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The success of chimeric antigen receptor T‐cell (CAR‐T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co‐stimulatory molecules like 4‐1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second‐generation CAR‐T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR‐T infusions and improving sustainability of responses derived with CAR‐T therapy. Here, we summarize the clinical trial data leading to approval CAR‐T therapies in MM and NHL, discuss the limitations with current CAR‐T therapy strategies and review emerging strategies for overcoming these limitations. [ABSTRACT FROM AUTHOR]

Of 13 patients, only 1 patient had primary BNS, identified concurrently with the initial diagnoses of WM. Among 9 patients in whom radiologic response data were available for initial therapy, a complete radiologic response was noted in only one patient whereas 4 patients each had a partial response and stable disease on neuroimaging. The median follow-up of the entire cohort of patients with WM was 8.9 (95% CI 8.4-10.1) years from the diagnosis of WM and 8.5 (95% CI 5.4-14.5) years for the patients with BNS. Waldenström macroglobulinemia (WM) is an indolent lymphoma characterized by lymphoplasmacytic infiltration of bone marrow and circulating monoclonal IgM protein [[1]]. [Extracted from the article]

Multiple myeloma (MM) is a clonal plasma cell malignancy with a heterogeneous disease course. Insights into the genetics of the disease have identified certain high-risk cytogenetic features that are associated with adverse outcomes. While the advances in therapy have translated into dramatic improvements in the outcome of patients with MM, those with high-risk genetic features continue to perform poorly. This has resulted in a need for clinical trials focusing on the high-risk subgroup of MM as they search for additional biomarkers and therapeutic targets continue. In this review, we discuss the currently existing data on prognostic and predictive biomarkers in MM and speculate the role of treatment stratification based on the genetic features of the disease. [ABSTRACT FROM AUTHOR]

Summary: Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow‐up of 9·5 [8·1–11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2‐microglobulin (β2M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time‐to‐progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7–8·7) vs. 4·7 (2·4–7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C‐X‐C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT, P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age‐, sex‐ and calendar year‐matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre‐emptive intervention in this patient population. [ABSTRACT FROM AUTHOR]

Waldenström Macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic involvement of the bone marrow and serum IgM monoclonal protein of any size [[1]]. Of 893 consecutively seen WM patients, with a median follow-up of 9 years (95% CI, 8.4-9.7), 387 patients were placed into either the short-term survival group ( I n i = 171, 19%) or the long survival group ( I n i = 216, 24%). The median OS for the long survival group was not reached (IQR = 13.5 years-not reached) and the median age at diagnosis was 62 years (31-85 years); 50 (76%) patients died from causes related to WM and 16 (24%) from causes unrelated to WM. Another study from our institution reported that 10-year OS was 66% for patients with I MYD88 SP WT sp i and 61% for patients with I MYD88 i SP L265P sp ( I p i = 0.52), despite patients with I MYD88 i SP WT sp having a shorter time-to-transformation (5-year rate of 16% for I MYD88 i SP WT sp vs. 2.8% for the I MYD88 i SP L265P sp ) [[19]]. [Extracted from the article]

Summary: Ibrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression. [ABSTRACT FROM AUTHOR]

The expression of PD-L1 ligand on tumor cells in PTCL has been consistently shown to suppress T-cell proliferation and play a role in immune evasion in the various subtypes of PTCLs [[10]]. But a high soluble PD-L1 level does not necessarily correlate with a high PD-L1 expression on the tumor, suggesting that soluble PD-L1 could be originating from the tumor microenvironment [[14]]. In another recent study reported in an abstract form at the American Society Hematology Meeting 2018, a high PD-L1 expression on histiocytes and low PD-L1 on tumor cells were independently associated with an inferior overall survival [[12]]. Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. [Extracted from the article]

Background: EGFR tyrosine kinase inhibitors (TKIs) have greatly improved the outcomes of EGFR mutation-positive adenocarcinomas of the lung. In contrast, the significance of EGFR mutation in metastatic squamous cell carcinoma (SCC) of the lung has been debated. Methods: All patients with metastatic SCC who underwent EGFR mutation testing at our center from 2010 to 2015 were included for analysis. EGFR kinase domain mutations were tested using Taqman-based real-time polymerase chain reaction (PCR). Response assessment was done using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Kaplan-Meier method was used for calculating progression-free survival (PFS) and overall survival (OS). Results: EGFR mutation was detected in 29 out of 639 patients with SCC. Furthermore, 19 out of the 29 patients received TKIs at some point during their treatment. TKI therapy led to a partial response in 5 out of 19 patients and stable disease in 4 out of 19 patients. The median PFS of patients treated with TKIs was 5.0 months. The median OS of the whole EGFR-positive SCC cohort was 6.6 months. On univariate analysis, patients having received TKI therapy was the only factor associated with a significantly better OS of 13.48 months versus 2.58 months (P=0.000). On multivariate analysis, patients receiving TKI therapy, Eastern Cooperative Oncology Group-Performance Scale (ECOG-PS) score <2, EGFR exon 19 mutation and nonsmoking status were associated with significantly better OS. Conclusion: EGFR mutation in SCC of the lung predicts a better outcome if the patient is given TKI, but it may be inferior to the outcomes seen in EGFR-positive adenocarcinomas treated with TKI. [ABSTRACT FROM AUTHOR]

BACKGROUND: A small proportion of Non-Small Cell Lung Cancers (NSCLC) are detected with Anaplastic Lymphoma Kinase (ALK) mutation by immunohistochemistry (IHC) but are negative by Fluorescence in situ Hybridization (FISH). Data on responses and outcome of this subset of patients when treated with crizotinib is limited. We analyzed the outcomes of such patients who received crizotinib. PATIENTS AND METHODS: Demographics, treatment details, response to treatment, date of progression and date of death were collected for patients who were IHC positive and FISH negative for ALK mutation from a prospectively maintained database. Depending upon feasibility, patients received either platinum based doublet chemotherapy or the ALK inhibitor crizotinib as first line therapy. Outcomes were compared to our previously published historical cohort of FISH positive patients who were treated with crizotinib. RESULTS: Thirteen patients were detected to be IHC+/FISH- and out of these seven received crizotinib. Objective response rate for crizotinib was 57.15% with an estimated mean PFS of 9.6 months (95% CI 3.8 -15.5 months). The difference in ORR of ALK IHC+/FISH- when compared to our historical cohort of ALK FISH positive treated with crizotinib was not statistically significant (57.15% vs 69.8%; P = 0.265). Estimated mean and median PFS was similar between the two cohorts (median PFS 6.0 months vs 14 months; mean PFS 9.6 months versus 14.7 months; P = 0.467). CONCLUSION: NSCLCs positive for ALK mutation by IHC but not detected by FISH show good response to crizotinib and merit treatment with the same. [ABSTRACT FROM AUTHOR]

Background: A small proportion of Non-Small Cell Lung Cancers (NSCLC) are detected with Anaplastic Lymphoma Kinase (ALK) mutation by immunohistochemistry (IHC) but are negative by Fluorescence in situ Hybridization (FISH). Data on responses and outcome of this subset of patients when treated with crizotinib is limited. We analyzed the outcomes of such patients who received crizotinib.Patients and Methods: Demographics, treatment details, response to treatment, date of progression and date of death were collected for patients who were IHC positive and FISH negative for ALK mutation from a prospectively maintained database. Depending upon feasibility, patients received either platinum based doublet chemotherapy or the ALK inhibitor crizotinib as first line therapy. Outcomes were compared to our previously published historical cohort of FISH positive patients who were treated with crizotinib.Results: Thirteen patients were detected to be IHC+/FISH- and out of these seven received crizotinib. Objective response rate for crizotinib was 57.15% with an estimated mean PFS of 9.6 months (95% CI 3.8 -15.5 months). The difference in ORR of ALK IHC+/FISH- when compared to our historical cohort of ALK FISH positive treated with crizotinib was not statistically significant (57.15% vs 69.8%; P = 0.265). Estimated mean and median PFS was similar between the two cohorts (median PFS 6.0 months vs 14 months; mean PFS 9.6 months versus 14.7 months; P = 0.467).Conclusion: NSCLCs positive for ALK mutation by IHC but not detected by FISH show good response to crizotinib and merit treatment with the same. [ABSTRACT FROM AUTHOR]

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations in China. While the EGFR mutation rate in SCCs is definitely much lower compared to their counterpart with ADCs, this still represents a substantial number of patients. The discovery of mutations in the epidermal growth factor receptor (EGFR) mutations in metastatic non-small cell lung cancer (NSCLC) has been a focal point in changing the treatment landscape of these tumors.[[1]] There is abundance of data with regard to the prevalence of EGFR mutation and the efficacy of small molecule tyrosine kinase inhibitors (TKIs) in targeting these driver mutations in metastatic adenocarcinomas (ADCs) of the lung.[[2]] The EGFR mutation rate in ADCs varies substantially with the population under study, with the prevalence being the lowest in the Northern American and European studies ranging from 10 to 15%, to approximately 25% in Indian setting and to an even higher prevalence in studies from Eastern Asia.[[3]] This marked heterogeneity in the mutation profile across patients with different ethnicities makes it tricky to interpret these data from a non-representative study population and apply them into practice. [Extracted from the article]

Central venous catheters (CVCs) represent a significant source of infection in patients undergoing hematopoietic stem cell transplantation and can add to the cost of care, morbidity, and mortality. Organisms forming biofilms on the inner surface of catheters require a much higher local antibiotic concentration to clear the pathogen growth. Antibiotic lock therapy (ALT) represents one such strategy to achieve such high intraluminal concentrations of antibiotics and can facilitate catheter salvage. Patients with catheter colonization (CC) or hemodynamically stable catheter‐related bloodstream infection (CRBSI) received ALT per institutional policy. We analyzed the incidence of CC and CRBSI and salvage rate of tunneled CVCs (Hickman) with ALT in patients undergoing hematopoietic stem cell transplant in this retrospective study. Catheter colonization was noted in 9.8% and CRBSI in 10.7% patients. Gram‐negative bacilli (GNB) accounted for 45% and 83% of isolates in CC and CRBSI, respectively. In patients with CRBSI, the rate of catheter salvage with the use of ALT in addition to systemic antibiotics was 86% compared to 55% in patients with systemic antibiotics use only (P = 0.06). There was no CRBSI related mortality, and no increase in resistant strains was noted at subsequent CRBSI. In conclusion, ALT represents an important strategy for catheter salvage, especially for gram‐negative infections, in a carefully selected patient population. [ABSTRACT FROM AUTHOR]

Background & objectives: Gemcitabine combined with non-cremophor-based paclitaxel is one of the standards of care in advanced inoperable pancreatic cancer. This study was undertaken to retrospectively evaluate real world non-trial outcomes with this combination. Methods: Patients with histologically proven advanced inoperable pancreatic adenocarcinoma (PDAC), treated with non-cremophor-based paclitaxel-gemcitabine combination (PG) (gemcitabine-nanoxel or gemcitabine-abraxane) between January 2012 and June 2015, were retrospectively analyzed. Response assessment was done every 8-12 wk with computed tomography scan and responses were measured as per the Response Evaluation Criteria in Solid Tumours 1.1 criteria where feasible. Toxicity was recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: A total of 78 patients with PDAC were treated with the combination. Of these, 83.3 per cent of patients had metastatic disease. The median number of chemotherapy cycles administered was three. The objective response rate for the whole group was 30.8 per cent. Grade III/IV toxicities were seen in 35.9 per cent of patients. Median PFS was 5.6 months and median OS was 11.6 months. Interpretation & conclusions: Non-cremophor-based paclitaxel in combination with gemcitabine appeared efficacious for advanced pancreatic cancers in routine clinical practice. Within the confines of a single-centre retrospective analysis, gemcitabine-nanoxel and gemcitabine-abraxane appeared to have similar efficacy and toxicity in advanced pancreatic cancers. [ABSTRACT FROM AUTHOR]

Summary: Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM. [ABSTRACT FROM AUTHOR]

Introduction. Sinonasal tumors are chemotherapy responsive which frequently present in advanced stages making NACT a promising option for improving resection and local control in borderline resectable and locally advanced tumours. Here we reviewed the results of 25 such cases treated with NACT. Materials and Methods. Sinonasal tumor patients treated with NACT were selected for this analysis. These patients received NACT with platinum and etoposide for 2 cycles. Patients who responded and were amenable for gross total resection underwent surgical resection and adjuvant CTRT. Those who responded but were not amenable for resection received radical CTRT. Patients who progressed on NACT received either radical CTRT or palliative radiotherapy. Results. The median age of the cohort was 42 years (IQR 37–47 years). Grades 3-4 toxicity with NACT were seen in 19 patients (76%). The response rate to NACT was 80%. Post-NACT surgery was done in 12 (48%) patients and radical chemoradiation in 9 (36%) patients. The 2-year progression free survival and overall survival were 75% and 78.5%, respectively. Conclusion. NACT in sinonasal tumours has a response rate of 80%. The protocol of NACT followed by local treatment is associated with improvement in outcomes as compared to our historical cohort. [ABSTRACT FROM AUTHOR]