Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13).

Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL. Methods: In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458. Findings: Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively. Interpretation: The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features. Funding: SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen.

Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine.

Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort.

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response.

Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS.

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85.

High thromboembolic event rate in patients with locally advanced oesophageal cancer during neoadjuvant therapy. An exploratory analysis of the prospective, randomised intergroup phase III trial SAKK 75/08.

BACKGROUND: High rates of venous thromboembolic events (VTEs), mainly in advanced disease, are reported for patients with cancer of the upper gastrointestinal tract (stomach, pancreas) and for treatment with cisplatin. METHODS: Exploratory analysis of VTEs reported as adverse events and serious adverse events in a prospective, randomised, multicentre, multimodal phase III trial according to VTEs reported as adverse events and severe adverse events. Patients with resectable oesophageal cancer (T2N1-3, T3-4aNx) were randomized to 2 cycles of chemotherapy with docetaxel 75 mg/m2, cisplatin 75 mg/m2 followed by chemo-radiotherapy (CRT) and subsequent surgery (control arm) or the same treatment with addition of cetuximab (investigational arm). RESULTS: VTEs occurred in 26 of 300 patients included in the trial, resulting in an incidence rate (IR) of 8.7% [95% CI 5.7-12.4%]. A total of 29 VTEs were reported:13 (45%) VTEs were grade 2, 13 (45%) grade 3 and three (10%) fatal grade 5 events. 72% (21/29) of all VTEs occurred preoperatively (IR 6.7%): 14% (4/29) during chemotherapy and 59% (17/29) during CRT. In multivariable logistic regression only adenocarcinoma (IR 11.1%, 21/189 patients) compared to squamous cell cancer (IR 4.5%, 5/111 patients) was significantly associated with VTE-risk during treatment, OR 2.9 [95%CI 1.0-8.4], p = 0.046. Baseline Khorana risk score was 0 in 73% (19/26), 1-2 in 23% (6/26) and 3 in only 4% (1/26) of patients with VTEs. CONCLUSION: A high incidence of VTEs during preoperative therapy of resectable oesophageal cancer is observed in this analysis, especially in patients with adenocarcinoma. The role of prophylactic anticoagulation during neoadjuvant therapy in resectable esophageal cancer should be further evaluated in prospective clinical trials. According to our data, which are in line with other analysis of VTE-risk in patients with oesophageal cancer patients treated with neoadjuvant cisplatin-based chemotherapy and CRT, prophylactic anticoagluation could be considered balanced against individual bleeding risks, especially in patients with adenocarcinoma. In addition to the established risk factors, oesophageal adenocarcinoma treated with neoadjuvant cisplatin-based therapy may be regarded as a high-risk situation for VTEs. TRIAL REGISTRATION: Registered at clinicaltrials.gov, NCT01107639, on 21 April 2010.

Multi-fungal sepsis and mucormycosis of the central nervous system in a patient treated with ibrutinib, a case report and review of the literature.

We report the case of a 71 years old patient with chronic lymphocytic leukemia (CLL), who developed a rapidly progressing multi-fungal infection including mucormycosis of the central nervous system (CNS) during treatment with ibrutinib. On autopsy mucorales species were demonstrated intravascularly by histomorphology of several organs and lymph nodes and were characterized as Rhizomucor pusillus by polymerase-chain reaction (PCR) - analysis. In addition, invasive pulmonary Aspergillus fumigatus was found and also confirmed by PCR. To the best of our knowledge, this is the first confirmation of a multi-fungal sepsis and invasive CNS-infection with mucorales species under ibrutinib. Knowing the risk for invasive fungal disease in patients under ibrutinib, identifying the pathogen and early initiation of specific treatment is crucial for a good clinical outcome especially in mucormycosis.

Multicenter Validation of the CamGFR Model for Estimated Glomerular Filtration Rate.

Important oncological management decisions rely on kidney function assessed by serum creatinine-based estimated glomerular filtration rate (eGFR). However, no large-scale multicenter comparisons of methods to determine eGFR in patients with cancer are available. To compare the performance of formulas for eGFR based on routine clinical parameters and serum creatinine not calibrated with isotope dilution mass spectrometry, we studied 3620 patients with cancer and 166 without cancer who had their glomerular filtration rate (GFR) measured with an exogenous nuclear tracer at one of seven clinical centers. The mean measured GFR was 86 mL/min. Accuracy of all models was center dependent, reflecting intercenter variability of isotope dilution mass spectrometry-creatinine measurements. CamGFR was the most accurate model for eGFR (root-mean-squared error 17.3 mL/min) followed by the Chronic Kidney Disease Epidemiology Collaboration model (root-mean-squared error 18.2 mL/min).

Carboplatin dose based on actual renal function: no excess of acute haematotoxicity in adjuvant treatment in seminoma stage I.

INTRODUCTION: The practice of carboplatin dosing is not concordant among different centres and oncologists. Some clinical guidelines recommend capping of the carboplatin dose at, for example, creatinine-clearance (Crea-Cl) of 125 mL/min because of concerns of excessive toxicity. Clinical data to support such recommendations are lacking, especially in patients with seminoma. METHODS: This is a retrospective analysis of acute haematotoxicity of patients with stage I seminoma treated with adjuvant carboplatin area under the curve (AUC) 7 in routine practice in two Swiss centres in 2005-2015, and a comparison of incidence and grade (according to Common Terminology Criteria for Adverse Events v4.0) of haematological adverse events (hAEs) in patients with Crea-Cl <125 mL/min vs >125 mL/min without dose capping. RESULTS: 74 patients with 229 documented measurements were included (median 3/patient). A total of 151 hAEs occurred. Platelet nadir occurred earlier than median white cell/neutrophil count (median day 15 vs day 22; P<0.0001). The majority of hAEs were mild, with more than 80% being of grade 1. Only two (2.7%) clinically relevant hAEs necessitating subsequent interventions occurred (one patient received platelet transfusion, one patient with febrile neutropaenia). Haematological toxicities were not statistically different in patients dosed with Crea-Cl >125 mL/min versus those with Crea-Cl <125 mL/min. No hAEs other than grade 1 occurred before day 10 and after day 24. CONCLUSIONS: Toxicity after single-dose carboplatin AUC 7 is generally mild. No excess of toxicity occurs in patients with high Crea-Cl above 125 mL/min, and therefore dose capping is not routinely necessary. In addition, this study provides a rationale for efficient use of healthcare services without compromising patients' safety.

Early Postoperative FDG-PET-CT Imaging Results in a Relevant Upstaging in the pN2 Subgroup of Stage III Colorectal Cancer Patients.

INTRODUCTION: Clinical practice guidelines regarding follow-up in patients after curative resection of colorectal cancer (CRC) vary widely. Current follow-up recommendations do not include additional postoperative imaging before starting adjuvant treatment in any patients. We evaluated the potential benefit of our institutional approach, recommending 18fluor-deoxy-glucose (FDG)-positron emission tomography (PET)-computed tomography (CT) imaging in CRC stage III patients with ≥4 locoregional lymph node metastases (pN2). PATIENTS AND METHODS: Our study included all patients from a single center with complete resection of a pT1-4, pN2, cM0 CRC. All patients were considered free of distant metastases on the basis of preoperative CT imaging of the chest, abdomen, and pelvis. The main objective of the present study was to assess the proportion of patients with changes of therapeutic management (defined as any other treatment than the preplanned adjuvant chemotherapy) because of the results of additional postoperative FDG-PET-CT imaging. RESULTS: Fifty patients (22 female/28 male) were included; the median age was 64 years (range, 37-78 years). Previously undiagnosed metastatic disease resulting in a change of the therapeutic management was detected using postoperative FDG-PET-CT imaging in 7 patients (14.0%; 95% confidence interval, 5.8%-26.7%). The number needed to screen to detect new or previously occult metastases was 7 (7 of 50). CONCLUSION: To our knowledge, this is the first study to evaluate the role of an additional postoperative FDG-PET-CT scan before adjuvant treatment in patients with completely resected CRC with ≥4 lymph node metastases (pT1-4, pN2) and without distant metastases on preoperative CT imaging (cM0). Postoperative FDG-PET-CT imaging represents a valuable tool for the detection of new macrometastases in the subgroup of pN2 cM0 CRC patients. The low number needed to screen for consequent therapeutic changes is clinically relevant and should be further evaluated.

Trends in incidence of oesophageal and gastric cancer according to morphology and anatomical location, in Switzerland 1982-2011.

QUESTION UNDER STUDY/PRINCIPLES: This study aimed to evaluate trends in the incidence of oesophageal and gastric cancer by anatomical location and histology using nationally representative Swiss data. METHODS: We included all oesophageal and gastric cancers recorded in 10 Swiss population-based cancer registries 1982-2011. We calculated age-standardised incidence rates (ASIRs) per 100 000 person-years (PY) (European standard) for both cancer sites stratified by sex, language region (German, French-Italian), morphology and anatomical location. To assess time trends, we estimated annual percentage changes (APCs) with 95% confidence intervals (95% CIs). RESULTS: ASIR of oesophageal adenocarcinoma increased in both sexes and language regions (p <0.001). The steepest increase occurred in males of the German-speaking region (APC 6.8%, 95% CI 5.8-7.8) with ASIRs of 0.8 per 100,000 PY in 1982-1987 and 3.9 per 100.000 PY in 2007-2011. Incidence of oesophageal squamous cell carcinoma decreased significantly in males of both language regions by around -1.5% per year. In contrast, a slight but significant increase (APC 1.4%, 95% CI 0.3-2.4]) of oesophageal squamous cell carcinoma was observed in females of the German-speaking region. We observed stable rates for cancer of the gastric cardia. The incidence of noncardia gastric cancer decreased substantially in both sexes and language regions (p <0.001). CONCLUSION: In Switzerland, the incidence of oesophageal adenocarcinoma has risen whereas incidence of noncardia gastric cancer has decreased substantially as observed in other developed countries.

Mind the sump! - diagnostic challenge of a rare complication of choledochoduodenostomy.

Sump syndrome is a rare long-term complication of side-to-side choledochoduodenostomy (CDD), a common surgical procedure in patients with biliary tract disease in the era before endoscopic retrograde cholangiopancreatography (ERCP). Frequently only pneumobilia, serving as sign for functioning biliary-enteric anastomosis, is reminiscent of the former surgery. We present the case of an 81-year-old patient with sump syndrome who presented with clinical signs of ascending cholangitis, decades after the initial CDD procedure. Finally the detailed medical history that was taken very thoroughly in combination with the presence of pneumobilia led to the suspicion of sump syndrome. Sump syndrome was diagnosed by ERCP, and after endoscopic debris extraction and antibiotic treatment the patient recovered quickly. In the ERCP era little is known about CDD and its long-term complications, especially by young colleagues and trainees. Therefore this report provides an excellent opportunity to refresh the knowledge and raise awareness for this syndrome.

Multidisciplinary care in patients with prostate cancer: room for improvement.

PURPOSE: New multimodality treatment approaches for prostate cancer require multidisciplinary management of patients. We aimed to assess the current practices of multidisciplinarity and their possible implications in treatment management in Switzerland. METHODS: In a survey, urologists and medical oncologists in Switzerland were asked to include at least 25 or 15 consecutive patients with the diagnosis of prostate cancer, respectively. Information about treatment patterns and multidisciplinary parameters of these patients was collected retrospectively. RESULTS: Thirty-seven urologists and 20 oncologists from the French- and German-speaking parts of Switzerland representing 7 out of 11 non-university tertiary centres and 20/10 % of all office-based urologists/oncologists in Switzerland collected data on 1,184 patients. Sixty-five percent of the office-based (16/24 urologists; 6/10 oncologists) and 95 % of the hospital-based (10/11 urologists; 8/8 oncologists) physicians participate in multidisciplinary tumour boards (MTBs). However, only 1.5 % of patients with a new diagnosis of prostate cancer (13 of 883) are discussed at a MTB. Overall, second opinions at diagnosis are requested in 23 % of patients, mainly from radiation oncologists (8.4 %) or fellow urologists (7.4 %). Second opinions are more often requested by urologists who participate at MTBs and in case of advanced stage. CONCLUSIONS: Participation at MTBs is high among Swiss urologists and oncologists in private practice and at non-university tertiary centers. In spite of that only a small minority of patietns with prostate cancer are presented at MTBs.

Spontaneous pneumothorax during chemotherapy: a case report.

BACKGROUND: Spontaneous pneumothorax (SP) associated with malignant disease is relatively infrequent but has important diagnostic and therapeutic implications. CASE REPORT: We describe a case of SP that occurred during chemotherapy with ifosfamide and doxorubicin in a patient with an advanced pleomorphic sarcoma. The pneumothorax developed secondary to the rapid regression of peripheral pulmonary metastases presumably resulting in bronchopleural fistula formation. After treatment with chest tube drainage, the patient recovered and chemotherapy could be continued without further complications. DISCUSSION: We discuss different pathophysiological mechanisms and the clinical context of SP in sarcoma patients and give an overview of the literature and different treatment options.

Primary manifestation of small lymphocytic lymphoma in the prostate.

BACKGROUND: Infiltration of non-haematopoietic organs by small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) is not unusual in late-stage disease and thus quite frequently encountered in post-mortem examinations. However, primary manifestation of SLL/CLL in the prostate is rarely diagnosed. PATIENTS AND METHODS: We report two cases of primary prostatic SLL/CLL, in one case in combination with prostate carcinoma, and discuss diagnostic pitfalls, pathophysiological mechanisms and therapeutic management, together with an overview of the literature. CONCLUSIONS: Lymphocytic infiltration of the prostate associated with obstructive symptoms is rare but can already occur in very early disease. Microscopically, SLL/CLL infiltration can be distinguished from chronic prostatitis by its pattern of infiltration and by immunohistochemistry. As the incidence of both SLL/CLL and prostatic carcinoma increases with age, composite tumours might occur more often in the future.

Influence of combinations of acetylsalicylic acid, acetaminophen, and diclofenac on platelet aggregation.

Acetylsalicylic acid (aspirin) is often given together with other nonsteroidal anti-inflammatory drugs and acetaminophen. The latter have been accused in epidemiologic studies to cause an increased cardiovascular risk. We have, therefore, analysed the influence of various such drug combinations on platelet aggregation in vitro. Citrated blood was incubated with either 25 microg/ml acetaminophen, 0.5 microg/ml aspirin, 0.04 microg/ml diclofenac, or buffer; followed by a second of the above-mentioned solutions. After a 20 min incubation, platelet aggregation was assessed with a platelet function analyser (PFA-100), which measures the pore closure time (CT) by aggregating platelets. The length of CT reflects the degree of platelet inhibition. Acetaminophen alone did not affect platelet aggregation. Aspirin and diclofenac both increased CT (184+/-69 s, P<0.01 and 196+/-54 s, P<0.001; control 120+/-13 s). Combinations of either aspirin and diclofenac, aspirin and acetaminophen, or diclofenac and acetaminophen increased CT further (290+/-22 s, 281+/-36 s, 288+/-25 s, respectively, P<0.001). The time sequence of drug application was important: when diclofenac or acetaminophen was added before aspirin, platelet aggregation was less inhibited than when given in opposite order, i.e. aspirin prior to diclofenac or acetaminophen. We conclude that acetaminophen by itself does not affect platelet aggregation, but potentiates the antiaggregatory effect of aspirin or diclofenac. Aspirin given before acetaminophen or diclofenac had a more potent antiaggregatory effect than vice versa. These observations may have clinical implications.

Influence of acute alcohol exposure on hemorheological parameters and platelet function in vivo and in vitro.

We have analysed the influence of acute alcohol exposure in vivo and in vitro on blood flow properties and platelet function. 12 healthy male volunteers drank either 4.36 ml red wine/kg body weight (=0.5 g ethanol/kg) or water at 06.00 p.m. under fasting conditions. Blood was drawn immediately before, and 1, 2, 4 and 13 h after alcohol ingestion. Alcohol had a detectable osmotic effect on erythrocytes; the mean cellular volume (MCV) was significantly smaller 1-4 h after ingestion. Whole blood viscosity remained unaffected, but blood viscosity at a standardized Hct of 45% measured at a high shear rate (94.5 s(-1)) was increased 2 h after wine ingestion. In the morning, 13 h after wine drinking, platelet aggregation measured with a platelet function analyser PFA-100 was increased to a greater extent than after water drinking. In vitro, no effect was seen when blood was incubated with 0, 12.5, 25, 50 and 100 mmol/l ethanol for 1 h at 37 degrees C. We conclude that an acute exposure to alcohol has only modest effects on hemorheological parameters and platelet aggregation in vivo and no effect in vitro, which suggests that other factors must be involved in both beneficial and harmful effects of wine drinking.