Use of a real-world synthetic control arm for direct comparison of lisocabtagene maraleucel and conventional therapy in relapsed/refractory large B-cell lymphoma.

This study used a real-world population as a synthetic comparator for the single-arm TRANSCEND NHL 001 study (TRANSCEND; NCT02631044) to evaluate the efficacy of lisocabtagene maraleucel (liso-cel) compared with conventional (noncellular) therapies in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Inclusion and exclusion criteria for the real-world study closely matched the enrollment criteria in TRANSCEND. The analytic comparator cohort was created by matching and balancing observed baseline characteristics of real-world patients with those in TRANSCEND using propensity score methodology. Efficacy outcomes comparing liso-cel- (n = 257) and conventional therapy-treated (n = 257) patients, respectively, significantly favored liso-cel: overall response rate (74% vs 39%; p < 0.0001), complete response rate (50% vs 24%; p < 0.0001), median overall survival (23.5 vs 6.8 months; p < 0.0001), and median progression-free survival (3.5 vs 2.2 months; p < 0.0001). These results demonstrated a statistically significant and clinically meaningful benefit of liso-cel in patients with third- or later-line R/R LBCL relative to conventional therapies.Clinical trial registration: ClinicalTrials.gov identifier: NCT02631044.

Phase 2 results of lisocabtagene maraleucel in Japanese patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell product, lisocabtagene maraleucel (liso-cel), is administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This analysis assessed safety and efficacy of liso-cel in Japanese patients with relapsed or refractory (R/R) aggressive large B-cell lymphoma (LBCL) in Cohort 3 of TRANSCEND WORLD (NCT03484702). Liso-cel (100 × 106 total CAR+ T cells) was administered 2-7 days after lymphodepletion. The primary efficacy endpoint was objective response rate (ORR; Lugano 2014 criteria) assessed by an independent review committee. Fourteen patients were enrolled; 10 received liso-cel infusion (median time to liso-cel availability, 23 days) and were evaluable at data cutoff (median follow-up, 12.5 months). Grade ≥ 3 treatment-emergent adverse events were neutropenia (90%), leukopenia (80%), anemia (70%), and thrombocytopenia (70%). All-grade cytokine release syndrome (CRS) was observed in 50% of patients, though no grade ≥3 CRS events were reported. Grade 1 neurological events occurred in 1 patient but were resolved without any intervention. Prolonged cytopenia (grade ≥ 3 at day 29) was reported for 60% of patients. The ORR was 70%, and complete response rate was 50%. The median duration of response was 9.1 months (95% confidence interval [CI], 2.1-not reached), and overall survival was 14.7 months (95% CI, 1.7-not reached). One patient diagnosed with central nervous system involvement after screening but before liso-cel infusion, responded to liso-cel. Liso-cel demonstrated meaningful efficacy and a manageable safety profile in Japanese patients with R/R LBCL.

Matching-adjusted indirect treatment comparison of chimeric antigen receptor T-cell therapies for third-line or later treatment of relapsed or refractory large B-cell lymphoma: lisocabtagene maraleucel versus tisagenlecleucel.

BACKGROUND: There are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel). METHODS: Individual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET. RESULTS: Results from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes. CONCLUSIONS: Overall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

Indirect Treatment Comparison of Liso-Cel vs. Salvage Chemotherapy in Diffuse Large B-Cell Lymphoma: TRANSCEND vs. SCHOLAR-1.

Most patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have exhausted their treatment options and are deemed palliative. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has recently been introduced as a new option for these patients. Lisocabtagene maraleucel (liso-cel) is an investigational CAR T-cell therapy that has shown promising activity in this setting. We used an unanchored matching-adjusted indirect comparison (MAIC) methodology to compare liso-cel, using individual patient-level data from the TRANSCEND NHL 001 (TRANSCEND; NCT02631044) trial, to salvage chemotherapy, using summary-level data from the SCHOLAR-1 study, for the treatment of patients with R/R LBCL. Standardized mean differences were used to evaluate imbalances between the TRANSCEND and SCHOLAR-1 studies. MAIC was conducted to determine the relative efficacy of liso-cel vs. salvage chemotherapy with regard to overall survival, complete response rate, and objective response rate. For all efficacy outcomes assessed, comparisons of clinical factors before MAIC showed that five of seven baseline characteristics were similar between the TRANSCEND and SCHOLAR-1 studies; however, age and R/R to last therapy status differed between studies, thus requiring matching and adjusting to ensure the validity of this analysis. The base case analyses demonstrated a significantly lower risk of mortality (hazard ratio, 0.5; 95% confidence interval [CI] 0.4-0.6; p < 0.001) with significantly higher rates of complete response (odds ratio, 12.9; 95% CI 8.0-20.7) and objective response (odds ratio, 7.0; 95% CI 4.6-10.5) for patients treated with liso-cel than patients treated with salvage chemotherapy. MAIC comparisons demonstrated favorable efficacy for liso-cel compared with salvage chemotherapy in the treatment of patients with R/R LBCL.Trial Registration ClinicalTrials.gov identifier: NCT02631044.

Everolimus.

Everolimus (RAD001) is an oral protein kinase inhibitor of the mTOR (mammalian target of rapamycin) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, proliferation and survival, and is frequently deregulated in cancer.The EMA has approved Everolimus as Afinitor® for the treatment of hormone receptor-positive, HER2/neu-negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a nonsteroidal aromatase inhibitor, for the treatment of unresectable or metastatic, well- or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease, and for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) nonfunctional neuroendocrine tumors of gastrointestinal or lung origin in adults with progressive disease, and for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy And as Votubia® for the treatment of adult patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC), who are at risk of complications (based on factors such as tumor size or presence of aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate surgery, and for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with TSC who require therapeutic intervention but are not amenable to surgery, and as an add-on treatment in patients from 2 years of age with seizures related to TSC that have not responded to other treatments ( https://www.novartis.com/news/media-releases/novartis-drug-votubiar-receives-eu-approval-treat-refractory-partial-onset ). The FDA has approved Everolimus as Afinitor® for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after the failure of treatment with letrozole or anastrozole, for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease, for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib, for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. for the treatment of adult and pediatric patients, 3 years of age or older, with SEGA associated with TSC who require therapeutic intervention but are not candidates for curative surgical resection. Everolimus shows promising clinical activity in additional indications. Multiple Phase II and Phase III trials of everolimus alone or in combination and will help to further elucidate the role of mTOR in oncology. For a review on everolimus as immunosuppressant, please consult other sources.

Sorafenib: targeting multiple tyrosine kinases in cancer.

Sorafenib (BAY 43-9006, Nexavar®) is an oral multiple tyrosine kinase inhibitor. Main targets are receptor tyrosine kinase pathways frequently deregulated in cancer such as the Raf-Ras pathway, vascular endothelial growth factor (VEGF) pathway, and FMS-like tyrosine kinase 3 (FLT3). Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer. Multiple clinical trials are undertaken to further investigate the role of sorafenib alone or in combination for the treatment of various tumor entities.

Everolimus.

Everolimus (RAD001, Afinitor®) is an oral protein kinase inhibitor of the mammalian target of rapamycin (mTOR) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, proliferation, and survival and is frequently deregulated in cancer. Everolimus has been approved by the FDA and the EMA for the treatment of advanced renal cell carcinoma (RCC), subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC), pancreatic neuroendocrine tumors (PNET), in combination with exemestane in advanced hormone-receptor (HR)-positive, HER2-negative breast cancer. Everolimus shows promising clinical activity in additional indications. Multiple phase 2 and phase 3 trials of everolimus alone or in combination are ongoing and will help to further elucidate the role of mTOR in oncology. For a review on everolimus as immunosuppressant, please consult other sources.

ID2 and ID3 protein expression mirrors granulopoietic maturation and discriminates between acute leukemia subtypes.

The inhibitors of DNA binding (ID) inhibit basic helix-loop-helix transcription factors and thereby guide cellular differentiation and proliferation. To elucidate the involvement of IDs in hematopoiesis and acute leukemias (AL), we analyzed ID2 and ID3 expression in hematopoiesis and leukemic blasts in bone marrow biopsies (BMB). BMB of healthy stem cell donors (n = 19) and BMB of patients with acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MD; n = 19), de novo AML (n = 20), B-acute lymphoblastic leukemia (B-ALL) (n = 23), T-ALL (n = 19), were immunohistochemically stained for ID2 and ID3 expression. The expression patterns were evaluated and quantified for each hematopoietic lineage and each leukemia subtype. In normal BMB, immature granulopoiesis showed weak ID2 and strong ID3 expression, which was lost during maturation (p < 0.001). Erythropoiesis remained negative for ID2/3 (p < 0.001). ID2/3 expression differed between immature granulopoiesis and leukemic blasts (p < 0.001). Moreover, differential ID2/3 expression was seen between AL subgroups: AML, especially AML-MD, had more ID2- (p < 0.001) and ID3-positive (p < 0.001) blasts than ALL. We show a comprehensive in situ picture of ID2/3 expression in hematopoiesis and AL. Morphologically, ID2/3 proteins seem to be involved in the granulopoietic maturation. Importantly, the distinct ID2/3 expression patterns in AL indicate a specific deregulation of ID2/3 in the various types of AL and may support subtyping of AL.

Inhibitor of differentiation proteins do not influence prognosis of biliary tract cancer.

AIM: To investigate the expression and clinical relevance of inhibitor of differentiation (ID) proteins in biliary tract cancer. METHODS: ID protein expression was analyzed in 129 samples from patients with advanced biliary tract cancer (BTC) (45 extrahepatic, 50 intrahepatic, and 34 gallbladder cancers), compared to normal controls and correlated with clinical an pathological parameters. RESULTS: ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed. No correlation between increased ID protein expression and tumor grading, tumor subtype or treatment response was detected. Survival was influenced primary tumor localization (extrahepatic vs intrahepatic and gall bladder cancer, OS 1.5 years vs 0.9 years vs 0.7 years, P = 0.002), by stage at diagnosis (OS 2.7 years in stage I vs 0.6 years in stage IV, P < 0.001), resection status and response to systemic chemotherapy. In a multivariate model, ID protein expression did not correlate with clinical prognosis. Nevertheless, there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression (P = 0.076). CONCLUSION: ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis. Their usefulness as prognostic biomarkers in BTC is very limited.

Safety, tolerability, and pharmacokinetics of a single dose of pasireotide long-acting release in healthy volunteers: a single-center Phase I study.

OBJECTIVE: This study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PKs) of different doses of a long-acting release (LAR) formulation of pasireotide in healthy subjects. DESIGN: Single-center, open-label, randomized Phase I study. METHODS: Twelve healthy male subjects received a single s.c. dose of pasireotide 300 µg followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of pasireotide -LAR 40 mg (n=5) or 60 mg (n=7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels. RESULTS: Pasireotide LAR showed an extended-release profile over 1 month with two concentration peaks observed 1 and around 20 days after injection. The area under curve exposure of pasireotide LAR was dose proportional when the dose levels were compared, and the bioavailability of the LAR relative to the s.c. formulation was complete. Administration of pasireotide LAR resulted in an increase in fasting and postprandial glucose levels; however, an attenuation of the hyperglycemic effect was observed after 15 days. The most frequently reported AEs were mild-to-moderate diarrhea, abdominal pain, and flatulence. Only gastrointestinal AEs and injection site reactions were suspected to be drug related. CONCLUSIONS: Pasireotide LAR was generally well tolerated with mostly mild AEs at doses up to 60 mg and showed a dose-proportional, extended-release profile in healthy subjects. Based on the favorable results of this study, further clinical development of pasireotide LAR is under way, which will give insight into the PKs, efficacy, and safety of pasireotide LAR in patient populations.

Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors.

Somatostatin receptors (sstrs) are G-protein-coupled receptors that mediate various physiological effects when activated by the neuropeptide somatostatin or its synthetic analogs. In addition to the well-documented antisecretory effects of sstr(2)-preferential somatostatin analogs octreotide and lanreotide, ligand binding to sstr initiates an inhibitory action on tumor growth. This effect may result from both indirect actions (suppression of growth factors and growth-promoting hormones [e.g., GH/IGF-1 axis] and inhibition of angiogenesis) and direct actions (activation of antigrowth activities [e.g., apoptosis]). As solid tumor cells express multiple sstrs, there is a rationale to evaluate the potential antitumor effects of pasireotide (SOM230), a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1-3) and sstr(5). Pasireotide reduces systemic IGF-1 levels more potently than currently available somatostatin analogs and has been well tolerated in clinical trials.

Association of multiple myeloma with different neoplasms: systematic analysis in consecutive patients with myeloma.

Multiple myeloma (MM) has been suggested to be associated with different neoplasms. Of 589 consecutive patients with MM, 59 (10%) had different neoplasms: solid tumors in 78% and hematological neoplasms in 22%. Different neoplasms were separated into those emerging prior or synchronously (p/s; n = 41) versus subsequently after the MM (n = 18). The rate of different neoplasms at the time of MM diagnosis was estimated as 6.6%, and estimated different neoplasm rates at 2, 5, and 10 years were 7.8%, 10.3%, and 11.6%, respectively. Patients with MM with p/s different neoplasms showed a hazard ratio (HR) for impaired overall survival of 1.2 (95% CI 0.8-2.0), whereas in those with subsequent neoplasms the HR was 2.5 (95% CI 1.4-4.4). This demonstrates that (1) p/s are more frequent compared with subsequent different neoplasms, and (2) the prognosis is more impaired with subsequent different neoplasms. Age ≥60 years was a confounding covariable with a HR of 2.021 (95% CI 1.6-2.6).

Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells.

Inhibitors of differentiation or DNA binding (Id) proteins have been shown to be involved in tumor growth, invasiveness, metastasis, and angiogenesis. Overexpression of Id proteins, especially Id1, correlates with unfavorable clinical prognosis. Thus, they are attractive molecular targets for anticancer therapy. Overexpression of Id proteins mediates breast cancer metastasis to lung. Targeting Id1 and Id3 expression in breast cancer cells reduces breast cancer metastasis in animal models. Different breast tumors failed to grow and/or metastasize in Id1 (+/-) Id3 (-/-) mice. Id1 and Id3 preferentially dimerize with the key regulatory E-proteins which inhibit the expression of different tumor suppressor genes. Nevertheless, the inhibition of tumorigenic activities of Id1 and Id3 at protein level has never been studied. Here, we isolated a novel peptide aptamer, Id1/3-PA7, specifically interacting with Id1 and Id3 from randomized combinatorial expression library using yeast and mammalian two-hybrid systems. Intracellular delivered Id1/3-PA7 co-localized to Id1 and Id3 and interfered with their functions. It repressed E47 protein sequestration by Id1 and Id3, activated the E-box promoter and increased the expression level of cyclin-dependent kinase inhibitors (CDKN1A and CDKN1B) in a dose-dependent fashion, paralleled by the cleavage of poly ADP ribose polymerase (PARP). These effects were counteracted by ectopically overexpressed Id1 and Id3. Peptide aptamer Id1/3-PA7 induced cell cycle arrest and apoptosis in breast cancer cells MCF7 and MDA-MB-231. In conclusion, Id1/3-PA7 could represent a nontoxic exogenous agent that can significantly provoke antiproliferative and apoptotic effects in breast cancer cells, which are associated with deregulated expression of Id1 and Id3.

Sorafenib.

Sorafenib (BAY 43-9006, Nexavar) is a novel oral kinase inhibitor that targets multiple tyrosine kinases in vivo and in vitro. Main targets are receptor tyrosine kinase pathways frequently deregulated in cancer such as the raf-ras pathway, vascular endothelial growth factor (VEGF) pathway, and FMS-like tyrosine kinase 3 (FLT3). Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer. Multiple clinical trials are undertaken to further investigate the role of sorafenib alone or in combination for the treatment of various tumor entities.

Elevated endogenous expression of the dominant negative basic helix-loop-helix protein ID1 correlates with significant centrosome abnormalities in human tumor cells.

BACKGROUND: ID proteins are dominant negative inhibitors of basic helix-loop-helix transcription factors that have multiple functions during development and cellular differentiation. Ectopic (over-)expression of ID1 extends the lifespan of primary human epithelial cells. High expression levels of ID1 have been detected in multiple human malignancies, and in some have been correlated with unfavorable clinical prognosis. ID1 protein is localized at the centrosomes and forced (over-)expression of ID1 results in errors during centrosome duplication. RESULTS: Here we analyzed the steady state expression levels of the four ID-proteins in 18 tumor cell lines and assessed the number of centrosome abnormalities. While expression of ID1, ID2, and ID3 was detected, we failed to detect protein expression of ID4. Expression of ID1 correlated with increased supernumerary centrosomes in most cell lines analyzed. CONCLUSIONS: This is the first report that shows that not only ectopic expression in tissue culture but endogenous levels of ID1 modulate centrosome numbers. Thus, our findings support the hypothesis that ID1 interferes with centrosome homeostasis, most likely contributing to genomic instability and associated tumor aggressiveness.

Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab.

Development of severe steroid-resistant acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with poor outcome. The humanized monoclonal antibody alemtuzumab was shown to be effective in GVHD prophylaxis in conditioning regimens before allogeneic HCT. We evaluated the efficacy and safety of alemtuzumab in 20 patients with histologically confirmed steroid refractory grade III and IV intestinal GVHD after related and unrelated HCT. Overall response rate was 70%, with complete response in 35%. Despite the severe grade of GVHD in our patients, the median survival of 280 days and 1-year overall survival (OS) of 50% were superior or comparable to those associated with other treatment options. Cytomegalovirus (CMV) reactivation, bacterial infection, and invasive aspergillosis were frequent complications; however, infection was not a significant predictor for survival. These data suggest that treatment with alemtuzumab has favorable activity in severe intestinal GVHD after allogeneic HCT, but emphasize the importance of careful monitoring and anti-infectious supportive care.

Severe Organizing Pneumonia after Two Cycles of Docetaxel as Fourth-Line Chemotherapy for Advanced Non-Small Cell Carcinoma of the Lung.

Organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia, BOOP) is an inflammatory process of the bronchioles that can lead to the destruction of small airways and surrounding lung tissue. Although the majority of cases are idiopathic, certain chemicals and drugs can induce OP. Here, we report a 54-year-old male patient with advanced non-small cell lung cancer (NSCLC) who developed therapy-associated OP. He had undergone several other chemotherapies before being switched to docetaxel as monotherapy (75 mg/m(2)). Treatment was initially well tolerated, but after the second cycle the patient developed increasing shortness of breath. Computed tomography (CT) for staging after the second cycle showed bilateral predominantly interstitial infiltration highly suggestive of acute lung fibrosis. Bronchoscopy revealed signs of chronic bronchitis and watery discharge from both lungs. Bronchoalveolar lavage and transbronchial needle biopsy was performed. Based on histopathologic examination, diagnosis of OP was made. After cessation of docetaxel and initial high dose steroids, the infiltration ameliorated rapidly. This is the second case in the literature that associates docetaxel with rapid onset of bronchiolitis obliterans. Therefore, patients with lung cancer receiving docetaxel who develop respiratory symptoms should be suspected to develop OP.

Complete caval thrombosis secondary to an implanted venous port--a case study.

HISTORY AND CLINICAL FINDINGS: We report the case of a woman who presented to the medical emergency room with upper thoracic inlet syndrome six months after being treated for cancer of the left breast with surgery, radiation, and chemotherapy. A port-related occlusion of the superior vena cava was diagnosed on the basis of the history, physical findings, and diagnostic images. METHODS: The local standards for the handling of port systems are presented. DISCUSSION: Implanted port systems facilitate the treatment of the chronically ill by enabling easy and safe venous access. As the number of patients with such systems is growing, there is an increased need for optimized handling and care, awareness of the risks (such as catheter occlusion, thrombosis, and infection), and recognition of complications when they arise.