Diagnosis Of Peripheral T-cell Lymphoma Research Articles

Recognizing puzzling PD1 + infiltrates in marginal zone lymphoma by integrating clonal and mutational findings: pitfalls in both nodal and transformed splenic cases

BackgroundA marked increase in PD1-positive TFH cells in nodal MZL cases (NMZL) was reported previously and could prompt suspicion for a diagnosis of peripheral T-cell lymphoma (PTCL), especially angioimmunoblastic T-cell lymphoma (AITL).Case presentationTo demonstrate that the pitfall might exist not only in NMZL but also in transformed splenic MZL (tSMZL), two NMZL cases (70 y/o female with enlarged left cervical lymph node and 75 y/o male with generalized lymphadenopathy) and one case of tSMZL (47 y/o male with nodal and extranodal involvement) with obvious PD1-positive T-cell hyperplasia were described here. Although all their initial diagnoses were prompted to be AITL, they were comprehensively characterized by clinical features, morphologic, immunophenotypic, clonality, and targeted exosome sequencing (TES) findings. Case 1 and Case 2 were NMZL with increased PD1 + T cells in the “peripheral pattern” or “mixed peripheral and central pattern”, and Case 3 was SMZL with abundant PD1-positive T cells in the “nodular pattern” that transformed to tSMZL (DLBCL) with PD1-positive T cells distributed in the “diffuse pattern.” In addition to the monoclonal IG rearrangement and polyclonal TCR rearrangement results, TES demonstrated enriched and recurrent mutations in MZLs and failed to find aberrations described in AITL- or TFH-derived lymphomas.ConclusionsIt is important to realize that this pitfall can also occur in more diagnostically difficult tSMZL cases; the integration of histopathology with clonality and mutation studies is also highlighted.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. Dizal Pharmaceutical.

Efficacy and Safety of Valemetostat Monotherapy in Patients with Relapsed or Refractory Peripheral T-Cell Lymphomas: Primary Results of the Phase 2 VALENTINE-PTCL01 Study

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin lymphoma (NHL), with limited available treatment options for patients (pts) with relapsed or refractory (R/R) disease. Valemetostat tosylate (valemetostat) is a novel and potent dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, which is approved in Japan for the treatment of R/R adult T-cell leukemia/lymphoma (ATLL). Here, we report primary results for pts with R/R PTCL treated with valemetostat in the open-label, single-arm, global, phase 2 VALENTINE-PTCL01 study (DS3201-A-U202; NCT04703192). Methods: Pts were ≥ 18 years of age, had a confirmed diagnosis of PTCL, had R/R disease after ≥ 1 prior line of systemic therapy, and pts with anaplastic large cell lymphoma (ALCL) had received prior brentuximab vedotin treatment. Pts received oral valemetostat 200 mg/day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review of PTCL following computed tomography (CT)-based response assessment according to Lugano 2014 criteria. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Positron emission tomography (PET)-CT-based response assessment by Lugano 2014 criteria was an exploratory endpoint. Efficacy analyses included all pts who received ≥ 1 dose of valemetostat and had an eligible PTCL subtype confirmed by central hematopathology review; safety analyses included all pts who received ≥ 1 dose of valemetostat. Results: A total of 133 pts with R/R PTCL were enrolled and received ≥ 1 dose of valemetostat. Pts had a median age of 69 years (range 22-85) and 91 pts (68.4%) were male. Pts had received a median of 2 prior lines of therapy (range 1-12) and 35 pts (26.3%) received prior hematopoietic cell transplant (HCT; autologous, n = 32; allogeneic, n = 5). PTCL subtype eligibility was confirmed in 119 pts: 42 pts (31.6%) had angioimmunoblastic T-cell lymphoma (AITL), 41 (30.8%) had PTCL, not otherwise specified (PTCL, NOS), 9 (6.8%) had ALCL (7 [5.3%] ALK-negative and 2 [1.5%] ALK-positive), 8 (6.0%) had nodal PTCL with T follicular helper cell phenotype, and 19 (14.3%) had other PTCL subtypes. As of data cutoff (May 5, 2023), 32 pts (24.1%) were still receiving treatment; reasons for treatment discontinuation included progressive or relapsed disease in 46 pts (34.6%), clinical progression in 19 pts (14.3%), adverse event in 13 pts (9.8%), and 12 pts (9.0%) discontinued study drug to proceed with allogeneic HCT. Median treatment duration was 18 weeks (range 0.3-93.4) and median duration of follow-up was 10.5 months (range 0.2-21.5). Among 119 efficacy-evaluable pts, the CT-based ORR was 43.7% (n = 52) (95% confidence interval [CI], 34.6-53.1), including 17 pts (14.3%) achieving CR and 35 pts (29.4%) achieving PR as best overall response. Median DOR was 11.9 months (95% CI, 7.8-not evaluable [NE]) and median time to response was 8.1 weeks (range 5-37). ORR by PTCL subtype ranged from 31.7% for PTCL, NOS to 54.8% for AITL (Table 1). Using PET-CT-based response assessment, ORR was 52.1% (n = 62) (95% CI, 42.8-61.3), including 32 pts (26.9%) with a complete metabolic response. Median CT-based PFS was 5.5 months (95% CI, 3.5-8.3) and median OS was 17.0 months (95% CI, 13.5-NE). Of 133 pts in the safety analysis set, 128 pts (96.2%) experienced ≥ 1 treatment-emergent adverse event (TEAE) of any grade, 77 pts (57.9%) experienced grade ≥ 3 TEAEs, and 53 pts (39.8%) experienced serious adverse events. The most common all grade and grade ≥ 3 TEAE was thrombocytopenia (Table 2). Overall, 13 pts (9.8%) experienced a TEAE that led to treatment discontinuation, 21 pts (15.8%) had a TEAE that led to dose reduction, and 66 pts (49.6%) had a TEAE that led to dose interruption. Conclusions: Valemetostat demonstrated a high ORR of 43.7% with durable responses (median DOR of 11.9 months) in pts with R/R PTCL, and responses were observed across all PTCL subtypes. A valemetostat dose of 200 mg/day was tolerable; safety analysis showed that the most common TEAEs were cytopenias. These primary results from the VALENTINE-PTCL01 study suggest that valemetostat provides a clinically meaningful benefit for pts with R/R PTCL.

FRI228 Primary Adrenal T-cell Lymphoma: A Case Report

Abstract Disclosure: H. Tabassum: None. S. Xu: None. A. Manavalan: None. Introduction: Primary T-cell adrenal lymphoma (PAL) is exceedingly rare. Adrenal insufficiency (AI) is common in these cases. Here we describe a patient with bilateral, large, T-cell PAL with rapid progression, without adrenal insufficiency. Clinical Case: A 62-year-old male, with coronary artery disease and recent coronary intervention, hyperlipidemia and hypertension presented to the hospital with abdominal pain, fever, night sweats and weight loss for a month. Work up revealed a 5.8 cm left adrenal mass with 14% absolute washout, measuring 34 Hounsfield Units (HU) pre-contrast, 68 HU postcontrast, and 63 HU on delayed images, and a 5.2 cm right adrenal mass with 42% absolute washout, measuring 35 HU pre-contrast, 81 HU postcontrast, and 62 HU on the delayed images with no other suspicious lesions or lymphadenopathy. The patient demonstrated no clinical symptoms or signs of adrenal hormone excess or deficiency. Levels of renin, aldosterone, serum cortisol, ACTH, 24-hour urine free cortisol, serum metanephrines, and thyroid function were normal. Additional tests to rule out adrenal cortical carcinoma (ACC) revealed normal levels of androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and estradiol. Persistent non-significant elevation of 11-deoxycortisol was observed at 51 ng/dL and 63ng/dL (Ref &amp;lt; 42 ng/dL). Adrenal biopsy was suggested but deferred due to the increased risk of hemorrhage given recent coronary revascularization and use of dual antiplatelet therapy. Follow up imaging in a few weeks revealed diffuse, retroperitoneal lymphadenopathy with unchanged adrenal masses. A lymph node biopsy confirmed a diagnosis of peripheral T-cell lymphoma. The left adrenal gland demonstrated an uptake SUV of 22.7 and the right, 19.17 on FDG PET. The patient was initiated on chemotherapy with etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin. Imaging three months later revealed a marked decrease in FDG activity SUV 6.98 g/mL on the left and SUV up to 3.32 g/mL on the right. Adrenal function remained intact on follow up. Conclusion: Peripheral T-cell lymphoma with adrenal involvement is an extremely rare and aggressive disease with rapid progression. Mostly seen in males over the age of 50, it may present with abdominal pain, B symptoms or both. While ACC is usually unilateral, lymphoma and metastatic disease may present bilaterally, however, other imaging features can be similar. AI is expected when 90% of the adrenal glands are destroyed by tumor infiltration, however, this does not always correlate with tumor size. In our patient, AI was not observed on presentation or follow up. As adrenal insufficiency can occur at any time in the disease course and may mimic symptoms of cancer or chemotherapy, the clinician should always be vigilant for its development in these cases. Presentation: Friday, June 16, 2023

PERIPHERAL T-CELL LYMPHOMA, NOS IN ORAL CAVITY: REPORT OF A RARE CASE

The manifestation of non-Hodgkin´s lymphoma (NHL) in the oral cavity represents 2% of all cases. This study presents a case of a 55-year-old male patient who presented an asymptomatic fast-growing mass on the right side of the face. Intraoral examination revealed a well circumscribed mass with ulcerated areas in the hard palate. The radiological examination reveals a unilocular radiolucent lesion with a displacement of adjacent teeth. An incisional biopsy was performed. Histopathological examination revealed a neoplastic proliferation of small, round, blue cells with moderate pleomorphism. The immunohistochemical examination showed positivity for LCA, CD3, and CD45RO, and negativity for CD20, Granzyme, Perforine, TDT, CD10, BCL6, CD30, and CD56. The cell proliferation index through Ki-67 was high. Investigation for EBV via in situ hybridization was negative. According to these findings, the diagnosis of peripheral T-cell lymphoma, NOS was established. The cancer treatment was started, but the patient died after 4 months. The manifestation of non-Hodgkin´s lymphoma (NHL) in the oral cavity represents 2% of all cases. This study presents a case of a 55-year-old male patient who presented an asymptomatic fast-growing mass on the right side of the face. Intraoral examination revealed a well circumscribed mass with ulcerated areas in the hard palate. The radiological examination reveals a unilocular radiolucent lesion with a displacement of adjacent teeth. An incisional biopsy was performed. Histopathological examination revealed a neoplastic proliferation of small, round, blue cells with moderate pleomorphism. The immunohistochemical examination showed positivity for LCA, CD3, and CD45RO, and negativity for CD20, Granzyme, Perforine, TDT, CD10, BCL6, CD30, and CD56. The cell proliferation index through Ki-67 was high. Investigation for EBV via in situ hybridization was negative. According to these findings, the diagnosis of peripheral T-cell lymphoma, NOS was established. The cancer treatment was started, but the patient died after 4 months.

Retrospective Analysis With Propensity Score Matching of Peripheral T-Cell Lymphoma Treated Frontline With Brentuximab Vedotin and Chemotherapy.

Since Food and Drug Administration approval of brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) as initial therapy for previously untreated CD30-expressing peripheral T-cell lymphoma (PTCL), there has been limited research on real-world patient characteristics, treatment patterns, and clinical outcomes. We retrospectively analyzed claims of patients with PTCL treated with frontline A + CHP or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) using the Symphony Health Solutions database. Adults with International Classification of Diseases-9/10 PTCL diagnosis codes who initiated A + CHP or CHOP between November 2018 and July 2021 were included. A 1:1 propensity score matching analysis was performed that adjusted for potential confounders between groups. A total of 1344 patients were included (A + CHP, n = 749; CHOP, n = 595). Before matching, 61% were men; median age at index was 62 (A + CHP) and 69 (CHOP) years. The most common A + CHP-treated PTCL subtypes were systemic anaplastic large cell lymphoma (sALCL; 51%), PTCL-not otherwise specified (NOS; 30%), and angioimmunoblastic T-cell lymphoma (AITL; 12%); the most common CHOP-treated subtypes were PTCL-NOS (51%) and AITL (19%). After matching, similar proportions of patients treated with A + CHP and CHOP received granulocyte colony-stimulating factor (89% vs. 86%, P = .3). Fewer patients treated with A + CHP received subsequent therapy than CHOP overall (20% vs. 30%, P < .001) and specifically with the sALCL subtype (15% vs. 28%, P = .025). Characteristics and management of this real-world PTCL population who were older and had a higher comorbidity burden than that in the ECHELON-2 trial demonstrate the importance of retrospective studies when assessing the impact of new regimens on clinical practice.

Classification and challenges in the histopathological diagnosis of peripheral T-cell lymphomas, emphasis on the WHO-HAEM5 updates.

Mature T-cell lymphomas represent neoplastic expansions of T-cell lymphocytes with a post-thymic derivation. Most of these tumors feature aggressive clinical behavior and challenging histopathological diagnosis and classification. Novel findings in the genomic landscape of T-cell lymphomas are helping to improve the understanding of the biology and the molecular mechanisms that underly its clinical behavior. The most recent WHO-HAEM5 classification of hematolymphoid tumors introduced novel molecular and histopathological findings that will aid in the diagnostic classification of this group of neoplasms. The current review article summarizes the most relevant diagnostic features of peripheral T-cell lymphomas with an emphasis on the updates that are incorporated at the WHO-HAEM5.

Pathological and Molecular Features of Nodal Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are uncommon neoplasms derived from mature T cells or NK cells. PTCLs comprise numerous disease entities, with over 30 distinct entities listed in the latest WHO classification. They predominantly affect adults and elderly people and usually exhibit an aggressive clinical course with poor prognosis. According to their presentation, PTCLs can be divided into nodal, extranodal or cutaneous, and leukemic types. The most frequent primary sites of PTCLs are lymph nodes, with over half of cases showing nodal presentation. Nodal PTCLs include ALK-positive and ALK-negative anaplastic large cell lymphoma; nodal T-cell lymphoma with T follicular helper cell origin; and PTCL, not otherwise specified. Adult T-cell leukemia/lymphoma also frequently affects lymph nodes. Recent pathological and molecular findings in nodal PTCLs have profoundly advanced the identification of tumor signatures and the refinement of the classification. Therefore, the therapies and pathological diagnosis of nodal PTCLs are continually evolving. This paper aims to provide a summary and update of the pathological and molecular features of nodal PTCLs, which will be helpful for diagnostic practice.

Diagnostic utility of the aberrant immunohistochemical expression of CD3 molecules for peripheral T-cell lymphomas

The histological diagnosis of peripheral T-cell lymphomas (PTCLs) is often challenging. Flow cytometry (FCM) sometimes shows the loss of pan-T-cell markers for PTCLs, suggesting the neoplastic nature of these cells. Immunohistochemically, the total loss of pan-T-cell markers has been demonstrated in PTCLs. Furthermore, except for the total loss, the aberrant immunohistochemical expressions of pan-T-cell markers have also been empirically observed in PTCLs, but the details remain unexamined. Therefore, the present study semi-quantitatively evaluated the aberrant expression of cytoplasmic CD3ε (cCD3ε), the most common immunohistochemical pan-T-cell marker, in 91 PTCL cases. The expressions of the other CD3 molecules, CD3δ, CD3γ, and CD3ζ were also examined. Frequencies of the total immunohistochemical loss of CD3 molecules and loss of surface CD3ε (sCD3ε) in FCM were analyzed for comparison. The results showed atypical, aberrant expression patterns for immunohistochemical CD3 molecules: perinuclear, cytoplasmic, membranous, and partial negative. The frequency of each molecule was as follows: cCD3ε 40.7 %, CD3δ 26.4 %, CD3γ 53.8 %, and CD3ζ 54.9 %, especially the latter two showed high frequency in peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and adult T-cell lymphoma/leukemia. Immunohistochemical total loss was less than aberrant expression in all CD3 molecules, with the frequency of cCD3ε being the lowest (6.6 %). The loss of sCD3ε in FCM was observed in 43.3 % of cases, with a similar frequency to the aberrant expression of cCD3ε. In conclusion, the aberrant immunohistochemical expression of cCD3ε was a useful finding as is sCD3ε loss in FCM, but CD3γ and CD3ζ were more useful, facilitating the diagnosis of PTCLs.

Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice.

Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis. We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays. In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners. We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.

Human T-Lymphotropic Virus 1 Related Adult T-Cell Lymphoma/Leukemia Presenting as a Lytic Lesion of the Mandible. The Importance of Serology in Accurately Defining the Entity

<h3>Introduction</h3> Adult T-cell lymphoma/leukemia (ATLL) is a rare T-cell neoplasm pathogenetically caused by human T-lymphotropic virus 1 (HTLV-1). HTLV-1 is the first human retrovirus shown to cause malignant transformation. ATLL is endemic in several regions of the world, most notably Japan, the Caribbean, parts of Africa and Iran. The disease has a long latency period, as individuals are infected by the virus early in life. Most cases of ATLL are diagnosed in adults with a male-to-female ratio of 1.5:1. ATLL most commonly affects the peripheral blood and skin. Oral involvement is extremely rare. <h3>Case Findings</h3> A 61-year-old female presented for evaluation of a large radiolucency involving the right posterior mandible with associated mobile teeth and pain. CT revealed an expansile lytic lesion extending from first premolar to the mandibular angle. Notably, there were two additional destructive lesions identified in the right sinonasal and tympanomastoid areas. <h3>Results</h3> The histopathology of the mandibular mass was that of a lymphoproliferative process. Lesional cells expressed CD25, CD2, CD3, CD4, CD5 and CD43, and did not express CD7, CD20, or PAX5. The Ki-67 proliferative index was 90%. A diagnosis of peripheral T-cell lymphoma was rendered. Serological testing with Western Blot was positive for HTLV-1, further supporting the diagnosis of ATLL. <h3>Conclusion</h3> Four clinical variants of ATLL are identified: acute, lymphomatous, chronic, and smoldering. Acute and lymphomatous are highly aggressive, whereas chronic and smoldering have a prolonged clinical course. Prognosis for ATLL is poor as it is resistant to conventional chemotherapy, with the acute and lymphomatous variants having a median survival of less than 1 year and the chronic and smoldering variants having a median survival of less than 5 years. The diagnosis of ATLL relies on immunohistochemistry supplemented with serology for HTLV-1. Lymphoproliferative processes with this immunoprofile require HTLV-1 serology for definitive classification.

The Combination of Bortezomib with Cyclophosphamide, Epirubicin, Etoposide and Prednisone (BCHEP) Regimen As First-Line Treatment for Untreated Patients with Peripheral T Cell Lymphoma: A Prospective, Single Arm, Phase II Study

Background: Peripheral T-cell lymphoma (PTCL) is a clinically and biologically heterogeneous disease with poor prognosis. The response rate of standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone) is only 50-60%, with a poor long-term survival rate of 10-30%. The addition of etoposide to CHOP increases response rate, but not progression free survival (PFS) or overall survival (OS). Recent study reported that nuclear factor kappa B (NF-κB) pathway plays a critical role in PTCL. Bortezomib, a potent and reversible proteasome inhibitor, can induce tumor cell apoptosis by inhibiting activation of NF-κB pathway and has been recommended as single agent option in relapse/refractory PTCL. We aimed to study the efficacy and safety of bortezomib in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BCHEP) in newly diagnosed PTCL patients for the first time.METHODS: A prospective, single arm, phase 2 study was conducted (NCT04061772). This is an interim analysis. Patients with newly diagnosis of PTCL were treated with up to 6 cycles of BCHEP regimen every 3 weeks. Bortezomib was subcutaneously administered on Days 1 and 8 at a dose of 1.3 mg/m 2 in combination with CHEP， consisting of 100 mg/m 2 etoposide on Days 1 to 3, 750mg/m 2 cyclophosphamide on Day 1, 75mg/m 2 epirubicin on Day 1 and 100mg prednisone on Days 1 to 5. The primary endpoint of the study was ORR including complete response (CR) and partial response (PR). The secondary endpoints included progression free survival (PFS), overall survival (OS) and adverse events (AEs).RESULTS: Between February 2019 and January 2021, a total of twenty-six patients were enrolled. Median age was 57 years (range 37-69) and six (23.1%) were female. Pathological subtypes included ALK-positive anaplastic cell lymphoma (ALCL, n=2), ALK-negative ALCL (n=4), PTCL, not otherwise specified (PTCL-NOS, n=9) and angioimmunoblastic T-cell lymphoma (AITL, n=11). Nineteen patients had stage III/IV disease and eleven had B symptoms, including weight loss in three cases and fever in eight. Ten patients had elevated serum lactate dehydrogenase (LDH), eleven had IPI score higher than 2. All patients had completed BCHEP treatment for at least two cycles and received imaging evaluation. Ten patients received prophylaxis of intrathecal chemotherapy with methotrexate at least once. Three patients received consolidated radiotherapy for metabolic residuals after chemotherapy, while one received autologous hematopoietic stem cell transplantation as consolidation treatment. This study had reached the primary end point at this interim analysis. The ORR was 92.3% (24/26) with a CR rate of 57.7% (15/26). Two patients had progression of disease within two cycles of chemotherapy. After a median follow-up of 16.3 months, twelve patients had disease progression, and six died. Median PFS was 10.9 months and 1-year PFS rate was 65.4%. Median OS was 14.6 months and 1-year OS rate was 88.5%. No patient presented with Grade 5 AE. The most frequent all-grade hematological toxicity was leucopenia (42.3%,11/26), anemia (50%,13/26) and thrombocytopenia (23.1%, 6/26). Other common toxicity included intestinal infection or pneumonia (19.2%, 5/26), Grade 1 peripheral neuropathy (15.4%, 4/26) and nausea (7.7%, 2/26). Dose reduction was performed in eight patients.CONCLUSIONS: Interim results showed that bortezomib in combination with CHEP is associated with high response rate and manageable toxicity in patients with previously untreated PTCL. The BCHEP regimen may serve as a novel first-line treatment option for patients with PTCL. The study is going on to enroll patients and updating results, including the prognostic value of serum inflammatory factors. Larger trials will be necessary to further verify the efficacy of this regimen in treatment naïve PTCL patients and to overcome relapse after remission. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) with Intention for Curative Therapy Incorporating High Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT)

Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) with Intention for Curative Therapy Incorporating High Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT)

The Role of Upfront Hematopoietic Stem Cell Transplantation (HSCT) in Peripheral T-Cell Lymphoma (PTCL) Patients in Complete Remission (CR) with a Special Focus on Nodal PTCL: Report from the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE), a Prospective Multicenter Cohort Study

The Role of Upfront Hematopoietic Stem Cell Transplantation (HSCT) in Peripheral T-Cell Lymphoma (PTCL) Patients in Complete Remission (CR) with a Special Focus on Nodal PTCL: Report from the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE), a Prospective Multicenter Cohort Study

Burden of illness and treatment patterns among patients with peripheral T-cell lymphoma in the US healthcare setting

Objective Limited real-world information exists on the characteristics or treatment patterns of patients with peripheral T-cell lymphoma (PTCL). We reported demographics, treatments and direct healthcare resource utilization (HRU) in a large cohort of US patients newly diagnosed with PTCL. Methods Patients aged ≥18 years with a PTCL diagnosis between January 2011 and December 2016 were identified from the Inovalon MORE2 Registry. Continuous medical/pharmacy enrollment 6-months prior to and ≥1-month after the first PTCL diagnosis was required. The main focus of this study was on newly diagnosed patients receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus other chemotherapy. Results A total 2971 patients with PTCL and chemotherapy information were included in the study; 1706 (57%) received CHOP and 1265 (43%) other chemotherapy. A majority of patients (51.7%) were female; mean (standard deviation) age at index was 61.0 (±16.0), Charlson score was 4.1 (±2.9), and follow-up time was 24.6 (±16.7) months. During the variable follow-up period, HRU was similar for the CHOP and other chemotherapy cohorts; 58.1% and 59.3% had ≥1 all-cause hospitalizations, respectively. The proportion of patients with ≥1 PTCL-related hospitalizations was higher in the CHOP than in the other chemotherapy cohort (40.3% vs. 9.7%, respectively) and mean length of stay was longer (4.6 vs. 3.7 days per patient per month, respectively). Conclusions This retrospective analysis of patients with PTCL revealed high levels of comorbidity and HRU; novel interventions that improve patient outcomes and reduce the HRU burden of PTCL are needed.

Allogeneic Transplant Outcomes for T-Cell Lymphomas: A Single Center Analysis

Introduction T-Cell Lymphoma (TCL) encompasses a wide range of lymphoid neoplasms that make up 10-20% of all non-Hodgkin lymphomas. Due to the heterogeneity of the disease compared with B-cell lymphomas, treatment algorithms vary widely. Autologous and allogeneic hematopoietic cell transplant (allo-HCT) have been utilized both in the frontline setting as a consolidative treatment and in the relapsed/refractory setting. Limited studies have reported that patients undergoing allo-HCT after salvage chemotherapy can achieve five-year overall survival (OS) rates above 60% (Kamarajah et al.). However, there remains a significant risk of relapse and non-relapse mortality in these patients, which has not been fully characterized. In this study, we evaluate outcomes of patients with TCL who have undergone allo-HCT. Methods We performed a retrospective, single center analysis of adult patients who received an allo-HCT with a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), cutaneous T-cell lymphoma (CTCL), anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL) since 2008. Patients with concurrent malignancies were excluded. Baseline characteristics were measured using standard descriptive statistics. The Kaplan-Meier methodology was used to calculate the primary outcome, OS, which was estimated from date of transplant to date of death. Secondary outcomes included progression free survival (PFS), relapse rates, and incidence of acute and chronic graft-versus-host disease (GVHD) after transplant. A log-rank test was used to evaluate the impact of patient level variables on OS. STATA version 13.1 (College Station, TX) was used for analysis. Results We identified a total of 23 patients who met the criteria (Table 1). The majority of patients carried a diagnosis of PTCL-NOS (n=11) followed by AITL (n=8). The median age at transplant was 56 years and most patients were male (74%). The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) score was ≥3 in 52% of patients (n=12) and Karnofosky Performance Status (KPS) at transplant was &amp;lt;90% in 78% (n=18). Most patients had advanced-stage disease at diagnosis and 35% (n=8) had a history of prior autologous HCT. 83% underwent allo-HCT for relapsed/refractory TCL (n=19), while the remaining received it as a consolidative procedure in first response. 61% of patients had residual disease entering transplant (n=14). Reduced intensity conditioning was used in 83% (n=19) of patients while the remaining received a myeloablative regimen. The median OS (Figure 1A) and PFS (Figure 1B) at 5 years was not reached in this cohort; furthermore, 74% of patients were alive one year post-transplant. 17% relapsed with their primary disease (n=4) and in total 9 patients have died since transplant, the majority from transplant related complications. 52% of patients had acute GVHD; similarly, 52% had chronic GVHD. Using the log-rank test, we found no difference in OS by donor type, conditioning intensity, stage at diagnosis, KPS&amp;lt;90%, prior autologous transplant, pre-transplant disease status, International Prognostic Index (IPI)≥3, and indication for transplant. Patients with HCT-CI ≥3 trended towards worse OS (p=0.09). Conclusion In the era of novel agents and cellular therapies, the role of allo-HCT in hematological malignancies must be redefined. While treatment options have expanded significantly in B-cell lymphomas, the same diversity of options is not available in TCLs, especially in the relapsed/refractory setting. We demonstrate here excellent outcomes in a small cohort of patients who mostly underwent allo-HCT for relapsed TCL. Despite several adverse characteristics (low KPS, elevated HCT-CI, advanced-stage disease) post-transplant relapse rates were low and both the 1-year OS and 5-year PFS/OS are encouraging and suggest that this modality of therapy continues to be relevant in the modern era. The apparent plateau in PFS and OS indicates that, even in this poor prognosis group of patients, allo-HCT provides a curative intent option. New strategies to ameliorate transplant-related complications could improve survival further. Disclosures Fenske: Medical College of Wisconsin: Current Employment. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&amp;D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. Hari:Incyte Corporation: Consultancy; Amgen: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; BMS: Consultancy. Shah:Lily: Consultancy, Honoraria; Verastim: Consultancy; TG Therapeutics: Consultancy; Miltenyi Biotec: Honoraria, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Cell Vault: Research Funding.

Health Care Resource Utilization and Costs Among Medicare Beneficiaries Newly Diagnosed With Peripheral T-cell Lymphoma: A Retrospective Claims Analysis

BackgroundThere are limited data on the treatment patterns, health care resource utilization (HRU), survival outcomes, and medical costs among Medicare beneficiaries newly diagnosed with peripheral T-cell lymphoma (PTCL). Patients and MethodsThis was a retrospective analysis of data from the Medicare Fee-For-Service claims database using the 100% sample of the Medicare research identifiable files. Patients identified for analysis were aged ≥ 65 years and had received a PTCL diagnosis between January 2011 and December 2017. Outcomes included patient characteristics, HRU, direct all-cause and PTCL-specific health care costs, treatment patterns, and overall survival. Patients were followed until disenrollment, death, or end of the study period. ResultsOverall, 2551 patients with PTCL were included, among whom 37% had ≥ 1 emergency department visit and 42% had ≥ 1 hospitalization during the pre-index period. During follow-up (median, 2.0 years), 70% of patients were hospitalized at least once (mean length of stay, 1.34 days); 22% advanced to hospice care. A total of 1593 patients received ≥ 1 identifiable treatment regimen post index, of whom 26% received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 3% CHOEP (CHOP plus etoposide), whereas 71% received other regimens. The median overall survival among patients receiving identifiable therapy was 4.6 years. The mean adjusted per-person-per-month all-cause costs among the overall PTCL cohort during follow-up were $5930; the mean disease-related costs were $2384. Costs were driven primarily by hospitalizations (38%) and outpatient services (28%). ConclusionsMedicare beneficiaries newly diagnosed with PTCL have high HRU and cost burden, with no evident standard of care in real-world practice.

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.

Expression of CDK6 and FOXM1 in peripheral T-cell lymphoma and their significance

Objective: To investigate the expression of CDK6 and FOXM1 in peripheral T-cell lymphoma (PTCL), and its correlation with clinicopathologic features and patient prognosis. Methods: The Oncomine was used for data mining and analyzing the expression levels of CDK6 and FOXM1 in PTCL. Immunohistochemistry (IHC) of EnVision method was used to detect the expression of CDK6 and FOXM1 proteins in 166 cases of PTCL diagnosed at Shanxi Provincial Cancer Hospital from January 2016 to December 2018, and 30 cases of lymph node with reactive hyperplasia as control. Results: Among the PTCL patients, 104 were male and 62 were female, aged from 3 to 85 years, with an average age of 53 years. Analyses of the Oncomine 4.5 database showed that mRNA expression of CDK6 and FOXM1 in PTCL tissues was significantly higher than that in normal tissue (P<0.05). IHC staining showed the positive rates of CDK6 and FOXM1 proteins in PTCL tissues were 27.7% (46/166) and 80.7% (134/166), respectively. The expression was mainly present in the nuclei of tumor cells, showing a diffuse, strongly positive pattern. The positive rates of CDK6 and FOXM1 proteins among the 30 cases of lymph-node reactive hyperplasia were 0 (0/30) and 30% (9/30), respectively. The expression of FOXM1 was mainly found in the lymphoid follicle germinal center, and not present in the T-zone cells. CDK6 protein, FOXM1 protein and the co-expression of CDK6 and FOXM1 proteins in PTCL were associated with higher Ann Arbor staging and international prognostication index score (P<0.05), and inversely associated with overall survival (P<0.05). Meanwhile, CDK6 protein expression was positively correlated with FOXM1 protein expression (P<0.05). Conclusions: CDK6 and FOXM1 may be new targets for the diagnosis and treatment of PTCL. The overexpression of CDK6 may lead to enhanced function of the transcription factor FOXM1, while the overexpression of CDK6 and FOXM1 also promotes the development and progression of PTCL.

Economic assessment of diagnostic revision in peripheral T-cell lymphoma.

e20039 Background: Peripheral T-cell lymphoma (PTCL) is a rare disease that is challenging to diagnose. A retrospective claims analysis and parallel electronic health records analysis estimated the rate of PTCL diagnostic revision (DR) either to or from other lymphomas at 29.3%, with significantly higher costs for DR than non-DR patients during follow-up. The current study used data from this analysis to estimate the cost of DR in PTCL to US health plans and quantify the potential impact of reducing DR in this population. Methods: A cost calculator was developed using pharmacy and medical costs for adult patients in the IBM MarketScan Commercial and Medicare Supplemental Databases with a PTCL diagnosis from 01/10-06/17, with or without DR (≥1 medical claim for a non-PTCL lymphoma in the year prior to or after the index PTCL diagnosis). Cost data were incorporated for non-DR, DR to PTCL, and DR from PTCL cohorts, and for the DR period (time from initial PTCL diagnosis to non-PTCL diagnosis or vice versa) and subsequent follow-up period. In the current scenario (based on the analysis of MarketScan data), rates of DR were 29.3%, of which 51.4% were DR to PTCL and 48.6% from PTCL. DR periods were 5.0 and 3.7 months, respectively, over a 1-year time horizon. A ‘new’ scenario was included that assumed a 50% reduction in the rate of DR to and from PTCL, and a 50% reduction in the length of DR period. Results: Total per patient per month (PPPM) costs for adults in a Medicare health plan diagnosed correctly or incorrectly with PTCL were estimated at $13,064 in the current scenario and $12,131 in the new scenario, representing a savings of $933 PPPM assuming a 50% reduction in both the rate of DR and the DR period. Savings were largely derived from reduced costs associated with other outpatient services ($385 PPPM) and inpatient services ($367 PPPM) in the new scenario (Table). In a hypothetical 1 million member Medicare plan, the estimated total plan savings annually in the new scenario would be $906,801, based on an estimated 81 PTCL patients among all plan members. Conclusions: Accurate and timely diagnosis of PTCL is essential to enable appropriate treatment. Interventions that reduce the rate of DR in PTCL are likely to result in potential cost-savings to US health plans. [Table: see text]