Natural Killer Cell Lymphoma Research Articles

Efficacy and safety of PD-1 inhibitor alone or combined with chemotherapy in patients with relapsed or refractory extranodal natural Killer/T cell lymphoma: A retrospective study.

Extranodal natural killer/T cell lymphoma (ENKTL) patients typically face a grim prognosis after relapse or progression following asparaginase-based chemotherapy. Currently, programmed cell death protein-1 (PD-1) immune checkpoint blockade has shown promising efficacy as an optimal regimen for relapsed or refractory ENKTL (rrENKTL) patients. This study retrospectively investigated the efficacy, safety, and factors influencing the survival of 26 rrENKTL patients who underwent monoclonal antibody treatment using PD-1 (Sintilimab or Camrelizumab) alone or combined with chemotherapy from January 2018 to February 2022. The disease control rate was 73.1%, and the objective response rate was 50.0%. 15.4% of the patients achieved complete remission, and 34.6% achieved partial remission (PR). After a median follow-up of 12 (range 3-47) months, the median progression-free survival (PFS) and overall survival (OS) were 6.5 and 13.3months. The 1-year PFS and OS rate were 23.1% and 53.8%. 96.2% of patients experienced at least one adverse event and 26.9% experienced grade 1-2 immune-related adverse events. PD-1 inhibitor improved rrENKTL patient survival, and the AEs were controlled. We also observed that the prognostic index for NK cell lymphoma including Epstein-Barr virus (EBV) (PINK-E) and the nomogram-revised risk indexz for ENKTL patients could help identify a potentially unfavorable prognosis in this era of immunotherapy. More attention should be paid to the presence of EBV after anti-PD-1 immunotherapy, as it more accurately indicates a poor prognosis.

MiR-363 suppresses the tumor growth of natural killer/T-cell lymphoma via the SIRT6/PI3K/AKT axis.

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive tumor of non-Hodgkin's lymphoma. The role of micro ribonucleic acid (RNA) (miR)-363 in NKTCL has not yet been elucidated. The present study aimed to investigate the potential role of miR-363 in NKTCL. The expression of the top five differentially expressed microRNAs (miRNAs) as well as sirtuin 6 (SIRT6) in NK normal cells and its tumor cell lines were explored. The clinical tissues of NKTCL patients were collected and analyzed for expression of miR-363 and SIRT6. In addition, human NK/T-cell lymphoma cells (SNK-6) were transfected into different groups to detect cell proliferation and apoptosis abilities through cell counting kit 8 (CCK-8) experiment and flow cytometry analysis. Western blot assay was employed to examine protein expression. NKTCL nude mice models were constructed by subcutaneous injection of stably transfected SNK-6 cells to validate the mechanism of miR-363 in NKTCL via SIRT6 in vivo. MiR-363 was down-regulated in NKTCL tissues and cell lines. Overexpression of miR-363 inhibited cell proliferation and promoted cell apoptosis. In contrast, SIRT6 was up-regulated in NKTCL and proved to be a downstream target of miR-363. SIRT6 could activate the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Also, miR-363 mimic could suppress the proliferation and induce the apoptosis of NKTCL via the SIRT6/PI3K/AKT axis both in vitro and in vivo. MiR-363 suppresses the SIRT6/PI3K/AKT pathway to restrain cell proliferation and accelerate cell apoptosis during NKTCL progression.

The spectrum of intestinal mature T- and NK-cell neoplasms in a tertiary center in Taiwan with a high frequency of perforation.

Primary intestinal T-cell lymphomas (PITLs) comprise enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), extranodal NK/T-cell lymphoma (ENKTL), anaplastic large cell lymphoma (ALCL), and intestinal T cell lymphoma, NOS (ITCL-NOS). MEITL is composed of monomorphic medium cells expressing CD8 and CD56, with a cytotoxic phenotype. We retrospectively analyzed 77 cases of intestinal T-cell lymphomas, 71 primary and six secondary, at a tertiary center in Taiwan from 2001 to 2021. Perforation occurred in 57 (74%) patients, including 56 (73%) at presentation and one after chemotherapy. The primary cases included MEITL (68%), ENKTL (14%), ITCL-NOS (13%), ALCL (4%), and EATL (1%). The perforation rate was 90%, 70%, and 22% in MEITL, ENKTL, and ITCL-NOS cases, respectively (p<0.0001, Fisher's exact test). Most (75%; n=36) MEITL cases were typical; while seven (15%) had atypical morphology and five (10%) exhibited atypical immunophenotype. The tumor cells of ITCL-NOS were pleomorphic, with various expression of CD8 or CD56. All METIL, ITCL-NOS and ALCL cases were negative for EBER; while all ENKTL cases, either primary or secondary, were positive for cytotoxic granules and EBER. The prognosis of PITL was poor, with a medium survival of 7.0, 3.3, and 3.7 months among patients with MEITL, ENKTL, and ITCL-NOS, respectively. Of the six secondary cases, the primary tumors orginated from nasal ENKTL (n=5) and cutaneous PTCL-NOS (n=1). We showed a wide spectrum of intestinal T-cell lymphomas in Taiwan, with MEITL as the most common PITL, a high rate of perforation, and a wider morphological and immunophenotypic spectrum.

Plasma EBV-DNA and peripheral blood mononuclear cell EBV-DNA have disparate clinical relevance in patients with extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related hematological malignancy. The presence of EBV-DNA in peripheral blood is a widely used ENKTCL tumor marker. However, there is no consensus on the preferred blood specimen type for EBV testing. Furthermore, discordance between EBV-based and imaging-based disease assessments is common, and how to interpret this discordance is important. We retrospectively analyzed the data of ENKTCL patients in the Affiliated Cancer Hospital of Zhengzhou university and Sun Yat-sen University Cancer Center. All EBV-DNA and imaging-based disease assessment data were collected at diagnosis, during treatment, at the end of treatment, and during follow-up. We compared matched plasma EBV-DNA and peripheral blood mononuclear cell (PBMC) EBV-DNA and matched EBV-based and imaging-based assessments to uncover their clinical relevance. A total of 450 patients with adequate data were included, of whom 278 had plasma EBV-DNA data, 250 had PBMC EBV-DNA data, and 78 had matched plasma and PBMC EBV-DNA data. No significant correlations were found between PBMC and plasma EBV-DNA and between PBMC EBV-DNA and imaging-based assessment, but patients with positive PBMC EBV-DNA at diagnosis or intermittently/persistently positive PBMC EBV-DNA during follow-up had poorer survival. In contrast, plasma EBV-DNA strongly correlated with lymphoma status. Detectable pre- and post-treatment plasma EBV-DNA was associated with significantly worse survival. Patients with early-stage disease who had detectable plasma EBV-DNA at the end of treatment shared similar survival to those with advanced-stage disease, even if their imaging-based assessments were negative. For disease relapse monitoring, 78 (55.7%) episodes of relapse were detected by both imaging and plasma EBV-DNA; 58 (41.4%) detected by plasma EBV-DNA earlier than imaging, with a median time of 9.3 (0.3 - 37.8) months; and only 4 (2.9%) detected by plasma EBV-DNA later than imaging. The sensitivities of plasma EBV-DNA, PET/CT, and CT/MRI were 97.1%, 76.8%, and 45.1%, respectively, and their specificities were 91.7%, 84.2%, and 96.7%, respectively. Analysis of EBV kinetic patterns in EBV+/imaging- episodes revealed that relapse occurred only in patients with intermittently/persistently positive plasma EBV-DNA. Persistent plasma EBV+ was also seen in patients after autologous hematopoietic stem cell transplantation. Occasional EBV+ was not associated with relapse. Plasma and PBMC EBV-DNA have different clinical relevance in ENKTCL patients. PBMC EBV-DNA does not correlate with imaging-based disease assessment. PBMC or even whole blood should not be used for response evaluation and relapse monitoring. However, PBMC EBV-DNA still has prognostic value. Plasma EBV-DNA is strongly related to tumor status and is not only a prognosticator at diagnosis and end of treatment, but also a sensitive marker in relapse monitoring compared to PET/CT and CT/MRI. The specificity of plasma EBV-DNA is relatively low, but when EBV-DNA kinetic patterns are considered, it can identify at-risk patients.

A Case of Nasal NK T-Cell Lymphoma Presenting With Persistent Epiphora

Nasal type natural killer/T-cell lymphoma (NNKTL) is a rare and aggressive subtype of non-Hodgkin lymphoma originating from a natural killer cell or γδ T cell infected by the Epstein-Barr virus. It usually invades the aerodigestive tract and can rapidly destroy the paranasal sinus, hard palate, and central nervous system. NNKTL is often mistaken for benign conditions such as chronic hypertrophic rhinosinusitis or mucosal inflammatory change, as endoscopic findings of NNKTL presenting nasal mucosal hypertrophy are similar to endoscopic findings for these abovementioned benign conditions. Here, the authors report the diagnosis and examination of NNKTL in a 58-year-old male patient who visited our clinic for nasal cavity discomfort after he underwent a dacryocystorhinostomy to treat dacryocystitis.

High-dose extended-field radiotherapy plus chemotherapy improved survival in extranodal NK/T-cell lymphoma in a real-life setting: results from the multicenter T-Cell Brazil Project

Extranodal natural-killer/T-cell lymphoma (ENKTL) is a rare and aggressive Epstein-Barr virus related mature T-cell and natural-killer malignancy. Although highly prevalent in South America, few studies covering data from this geographic location have been published. Therefore, this study aims to report clinical characteristics, prognostic factors, and outcomes in a multicenter cohort of ENKTL patients from Brazil. This retrospective, observational and multicenter study included 98 ENKTL patients treated during two decades in Brazil. Data were extracted from the T-Cell Brazil Project database. In our cohort, 59/98 patients (60.2%) were male, with a median age of 50 years. Sixty-two patients (63.3%) had B-symptoms, 26/98 (26.5%) had Eastern Cooperative Oncology Group scale ≥ 2; 16/98 (16.3%) presented extranasal disease and 34.7% (34/98) were advanced-stage (Ann Arbor/Cotswolds III/IV). The median follow-up for the whole cohort was 49 months, with an estimated 2-year overall survival (OS) and progression-free survival (PFS) of 51.1% and 17.7%, respectively. In early-stage disease (IE/IIE), the median OS was 21.8 months for patients treated with concurrent radiotherapy plus chemotherapy (CCRT-VIPD [etoposide/vp-16, ifosfamide, cisplatin and dexamethasone), 16.2 months for sequential chemoradiotherapy (SCRT) followed by asparaginase-based regimens, and 56.7 months for SCRT followed by CHOP-like (cyclophosphamide, doxorrubicin, vincristine and prednisone) treatments, p = 0.211. CCRT was associated with higher rates of early-mortality, hematological toxicity, and mucositis. Median OS was 8.2 months for patients with advanced-stage disease receiving regimens containing asparaginase compared to 3.2 months for anthracycline-based therapy, p = 0.851. Chemo-radiotherapy (CRT) regimens demonstrated better OS (p = 0.001) and PFS (p = 0.007) than chemotherapy alone. Multivariate analysis revealed anemia, relapsed/refractory (R/R) disease and radiotherapy omission as poor outcome predictors for OS. Lymphopenia and radiotherapy omission adversely affected PFS. Concerning progression of disease within 24-months (POD-24), clinical stage III/IV was a poor outcome predictor. In this real-life Brazilian cohort, ENKTL presented dismal outcomes. Radiation therapy was an independent factor for increased OS and PFS, but CCRT regimens were associated with higher toxicities. Polychemotherapy based on anti-multi drug resistant agents was not associated with survival benefit in either early or advanced-stage disease in our patient cohort.

Differential diagnosis and identification of prognostic markers for peripheral T-cell lymphoma subtypes based on flow cytometry immunophenotype profiles.

We compared the differential expression of 15 markers in PTCL (Peripheral T-cell lymphoma) subtypes and T-CUS (T-cell clones of uncertain significance), and summarized the specific immunophenotype profiles of each subtype and its impact on prognosis. PD-1 and CD10 are diagnostic markers for AITL (angioimmunoblastic T-cell lymphoma). To avoid confusion with T-CUS of benign clones, it is recommended to define AITL as bounded by PD-1+%>38.01 and/or CD10+%>7.46. T cell-derived ENKTL-N (extranodal NKT cell lymphoma) specifically expresses CD56. ALCL (anaplastic large cell lymphoma) characteristically expresses CD30 and HLA-DR. PTCL-NOS (peripheral T-cell lymphoma unspecified) still lacks a relatively specific phenotype and is prone to loss of basic lineage markers CD3, CD5, and CD7. The determination of T-CUS can be verified by the overall assessment of the bone marrow and a certain period of follow-up. The clustering results showed that the expression of 8 specific markers was significantly different among the 5 groups, suggesting that a combination of related markers can be analyzed in the identification of PTCLs subtypes. The study explores the advantages of TRBC1 combined with CD45RA/CD45RO in detecting T cell clonality, which can efficiently and sensitively analyze multiple target T cell populations at the same time. The sensitivity of PB to replace BM to monitor the tumor burden or MRD (minimal residual disease) of PTCLs is as high as 85.71%, which can relieve the huge pressure of clinical sampling and improve patient compliance. CD7, CD38, and Ki-67 are prognostic indicators for AITL. CD3 and CD8 on PTCL-NOS, and CD56 and HLA-DR on ENKTL-N have prognostic role. This study supports and validates the current classification of PTCL subtypes and establishes an immunophenotypic profile that can be used for precise diagnosis. The important clinical value of PTCLs immunophenotype in routine classification diagnosis, clonality confirmation, prognosis prediction, and treatment target selection was emphasized.

Methyltransferase-like 3 enhances cell proliferation and cisplatin resistance in natural killer/T-cell lymphoma through promoting N6-methyladenosine modification and the stability of staphylococcal nuclease and Tudor domain-containing protein 1 mRNA.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is a typical class of non-Hodgkin's lymphoma, which is quite malignant because of its high resistance to chemotherapy. N6-methyladenosine (m6A) modification, a prevalent modification of eukaryotic RNA, was emerging as an important regulatory mechanism in progression of various tumors. Here, we demonstrated that methyltransferase-like 3 (METTL3), an RNA methyltransferase, was obviously upregulated in human NKTCL cell lines (NK-92, YTS, SNT-8, and SNK-6) compared with normal NK cells. Knockdown of METTL3 noticeably repressed proliferation and facilitated apoptosis in SNT-8 cells, whereas overexpression of METTL3 showed opposite results in SNK-6 cells. In the mechanism exploration, we found that METTL3 stimulated the m6A modification of staphylococcal nuclease and Tudor domain-containing protein 1 (SND1) mRNA, recruited YTH m6A RNA binding protein 1 to recognize the m6A site, thereby enhancing its mRNA stability. Rescue experiments demonstrated that METTL3 significantly prohibited NKTCL cell chemotherapy sensitivity to cisplatin (DDP) through regulating SND1 expression. Furthermore, knockdown of SND1 suppressed tumor growth and reduced DDP resistance in vivo . Taken together, our findings uncovered the role of METTL3 in the regulation of chemotherapy resistance in NKTCL oncogenesis.

Exosomal and Soluble Programed Death-Ligand 1 (PD-L1) Predicts Responses to Pembrolizumab in Patients with Extranodal NK/T-Cell Lymphoma.

Soluble and exosomal programed death-ligand 1 (PD-L1) can be upregulated in extranodal natural killer/T-cell lymphoma (ENKTL). However, its clinical role in predicting outcomes after pembrolizumab treatment has yet to be studied in ENKTL patients. We investigated the association between pre-treatment soluble and exosomal PD-L1 and outcomes in ENKTL patients who received pembrolizumab as a salvage treatment. The production of soluble and exosomal PD-L1 was analyzed in vitro using an etoposide-resistant ENKTL cell line. Serum levels of soluble and exosomal PD-L1 were measured in patients with relapsed or refractory ENKTL prior to treatment with pembrolizumab. Relapsed or refractory ENKTL patients who received pembrolizumab as a salvage therapy between May 2017 and March 2021 were analyzed at our institute. Soluble and exosomal PD-L1 was significantly higher in serum samples of relapsed or refractory ENKTL patients compared with healthy controls, which is consistent with increased production of soluble and exosomal PD-L1 in an etoposide-resistant ENKTL cell line (SNK6R), which was found to show increased expression of soluble and exosomal PD-L1. Serum-soluble PD-L1 levels were significantly correlated with exosomal PD-L1, and were significantly lower in responders to pembrolizumab compared with non-responders. Longitudinal analysis after pembrolizumab also revealed a relationship between PD-L1 levels and responses. Treatment outcomes and overall survival after pembrolizumab were significantly better in patients with low soluble and exosomal PD-L1. In conclusion, soluble and exosomal PD-L1 can predict responses to pembrolizumab in ENKTL patients, making it a useful pre-treatment biomarker for ENKTL patients receiving pembrolizumab.

Sintilimab Plus P-Gemox (Pegaspargase, Gemcitabine and Oxaliplatin) Regimen for Newly-Diagnosed Advanced, Extranodal Natural Killer/T Cell Lymphoma, Nasal Type: A Multicenter, Phase 2 Cohort of the Open-Label Spirit Study

Background: Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma with a high incidence in Asian and south American populations. Pegaspargase, oxaliplatin plus gemcitabine are considered as the standard first-line therapy for advanced ENKTL, but the prognosis remains poor. In ENKTL, most patients overexpress PD-L1 protein, which is associated with a poor prognosis, and suggests that ENKTL should be sensitive to PD-1/PD-L1 axis blockade. In a phase II trial, the PD-1 mAb sintilimab showed promising efficacy as monotherapy in r/r ENKTL (Tao, Signal Transduct Target Ther, 2022). Additionally, we previously conducted a retrospective study of PD-1 mAb combined P-GEMOX for the treatment of advanced ENKTL patients (pts), which showing favorable antitumor activity with a non-overlapping toxicity profile (Cai, Signal Transduct Target Ther, 2020). Therefore, we conducted this prospective phase II trial to evaluate the efficacy and safety of sintilimab plus P-GEMOX as first-line therapy in pts with advanced ENKTL. Methods: This is a prospective, single-arm, open-label, multi-center, phase II clinical trial. Adult treatment-naive pts with histologically confirmed ENKTL nasal type had at least one measurable or evaluable lesion were enrolled to receive six cycles of sintilimab 200 mg plus pegaspargase 2000 U/m2 (day 1), gemcitabine 1g/m2 (days 1 and 8), and oxaliplatin 130 mg/m2 (day 1) (induction phase), followed by sintilimab 200 mg maintenance every 3 weeks (maintenance phase) for up to 2 years or until disease progression or unacceptable toxicities. Involved field radiotherapy (IFRT) is allowed for residual lesions after induction therapy. The primary endpoint was the proportion of pts who achieved complete response rate (CR) in response evaluable population. Secondary endpoints included overall response rate (ORR), response at the end of induction therapy (EoT), duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Treatment related adverse events (TRAE) were rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 5.0. This trial is registered with ClinicalTrials.gov, number NCT04127227. Results: From November 2019 to April 2022, 27 eligible pts were enrolled. Median age was 38 years (range, 25-72), 19 (70.4%) were male, 14 (22.2%) pts had PINK-E score ≥ 3 points (Table 1). Of 24 response evaluable pts, the ORR was 100% (24/24), and the CR rate reached 87.5% (21/24, figure 1, 2). At data cut-off, 18 pts completed 6 cycles of induction therapy and entered the maintenance phase, 1 patient experienced disease progression after 4 cycles of the treatment, and the EoT CR rate of induction phase is 13/19 (68.4%). The median time to response (TTR) was 1.6 (1.4-3.8) months. During the maintenance phase, 5 more pts achieved CR and at the time of analysis, The median follow-up time was 16.7 (3.0-32.0) months. The mOS and mPFS were not reached, estimated 1-year OS rate was 100%, 1-year PFS rate was 95%.All (100%) pts experienced TRAE at any grade. The most common toxicity was neutropenia (96.3%) and the majority of TRAEs were reported during the first two cycles of the induction therapy. Grade 3-4 TRAE reported in ≥5% of pts included neutropenia (48.1%), triglycerides increased (37.0%), leukopenia (29.5%), anemia (25.9%), thrombocytopenia (25.9%), albumin decreased (7.4%), and lipase increased (7.4%). Immune-related AEs (irAEs) were reported in 16 pts, including a grade 3 hypothyroidism which led to permanent treatment discontinuation in 1 (3.7%) patient, and the remaining irAEs were all grade 1-2. All TRAEs were manageable and only 1 patient discontinued treatment due to TRAEs during maintenance phase. Conclusions: Combination of sintilimab plus P-GEMOX Regimen yielded promising clinical activity with a manageable safety profile, supporting immunochemotherapy as a new first-line treatment option for pts with advanced ENKTL. Treatment and follow-up are currently ongoing and further studies have been initiated to explore biomarkers to better predict response and long-term survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Comprehensive, Multiomics Analysis of Natural Killer-Cell Malignancies

Natural killer/T cell lymphoma (NKTCL) and aggressive NK cell leukemia (ANKL) are rare mature NK cell malignancies which show a geographic predilection for Asia and Central/South America and are strongly associated with EBV infection. Despite recent advances in chemotherapeutical agents, the prognosis (especially for ANKL) remain poor. On the contrary, NK cell proliferations of a more indolent nature also exist. NK-large granular lymphocytic leukemia (NK-LGLL) is a disorder of NK cells with indolent clinical manifestation. Additionally, chronic active Epstein-Barr virus infection (CAEBV) affecting NK cells can have variable presentation, between indolent and aggressive. Due to their rarity, a comprehensive understanding of the events differentiating the wide spectrum of NK malignancies remains elusive. Here, we use a multi-omics approach to investigate the genetic differences underlying the different clinical manifestations of NK malignancies. To discover the pathogenesis behind indolent and aggressive NK malignancies, we studied whole-genome/exome sequencing and whole transcriptome sequencing (RNA-seq) data from over 200 NK-cases collected from 11 previous publications. We investigated driver genes from 145 WES and WGS samples, and transcriptomes from 91 samples. Single-cell RNA-seq analysis was performed to identify and characterize distinct NK-cell subsets. We used pooled CRISPR screens with a single-cell RNA sequencing readout (CROP-seq) to investigate the effect of knocking out the most frequently mutated genes on the transcriptome of NKTCL cells under the effect of commonly used chemotherapeutic agents. We also aim to construct a comprehensive host-EBV interaction map to elucidate the role of EBV in the pathogenesis of NK malignancies We validated previously found driver genes STAT3 and DDX3X as the most frequently mutated genes in NK malignancies, being mutated in 15% and 14% of samples, respectively. STAT3 mutations were found only in NKTCL and ANKL samples. Additionally, our combinatorial analysis allowed for identification of previously unappreciated putative driver genes, MSN and HLA-A, which were mutated in 8% and 4% of samples, respectively. We also discovered associations between important genes, such as significant co-occurrence of mutations in STAT3 and novel driver gene MSN (p <0.05). Samples originating from different diseases were intermingled in non-negative matrix factorization (NMF) analyses, highlighting the effect of mutational profile, rather than disease type, on sample clustering. Using RNA-seq, differentially expressed genes (Q-value < 0.01) were identified between ANKL, NKTCL and healthy samples. Gene set enrichment analysis revealed differential enrichment and depletion of biological processes in ANKL and NKTCL. Upregulation of chemokine signalling and macrophage-associated processes in NKTCL reflected the inflammatory microenvironment of the disease. Of 17 putative driver genes, CRISPR knockout of STAT3 and TP53 led to most transcriptional changes. Knockout of STAT3 caused upregulation of HLA I and II molecules and downregulation of IL10 signaling, thus promoting tumor cell immune evasion. Our preliminary results indicate that NK malignancies are, contrary to previous knowledge, a spectrum of manifestations rather than distinct diseases. Our results concerning the heterogeneous genetic landscape of NK malignancies can lead to better and faster diagnosis as well as improved treatment stratification in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival of Patients with Extranodal NK-Cell Lymphoma in the United States

Background: Extranodal NK/T-cell lymphoma (ENKL) is an EBV-associated malignancy of rare occurrence in Western countries. There is limited data on the survival of patients with ENKL in the United States (US). Objective: To describe survival of US patients with ENKL, to inquire if the long-term survival has improved in the most recent years, and to evaluate factors possibly associated with survival among ENKL patients. Design/Method: We used the National Cancer Institute' Surveillance Epidemiology and End Results (SEER-18) database to determine the survival of patients with ENKL. Inclusion criteria was the diagnosis of ENKL occurring at any age, as first malignant neoplasm diagnosed between 2000 and 2018. Follow-up data was available to the end of 2020. Cases were divided in two "eras", 2000-2009 and 2010-2018, with the latter being expected to reflect the use of asparaginase-base chemotherapy regimens. Survival was estimated using the method of Kaplan-Meier. The impact of era, age, race, gender, and stage on survival were accessed utilizing multivariate analysis. Results: A total of 967 cases were included. Median age of patients was 52 years, 267 (28%) were < 40 at time of diagnosis, 630 (65%) were male and 599 (62%) had early stage disease. There were 430 patients in the 2000-2009 era and 537 patients in the 2010-2018 era. A high proportion of patients was Hispanic (367, 38%) or Asian/Pacific Islander (215, 22%). The median survival for patients < 40 years was 30 months (95% C.I. 0-60.4), and 19 months for patients ≥ 40 (95% C.I. 11.8-26.1, P=0.047) (Figure). Median survival was better for patients diagnosed in the 2010-2018 era (35 months, 95% C.I. 21-48.9 vs. 13 months, 95% C.I. 8.2-17.7, P=0.003). For patients < 40, median survival was 16 months in 2000-2009 and 61 months in 2010-2018 (P=n.s.). For patients ≥ 40 years, median survival improved from 12 to 33 months respectively (P=0.003). Survival improved for those with limited disease (median n.r. vs. 31 months, P< 0.0001), but not for those with advanced stage (6 months in both eras, P=0.3). In multivariable analysis, diagnosis of ENKL in the 2010-2018 era (HR=0.8, 95% C.I. 0.65-0.91, P=0.003), age ≥ 40 (HR=1.2, 95% C.I. 1.0-1.4, P=0.036), and early stage (HR=0.54, 95% C.I. 0.3-0.7, P<0.01) were associated with survival. Conclusion: Survival improved for patients with ENKL in the US particularly for patients with localized disease. There is urgent need for different treatment strategies for ENKL patients, especially for those with advanced disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes, Prognostic Factors and Therapeutic Management in Extranodal Natural-Killer/T-Cell Lymphoma, Nasal-Type (ENKTL-NT) - Results of the Multicenter T-Cell Brazil Project

Introduction: Extranodal natural-killer/T-cell lymphoma, nasal-type (ENKTL-NT) is an aggressive, angiocentric, and extensively necrotic malignancy, universally associated with Epstein-Barr virus (EBV) infection. Although highly prevalent in South America, few studies involving cohorts from this region have been published. Brazil is the largest and most populous country in South America, but Brazilian data on ENKTL-NT are extremely scare. In order to fill this gap, the current study aims to describe clinical and laboratory characteristics, assess clinical outcomes, determine predictors of survival and compare responses between different therapeutic modalities applied in a multicenter cohort of Brazilian patients with ENKTL-NT. Methods: This is a retrospective, observational and multicenter study, involving 98 patients with ENKTL-NT diagnosed and treated at 20 different Brazilian institutions between January 2000 and December 2021. Endpoints included overall response rate (ORR), overall survival (OS) and progression-free survival (PFS). Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The results were presented in hazard ratio (HR) and 95% confidence interval (95% CI) and a p-value ≤ 0.05 was considered statistically significant. Results: The median age was 50 years (IqR 40-58) and 60.2% (59/98) were male. Sixty-three percent (62/98) had B-symptoms, 26.5% (26/98) had ECOG ≥ 2, 16.3% (16/98) had extranasal disease, 34.7% had advanced-stage III/IV, and 30.2% (29/98) had high-risk PINK score [Table 1A]. Table 1B summarizes the main therapeutic modalities, responses and associated adverse event profile among the 89/98 patients undergoing up-front treatment. With a median follow-up of 49.0 months (95% CI: 35.8-62.3), the estimated 2-year OS and PFS were 51.1% (95% CI: 40.4-61.6) and 17.7% (95% CI: 4.5-30.8), respectively. Among early-stage disease (IE/IIE) patients, the estimated 2-year OS were 81.3% (95% CI: 64.8-97.7) for SCRT (sequential chemoradiotherapy) followed by CHOP-like, 53.2% (95% CI: 29.3-77.1) for CCRT (concurrent chemoradiotherapy) followed by VIPD, and 50.5% (95% CI:21.4-79.5) for SCRT followed by asparaginase-based regimens, p=0.221 [Figure 1B]. CCRT-VIPD was associated with higher early-mortality (p=0.034), and higher rates of neutropenia (p=0.075), febrile neutropenia (p=0.043) and mucositis (p<0.001) [Table 1B]. Among advanced-stage (III/IV) disease, the estimated 2-year OS were 37.0% (95% CI: 8.9-65.0) for asparaginase-based regimens and 33.0% (95% CI: 1.9-68.5) for anthracycline-based regimens, p=0.851 [Figure 1C]. Chemoradiotherapy (CRT) was associated with benefit for OS (p=0.001) and PFS (p=0.007) compared to chemotherapy alone [Figure 1D and 1E]. In multivariate analysis, anemia (HR 2.052, p=0.038), lymphopenia [HR 3.600, p=0.012], advanced- stage disease (III/IV) [HR 3.101, p=0.007], bone marrow infiltration [HR 5.406, p=0.034] and omission of RT in up-front therapy [HR 2.791, p=0.023] were independent factors associated with decreased survival. Conclusion: High-dose EF-RT proved to be the cornerstone for the treatment of early-stage ENKTL-NT, and omission of this therapeutic modality was associated with decreased OS and PFS in Brazilian patients. In our real-life study, CCRT-VIPD regimen was poorly tolerated, and surprinsingly protocols based on anti-MDR agents were not associated with increased survival either in early- or advanced-stage disease. We also found that anemia, lymphopenia, advanced-stage (III/IV) and bone marrow involvement were independent predictors associated with poor clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cutaneous/ Subcutaneous Involvement - an Immuneprivileged Site Associated with Poor Outcomes in Systemic Peripheral T/ NK Cell Lymphoma.

Introduction Patients (pts) with systemic peripheral T/NK-cell lymphomas can have cutaneous involvement and their outcomes data are limited in the modern era. We aimed to retrospectively analyse pts who had T/NK-cell lymphomas with cutaneous involvement - PTCL-NOS or extranodal NK/T-cell lymphoma (ENKTL). We excluded cases if they ever had diagnosis of any Primary cutaneous T-cell lymphomas. Methods We conducted a retrospective study of pts with a histopathological diagnosis of T/NK-cell lymphoma established between 2002 and 2022 and identified from the Lymphoma Outcome Database at our center. Pts with a specific diagnosis of PTCL-NOS and ENKTL according to the WHO classification were included if they had biopsy proven involvement of skin. These pts were retrospectively assessed for demographic, clinical, laboratory data, pathology variables, response to treatment and survival outcomes. Fisher's exact test or Chi-square test was used to evaluate the association between two categorical variables. Kaplan-Meier method was used to estimate the time-to-event endpoints including progression-free survival (PFS) and overall survival (OS). Patients without progression or death were censored at the last follow-up date. Appropriate approval was gained from our institution's IRB. RESULTS A total of 356 pts with cutaneous involvement by T/NK-cell lymphoma were analyzed and on further review 45 pts were found to meet the diagnosis of PTCL-NOS ( n=29) or ENKTL ( n=16) with histologically proven cutaneous/subcutaneous involvement according to WHO guidelines. The median follow-up time was 14.5 months (range: 1.84-128.6 months). Twenty-three (51%) pts were men and 22 (49%) women. Median age at diagnosis was 56 years (range, 46-66), with 60% pts less than 60 years old. Thirty (70%) pts were diagnosed as having stage IV disease per Ann Arbor classification. Seven (28%) pts had involvement of an extranodal site other than skin. ECOG PS was 0 in 75% of evaluable pts. Among PTCL-NOS pts, 14/23 (48%) neoplasms were CD4+, 5 (17%) were CD8+; 5 were TCR-gamma+ and 6 pts were TCR-beta+. Of the samples evaluated, CD30 was expressed in 14/28 (50%) cases of PTCL-NOS and 6/12 (50%) of ENKTCL. Bone Marrow involvement was present in 10% of pts. There was no standard frontline systemic therapy approach in this cohort. CHOP-based therapy was used in 15/29 (52%) pts with PTCL-NOS; 8/16 (50%) pts with ENKTL while received asparaginase base therapy. No pts received frontline radiation in the advanced stage setting. Among the 33 evaluable pts in the cohort, the rate of OR to the 1st line treatment was 57.6% (95% CI: 39.2 ~ 74.5%). The rate of CR to the 1st line treatment was 54.5% (95% CI: 36.4 ~ 71.9%). Among PTCL-NOS pts, 12/20 (60%) achieved CR, whereas in ENKTL pts 6/13 (46%) achieved CR to frontline treatment. Fifteen (30%) pts in the cohort had primary refractory disease. Seven pts with PTCL NOS had limited cutaneous/ subcutaneous involvement and received only skin directed therapy without systemic therapy. This pt subset had no evidence of progression, a behavior consistent with primary cutaneous PTCL-NOS. Advanced stage disease was the only variable that had an association with response ( p=0.004). In the whole cohort, the 2=year PFS was 28% with a median PFS of 9.07 (95% CI 4.5-21.98) months. For pts with stage I/II disease, the 2-year PFS was 71% ( 95%CI 0.45 - 1 ) with a median PFS of 177.4 months (95%CI -11.79 - NA). For pts with stage III/ IV disease, the 2-year PFS was 14% (95%CI 0.05 - 0.38 ) with a median PFS of 4.8 months (95%CI 3.19 - 11.99)(p=0.0018). In the whole cohort, the 2-year OS was 47% with median OS of 22.67 ( 95%CI 13.53 - NA) months. For pts with stage I/II disease, the median OS was 177.37 months and for pts with stage III/ IV disease, the median OS was 13.63 months (95%CI 11.99 - NA) (p=0.0018 ) CONCLUSION: Cutaneous / subcutaneous involvement is an uncommon occurrence in pts with T/ NK cell lymphoma and is currently not incorporated in any prognostic scoring system. Systemic T/NK- lymphomas with cutaneous involvement have poor prognosis in our series and underscore the importance of considering skin biopsy in pts presenting with suspicious lesions. We hypothesize that the cutaneous/ subcutaneous tumor microenvironment creates an immune privileged site for chemo-refractoriness. A better understanding incorporating a combined modality approach and novel therapies are needed to improve the outcomes for these pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim PET-CT Scan to Improve Risk Modeling for Patients with Extranodal Natural Killer/T-Cell Lymphoma Treated with Non-Anthracycline Containing L-Asparaginase Based Regimen

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare and distinct subtype of non-Hodgkin lymphoma characterized by predominant involvement of the nasal cavity and nasopharynx and the application of L-asparaginase (L-asp) based non-anthracycline containing induction therapy has improved clinical outcomes of the patients. Currently, prognostic index of natural killer lymphoma plus Epstein-Barr virus is widely used to evaluate prognosis of patients with ENKTL. In this study, we evaluated the value of interim fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for the better prognostication of ENKTL patients. Methods Patients with histologic diagnosis of ENKTL from May 2009 to May 2020 treated with L-asp based non-anthracycline containing induction regimen and who had interim PET-CT analysis at Asan Medical Center, Seoul, Korea were included. Response was assessed using the Deauville 5-point scales (DS). Progression-free survival (PFS) was defined as time from the induction therapy to disease progression or any cause of death, and overall survival (OS) was defined as time from the induction therapy to any cause of death. Survival curves were estimated by Kaplan-Meier method and compared using log-rank test. Key baseline characteristics and candidate prognostic factors including age, Eastern Cooperative Oncology Group performance status, Epstein-Barr virus (EBV) detection from blood at baseline, distant lymph node (LN) involvement, initial stage, location of disease (nasal vs. non-nasal), and serum lactate dehydrogenase level were included in the univariate analysis. In the multivariate analysis, variables exhibiting a potential association with survival (p < 0.05) in the univariate analysis were included. Results A total of 58 patients were included in the analysis. Median age was 55 years (range, 19-80), 34 patients (58.6%) were male, 19 patients (32.8%) had non-nasal disease and 43 patients (74.1%) had stage 4 disease at diagnosis. Among 43 patients with stage 4 disease, 19 patients (44.2%) received VIDL regimen consisting of etoposide, ifosfamide, dexamethasone and L-asp while 23 patients (55.8%) received SMILE regimen consisting of ifosfamide, etoposide, methotrexate, dexamethasone and L-asp as induction treatment. All 15 patients with stage 1 or 2 disease received combined modality treatment with cisplatin-based concurrent chemoradiation and L-asp containing chemotherapy. With median follow-up duration of 52.7 months (95% confidence interval [CI] 37.7-81.3), median PFS and OS were 9.9 months (95% CI 4.8-28.6) and 25.6 months (95% CI 13.3-not applicable), respectively. Thirty-two patients (55.2%) had interim PET-CT DS (iDS) of 4-5. Patients with iDS 4-5 showed significantly worse outcomes in terms of both PFS and OS compared to patients with iDS 1-3 with hazards ratio (HR) of 2.13 (95% CI 1.11-4.06, p = 0.019) and 2.51 (95% CI 1.19-5.33, p = 0.013), respectively. The 2-years PFS rates for patients with iDS 4-5 and iDS 1-3 were 27.3% (95% CI 15.3-44.8) and 49.0% (95% CI 32.9-69.3), respectively. The 2-years OS rates were 35.6% (95% CI 22.1-54.0) and 64.3% (95% CI 48.0-86.2), respectively. In the univariate analysis, age, EBV detection from blood at baseline, initial stage, location of disease (nasal vs. non-nasal), distant LN involvement and iDS showed potential association (p < 0.05) with OS. In multivariate analysis, iDS were independently associated with OS with HR of 3.96 (iDS 4-5 vs. 1-3, 95% CI 1.76-8.94, p < 0.001), along with location of disease with HR of 4.03 (non-nasal vs. nasal, 95% CI 1.83-8.91, p < 0.001). Conclusion The interim PET-CT response based on the DS is useful for predicting OS of patients with ENKTL in the era of non-anthracycline-based L-asp containing induction therapy.

Allogeneic Hematopoietic Stem Cell Transplantation Achieves Long-Term Survival in Extranodal Natural Killer/T-Cell Lymphoma: A Retrospective Analysis of the EBMT Lymphoma Working Party

Introduction Extranodal NK/T-cell lymphomas (ENKTL) represent aggressive lymphoid malignancies predominantly occurring in Asia and South America being rare in the Western world. Stage I/II patients are treated with asparaginase-containing (ASP) chemotherapy and local radiotherapy. For advanced stages III/IV and patients (pts) with relapsed/refractory disease current guidelines recommend ASP-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). These recommendations, however, are mostly based on small series of patients (<20 pts) partly reported decades ago. The largest series reported by CIBMTR comprised 82 pts, most of them still having been treated with anthracycline-containing regimens before HSCT (Kanate AS Br J Haematol 2018,182, 909). Methods We conducted a retrospective analysis of EBMT registry data and data from registries of cooperating Asian centers in China and South Korea. The following inclusion criteria were applied: pts with confirmed ENKTL, age ≥18 years, first HSCT between 2013 and 2020, previous autologous stem cell transplantation allowed. Outcome data were calculated from the day of HSCT until the respective event. Results In total, 137 pts were identified with a median age of 43.4 years (95% CI: 18.3 - 67.7 years) at the time of HSCT; 68.6% were male. Median follow-up was 4.8 years (95% CI: 3.7 - 5.9 years). Recipients were predominantly European (99 pts), 38 pts were of Asian ethnicity. High PINK scores at diagnosis were reported for 67.8%; 32.2% had low/intermediate PINK scores. Two or more treatment lines had been applied in 79.5% of cases prior to HSCT. Importantly, 73.5% of our pts had received ASP-containing regimens prior to HSCT. Autologous transplantation prior to HSCT had been performed in 21.9% of cases. Remission status at the time of HSCT was complete remission (CR) in 53.7%, partial remission (PR) in 26.5%, and chemorefractory/progressive disease in 12.5%. Reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) were used in 46.7% and 53.3% of cases, respectively. The 1-year and 3-year progression-free survival (PFS) rate for all pts on the study was 55.5% (95% CI: 46.6 - 63.6%) and 48.6% (95% CI: 39.7 - 57%), respectively. The corresponding overall survival (OS) rates were 66.6% (95% CI: 58 - 73.9%) and 55.6% (95% CI: 46.5 - 63.7%), respectively. The cumulative incidence of non-relapse mortality (NRM) at 1 year and 3 years was 15.3% (95% CI: 9.7 - 22.1%) and 17.8% (95% CI: 11.8 - 24.9%) with a relapse incidence (RI) of 29.1% (95% CI: 21.6 - 37.1%) and 33.5% (95% CI: 25.4 - 41.8%) at 1 year and 3 years, respectively. Of note, no relapse was noted beyond 3 years after HSCT. In univariate analyses, ethnicity (European vs. Asian) did not significantly influence PFS (p=0.57), OS (p=0.57), NRM (p=0.79) or RI (p=0.65). Among patients receiving RIC vs. MAC regimens, the relapse incidence (p=0.29) and NRM (p=0.20) were not significantly different. For haploidentical (n=27 pts) vs. HLA-matched related and unrelated donors, no significant differences in terms of PFS (39% (95% CI: 20.2 - 57.4%) vs. 51% (95% CI: 40.9 - 60.2%)), OS (52.6% (95% CI: 31.5 - 70%) vs. 56.1% (95% CI: 46 - 65.1%)), NRM (20.3 (95% CI: 7.1 - 38.3%) vs. 17.3% (95% CI: 10.7 - 25.2%)) and RI (40.7% (95% CI: 21 - 59.6%) vs. 31.7% (95% CI: 22.9 - 40.8%)) at 3 years were observed. For the group of ASP-pretreated patients, 3 year PFS, OS, RI and NRM were 42.4% (95% CI: 32.1 - 52.2%), 52.2% (95% CI: 41.5 - 61.8%), 39.6% (29.5 - 49.5%) and 18.1% (95% CI: 11 - 26.6%), respectively. PD-1 treatment prior to HSCT was applied in 13 patients; these pts did not show significant differences in PFS or OS as compared to all other pts. We also did not observe an increased risk for NRM or acute/chronic GvHD in these pts. Conclusions In a large cohort of Asian and European pts, we demonstrate that HSCT is an effective treatment approach for advanced ENKTL with almost half of the pts achieving long-term survival. These results obtained with the majority of pts having been treated with state-of-the-art ASP-containing therapy prior to transplant compare favorably to previous analyses and show that HSCT is the preferred option for younger pts with ENKTL. PD-1 antibodies given prior to HSCT may help to bring more pts to HSCT without negatively influencing treatment outcomes or GvHD.

Therapeutic Repurposing of Brincidofovir in Natural Killer/T-Cell Lymphoma Reveals Potent Induction of Replication Stress, Sting Pathway Activation and Immunogenic Cell Death

Introduction Natural killer/T-cell lymphoma (NKTCL) is an aggressive subtype of non-Hodgkin lymphoma associated with Epstein-Barr virus (EBV) infection. Brincidofovir (BCV), a lipid conjugated form of cidofovir, is a biologically active acyclic nucleoside phosphonate known for both antiviral and antiproliferative properties. Methods We investigated BCV in a panel of NKTCL cell lines (n=11) and mouse xenograft models. The mechanism of action was examined using bulk and single cell RNA sequencing (10X Chromium 3' Gene Expression Profiling), and validated in orthogonal assays. Results BCV evoked a dose- and time-dependent inhibition of cell viability in all NKTCL cell lines, independent of EBV presence. Exquisite sensitivity was observed in 4 cell lines KAI-3, NK-S1, NK-92 and KHYG-1 (IC50 range, 36.0 to 303.6 ng/ml), accompanied by increase in sub-G1 fraction and S-phase arrest on cell cycle analyses. Bulk RNA sequencing of BCV-treated cell lines (KAI-3 and NK-S1) revealed pervasive downregulation of MYC target pathways, along with upregulation of immune-related and DNA repair pathways. Single cell RNA sequencing revealed distinct temporal cell states evoked by BCV. In KAI-3 cells, a significant shift in transcriptomic cell states occurred upon BCV treatment for 48h, with appearance of cell clusters enriched for type I interferon and cytokine signaling pathways, as well as activation of p53 and apoptosis pathways. Cell cycle and DNA repair pathways were also evident. At 72h post-BCV treatment, type II interferon signaling and endoplasmic reticulum stress response pathways were prominent. Similarly in NK-S1 cells, cell clusters enriched for immune signals, including interleukin-18 and cytokine pathways emerged, as did cell cycle, DNA repair, and apoptosis pathways. Western blot demonstrated increase in replication stress markers (p-CHK1 S317 and S345, RRM2, p-RPA2 S33), p-H2AX (DNA double strand break) and p-TBK1 (STING pathway activation). In keeping with this result, BCV triggered micronuclei formation, DNA fragmentation, and cytoplasmic DNA release. Gene expression levels of type I (IFNA, IFNB1) and II (IFNY) interferons and cytokines (CCL5, CXCL10) were upregulated following BCV treatment, as did the proportion of calreticulin-expressing cells and amount of extracellular HMGB1 released, indicative of immunogenic cell death. Notably, nuclear and membranous protein expression of the immune checkpoint protein PD-L1 also markedly increased. Intraperitoneal administration of BCV (40 mg/kg, twice per week) inhibited tumor volume in NOD/SCID mouse xenografts of NKTCL, compared with vehicle alone (p=0.0005, two-tailed t-test). On immunohistochemistry, PD-L1 was significantly overexpressed in BCV-treated tumor xenografts compared with control, with a 1.9-fold higher median H-score (p=0.0007, Mann-Whitney test). Conclusions Taken together, these results demonstrate a novel repurposed role of BCV in the treatment of NKTCL. The activation of DNA damage-induced STING pathway and immune-related signals suggests a further potential for combination with checkpoint immunotherapy.

Phase II Study of Pembrolizumab and Fractionated External Beam Radiotherapy in Patients with Relapsed and Refractory Large B-Cell Lymphoma

Background: Relapsed/refractory (R/R) large B-cell lymphoma (LBCL) poses a therapeutic challenge, however immune based interventions are changing the landscape of salvage therapy. Manipulation of immune checkpoint pathways involving programmed cell death protein 1 (PD-1) and its ligands PD-L1/PD-L2 can trigger anti-tumor effects in LBCL. However, results with checkpoint inhibitor monotherapy for LBCL have been disappointing with reported overall response rates (ORR) of 10% for patients who experienced relapse after autologous stem cell transplantation (ASCT) and 3% for those ineligible for ASCT (Lesokhin AM et al J Clin Oncol. 2016). Radiation therapy (RT) is highly effective in R/R LBCL and may enhance response when coupled with immune based therapy. We sought to evaluate the efficacy of RT combined with pembrolizumab among patients with R/R non-Hodgkin Lymphoma (NHL) treated with RT to 1-2 sites of refractory disease with at least one index lesion excluded from the RT field for evaluation of abscopal effect. Methods: We conducted a single center, open label, phase II trial of patients with R/R NHL with progressive lymphoma after 2 or more lines of therapy. Eligible patients had PET avid disease amenable to RT and at least one distinct lesion outside of the planned RT field that would serve as the index (abscopal) lesion(s) by which the response to therapy would be defined. Patients were administered a fixed dose of 200 mg of pembrolizumab intravenously every 21 days beginning on day 2 of RT planned for 24 months or until progression. External beam RT was planned to dose of 40-50 Gy in ≤3 Gy fractions. The primary endpoint was ORR (defined as complete and partial response) of the unirradiated lesion(s) at 3 months (after completion of RT and 3 cycles of pembrolizumab). Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). ORR and dose limiting toxicity (DLT) were monitored simultaneously using Bayesian stopping boundaries based on an ORR of at least 35% at 3 months and DLT rate at cycle one below 30%. A sample size of 20 was planned. Results: Between February 2018 and November 2020, 17 patients were enrolled on the study and received at least 1 cycle of pembrolizumab and at least 1 fraction of RT. The median age was 66 years (range 24 - 83); 29% (n=5) of patients were female. Most patients had LBCL (88%, n=15, double hit, n=5), one patient had PMBCL (6%) and one patient had NK T-cell lymphoma (6%). The median number of prior therapies was 3 (range 2-13) with 53% (n=9) of patients having received ≥3 prior lines of treatment. Eighteen percent (n=3) of patients received prior ASCT and 53% (n=9) received CAR-T cell therapy prior to enrollment. The median number of unirradiated lesions excluded from the RT field was 2 (range 1-24). The median diameter of the largest unirradiated lesion was 2.4 cm (range 1.1 - 8.0 cm). The median RT dose delivered was 45 Gy (range 22.5 -50). The median follow up for the 17 patients was 34.75 months. Sixteen patients had a response assessment, one patient suffered from a stroke and response was not assessed. The ORR was 28% (CR 23% [n=3] and PR 15% [n=2]). Local control within the radiated field was achieved in 11 of the 16 patients (69%). For all 17 patients, the median PFS and OS were 2.7 months and 6.3 months respectively. The 2 year PFS and OS rates were 11.8% and 23.5% respectively (Figure 1). There were 13 deaths, 12 due to lymphoma and 1 due to stroke. For the five responding patients, the median duration of response was 13.3 months (range 5.0 - 50.5 months). Two patients remain in CR 37.6 (PMBCL) and 50.5 (double hit LBCL) months after protocol therapy. The trial was terminated early due to poor accrual. Treatment was generally well tolerated. One of the long term survivors with a history of chronic steroid use experienced grade 4 avascular necrosis in the RT field. Conclusion: In this single center, phase II trial of pembrolizumab and concurrent RT among patients with highly refractory LBCL, local control within the radiation field was encouraging however abscopal responses were minimal. Further exploration of the mechanism behind the exceptional responses in two patients treated with RT and pembrolizumab in this high-risk population is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Feasibility of low-dose radiotherapy for patients with stage I/II extranodal NK-/T-cell lymphoma, nasal type achieving complete response after l-asparaginase-containing chemotherapy

PurposeTo assess treatment outcomes in patients with stage I/II extranodal NK-/T-cell lymphoma, nasal type (ENKTCL-NT) and the feasibility of low-dose radiotherapy (RT) for achieving complete response (CR, defined as showing no residual hypermetabolic uptake on positron emission tomography [PET] or no residual lesions on computed tomography [CT]) after l-asparaginase-containing chemotherapy (l-ASP). Materials and methodsBetween 1992 and 2018, 76 patients with early-stage ENKTCL-NT who achieved CR or partial response (PR) after induction chemotherapy received adjuvant RT. RT doses (using biologically equivalent doses in 2 Gy fractions [EQD2]) and rates of local recurrence-free survival (LRFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. ResultsMedian follow-up was 5.1 years (range, 0.5–20.8). The median RT dose was 45 Gy (range, 20–54). The 5-year LRFS, LRRFS, DMFS, PFS, and CSS rates were 82.7 %, 78.2 %, 81.1 %, 68.7 %, and 84.4 %, respectively. CR after induction chemotherapy was notably linked to better survival outcomes across each endpoint. Survival outcomes were not affected either by the administration of l-ASP or EQD2 < 40 Gy in patients displaying CR after l-ASP. Adverse events (AEs) ≥ Grade 2 were significantly reduced with EQD2 < 40 Gy, compared with EQD2 ≥ 40 Gy. ConclusionAchieving CR after chemotherapy was the most predictive factor of survival outcomes in early-stage ENKTCL-NT. Decreasing RT doses in patients with CR after l-ASP appeared to minimize the occurrence of AE without compromising LRR risk; however, longer follow-ups and cautious application are warranted.

Deep remission from induction chemotherapy predicts favorable long-term survivals in early stage extranodal nasal NK/T-cell lymphoma receiving sequential chemotherapy and radiation.

We aimed to assess the association between induction chemotherapy (CT) response and survivals and to explore an induction CT response-adapted treatment strategy for localized extranodal NK/T-cell lymphoma (NKTCL) receiving first-line sequential CT and radiation (RT). We retrospectively reviewed the data of patients with localized NKTCL receiving first-line CT+RT from 2010 to 2020 at two independent institutes (primary cohort, n = 203; validation cohort, n = 67). Responses after induction CT (initial response), RT (final response) and survivals were analyzed. Patients with initial complete remission (CR) had higher final CR rate than the others (99.1% vs. 78.7%, P < 0.001). Initial CR was associated with superior 5-year progression-free survival (PFS, 90.0% vs. 61.4% vs. 30.8%, P < 0.001) and overall survival (OS, 93.5% vs. 70.7% vs. 60.6%, P < 0.001), as compared to initial partial remission or non-response. Though majority of cases with initial non-CR achieved final CR after RT, they still had a tendency of shortened OS compared with initial CRs (86.9% vs. 90.6%, P = 0.063). Multivariate analysis demonstrated patients with initial non-CR had higher relapse (HR = 4.748, 95% CI, 2.396-9.407, P < 0.001) and death hazard (HR = 4.296, 95% CI, 1.802-10.24, P = 0.001). Furthermore, more intensive therapy of ≥6 total cycles of CT yielded significantly superior 5-year OS for patients with initial non-CR (76.7% vs. 54.7%, P = 0.026) rather than patients with initial CR. Deep remission from induction CT was associated with favorable survivals in localized NKTCL receiving CT+RT, and an induction CT response-adapted individualized treatment strategy might be recommended in clinical practice.