Treatment outcomes between cyclosporin and chemotherapy in adult subcutaneous panniculitis-like T-cell lymphoma: a report from nation-wide Thai lymphoma study group registry.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of T-cell lymphomas with a characteristic feature of subcutaneous nodules associated with hemophagocytic lymphohistiocytosis (HLH). Treatment options for SPTCL are mainly chemotherapy (CMT) or immunosuppressive agents with selection currently dependent on physician decisions. Outcomes between the 2 treatment remedies have not yet been comprehensively compared. This study aimed to compare complete remission (CR) rates between SPTCL patients receiving cyclosporin (CSA)-based regimen (CSA +/- steroid) and CMT. The 5-year overall survival (OS) and 5-year progression free survival (PFS) were also analyzed. Clinical data from patients with SPTCL were drawn from the Thai Lymphoma Study Group registry who were newly diagnosed between 2007 and 2023. A total of 93 patients were selected with 45 cases having received CSA-based regimen and 48 cases having received CMT. There were more patients with limited stage at skin in the CSA group (63.8% vs. 36.2%, p = 0.003), while more patients with hepato- and/or splenomegaly were found in the CMT group (56.2% vs. 24.5%; p = 0.002). Germline HAVCR2 mutations were detected in 26/33 (78.8%) cases. The CR rate was significantly higher in patients treated with CSA (87% vs. 58.3%; OR = 6.5 [95%CI, 2.7-15.3]; p = 0.002). At a median follow-up of 87.8 months (range 0-185), the 5-year OS (98% vs. 87%, p = 0.19) and PFS (72.4% vs. 69.2%, p = 0.19) showed a trend favoring patients treated with CSA. Based on our study, CSA-based regimens are the preferred first-line treatment remedy for newly diagnosed SPTCL, especially in patients with limited cutaneous involvement.

Prognostic Factors of Adult Hemophagocytic Lymphohistiocytosis and Clinical Utility of HLH-2004 Diagnostic Criteria and HScore: A Real-World Multicenter Study from Thailand.

INTRODUCTION: Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. METHODS: This multicenter retrospective study investigated the etiologies, survival, and prognostic factors of HLH, including the utility of HLH-2004 criteria and HScore in real-life clinical practice. RESULTS: A total of 147 HLH patients were identified by using a combination of hemophagocytosis identification in bone marrow and the HLH-related international classification disease-10. A total of 116 (78.9%) patients fulfilled the HLH diagnosis by HScore, while 91 (61.9%) patients fulfilled 5 of 8 HLH-2004 criteria. In Thailand, the clinical application of HLH-2004 criteria needed to be reduced from 8 to 6 due to a lack of sCD25 and natural killer cell activity tests. Using the adapted HLH-2004 with a cutoff value of 4 resulted in 132 (89.9%) cases meeting the diagnostic criteria. Among these 132 confirmed HLH patients by using adapted HLH-2004, HLH was triggered by infection (29.5%), autoimmune disease (12.9%), malignancy (40.9%), and unknown cause (16.7%). Median overall survival of HLH patients was extremely short (67 days). Ferritin >6,000 µg/L, HLH from infection, malignancy, and unknown etiology were demonstrated as independent prognostic factors for inferior survival (hazard ratio [HR] 2.47; 95% confidence interval [CI] 1.39-4.37, HR 4.69; 95% CI 1.38-15.92, HR 6.09; 95% CI 1.84-20.14, and HR 6.02; 95% CI 1.64-22.05, respectively). CONCLUSION: Ferritin is a helpful biomarker for HLH diagnosis and prognostic prediction. Autoimmune disease-triggered HLH has favorable outcomes. Future prospective study is required to verify the use of the adapted HLH-2004 criteria.

Endothelial activation and stress index as a prognostic factor of diffuse large B-cell lymphoma: the report from the nationwide multi-center Thai Lymphoma Study Group.

Several prognostic models have been introduced to predict outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Endothelial activation and stress index (EASIX) is a surrogate of endothelial dysfunction which has been shown to predict outcomes of patients with various hematologic malignancies. However, the prognostic implication of EASIX for DLBCL is limited and warrants exploration. We conducted a retrospective study enrolling adult DLBCL patients including a discovery cohort from the single-centered university hospital database and a validation cohort from the independent nationwide multi-center registry. EASIX scores were calculated using creatinine, lactate dehydrogenase, and platelet levels. The receiver operating characteristic curve analysis was used to determine optimal cutoff. Statistical analysis explored the impact of EASIX on survival outcomes. A total of 323 patients were included in the discovery cohort. The optimal EASIX cutoff was 1.07 stratifying patients into low (53.9%) and high EASIX (46.1%) groups. Patients with high EASIX had worse 2-year progression-free survival (PFS) (53.4% vs. 81.5%, p<0.001) and overall survival (OS) (64.4% vs. 88.7%, p<0.001) than patients with low EASIX. Multivariate analysis revealed that older age, bulky disease, impaired performance status, and high EASIX were associated with an unfavorable OS. In the validation cohort of 499 patients, the optimal EASIX cutoff was 1.04. Similar to the discovery cohort, high EASIX score was associated with high-risk diseases, worse PFS, and inferior OS. In conclusion, EASIX score was significantly associated with survival outcomes and may be used as a simple prognostic tool to better risk-classify DLBCL.

Outcomes of polatuzumab vedotin-containing regimens in real-world setting of relapsed and or refractory diffuse large B-cell lymphoma patients: a matched-control analysis from the Thai Lymphoma Study Group (TLSG).

Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is a challenging condition to treat, and there is an unmet clinical need for effective therapies. Recently, polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADC), combined with bendamustine-rituximab (BR), has been approved for R/R DLBCL patients. However, real-world data on Pola-based regimens in R/R DLBCL patients, especially in Thailand, are limited. This study aimed to evaluate the efficacy and safety of Pola-based salvage treatment in R/R DLBCL patients in Thailand. Thirty-five patients who received Pola-based treatment were included in the study, and their data were compared to 180 matched patients who received non-Pola-based therapy. The overall response rate (ORR) in the Pola group was 62.8%, with complete remission and partial remission rates of 17.1% and 45.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 10.6 months and 12.8 months, respectively. The study found a significantly higher ORR in Pola-based salvage treatments compared to non-Pola-based therapy (62.8% vs. 33.3%). The survival outcomes were also significantly superior in the Pola group, with longer median PFS and OS than the control group. Grades 3-4 adverse events (AEs) were mainly hematological, and they were tolerable. In conclusion, this study provides real-world evidence of the efficacy and safety of Pola-based salvage treatment in R/R DLBCL patients in Thailand. The results of this study are promising and suggest that Pola-based salvage treatment could be a viable option for R/R DLBCL patients who have limited treatment options.

Spacer Length Modification Facilitates Discrimination between Normal and Neoplastic Cells and Provides Clinically Relevant CD37 CAR T Cells.

Despite the remarkable initial efficacy of CD19 chimeric Ag receptor T (CAR-T) cell therapy, a high incidence of relapse has been observed. To further increase treatment efficacy and reduce the rate of escape of Ag-negative cells, we need to develop CAR-T cells that target other Ags. Given its restricted expression pattern, CD37 was considered a preferred novel target for immunotherapy in hematopoietic malignancies. Therefore, we designed a CD37-targeting CAR-T (CD37CAR-T) using the single-chain variable fragment of a humanized anti-CD37 Ab, transmembrane and intracellular domains of CD28, and CD3ζ signaling domains. High levels of CD37 expression were confirmed in B cells from human peripheral blood and bone marrow B cell precursors at late developmental stages; by contrast, more limited expression of CD37 was observed in early precursor B cells. Furthermore, we found that human CD37CAR-T cells with longer spacer lengths exhibited high gene transduction efficacy but reduced capacity to proliferate; this may be due to overactivation and fratricide. Spacer length optimization resulted in a modest transduction efficiency together with robust capacity to proliferate. CD37CAR-T cells with optimized spacer length efficiently targeted various CD37+ human tumor cell lines but had no impact on normal leukocytes both in vitro and in vivo. CD37CAR-T cells effectively eradicated Raji cells in xenograft model. Collectively, these results suggested that spacer-optimized CD37CAR-T cells could target CD37-high neoplastic B cells both in vitro and in vivo, with only limited interactions with their normal leukocyte lineages, thereby providing an additional promising therapeutic intervention for patients with B cell malignancies.

Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival.

Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19+ target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19+ target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.

Quantitative Assessment of T Cell Clonotypes in Human Acute Graft-versus-Host Disease Tissues.

Owing to the difficulty in isolating T cells from human biopsy samples, the characteristics of T cells that are infiltratinghuman acute graft-versus-host disease (GVHD) tissues remain largely uninvestigated. In the present study, TCR-ß deep sequencing of various GVHD tissue samples and concurrent peripheral blood obtained from transplant recipients was performed in combination with functional assays of tissue-infiltrating T cell clones. The T cell repertoire was more skewed in GVHD tissues than in the peripheral blood. The frequent clonotypes differed from tissue to tissue in the same patient, and the frequent clonotypes in the same tissue differed from patient to patient. Two T cell clones were successfully isolated from GVHD skin of a patient. In a cytotoxicity assay, both Tcell clones lysed patient peripheral blood mononuclear cells, but not donor-derived Epstein-Barr virus-transformed lymphoblastoid cells. Their clonotypes were identical to the most and second most frequent T cell clonotypes in the original GVHD skin and accounted for almost all of the skin-infiltrating T cells. These results suggest that human acute GVHD may result from only a few different alloreactive cytotoxic T cell clones, which differ from tissue to tissue and from patient to patient. The characterization of T cells infiltrating human GVHD tissues should be further investigated.

Event free survival at 24 months is a strong surrogate prognostic endpoint of peripheral T cell lymphoma.

Event free survival at 24 months (EFS24) has been described as a powerful predictor for outcome in several subtypes of B cell lymphoma. However, it was limitedly described in T cell lymphoma. We explored the implication of EFS24 as a predictor marker for peripheral T cell lymphoma (PTCL). We reviewed 293 systemic PTCL patients at 13 nationwide major university hospitals in Thailand from 2007 to 2014. The median event free survival (EFS) and overall survival (OS) of PTCL patients in our cohort was 16.3 and 27.7 months with corresponding 2-year EFS and 2-year OS of 45.8% and 51.9%, respectively. A total of 118 patients achieved EFS24 (no events during the first 24 mo). Patients who achieved EFS24 had better OS than patients who did not (2-y OS 92% vs 18.8%; HR, 0.1; P < .001). The standardized mortality ratio of patients achieving EFS24 was 18.7 (95% CI, 14.6-22.8). Multivariable analysis demonstrated performance status, histologic subtype, remission status, and EFS24 achievement as independent predictors for OS. Our study affirmed the value of EFS24 as a powerful prognostic factor for PTCL. Further validation in prospective study setting is warranted.

Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

The Expressions of P53, Bcl-2, and P-Glycoprotein and Prognostic Impact in Patients with Peripheral T-Cell Lymphoma (PTCL).

OBJECTIVE: To define the expressions of p53, Bcl-2, and p-glycoprotein and prognostic impact in patients with peripheral T-cell lymphoma (PTCL). MATERIAL AND METHOD: Adult patients with newly diagnosed as PTCL were reviewedfrom 2001 to 2012. Clinical parameters and outcome data were extracted The specimens were stained for p53, Bcl-2, and p-glycoprotein. The results were analyzed for association with disease stage, International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), overall response rate (ORR), and overall survival (OS). RESULTS: Of eligible 159 patients (113 males, 46 females), median age was 53 years old The histological subtypes included peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) 35.8%, angioimmunoblastic T-cell lymphoma (AITL) 18.2%, extranodal NK/T-cell lymphoma (ENKL) 17.0%, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) 12.6%, cutaneous T-cell lymphoma (CTCL) 11.3%, anaplastic large cell lymphoma (ALCL) 4.4%, and enteropathy-associated T-cell lymphoma (EATL) 0.6%. Tissue samples were obtainedfor analysis in 135 patients. P53, Bcl-2, and p-glycoprotein were positive in 87%, 49%, and 28%, respectively. Median OS was 25 months. The expressions of p53, Bcl-2, and p-glycoprotein were not significantly correlated with advanced stage, high prognostic scores, ORR, and OS. However Bcl-2 expression was statistically associated with histological subtypes. From Cox regression analyses, advanced stage, high prognostic scores, and histological subtypes were independent prognostic factors for OS. CONCLUSION: The biomarker expressions varied in different types of PTCL and did not show any correlation with prognostic factors, ORR, or OS.

Generation of ex vivo autologous hematopoietic stem cell-derived T lymphocytes for cancer immunotherapy.

CD19CAR-T cell therapy demonstrated promising outcomes in relapsed/refractory B-cell malignancies. Nonetheless, the limited T-cell function and ineffective T-cell apheresis for therapeutic purposes are still concern in heavily pretreated patients. We investigated the feasibility of generating hematopoietic stem cell-derived T lymphocytes (HSC-T) for cancer immunotherapy. The patients' autologous peripheral blood HSCs were enriched for CD34+ and CD3+ cells. The CD34+ cells were then cultured following three steps of lymphoid progenitor differentiation, T-cell differentiation, and T-cell maturation processes. HSC-T cells were successfully generated with robust fold expansion of 3735 times. After lymphoid progenitor differentiation, CD5+ and CD7+ cells remarkably increased (65-84 %) while CD34+ cells consequentially declined. The mature CD3+ cells were detected up to 40 % and 90 % on days 42 and 52, respectively. The majority of HSC-T population was naïve phenotype compared to CD3-T cells (73 % vs 34 %) and CD8:CD4 ratio was 2:1. The higher level of cytokine and cytotoxic granule secretion in HSC-T was observed after activation. HSC-T cells were assessed for clinical application and found that CD19CAR-transduced HSC-T cells demonstrated higher cytokine secretion and a trend of superior cytotoxicity against CD19+ target cells compared to control CAR-T cells. A chronic antigen stimulation assay revealed similar T-cell proliferation, stemness, and exhaustion phenotypes among CAR-T cell types. In conclusions, autologous HSC-T was feasible to generate with preserved T-cell efficacy. The HSC-T cells are potentially utilized as an alternative option for cellular immunotherapy.

Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness.

CD19 chimeric antigen receptor T (CD19CAR-T) cells have achieved promising outcomes in relapsed/refractory B cell malignancies. However, recurrences occur due to the loss of CAR-T cell persistence. We developed dual T/B cell co-stimulatory molecules (CD28 and CD40) in CAR-T cells to enhance intense tumoricidal activity and persistence. CD19.28.40z CAR-T cells promoted pNF-κB and pRelB downstream signaling while diminishing NFAT signaling upon antigen exposure. CD19.28.40z CAR-T cells demonstrated greater proliferation, which translated into effective anti-tumor cytotoxicity in long-term co-culture assay. Repetitive weekly antigen stimulation unveiled continuous CAR-T cell expansion while preserving central memory T cell subset and lower expression of exhaustion phenotypes. The intrinsic genes underlying CD19.28.40z CAR-T cell responses were compared with conventional CARs and demonstrated the up-regulated genes associated with T cell proliferation and memory as well as down-regulated genes related to apoptosis, exhaustion, and glycolysis pathway. Enrichment of genes toward T cell stemness, particularly SELL, IL-7r, TCF7, and KLF2, was observed. Effective and continuing anti-tumor cytotoxicity in vivo was exhibited in both B cell lymphoblastic leukemia and B cell non-Hodgkin lymphoma xenograft models while demonstrating persistent T cell memory signatures. The functional enhancement of CD37.28.40z CAR-T cell activities against CD37+ tumor cells was further validated. The modification of dual T/B cell signaling molecules remarkably maximized the efficacy of CAR-T cell therapy.

Non-Cryopreserved Peripheral Blood Stem Cell Graft for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma and Lymphoma Patients.

BACKGROUND Hematopoietic stem cell transplantation (HSCT) using cryopreserved grafts is time-consuming, expensive treatment, and may associated with dimethyl sulfoxide (DMSO) toxicity. Here, we assess the clinical utility and safety of non-cryopreserved peripheral blood stem cell graft in autologous HSCT. MATERIAL AND METHODS Medical data of multiple myeloma or lymphoma patients who underwent autologous non-cryopreserved HSCT were reviewed. RESULTS A total of 58 patients (40 myeloma and 18 lymphoma) were reviewed. The median myeloma and lymphoma CD34⁺ cell doses were 7.59 and 6.9 million/kg, respectively, with good viability after storage. The median times in neutrophil and platelet engraftment were 9 and 13 days and 11 and 14 days in myeloma and lymphoma, respectively. Only 5 patients in this cohort developed serious post-transplant complications. After transplantation, the cumulative incidence of relapse at 5 years was 34.4% in myeloma versus 19.1% in lymphoma patients. Notably, the mortality incidence rate rapidly increased within the first year and reached a plateau after 4 years, with cumulative incidence of 5.9% and 30.9% in myeloma and lymphoma, respectively. With a median follow-up time of 60 months, the median progression-free survival (PFS) and overall survival (OS) for lymphoma patients was 123.8 and 130 months, respectively. For the myeloma group, the median follow-up time was 38.6 months, the median PFS was 99.5 months, and OS was 157 months. CONCLUSIONS Non-cryopreserved HSCT is effective and safe. The long-term survival outcomes could be achieved by the shortening the duration of neutrophil and platelet engraftments and the complication rates are acceptable.

Proteome Analysis of the Antiproliferative Activity of the Novel Chitooligosaccharide-Gallic Acid Conjugate against the SW620 Colon Cancer Cell Line.

Chitooligosaccharide (COS) and gallic acid (GA) are natural compounds with anti-cancer properties, and their conjugate (COS-GA) has several biological activities. Herein, the anti-cancer activity of COS-GA in SW620 colon cancer cells was investigated. MTT assay was used to evaluate cell viability after treatment with 62.5, 122, and 250 µg/mL of COS, GA, and COS-GA for 24 and 48 h. The number of apoptotic cells was determined using flow cytometry. Proteomic analysis was used to explore the mechanisms of action of different compounds. COS-GA and GA showed a stronger anti-cancer effect than COS by reducing SW620 cell proliferation at 125 and 250 µg/mL within 24 h. Flow cytometry revealed 20% apoptosis after COS-GA treatment for 24 h. Thus, GA majorly contributed to the enhanced anti-cancer activity of COS via conjugation. Proteomic analysis revealed alterations in protein translation and DNA duplication in the COS group and the structural constituents of the cytoskeleton, intermediate filament organization, the mitochondrial nucleoid, and glycolytic processes in the COS-GA group. Anti-cancer-activity-related proteins were altered, including CLTA, HSPA9, HIST2H2BF, KRT18, HINT1, DSP, and VIM. Overall, the COS-GA conjugate can serve as a potential anti-cancer agent for the safe and effective treatment of colon cancer.

Does leukocytosis remain a predictive factor for survival outcomes in patients with acute promyelocytic leukemia receiving ATRA plus a chemotherapy-based regimen? A prospective multicenter analysis from TALWG.

INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique clinical presentation and prognosis. This study aimed to investigate the epidemiology, clinical characteristics, treatments, and clinical outcomes of Thai APL patients dominantly treated with all-trans-retinoic acid (ATRA) combined with a chemotherapy-based therapy. METHODS: This was an eight-year prospective, observational study from nine academic hospitals in the Thai Acute Leukemia Working Group (TALWG) of the Thai Society of Hematology, which included newly diagnosed Thai APL patients, aged 18 years or older. The web-based registration collected baseline charateristic, and clinical outcomes. RESULTS: From 992 newly diagnosed AML patients, 79 APL patients were enrolled in this study. Almost all subjects were de novo APL (94.9%), while the others were therapy-related APL. The commonest clinical presentation was disseminated intravascular coagulation (38%). One-third of the patients were categorized as high risk according to the initial WBC. Almost all patients received ATRA combined with idarubicin regimen. The complete response rate was as high as 95.7%, which translated into excellent four-year overall survival (OS) (75.6%) and four-year leukemia-free survival (LFS) (75.4%). The multivariate analysis demonstrated that the older age and WBC count >20 × 109/L conferred a significantly unfavorable OS with the hazard ratios of 3.03 (95% confidence interval [CI]: 1.14-8.05) and 4.18 (95%CI: 1.69-10.35), respectively. Similarly, these two parameters remained independent of the poor prognosis factors for LFS. CONCLUSION: This report confirmed that APL had a favorable prognosis. However, advanced age and high WBC count >20 × 109/L contributed to a worse outcome. ABBREVIATIONS: APL; acute promyelocytic leukemia; ATRA; all-transretinoic acid; CR; complete remission; DS; differentiation syndrome; ECOG; Eastern Cooperative Oncology Group; ED; early death; HR; hazard ratio; IQR; interquartile range; LFS; leukemia-free survival; OS; overall survival; WBC; white blood cell.

Computational discovery of binding mode of anti-TRBC1 antibody and predicted key amino acids of TRBC1.

Peripheral T-cell lymphoma (PTCL) is a type of non-Hodgkin lymphoma that progresses aggressively with poor survival rate. CAR T cell targeting T-cell receptor ß-chain constant domains 1 (TRBC1) of malignant T cells has been developed recently by using JOVI.1 monoclonal antibody as a template. However, the mode of JOVI.1 binding is still unknown. This study aimed to investigate the molecular interaction between JOVI.1 antibody and TRBC1 by using computational methods and molecular docking. Therefore, the TRBC protein crystal structures (TRBC1 and TRBC2) as well as the sequences of JOVI.1 CDR were chosen as the starting materials. TRBC1 and TRBC2 epitopes were predicted, and molecular dynamic (MD) simulation was used to visualize the protein dynamic behavior. The structure of JOVI.1 antibody was also generated before the binding mode was predicted using molecular docking with an antibody mode. Epitope prediction suggested that the N3K4 region of TRBC1 may be a key to distinguish TRBC1 from TCBC2. MD simulation showed the major different surface conformation in this area between two TRBCs. The JOVI.1-TRBC1 structures with three binding modes demonstrated JOVI.1 interacted TRBC1 at N3K4 residues, with the predicted dissociation constant (Kd) ranging from 1.5 × 108 to 1.1 × 1010 M. The analysis demonstrated JOVI.1 needed D1 residues of TRBC1 for the interaction formation to N3K4 in all binding modes. In conclusion, we proposed the three binding modes of the JOVI.1 antibody to TRBC1 with the new key residue (D1) necessary for N3K4 interaction. This data was useful for JOVI.1 redesign to improve the PTCL-targeting CAR T cell.

Enrichment of T-cell proliferation and memory gene signatures of CD79A/CD40 costimulatory domain potentiates CD19CAR-T cell functions.

CD19 chimeric antigen receptor (CAR) T-cells have demonstrated remarkable outcomes in B-cell malignancies. Recently, the novel CD19CAR-T cells incorporated with B-cell costimulatory molecules of CD79A/CD40 demonstrated superior antitumor activity in the B-cell lymphoma model compared with CD28 or 4-1BB. Here, we investigated the intrinsic transcriptional gene underlying the functional advantage of CD19.79A.40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB. Notably, CD19.79A.40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF-κB signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19.79A.40z CAR- and CD19.BBz CAR-T cells were enriched in almost similar pathways. Furthermore, gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and naïve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19.79A.40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells. Our study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain.

Prevalence and management of eosinophilia based on periodic health examinations in primary care clinics.

Background: Eosinophilia is a common, hematologic abnormality detected in periodic health checkups with diverse etiologies. There are a few clinical practice guidelines for the management of eosinophilia. Objectives: To determine the prevalence of eosinophilia among patients undergoing periodic health examinations, evaluate its management and outcomes, and identify its associated factors. Methods: We conducted a retrospective study that included patients with eosinophilia diagnosed during the 2018 periodic health examinations at Songklanagarind Hospital. Results: The prevalence rate of eosinophilia was 9.6% (988/10,299), and most patients (52.6%) were male with a median age of 53.0 (42.0-61.0) years. Only 174 patients (17.6%) were diagnosed and further examined to identify the cause of eosinophilia; including an examination of medical history (18.4%), physical examination (93.1%), laboratory analysis (9.2%), and consultation with internists (14.9%). Empirical anthelmintic therapy was administered in 130 patients (74.7%), and 49.2% achieved resolution. The possible causes of eosinophilia were identified in 20.7% (204/988), the most common cause being atopic disease (51.5%). Patients with moderate-to-severe eosinophilia were significantly more likely to be diagnosed, undergo further laboratory tests, and proceed with consultations with internists (adjusted OR [95% CI] = 3.52 [1.97-6.32], 17.13 [5.74-51.11], and 6.38 [1.95-20.93], respectively). Conclusions: Eosinophilia is commonly identified in periodic health examinations, and most primary physicians lack knowledge regarding the diagnostic work-up required to determine the cause of eosinophilia. Empirical anthelmintic therapy showed satisfactory efficacy for the management of eosinophilia in areas where parasite infection is endemic.

Comparison of Three Doses of Cytarabine Consolidation for Intermediate- and Adverse-risk Acute Myeloid Leukemia: Real World Evidence From Thai Acute Myeloid Leukemia Registry.

BACKGROUND: Intermediate or high doses of cytarabine (IDAC or HiDAC) were recommended as postremission chemotherapy for acute myeloid leukemia (AML). This retrospective study investigated the real-world outcomes of 3-different cytarabine doses from the multicenter Thai AML registry database. PATIENTS AND METHODS: The intermediate- and adverse-risk AML patients (N = 258) who achieved complete remission and proceeded to single-agent cytarabine consolidation were enrolled. RESULTS: The median relapse-free survival (RFS) using IDAC 1.5 g/m2, high-dose cytarabine (HiDAC) 2 g/m2, and HiDAC 3 g/m2 were 12.6, 11.7, and 13 months, respectively. The median overall survival (OS) using IDAC 1.5 g/m2, HiDAC 2 g/m2, and HiDAC 3 g/m2 were 34.9, 22.7, and 23.7 months, respectively. No significant difference in RFS and OS was detected between the 3 doses. Secondary AML, white blood cell > 100×109/L and the adverse-risk AML were independent prognostic factors for inferior survival (P= .008, P < .001, P= .014). Patients who completed 3 to 4 cycles of consolidation had significantly superior RFS and OS (P< .001, P< .001). Febrile neutropenia occurred in 72.9% of IDAC, 73.8% of HiDAC 2 g/m2, and 78.1% of HiDAC 3 g/m2 without statistical significance. However, the incidence of septic shock was significantly higher after HiDAC 3 g/m2 compared to IDAC regimen (8% vs. 3%, P= .037). CONCLUSION: IDAC is an appropriate regimen for postremission chemotherapy for intermediate- and adverse-risk AML. The higher dosing levels may not produce any benefits to patients and may increase incidence of septic shock. The number of consolidation cycles may impact on survivals rather than the intensity of cytarabine.

Characteristics and Outcomes of Secondary Acute Myeloid Leukemia and Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Multicenter Study From the Thai Acute Leukemia Study Group.

BACKGROUND: Secondary acute myeloid leukemia (sAML) and AML with myelodysplasia-related changes (AML-MRC) both result in dismal outcomes. This retrospective study aimed to determine whether these features are poor prognostic factors independent of older age and adverse cytogenetics, which are commonly associated with a poor prognosis. METHODS: The characteristics and real-world outcomes of sAML and AML-MRC from the Thai AML registry database were investigated. RESULTS: From a total of 992 newly diagnosed AML patients, 315 (31.8%) patients were classified into sAML or AML-MRC subtypes. Older age, low white blood cell (WBC) count, low bone marrow blast, and adverse cytogenetic risk were commonly present in sAML and AML-MRC compared to de novo AML. Complete remission after 7 + 3 induction therapy occurred in 42.3% of patients with sAML or AML-MRC and 62.4% of de novo AML (P < .001). The median overall survival (OS) of sAML, AML-MRC, and de novo AML were 6.9, 7.0, and 12.2 months, respectively (P < .001). The independent prognostic factors for inferior OS were older age, intermediate-risk or adverse-risk cytogenetics, WBC count > 100 × 109/L, poor performance status, and a subgroup of AML-MRC with the morphologic criteria of multilineage dysplasia (AML-MRC-M). In addition, sAML, AML-MRC, and a WBC count > 100 × 109/L were pre-treatment prognostic factors associated with poor relapse-free survival (P = .006, P = .017, and P < .001, respectively). CONCLUSION: Both sAML and AML-MRC are independently associated with poor outcomes in Thai patients. Our study supports AML-MRC-M as an adverse prognostic factor for OS.