Transformation to diffuse large B-cell lymphoma and its impact on survival in patients with marginal zone lymphoma: A population-based study.

Some patients with marginal zone lymphoma (MZL) experience histological transformation to diffuse large B-cell lymphoma (DLBCL). Because of the paucity of long-term data on transformation, we conducted a population-based study to estimate the risk of transformation and its impact on survival in MZL. Using the Surveillance, Epidemiology and End Results database, we identified 23 221 patients with histology-proven MZL between 2000 and 2018. Competing risk method, Kaplan-Meier and Cox proportional hazards regression were performed to analyze time-to-event outcomes. Based on 420 events of transformation, the 10-year cumulative incidence rate of transformation is 2.23% (95% CI: 2.00%-2.46%) in MZL, 1.5% (95% CI: 1.3%-1.8%), 2.7% (95% CI: 2.3%-3.2%) and 5.8% (95% CI: 4.6%-7.1%) in extranodal, nodal and splenic MZL (EMZL, NMZL and SMZL), respectively. Patients with SMZL (subdistribution hazard ratio [SHR], 2.96; 95% CI: 2.21-3.96) or NMZL (SHR, 1.49; 95% CI: 1.17-1.90) have a higher risk of transformation than those with EMZL. For each MZL subtype, patients with transformation had a significantly shorter overall survival. Patients with transformation >18 months since MZL diagnosis had longer OS than those who presented within 18 months (5-year rate, 87.4% [95% CI: 83.7%-91.2%] vs 47.9% [95% CI: 38.8%-59.0%]; P < .001). Compared to patients with matched de novo DLBCL, those whose DLBCL was transformed from MZL had a shorter OS (5-year rate, 56.6% [95% CI: 51.9%-61.8%] vs 46.1% [95% CI: 40.9%-51.9%]; P < .001). We concluded that patients with SMZL had the highest risk of transformation. Regardless of MZL subtype, transformation resulted in significantly increased mortality.

Incidence and survival of patients with primary gastrointestinal melanoma: a population-based study.

BACKGROUND: Primary gastrointestinal melanoma (PGIM) has received more attention because of its inferior prognosis. Less is known about the incidence and survival rate of PGIM. METHODS: PGIM data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The incidence was estimated by age, sex, race, and primary site. Trends in incidence were described as annual percent change (APC). Cancer-specific survival (CSS) and overall survival (OS) rates were estimated and compared using log-rank tests. Cox regression analyses were performed to identify independent prognostic factors. RESULTS: The overall incidence of PGIM was 0.360/1,000,000 with a significant upward trend (APC = 1.77%; 95% CI 0.89%-2.67%, p < 0.001) from 1975 to 2016. Most PGIM occurred in the large intestine (0.127/1,000,000) and anorectum (0.182/1,000,000), and both incidences were almost 10 times higher than those of other sites, including the esophagus, stomach, and small intestine. The median survival time was 16 months (IQR, 7-47 months) for CSS and 15 months (IQR, 6-37 months) for OS, and the 3-year CSS and OS rates were 29.5% and 25.4%, respectively. Older age, advanced stage, absence of surgery, and melanoma in the stomach were the independent risk indicators of survival and associated with worse CSS and OS. CONCLUSION: The incidence of PGIM has been increasing over the past decades and the prognosis is poor. Thus, further studies are warranted to improve the survival, and more attention should be paid to the patients that are elderly, patients with advanced stage, and patients with melanoma in the stomach.

Risk and outcome of acute myeloid leukaemia among survivors of primary diffuse large B-cell lymphoma: a retrospective observational study based on SEER database.

OBJECTIVES: Survivors of diffuse large B-cell lymphoma (DLBCL) are at an increased risk of developing second primary malignancies. However, the risk of secondary acute myeloid leukaemia (sAML) has not been previously described in detail, and the outcomes of patients with sAML are also undiscovered compared with their de novo counterparts (de novo acute myeloid leukaemia, dnAML). DESIGN: This study is a retrospective database study. SETTING AND PARTICIPANTS: A total of 70 280 patients with primary DLBCL, diagnosed between 2000 and 2016, were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Another cohort with dnAML matching with sAML was also obtained from SEER database. RESULTS: The standardised incidence ratio was 6.23 (95% CI: 5.50 to 7.03) for sAML among survivors of DLBCL. The estimated cumulative incidence of sAML was 0.61% 15 years after the diagnosis of DLBCL. Patients aged 60-74 years were more likely to have sAML than those <60 years (subdistribution HR (sHR)=1.417; 95% CI: 1.087 to 1.850), whereas patients aged ≥75 years were less likely to have sAML (sHR=0.648; 95% CI: 0.452 to 0.930). Patients with advanced-stage DLBCL were more prone to sAML than those with early-stage disease (sHR=1.307; 95% CI: 1.012 to 1.690). There was a significant difference of survival between patients with dnAML and those with sAML (HR=1.25; 95% CI: 1.01 to 1.53). CONCLUSIONS: The risk of developing sAML after DLBCL is substantial. Patients aged 60-74 years and with advanced-stage are more prone to sAML. And, compared with their dnAML counterparts, patients with sAML have a worse prognosis.

Inherited heterozygous Fanconi anemia gene mutations in a therapy-related CMML patient with a rare NUP98-HOXC11 fusion: A case report.

Fanconi anemia (FA) genes play critical roles in the repair of DNA lesions. Non-FA (or underlying FA) patients harboring heterozygous germline FA gene mutations may also face an increased risk of developing bone marrow failure, primary immunodeficiency disease, and hereditary cancer predisposition syndromes. We report a female patient who suffered from ovarian cancer at 50 years of age. During the initial treatment, six cycles of docetaxel and carboplatin (DC) combination chemotherapy were administered followed by two cycles of docetaxel maintenance therapy. Then, she received a routine follow-up every 3 months for the next 3 years, and all the results of the examination and laboratory tests were normal. Unfortunately, at 54 years of age, she developed a secondary cancer of therapy-related (t-) chronic myelomonocytic leukemia (t-CMML). After two courses of a highly intensive induction chemotherapy regimen with DAC (decitabine) and HAA (homoharringtonine, cytarabine), the patient suffered from severe and persistent bone marrow failure (BMF). Targeted next-generation sequencing (NGS) of a panel of 80 genes was performed on her initial bone marrow aspirate sample and identified PTPN11, NRAS, and DNMT3A somatic mutations. In addition, RNA sequencing (RNA-seq) revealed a rare NUP98-HOXC11 fusion. Whole-exome sequencing (WES) verified RAD51C, BRIP1, PALB2, and FANCG heterozygous germline mutations of the FA pathway, which were further confirmed in buccal swab samples by Sanger sequencing. For this patient, we hypothesized that an altered FA pathway resulted in genomic instability, hypersensitivity to DNA-crosslinking agents or cytotoxic chemotherapeutics, and unsuccessful DNA damage repair. Consequently, she developed ovarian cancer and secondary t-CMML and then suffered from BMF and delayed post-chemotherapy bone marrow recovery after several chemotherapy courses. This case highlights the importance of genetic counseling in patients with hematopoietic neoplasms with high clinical suspicion for carrying cancer susceptibility gene mutations, which require timely diagnosis and personalized management.

IGH Translocations in Chinese Patients With Chronic Lymphocytic Leukemia: Clinicopathologic Characteristics and Genetic Profile.

Immunoglobulin heavy chain translocations (IGH-t) have occasionally been reported in Chinese patients with chronic lymphocytic leukemia (CLL). The objective of the present study was to identify the clinicopathologic features of patients with IGH-t CLL and compare them with those of patients with non-IGH-t CLL. We performed fluorescence in situ hybridization (FISH) based on a routine CLL prognostic FISH panel using IGH, IGH-BCL2, BCL3, IGH-CMYC, and BCL6 FISH probes. Furthermore, we retrospectively evaluated the clinical features of 138 newly diagnosed CLL patients via chromosome banding analysis (CBA), FISH, and targeted next-generation sequencing. IGH-t was identified in 25 patients (18.1%). Patients with IGH-t CLL had lower flow scores than those with non-IGH-t CLL. The most frequent translocation was t(14;18) (10 patients), followed by t(14;19) (3 patients), and t(2;14)(p13;q32), t(7;14)(q21.2;q12), t(9;14)(p13;q32) (3 patients). The remaining nine patients included three with abnormal karyotypes without translocation involving 14q32, four with a normal karyotype, and two who failed CBA. The most frequently concomitant FISH-detected aberrations were 13q deletion, followed by +12 and TP53 deletion, while one case involved ATM deletion. Complex karyotypes were detected in five patients with IGH-t CLL, in whom all partner genes were non-BCL2. Available mutational information indicated that KMT2D mutation was the most frequent mutation among tested 70 patients, while TP53 mutation was the most frequent mutation in the IGH-t group. Moreover, the IGH-t group had higher FBXW7 (P=0.014) and ATM (P=0.004) mutations than the non-IGH-t group, and this difference was statistically significant. Our study demonstrates that IGH-t is not uncommon among Chinese CLL patients, and that its partner genes are multiple. The gene mutational profile of the IGH-t group was distinct from that of the non-IGH-t group, and the concomitant chromosomal abnormalities within the IGH-t CLL group differed. Thus, identification of IGH-t and its partner genes in CLL patients may help further refine risk stratification and strengthen the accurate management in CLL patients.

FISH improves risk stratification in acute leukemia by identifying KMT2A abnormal copy number and rearrangements.

Most cases of acute leukemia (AL) with KMT2A rearrangement (KMT2A-r) have a dismal prognosis. Detection of this aberration in Chinese adult patients relies on reverse transcription polymerase chain reaction (RT-PCR) and chromosome banding analysis (CBA). The fluorescence in situ hybridization (FISH) probe for KMT2A detects KMT2A-r and copy number variation (CNV) but is not routinely used as a detection technique. This study investigated the potential value of FISH in the treatment of AL by performing FISH along with CBA and RT-PCR in 269 de novo cases of AL. The three detection techniques were compared in identification of KMT2A-r, and the applicability of FISH for detecting KMT2A CNV was evaluated. Twenty-three samples were identified as positive for KMT2A-r (20 using FISH, 15 using RT-PCR, 16 using CBA, and eight according to all three). FISH also identified 17 KMT2A CNV, 15 with gains and two with deletions. Ten patients with acute myeloid leukemia (AML) harboring KMT2A CNV had a complex karyotype, a negative prognostic factor in AML. Adding FISH of KMT2A to routine detection leads to more accurate detection of KMT2A-r and improved identification of KMT2A CNV, which would benefit patients by improving the risk stratification in AL.

T Cell Defects: New Insights Into the Primary Resistance Factor to CD19/CD22 Cocktail CAR T-Cell Immunotherapy in Diffuse Large B-Cell Lymphoma.

Despite impressive progress, a significant portion of patients still experience primary or secondary resistance to chimeric antigen receptor (CAR) T-cell immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The mechanism of primary resistance involves T-cell extrinsic and intrinsic dysfunction. In the present study, a total of 135 patients of DLBCL treated with murine CD19/CD22 cocktail CAR T-therapy were assessed retrospectively. Based on four criteria (maximal expansion of the transgene/CAR-positive T-cell levels post-infusion [Cmax], initial persistence of the transgene by the CAR transgene level at +3 months [Tlast], CD19+ B-cell levels [B-cell recovery], and the initial response to CAR T-cell therapy), 48 patients were included in the research and divided into two groups (a T-normal group [n=22] and a T-defect [n=26] group). According to univariate and multivariate regression analyses, higher lactate dehydrogenase (LDH) levels before leukapheresis (hazard ratio (HR) = 1.922; p = 0.045) and lower cytokine release syndrome (CRS) grade after CAR T-cell infusion (HR = 0.150; p = 0.026) were independent risk factors of T-cell dysfunction. Moreover, using whole-exon sequencing, we found that germline variants in 47 genes were significantly enriched in the T-defect group compared to the T-normal group (96% vs. 41%; p<0.0001), these genes consisted of CAR structure genes (n=3), T-cell signal 1 to signal 3 genes (n=13), T cell immune regulation- and checkpoint-related genes (n=9), cytokine- and chemokine-related genes (n=13), and T-cell metabolism-related genes (n=9). Heterozygous germline UNC13D mutations had the highest intergroup differences (26.9% vs. 0%; p=0.008). Compound heterozygous CX3CR1I249/M280 variants, referred to as pathogenic and risk factors according to the ClinVar database, were enriched in the T-defect group (3 of 26). In summary, the clinical characteristics and T-cell immunodeficiency genetic features may help explain the underlying mechanism of treatment primary resistance and provide novel insights into CAR T-cell immunotherapy.

A Model Perspective Explanation of the Long-Term Sustainability of a Fully Human BCMA-Targeting CAR (CT103A) T-Cell Immunotherapy.

Different from canonical drugs, CAR T-cells are "living drugs", which derived from patient's own blood. Studies of the pharmacokinetics of CAR T-cells could improve our understanding of their efficacy, safety, optimal dosage, and other characterizes. We previously reported a phase I study of a novel fully human BCMA-targeting CAR (CT103A) in 18 patients with relapsed/refractory multiple myeloma. CT103A exhibited extraordinary persistence with low anti-drug antibody positivity. To figure out the pharmacokinetic characterizes and investigate the potential reason of CT103A's long-term persistence, we established a population pharmacokinetic (PopPK) model of CT103A based on 18 patients cohort by applying nonlinear mixed-effects modeling and analyzed the CAR T-cell clonal evolution. The results suggested that extramedullary spreading was found to impair Cmax and was therefore added as a covariate to the modified model. The model revealed tocilizumab and corticosteroids showed no impact on the CT103A expansion rate. No dominant clone existed in patients with persistently high peripheral CT103A by CAR integration sites analysis. Finally, patients with lower contraction rate constants and higher Cmax as well as memory CT103A fraction could achieve better clinical responses. Taken together, this study developed a PopPK model of a fully human anti-BCMA CAR T-cell therapy, and summarized its model characteristics. We suggested that the long-term persistence of CT103A was attributed to the memory CAR T-cell fraction but not the clonal evolution. This study will improve people's understanding of pharmacokinetics and PopPK of CAR T-cell immunotherapy.

Case Report: Chronic Lymphocytic Leukemia With a Rare Translocation t(14;19)(q32;q13) Involving IGH/BCL3 Rearrangements: Report of Three Chinese Cases and Literature Review.

BACKGROUND: A translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 which is a rare cytogenetic abnormality in CLL patients, has a more aggressive clinical course with a shorter time to first treatment (TTT) and worse overall survival (OS). To date, there is no literature reporting the identification of the t(14;19) in Chinese CLL patients and the reviewing the characteristic of all patients with this abnormality reported previously in the literature. PATIENTS AND METHODS: We first demonstrate three cases of t(14;19) translocation among the 200 CLL patients from 2017 to 2019 in our hospital. We investigated several aspects such as clinicopathologic features, cytogenetic analysis, IGHV mutations, next-generation sequencing technology (NGS), and histopathological characteristics in order to clearly define the features of this entity in Chinese patients and compare them with patients reported previously in western countries. RESULTS: The clinical and pathological features of our three cases resemble those of earlier reports. All patients had atypical morphologic features and atypical immunophenotypes with low CLL scores detected by flow cytometry. All cases were unmutated in the IGHV mutations. Two cases showed complex karyotype and one case demonstrate missense mutations of TP53 and FBXW7. CONCLUSION: In conclusion, this is the first report on IGH/BCL3-positive B-CLLs in Chinese people, which provided a comprehensive analysis of clinical and pathological characteristics. In addition to some similar clinical and laboratory features reported in the previous literature, we first found that CLL with t(14;19) has a higher possibility of being accompanied with high complex karyotype (high-CK), which is now regarded as a novel negative prognostic marker. Early identification of this abnormality in CLL patients is so important that patients can benefit from the more aggressive treatments at the onset of the disease.

Clinical Features and MicroRNA Expression Patterns Between AML Patients With DNMT3A R882 and Frameshift Mutations.

Background: DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. While the influences of DNMT3A mutation subtypes are still under debate. Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations. Methods: Next generation of sequencing (NGS) and clinical data of 118 AML patients in our center were analyzed and compared. NGS, mRNA and miRNA profiling and clinical data from 12 patients in TCGA database were integrative analyzed. Results: Among all patients enrolled, 113 patients were positive for the variants of interest. Overall, a total of 295 variants were discovered, among which 24 DNMT3A mutations were detected, including 1 non-sense, 20 missense, 3 frameshift mutations. And 7 DNMT3A R882 mutations (3 R882H, 2 R882C, and 2 R882P) were found. Clinical analysis from our cohort and TCGA database indicated that patients carrying DNMT3A R882 mutation exhibited significantly higher levels of peripheral blood hemoglobin and non-significantly inferior prognosis compared with patients with DNMT3A frameshift mutations. Integrative analysis indicated that miR-10b, miR-143, and miR-30a were significantly decreased in the DNMT3A R882 group. High miR-143 expression is significantly associated with better prognosis in AML patients with DNMT3A mutations. Conclusion: Different molecular and clinical characteristics existed between patients with DNMT3A variant subtypes. The distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations.

Clinical Characteristics and Prognosis of MAF Deletion in Chinese Patients With Multiple Myeloma.

BACKGROUND: In this study, we analyzed the frequency, clinical characteristics, and prognosis of MAF deletion in Chinese patients with multiple myeloma (MM). PATIENTS AND METHODS: Two hundred consecutive patients with newly diagnosed MM were analyzed. Patient samples were evaluated using a fluorescence in situ hybridization probe set, including 13q deletion, 17p deletion, and 1q21 gain, as well as immunoglobulin heavy chain gene (IgH) rearrangement, IgH/cyclin D1, IgH/fibroblast growth factor receptor 3 (FGFR3), and IgH/MAF. The frequency of MAF deletion and the clinical characteristics and overall survival of patients with MAF deletion were analyzed. RESULTS: The incidence rate of MAF deletion was 15.0% (30/200) in newly diagnosed patients and all of them were monoallelic of MAF deletion. MAF deletion was associated with sex (P = .008), lactate dehydrogenase level (P = .026), 13q deletion (P = .028), FGFR3 deletion (P = .006), and IgH deletion (P = .018). Additionally, in an analysis of the overall survival rates of patients with MAF deletion who received a bortezomib-based regimen treatment, no significant differences were found in overall survival between positive and negative groups (P = .365). CONCLUSION: MAF deletion was more frequent than MAF translocation with IgH in patients with MM and was more commonly observed in women. Moreover, MAF deletion was often combined with 13q, FGFR3, and IgH deletion. MAF deletion did not influence prognosis in patients with MM who were given a bortezomib-based chemotherapy regimen.

A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen-4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment.

Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) treatment is effective for the treatment of primary tumors, but not sufficient for the treatment of metastatic tumors, likely owing to the effects of the tumor microenvironment. In this study, we aimed to determine the therapeutic effects of combined treatment with a matrix metalloproteinase (MMP) inhibitor (MMPI) and anti-CTLA-4 antibody in a breast cancer model in mice. Interestingly, combined treatment with MMPI and anti-CTLA-4 antibody delayed tumor growth and reduced lung and liver metastases compared with anti-CTLA-4 alone or vehicle treatment. The functions of the liver and kidney in mice in the different groups did not differ significantly compared with that in normal mice. The CD8+/CD4+ ratio in T cells in the spleen and tumor were increased after monotherapy or combined anti-CTLA-4 antibody plus MMPI therapy compared with that in vehicle-treated mice. Anti-CTLA-4 antibody plus MMPI therapy reduced the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and decreased the Treg/Th17 cell ratio in the spleen compared with those in the vehicle-treated group. Additionally, anti-CTLA-4 antibody plus MMPI therapy reduced the percentages of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Th17 cells in tumors compared with that in the vehicle-treated group. Moreover, combined treatment with MMPI and anti-CTLA-4 antibody reduced the microvessel density (MVD) in tumors compared with that in vehicle or MMPI-treated mice. There was a negative correlation between MVD and the CD8+ T cell percentage, CD4+ T cell percentage, and CD8+/CD4+ T cell ratio, but a positive correlation with Tregs, Th17 cells, Treg/Th17 cell ratio, and MDSCs. Thus, these data demonstrated that addition of MMPI enhanced the effects of anti-CTLA-4 antibody treatment in a mouse model of breast cancer by delaying tumor growth and reducing metastases.