Conventional Chemotherapy Regimens Research Articles

Combination of PD-1 inhibitor with GVD (gemcitabine, vinorelbine, liposomal doxorubicin) versus GVD regimen as second-line therapy for relapsed/refractory classical Hodgkin lymphoma.

Patients with classical Hodgkin lymphoma (cHL) who do not achieve complete remission (CR) after second-line chemotherapy have poor clinical outcomes. Besides, conventional salvage chemotherapy regimens have an unsatisfactory CR rate. The present retrospective study reports the efficacy and toxicity of the GVD (gemcitabine, vinorelbine, liposomal doxorubicin) regimen with or without programmed cell death 1 (PD-1) inhibitor for patients with cHL who failed first-line treatment. A total of 103 patients with cHL (GVD+PD-1 group, n = 27; GVD group, n = 76) with response assessment based on positron emission tomography were included. The GVD+PD-1 group tended to have a higher CR rate than GVD group (85·2% vs. 65·8%, P = 0·057) and had a better event-free survival (EFS) (P = 0·034). Subgroup analysis showed that patients with low-risk second-line International Prognostic Score might benefit from the addition of PD-1 inhibitor (GVD+PD-1 vs. GVD, 100·0% vs. 64·7%, P = 0·028) and had better EFS than GVD alone (P = 0·016). Further analysis demonstrated that PD-1 consolidation therapy might provide an EFS benefit (P = 0·007). The toxicity of the GVD+PD-1 regimen was comparable to the GVD regimen, except for higher rates of hypothyroidism and autoimmune pneumonitis, which were manageable. In conclusion, combining a PD-1 inhibitor with a GVD regimen could be a potentially effective second-line therapy for patients with cHL.

Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma

AbstractWe performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale–Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

Role of High Dose Chemotherapy and Autologous Stem Cell Transplant in Relapsed Ewing's Sarcoma — a Systematic Review

Introduction: Relapsed Ewing's sarcoma (ES) is an aggressive malignancy with poor survival. Conventional dose salvage chemotherapy (CC) regimens given at the time of relapse led to response rate up to 28-68% with reported event free survival (EFS) of 29% at 2 years and Overall survival (OS) of 49 % at 1 year and 28-31 % at 2 years (Van Winkle, P. et al. 2005, Magnan et al. 2015). High dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given as induction or as part of consolidation treatment after few cycles of CC has shown benefit in improving OS and EFS in single center studies. (McTiernan et al. 2006, Barker et al. 2005) Despite report of its utility, HDCT is not generally used in United states for relapsed ES and a comprehensive search and systemic review was performed to evaluate the benefits of HDCT for this disease.Methods: Comprehensive literature search was conducted in Medline (PubMed and Ovid SP), Embase and Cochrane Database of Systematic Review (CDSR). These databases were searched from the inception of databases till present. In addition, we manually selected more studies from bibliography data. We included studies that had relapsed Ewing's sarcoma patients and those which had mixed data for relapsed as well as primary metastatic disease treated with HDCT.Results: Through literature and bibliography search, 1005 studies were identified and after screening, 24 studies containing a total of 1459 patients were included in the final analysis. Seventeen studies had patients with primary metastatic disease and relapsed Ewing's sarcoma. Seven had only relapsed ES patients. In the studies with relapsed patients (n = 809), EFS for most studies at two and five years ranged from 42-44% and 24-43% respectively. The OS at two years and three to five years ranged from 50-66% and 21-50% respectively. In studies with combined primary metastatic and relapsed patients (n=650), EFS at one to two years and three to five years was 45-60% and 17-47% respectively. The OS at one to two years and three to five years was 40-70% and 31-50% respectively.Five studies (n=709) (Table 1) compared results of patients who received HDCT along with ASCT after CC to those who received only CC. Two to three and four to five years EFS for patients who received HDCT was 39-44% and 17-61% respectively, whereas it was 10-32% and 2-7% for patients who received only conventional dose therapy. OS of patients who received HDCT was 50-66% at two to three years and 42-77% at four to five years, whereas it was 14-34% and 7-10% respectively for patients who received only CC. Patients selected to receive HDCT in most of these studies were those who showed a response to initial CC (chemosensitive), either complete or partial response (CR/PR) (Rasper et al. 2014, Dirkson et al. 2014, Barker et al. 2005, Al faris et al. 2007, Frolich et al. 1999).Relapsed patients in Pole et al. (1984) survived only for three to six months. They had metastatic disease at relapse and did not receive conventional therapy prior to HDCT, possibly contributing to their decreased survival. Shankar et al 2003 reported EFS and OS at three and half years to be 14% and 28% respectively in spite of receiving CC followed by HDCT and ASCT.Conclusions: Most studies showed that HDCT followed by ASCT given as consolidation regimen improved OS and EFS compared to CC. Two studies (Pole et al. 1984 and Shankar et al. 2003) showed lower survival after HDCT when compared to CC. Patients in Pole et al study had metastatic disease at relapse and also did not receive CC prior to HDCT, which may have affected the survival. The reason for decreased survival in Shankar et al study is not clear. Five studies which compared patients who received HDCT and ASCT in addition to CC with patients who received only CC showed improved survival in patients who received HDCT followed by ASCT. Patients selected to receive HDCT showed initial chemosensitivity (by achieving CR or PR) to CC, suggesting that proof of chemosensitive disease is an important prognostic factor for improving survival with HDCT. The heterogeneity in the data prevented us from conducting a meta-analysis. Large scale randomized control studies are needed to determine true clinical benefit of HDCT followed by ASCT in patients with relapsed Ewing's sarcoma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

CPX-351: an attractive option for the treatment of older patients with high-risk or secondary acute myeloid leukaemia

Therapy-related acute myeloid leukaemia and acute myeloid leukaemia with myelodysplasia-related changes are aggressive diseases with a worse prognosis than de novo acute myeloid leukaemia, especially in older patients. In these acute myeloid leukaemia subtypes, conventional chemotherapy regimens produce particularly poor results. Only allogeneic haematopoietic stem-cell transplantation (HSCT) done when a patient is in good response or remission can be considered for longer survival. There is therefore a need to develop new therapeutics to increase frequency and depth of response to treatment.

Conventional myelosuppressive chemotherapy for non-haematological malignancy disrupts the intestinal microbiome

BackgroundThe gut microbiota influences many aspects of host physiology, including immune regulation, and is predictive of outcomes in cancer patients. However, whether conventional myelosuppressive chemotherapy affects the gut microbiota in humans with non-haematological malignancy, independent of antibiotic exposure, is unknown.MethodsFaecal samples from 19 participants with non-haematological malignancy, who were receiving conventional chemotherapy regimens but not antibiotics, were examined prior to chemotherapy, 7–12 days after chemotherapy, and at the end of the first cycle of treatment. Gut microbiota diversity and composition was determined by 16S rRNA gene amplicon sequencing.ResultsCompared to pre-chemotherapy samples, samples collected 7–12 days following chemotherapy exhibited increased richness (mean 120 observed species ± SD 38 vs 134 ± 40; p = 0.007) and diversity (Shannon diversity: mean 6.4 ± 0.43 vs 6.6 ± 0.41; p = 0.02). Composition was significantly altered, with a significant decrease in the relative abundance of gram-positive bacteria in the phylum Firmicutes (pre-chemotherapy median relative abundance [IQR] 0.78 [0.11] vs 0.75 [0.11]; p = 0.003), and an increase in the relative abundance of gram-negative bacteria (Bacteroidetes: median [IQR] 0.16 [0.13] vs 0.21 [0.13]; p = 0.01 and Proteobacteria: 0.015 [0.018] vs 0.03 [0.03]; p = 0.02). Differences in microbiota characteristics from baseline were no longer significant at the end of the chemotherapy cycle.ConclusionsConventional chemotherapy results in significant changes in gut microbiota characteristics during the period of predicted myelosuppression post-chemotherapy. Further study is indicated to link microbiome changes during chemotherapy to clinical outcomes.

A narrative review of current and potential prognostic biomarkers for immunotherapy in small-cell lung cancer.

Small-cell lung cancer (SCLC) is a highly invasive and rapidly proliferating pathologic subtype that accounts for 13–15% of all lung cancer cases. Recently in extensive-stage SCLC, treatments that combine immunotherapy and chemotherapy showed increased efficacy compared to chemotherapy alone in several trials. However, the combination of immunotherapy and conventional chemotherapy regimens was introduced only recently for extensive-stage SCLC, with relatively little real-world data. The demand for reliable biomarkers that can predict the efficacy of immunotherapy in SCLC is high. Several studies evaluated various parameters including programmed cell death ligand-1 (PD-L1) expression, tumor mutation burden (TMB), gene expression profiling, autoantibody, and blood cytokines for predictive value for response to immunotherapy in SCLC. Despite some observed correlations, there is a lack of concrete support for the use of PD-L1 expression levels for readily available biomarker. High TMB in combination with smoking history is predictive of a better response to immunotherapy, but validation of cutoffs and testing methods is necessary before it can be widely applied in clinical settings. Other candidate biomarkers such as immune cell distribution among tumor microenvironment, and systemic inflammatory markers can also be evaluated, after an accumulation of real-life data from SCLC patients under immunotherapy.

Clinical features and treatment outcomes of 14 patients with hepatosplenic γ δ T-cell lymphoma.

Hepatosplenic γ δ T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma (PTCL) with aggressive clinical behavior. To date, no standard therapy for HSTCL has been established. This study analyzed the clinical features, treatment, and prognosis for patients with HSTCL to determine the best therapeutic approach. We reviewed the clinical characteristics, treatments, and responses to treatment of patients in our center between January 2001 and June 2021, and also reviewed related literature. Median patient age was 38years (range 16-60years) and the patients included eight males and six females. HSTCL in these patients typically presented with B symptoms (71.4%), splenomegaly (100%), and hepatomegaly (50.0%), but lymphadenopathy was extremely rare. In these patients, routine laboratory testing showed elevated lactate dehydrogenase (71.4%), liver dysfunction (42.9%), and decreased fibrinogen (35.7%). In the induction phase, five of the 14 patients received chemotherapy regimens containing anthracycline (CHOP, or CHOP plus bortezomib or Chidamide), and six were treated with non-CHOP chemotherapy. Seven patients responded to induction treatment, four of whom received allogeneic hematopoietic cell transplantation and then achieved a complete response in the consolidation phase. survival time of patients who received alloHCT range from 10 to 27months. Hepatosplenic γ δ T-cell lacks a standard therapy and is often refractory to conventional chemotherapy regimens. Intensive induction chemotherapy followed by hematopoietic cell transplantation may improve the prognosis of HSTCL.

Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study.

BackgroundNeoadjuvant therapy has significantly improved the 5-year overall survival (OS) of patients with resectable non-small cell lung cancer (NSCLC). The CheckMate 159 trial showed that neoadjuvant therapy with a single-drug programmed cell death protein 1 (PD-1) inhibitor (nivolumab) achieved major pathological response (MPR) and pathological complete response (pCR) in 45% and 15%of participants, respectively. We conducted an open-label single-arm study to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy in the treatment of resectable NSCLC.MethodsThis study was conducted in a total of 2 hospitals in the Chinese cities of Xi’an and Chongqing, and included eligible patients over 18 years of age with clinically staged IIA–IIIB NSCLC. All patients were scheduled to receive surgery within 4–6 weeks after neoadjuvant treatment (3–4 cycles) consisting of PD-1 inhibitors combined with a conventional chemotherapy regimen on day 1 of each 21-day cycle.ResultsTwenty-three patients, 22 males, and 1 female with just one of them with no smoking habits) were diagnosed with NSCL C in a stage IIA (3 cases), IIB (3 cases), IIIA (8 cases), and IIIB (9cases) and no druggable driver mutations/translocations were addressed to receive neoadjuvant treatment between June 2018 and June 2020. The treatment was well tolerated with just 3 typical immune-related adverse events (hyperthyroidism, hyperglycemia, and rash) recorded. There was a partial response (PR) and stable disease (SD) in 17 (73.9%) and 6 (26.1%) patients, with an overall response rate (ORR) of 73.9% according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Six of these patients resulted in pCR (30%) while ten of them showed a MPR (50%). Twenty patients underwent surgical resection after treatment, while further 3 refused surgery. Surgical procedure included video-assisted thoracoscopic resection (10 cases), Vinci Robot surgery (4 cases), and thoracotomy in 4 cases while there were secondary compliance-related thoracotomy in two cases. The pathology analysis revealed a R0 in 19 cases (19/20, 95%).ConclusionsOur results suggest that the neoadjuvant approach with chemotherapy and PD-1 blocking mAbs is safe and active in patients with resectable NSCLC where is associated with a promising high ORR, MPR and pCR.

PD-L1 Expression in colorectal carcinoma and its correlation with clinicopathological parameters, microsatellite instability and BRAF mutation.

: Programmed cell death ligand-1 (PD-L1) is the key inhibitor of the cytotoxic immune response thus causing progression of tumors and adverse prognosis in many malignancies. The current study investigates PD-L1 expression in colorectal carcinoma and its correlation with clinicopathological parameters, microsatellite instability, and BRAF mutation. 110 cases of colorectal carcinoma were evaluated for PD-L1 expression using SP263 clone in tissue microarray. Clinico-pathological characteristics and survival data were correlated with PD-L1 expression analyzed at different cut-offs of ≥1%, ≥10% and ≥50% in tumor cells and tumor infiltrating lymphocytes along with its correlation with BRAF expression and microsatellite instability status in these cases. Mean age was 49 years with male to female ratio of 1.5:1. 52.7% cases presented with stage 3/4 disease and 14.7% with >10 cm tumor size. Tumor cells expressed PD-L1 in 40% and TILs in 45.4% cases at a cut off of ≥1% was 17.3%, at ≥10% was 15.5% and at ≥50% was 7.3%. Significant association was seen between tumor proportion score (TPS) and increasing age, histological type, histological grade, tumor size, higher T stage (p = 0.03), TILs (p = 0.04), lymph vascular invasion, and perineural invasion. PDL-1 correlated with BRAF expression and microsatellite instability (MLH-1/PMS-2 expression loss). The overall survival was significantly higher (p < 0.001) with negative PDL1 expression in cases of colorectal carcinoma. Immunotherapy may be used as potential therapeutic option in colorectal carcinoma cases showing microsatellite instability and BRAF mutations which show poor response to conventional chemotherapy regimen and anti-EGFR therapy.

Undifferentiated and dedifferentiated neoplasms of the female genital tract.

Undifferentiated neoplasms in the female gynecologic tract comprise two main groups-undifferentiated carcinoma, most common in the endometrium and ovary, and undifferentiated uterine sarcoma, although tumors with an undifferentiated appearance may occur in all gynecologic organs. Their differential diagnosis is broad and generous sampling, careful morphological evaluation, judicious use of immunohistochemistry, and in many cases, molecular testing is often essential in the diagnostic work-up. As some of these neoplasms fail to respond to conventional chemotherapy regimens and/or radiation therapy, targeted therapy may be valuable in treating these highly aggressive tumors, thus the importance of precise diagnosis. In this review we discuss the clinicopathological features of undifferentiated carcinoma, dedifferentiated carcinoma, and undifferentiated uterine sarcoma, followed by a comprehensive analysis of morphological mimickers. Finally, we briefly review ovarian and lower genital tract tumors with an undifferentiated histological appearance.

Treatment Strategies and Outcomes for Patients with Peripheral T-Cell Lymphoma and Its Subtypes

Introduction Peripheral T-cell lymphoma (PTCL) is diverse group of an uncommon and aggressive type of non-Hodgkin lymphoma (NHL). It generally affects people aged 60 years and above and is diagnosed slightly more often in men than in women. However, younger adults and children are also diagnosed with PTCL. Being a rare entity, the best treatment regimen has not been established for newly diagnosed patients or for relapsed/refractory patients with PTCL. In general, treatment outcomes have been poor with conventional chemotherapy regimens. Methods We performed a retrospective cohort study of patients with newly diagnosed and relapsed PTCL, and its subtypes, who are seen in the hematology-oncology clinic at the University of Arkansas for Medical Sciences from July 2014 to December 2019. The demographics of the study population, the frontline and second-line treatment strategies for all the subtypes and the response to the treatment were studied. Also, the role of high dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) in the overall survival (OS) and progression-free survival (PFS) is analyzed. Results Out of the 48 patients, 45.8% (n=22) patients had PTCL not otherwise specified (PTCL NOS) type, 29% (n=14) had Anaplastic large cell lymphoma ALK-negative subtype, 4.2 % (n=2) had Anaplastic large cell lymphoma ALK-positive subtype, Angioimmunoblastic T-cell lymphoma, Extra nodal NK/T cell lymphoma, Enteropathy associated T- cell lymphoma each. The mean age of diagnosis was 58 ± 2. Males were affected more when compared to females (66.6% vs 33.3%). Also, Caucasians were more affected than African Americans (73% vs 25%). The mortality of PTCL was found to be 40%. After frontline treatment, complete response (CR) was observed in 43.7% (n= 21) patients, partial response (PR) was observed in 18.7% (n= 9) patients, stable disease (SD) was seen in 4% (n=2), progression of disease (PD) was observed in 12.5% (n= 6) patients. Stem cell transplant (HDT-ASCT) was done for 28% (n=13) of patients who achieved CR after frontline chemotherapy (CR1). Relapse was observed in 60% of patients. Patients with stage III and IV on the initial diagnosis had a higher chance of relapse or refractory disease. After the second-line treatment, out of 20 patients, 9 patients had CR, 5 had PR, 5 patients had PD, 1 patient had SD. CR was observed in 7 patients with either brentuximab vedotin alone or brentuximab vedotin with combination chemotherapy as second-line treatment. The OS and PFS were found to be higher in patients who received HDT-ASCT after CR1. Conclusion PTCL has a high risk of relapse and there are no uniform guidelines for the treatment of PTCL in relapsed or refractory setting. The currently available second line treatment options have shown modest response rates. Our study has shown that brentuximab vedotin, when used alone or in combination, showed better response rate in the relapsed setting. Also, stem cell transplant improved the overall survival and progression-free survival in patients with PTCL after frontline chemotherapy. Disclosures No relevant conflicts of interest to declare.

Clinical, Laboratory, and Genetic Features of Erdheim-Chester Disease Patients from Two Reference Centers in a Developing Country

INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare histiocytic neoplasm with a heterogenous clinical course with asymptomatic localized course or systemic compromise involving multiples organs causing significant morbidity and mortality. There are few cohorts published however mainly from North America and Europe. Given the scarcity of data on ECD in Latin America, we have established a local registry in the city of São Paulo to collect clinical and biological material of ECD patients. METHODS: We retrospectively collected clinical data on biopsy-proven ECD patients diagnosed and treated at two reference centers for histiocytic disorders (Hospital das Clínicas da Universidade de São Paulo e Hospital Sírio-Libanês, Brazil) from January 2006 to February 2020. RESULTS: Sixteen patients with confirmed diagnosis of ECD were included with median age of 53 years. 75% were males and a median follow-up time of 50 months (7-163). Median time from onset of symptoms to diagnosis was 13 months (0.1-142). Immunohistochemistry (IHC) findings showed positivity for CD68 in 15/16 (94%) and for S100 in 3/16 (19%) patients, no case had CD1a positivity. The most frequent organs involved were: bone (75%), skin (44%), central nervous system (CNS) (44%), lymph nodes (31%), lung (13%), liver (6%), spleen (6%), and gastrointestinal tract (6%) of cases. CNS lesions involvement occurred mostly in the pituitary gland (86%). Twelve of 16 (75%) patients presented disease in more than one organ. Xanthelasma and xanthoma were the most common skin lesions (44%). The most frequent histiocytosis-related clinical manifestations were bone pain (44%) and diabetes insipidus (38%). The most frequent radiologic findings were osteosclerosis in 12/16 (75%) patients, retroperitoneal fibrosis around the kidneys in 6/16 (38%), the coated aorta sign and orbital infiltration were found in 4/16 (25%) of cases. 18FDG/PET-CT was performed in all patients, of whom 13 (81%) had hypermetabolic lesions. BRAF status at diagnosis was available in 13/16 patients using the technique of Sanger in 5/13, pyrosequencing in 3/13, IHC in 3/13 and polymerase chain reaction (PCR) in 2/13. Mutations were detected in only 3/16 (19%) cases. All patients received treatment due to symptomatic disease with a median of two lines of therapy (1-7). Median time between diagnosis and the first treatment was one month. First-line treatments were interferon in 12/16 patients, steroids in 5/16, and each one of thalidomide, vemurafenib and tumoral resection in one patient. Beyond first-line therapy, the most conventional chemotherapy regimens used were cladribine (4/16 patients) and LCH-like etoposide-containing vinblastine, methotrexate and mercaptopurine (2/16 patients). Other treatments included radiotherapy (4/16 patients) and a single patient used cobimetinib, imatinib and infliximab. Median progression free survival (PFS) after the first line treatment was 7.5 months (95% CI 5-10), and median overall survival (OS) was not reached to this date. Time to next treatment was 9 months in patients who did not achieved at least partial response after first line, and 15 months in those who attained it. PFS at 2 years was 45% (95% CI 0.17-0.71), and OS at 2 years was 100%. One patient died due to infection complication after the first cycle of cladribine after 50 months of follow-up. CONCLUSION: To our knowledge, despite the low number of patients, this is the largest Latin American cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups. However, it is noteworthy that the proportion of ECD patients bearing a BRAF mutation (18.8%) was pretty lower than previously reported (approximately 50%). This needs to be taken cautiously due to the small number of subjects and due to technical issues, since all samples analyzed by PCR or Sanger were negative for BRAF mutation. A national registry of histiocytosis is needed to confirm these preliminary data. Disclosures No relevant conflicts of interest to declare.

Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm

Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm

Phase I Study of Lenalidomide Combined with Dose-Adjusted EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma in Participants with or without HIV (NCT02911142)

Phase I Study of Lenalidomide Combined with Dose-Adjusted EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma in Participants with or without HIV (NCT02911142)

Antitumor Effect of Sugar-Modified Cytosine Nucleosides on Growth of Adult T-Cell Leukemia Cells in Mice.

Adult T-cell leukemia (ATL) is a CD4+ T-cell neoplasm caused by human T-cell leukemia virus type I. As the prognosis for patients with ATL remains extremely poor due to resistance to conventional chemotherapy regimens, introduction of novel therapeutic agents is needed. Previous studies have reported that nucleosides 2′-deoxy-2′-methylidenecytidine (DMDC) and its derivative 2′-deoxy-2′-methylidene-5-fluorocytidine (FDMDC) exhibit antitumor activities in T-cell acute lymphoblastic leukemia (T-ALL) and solid tumor cell lines. Another nucleoside, 1-(2-azido-2-deoxy-β-D-arabinofuranosyl)cytosine (cytarazid), is considered a therapeutic drug with antitumor activity in human solid tumors. In this study, we investigated the effects of these nucleosides on cell growth in vitro and in vivo using relevant leukemia cell lines and NOD/Shi-scid, IL-2Rgnull (NOG) mice, respectively. The nucleosides demonstrated significant cytotoxic effects in ATL and T-ALL cell lines. Intraperitoneal administration of FDMDC and DMDC into tumor-bearing NOG mice resulted in significant suppression of tumor growth without lethal side effects. Our findings support a therapeutic application of these nucleosides against tumor progression by targeting DNA polymerase-dependent DNA synthesis in patients with ATL.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Uterine carcinosarcomas and metaplastic breast carcinomas: Genetically related cancers?

Objective: Uterine carcinosarcoma (UCS) and metaplastic breast carcinoma (MBC) are aggressive cancers characterized by an admixture of epithelial and mesenchymal-appearing histologic components, poor clinical outcome, and relative resistance to conventional chemotherapy regimens. We sought to define whether UCSs and MBCs harbor similar patterns of genetic alterations, and whether the different histologic components of UCSs and MBCs are clonally related.

The BCL-2 family protein inhibitor ABT-737 as an additional tool for the treatment of EBV-associated post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) and Burkitt's lymphoma (BL) are B-cell malignancies strongly associated with Epstein-Barr virus (EBV) infection. In these lymphoproliferative disorders, EBV infection induces an increase in the expression of the anti-apoptotic protein BCL-2. Given its chemoprotective effect, BCL-2 constitutes an attractive target for new therapeutic strategies for EBV-positive B-cell malignancies. Here, we show that ABT-737, a small inhibitor of BCL-2, BCL-X(L), and BCL-w, strongly induced apoptosis invitro in EBV-positive lymphoblastoid cell lines (which is a model for PTLD), whereas BL was less sensitive. ABT-737 reduced tumor growth and increased the overall survival of mice in a xenograft model of PTLD but had no effect on BL xenograft mice. ABT-737 combined with a low dose of cyclophosphamide, a major component of the conventional CHOP chemotherapy regimen for BL patients, reduced tumor growth during treatment but failed to improve the overall survival of BL xenograft mice. By contrast, the combination of ABT-737 and rituximab, one of the main options for the treatment of PTLD, was highly efficient and induced approximately 70% remission in PTLD xenograft mice. These results suggest that the use of agents targeting BCL-2, either alone or in combination with other conventional drugs, represents a novel promising approach for post-transplant EBV-positive B lymphoproliferative disorders.

A Novel Combination of Pterostilbene and Dexamethasone Enhances Anti-proliferation and Apoptosis Induction Properties in Lymphoblastic Leukemia Cell Line

Background: T-cell acute lymphoblastic leukemia is an aggressive hematologic malignancy that results from the transformation of T-cell progenitors. Despite the significant advances in the current treatments, the side effects of conventional chemotherapy regimens are still a major concern. Pterostilbene (PT) is a natural compound reported to have anti-tumor effects. This study aimed to investigate the effect of PT combined with dexamethasone on the proliferation inhibition and apoptosis stimulation in a lymphoblastic leukemia cell line. Methods: In this experimental study, we cultured Jurkat cell line in RPMI1640 culture medium under standard conditions. We incubated the cells with different concentrations of PT and dexamethasone separately or in combination for 48 h. MTS assay investigated the cell viability. We assessed apoptosis induction by annexin V-FITC/PI and flow cytometry analysis. Results: PT and dexamethasone reduced the viability of the cells with inhibition concentrations of 60.97±3.36 and 451.1±10.1 µM, respectively, in 48 hours. None of the concentrations of dexamethasone, employed alone, significantly reduced the cell viability. The combination of 450 µM dexamethasone with 60 µM PT induced apoptosis in more than 70% of the cells with a significant difference compared to control. Conclusion: PT increased the anti-proliferative and apoptosis-inducing activity of dexamethasone in Jurkat cell line. This combination drug strategy can be a novel approach for a more powerful anti-cancer therapy.

Effect of interferon-α-2b and interleukin-2 combined with chemotherapy in metastatic melanoma.

To explore the efficacy and safety of interferon-α-2b and interleukin-2 combined with chemotherapy in treating patients with metastatic melanoma. The patients with metastatic melanoma in control group (N.=52) were treated with conventional DDAVC chemotherapy regimen, while those in combination group (N.=52) received biotherapy with interferon-α-2b and interleukin-2 in addition to the chemotherapy in control group. At the end of the treatments, the serum immune function indicators, short-term efficacy and incidence of adverse reactions were compared between the two groups of patients, and patient's survival was followed up and recorded. At 1 week after treatment, it was found that the overall response rate in combination group was substantially higher than that in control group (P=0.027). Besides, according to the serologic test results at 1 week after the chemotherapy, T lymphocyte subset activity was enhanced in patients in combination group compared with that before chemotherapy, with no statistically significant difference (P>0.05), but it was notably weakened in control group in comparison with that before chemotherapy (P<0.05). Finally, it was discovered through the log-rank test that the overall survival (OS) rate in combination group was remarkably superior to that in control group (P=0.029), but there was no statistically significant difference in the progression-free survival (PFS) rate between the two groups (P=0.076). Compared with chemotherapy alone, interferon-α-2b and interleukin-2 combined with chemotherapy can raise the clinical short-term efficacy and long-term OS rate in the patients with metastatic melanoma and alleviate their toxic side reactions, with higher safety.