3).We retrospectively evaluated (1) the best overall response, (2) progression-free survival (PFS), (3) overall survival (OS), (4) the best response according to disease site(peripheral blood; PB, lymph nodes; LN and skin) and (5) safety. Response assessments were performed after eighth mogamulizumab infusions according to the 1999 IWG criteria guidelines for response assessments for NHL (IWG-NHL). Treatment efficacy in patients with CTCL was evaluated by using a Global Response Score. Treatment was discontinued if progressive disease (PD) was evident.For safety evaluations, adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs, version 4.0.Results; The median age was 69 years old (range 48-85). Eight patients are male. The diagnosis comprised PTCLs (n=12) and CTCL (n=2). The median follow up periods and median number of Mogamulizumab infusion were 293 days (range 49- 681) and 8 courses (range 2- 9). (1) Complete remission (CR) was achieved in two patients (16.7%) and partial remission in one patients (8.3%), stable disease (SD) in two patients (16.7%), respectively. And (2) median PFS was 88 days and (3) median OS was 475 days. Peripheral blood, lymph node and skin lesion were affected in two, ten, and six patients, respectively. (4) In PB, complete response (CR) was obtained in all two patients (100%) and two patients were achieved CR in skin lesion (33.3%). In LN, only one of ten patient manifested CR(10.0%). This patient's tumor burden is low. (5) With regard to safety issues, hematological AEs were frequently observed, and lymphocytopenia occurred in 62.5% of patients. However, the AEs were controllable and tolerated. Non-hematological AEs, including fever, infusion reactions and skin trouble , were frequently observed (37.5%, 25.0%, and 37.5%, respectively). Grade 3/4 non-hematological AEs were scarcely observed.Conclusions; Although Mogamulizumab monotherapy is effective with highly safety, the patients who had swollen lymph node may need combination chemotherapy with mogamulizumab. The number of patients was small in this retrospective analysis, further investigation are required. DisclosuresNo relevant conflicts of interest to declare.

A Phase 1 Trial of Alisertib and Romidepsin for Relapsed/Refractory Aggressive B-Cell and T-Cell Lymphomas

A Phase 1 Trial of Alisertib and Romidepsin for Relapsed/Refractory Aggressive B-Cell and T-Cell Lymphomas

Outcomes in Patients with Enteropathy-Associated T-Cell Lymphoma (EATL) and Hepatosplenic T-Cell Lymphoma (HSTCL): A Population Based Analysis Using the SEER Data

Introduction and AimHepatosplenic T-cell lymphoma (HSTCL) and Enteropathy-associated T-cell Lymphoma (EATL) are rare aggressive peripheral T-cell lymphomas with dismal outcomes. Due to their rarity there is paucity of data on disease epidemiology and survival outcomes. We analyzed these rare diseases using Surveillance, Epidemiology and End Results (SEER) data to identify patient and disease factors that impact survival.MethodsUsing the SEER data, cases of HSTCL and EATL diagnosed between 1996 and 2014 were identified based on the ICD-O3 codes 9716 and 9717, respectively. Proportions were compared using chi-squared tests. Multivariable Cox proportional hazards models and stepwise regression were used to analyze disease-specific overall survival. Computations were performed in R.ResultsWe identified 122 patients with HSTCL and 163 with EATL; both had male predominance with 69% in HSTCL and 58% in EATL (p=0.07). Median age was 38 years (range 4-83) in HSTCL and 64 years (range 23-96) in EATL patients. The HSTCL group was much younger with 79% aged <55 years compared to only 26% in the EATL group (P=<0.0001) (Table 1). Although both groups were primarily Caucasian - 61% in HSTCL and 77% in EATL, 27% of HSTCL patients were of African American race. While the majority of the HSTCL (53%) were diagnosed in 2008-2014, 55% of EATL pts were diagnosed in 1996-2008. Disease characteristics also differed between these entities with HSTCL mostly being advanced stage (81%) and EATL largely early stage (58%) at diagnosis; 79% of HSTCL patients had stage IV compared to only 31% in EATL (p<0.0001). Treatments in HSTCL pts included chemotherapy (83%) surgery (43%) radiation therapy (10%). On the contrary, surgery (70%) was the most common treatment in EATL followed by chemotherapy (55%) and radiation therapy (3%). Median OS for EATL and HSTCL were 9 (95% CI 715) and 5 months (95% CI 37), respectively (log-rank P= 0.0018 (Figure 1A). In univariate analysis, surgery (HR: 0.62, 95% CI: 0.39-0.96, p=0.032), and radiation therapy (HR: 0.3, 95% CI: 0.16-0.96, p=0.042) was associated with superior OS, while there was increased risk of mortality with advanced age (HR: 1.6, 95% CI: 1.01-2.79, p=0.043) in HSTCL patients. Sex, race, marital status, year of diagnosis, use of chemotherapy and stage failed to predict survival in HSTCL. However, in EATL advanced stage (HR: 1.48, 95% CI: 0.99-2.20, p=.052) was associated with inferior OS and use of chemotherapy (HR: 0.46, 95% CI: 0.31-0.67, p=.0001) was a positive predictor for OS. On stepwise regression analysis, surgery (HR 0.57; p=0.014) and radiation therapy (HR 0.33; p= 0.019) were associated with improved survival in patients with HSTCL, whereas in EATL patients receiving chemotherapy improved survival (HR 0.42; p<0.001) (Figure 1B) and advanced stage correlated with reduced survival (HR 1.60; p=0.01).ConclusionTo our knowledge, this is the first and largest United States population based study of patients diagnosed with HSTCL and EATL. Our analysis showed that HSTCL is commonly diagnosed in younger, males with increased incidence in African American population compared to EATL. Although surgical interventions were commonly used in both entities, it was more frequent in EATL. While surgery and radiation improved survival in HSTL, chemotherapy was the significant factor in EATL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cutaneous T-cell lymphomas-An update 2021.

Cutaneous T-cell lymphomas (CTCL) represent the majority of primary cutaneous lymphomas (CL). Mycosis fungoides (MF) and cutaneous CD30+ lymphoproliferative disorders account for 80% of all CTCL. CTCL show overlapping histological features. Thus clinical-pathological correlation is of importance to achieve final diagnosis. MF shows a characteristic evolution with patches, plaques, and in a subset of patients (10%-20%) with tumors. Therapy is stage-adapted with skin-directed therapies such as UV-light therapies and corticosteroids in early disease stage (i.e., patch and limited plaque stage) and systemic therapies (retinoids, interferon, mono chemotherapy, targeted therapy) and/or radiation therapy (local or total skin beam electron) in advanced stages. Novel therapies include targeted therapy such as mogamulizumab (anti-CCR4) or brentuximab vedotin (anti-CD30) and histone deacetylase inhibitors. Considering the impact of targeted therapies, biomarkers such as CD30 are not only crucial for the diagnosis and correct classification of an individual lymphoma case, but also for therapy as they may represent therapeutic targets. In the recently revised WHO classification 2017 and the updated WHO-EORTC classification for CL 2018, primary cutaneous CD8+ acral T-cell lymphoma has been introduced as a new still provisional entity. It displays characteristic clinical, histological, and phenotypic features and exhibits an excellent prognosis. Rare, but aggressive CTCL include cutaneous primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma, which present with rapid onset of necrotic or ulcerated plaques and tumors. As they have a poor prognosis, treatment includes multiagent chemotherapy and hematopoietic stem cell transplantation.

The value of complete remission according to positron emission tomography prior to autologous stem cell transplantation in lymphoma: a population-based study showing improved outcome

BackgroundChimeric antigen-receptor T-cell and bispecific antibody therapies will likely necessitate a reconsideration of the role of autologous stem-cell transplantation (ASCT) in lymphoma. Patients who are likely to profit from ASCT need to be better identified.MethodsHere, we investigated the value of positron emission tomography/computerized tomography (PET/CT) before ASCT. All 521 patients transplanted for lymphoma 1994–2019 at Karolinska (497 conditioned with BEAM) were included.ResultsOutcome improved over three calendar periods 1994–2004, 2005–2014, 2015–2019 (2-year overall survival [OS]: 66, 73, 83%; P = 0.018). Non-relapse mortality (NRM) at 100 days over the three periods were 9.8, 3.9, 2.9%, respectively. The OS improvement between 1994 and 2004 and 2005–2014 was due to lower NRM (P = 0.027), but the large OS advance from 2015 was not accompanied by a significant reduction in NRM (P = 0.6). The fraction of PET/CT as pre-ASCT assessment also increased over time: 1994–2004, 2%; 2005–2014, 24%; 2015–2019, 60% (P < 0.00005). Complete responses (PET/CT-CR) were observed in 77% and metabolically active partial responses (PET/CT-PR) in 23%. PET/CT-CR was a predictor for survival in the entire population (P = 0.0003), also in the subpopulations of aggressive B-cell (P = 0.004) and peripheral T-cell (P = 0.024) lymphomas. Two-year OS and progression-free survival (OS/PFS) for patients in PET/CT-CR were in relapsed/refractory aggressive B-cell lymphoma 87%/75% and peripheral T-cell lymphoma 91%/78%. The corresponding figures in PET/CT-PR were 43%/44 and 33%/33%. Patients with solitary PET/CT-positive lesions showed acceptable outcome with ASCT followed by local irradiation (2-year OS/PFS 80%/60%). CT was less discriminative: 2-year OS/PFS: CT-CR, 76%/66%; CT-PR, 62%/51%. Outcome was inferior after BEAC compared with BEAM conditioning.ConclusionsWe conclude that the improved outcome reflects better, PET/CT-informed, identification of patients who should proceed to ASCT. The excellent survival of patients in PET/CT-CR indicates that ASCT should remain part of standard therapy for lymphoma.

A probable case of aggressive extranodal natural killer T-cell lymphoma in a 19th century Qing Dynasty painting

“Ashun of Ko Tung aged 34, a carpenter. The disease commenced a little more than a year ago. Formerly it communicated both with the mouth and nose, and discharged a yellowish fluid. On a former occasion he performed an operation upon himself, and with the aid of his knife and looking glass, evacuated its contents; but the disease returned”. So wrote Reverend Dr Peter Parker (1804–88), an American medical missionary and graduate of Yale University (New Haven, CT, USA) in his notes on March 5, 1836, in Reports of the Ophthalmic Hospital at Canton (China; figure).