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Purpose: Pregnancies in women with essential thrombocythemia (ET) are at a higher risk for obstetrical complications. Acetylsalicylic acid (ASA) and low-molecular weight heparin (LMWH) are common options to prevent miscarriages and maternal complications, whereas interferon alpha (IFN) seems to be the cytoreductive therapy of choice. This retrospective study analyzes the largest number of IFN pregnancies to date in terms of outcome and safety., Methods: Data of 34 high-risk pregnancies in 23 women presenting at the University hospitals of Minden and Jena from 01-Jun-2007 to 01-Jun-2020 were collected. Reasons defining high-risk ET pregnancy in all 23 patients were: Thrombosis (n = 9) or severe hemorrhage (n = 2) in history, platelet count ≥ 1500 × 10 3 /µl (n = 8) or severe microcirculatory disturbances not completely responding to ASA (n = 4)., Results: Without the use of IFN, live birth rate was 60% (6/10), however, after the use of IFN live birth rate increased to 73.5% (25/34 pregnancies). Nine pregnancies ended in miscarriages (9/34; 26.5%); all of them spontaneous abortions. Live birth rate significantly improved with ASA (90% versus 50%, p = 0.0168), however, if ASA and LMWH was added (n = 14), live birth rate was 100%. IFN compound (PEGylated versus standard IFN) and JAK2-driver mutation had no impact on pregnancy outcome. One major maternal complication occurred as a major peripartal bleeding after abortion curettage., Conclusion: IFN was associated with an encouraging live birth rate of 73.5% with no fatal maternal events and manageable side effects.

Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the "real-world" setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany., Patients and Methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1., Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4-10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9-9.2) with druggable ALK alterations., Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, is approved for second-line therapy in patients with polycythemia vera (PV) who are resistant or intolerant to hydroxyurea. Due to the immunomodulatory and immunosuppressive effect of RUX, there is an increased susceptibility to infections. However, an increased risk of infection is inherent to even untreated myeloproliferative neoplasms (MPN). To obtain more information on the clinical significance of RUX-associated infections in PV, we reviewed the available literature. There is no evidence-based approach to managing infection risks. Most data on RUX-associated infections are available for MF. In all studies, the infection rates in the RUX and control groups were fairly similar, with the exception of infections with the varicella zoster virus (VZV). However, individual cases of bilateral toxoplasmosis retinitis, disseminated molluscum contagiosum, or a mycobacterium tuberculosis infection or a hepatitis B reactivation are reported. A careful assessment of the risk of infection for PV patients is required at the initial presentation and before the start of RUX. Screening for hepatitis B is recommended in all patients. The risk of RUX-associated infections is lower with PV than with MF, but compared to a normal population there is an increased risk of VZV infection. However, primary VZV prophylaxis for PV patients is not recommended, while secondary prophylaxis can be considered individually. As early treatment is most effective for VZV, patients should be properly informed and trained to seek medical advice immediately if cutaneous signs of VZV develop. Vaccination against influenza, herpes zoster, and pneumococci should be considered in all PV patients at risk of infection, especially if RUX treatment is planned. Current recommendations do not support adjusting or discontinuing JAK inhibition in MPN patients to reduce the risk of COVID-19.

Background: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT 572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC)., Methods: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS., Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004)., Conclusion: Vx-001 could induce specific CD8 + immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001., Clinical Trial Registration: NCT01935154.

Due to its rare incidence, erythrocytosis frequently represents a challenge for the treating doctors. The erythropoiesis (= production of erythrocytes) is located in the bone marrow, and the hormone erythropoietin (EPO) takes control in its regulation. Therefore, measurement of EPO in serum is one of the main diagnostic steps. In erythrocytosis, congenital causes have to be distinguished from acquired ones. Furthermore, there are primary and secondary forms. Congenital causes of erythrocytoses occur very infrequently, are mainly diagnosed in young age and should be treated in specialized centers. Polycythemia vera (PV), a clonal disorder and one of the main myeloproliferative neoplasms (beside essential thrombocythemia and primary myelofibrosis), represents the most frequent primary acquired cause of erythrocytosis. Clinically, increased thrombophilia and microvascular disturbance occur. The first-line treatment in patients with PV includes administration of aspirin and phlebotomies. Secondary acquired forms of erythrocytosis mainly occur due to hypoxia triggered by nicotine abuse or chronic heart and lung diseases. Regarding other differential diagnoses, a cancer-associated EPO production, kidney diseases or exogenous supply with EPO (= EPO doping) have to be considered., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: The management of pregnancy during the course of BCR-ABL1-negative myeloproliferative neoplasms (MPN) is an increasingly relevant problem. This is mostly due to earlier and better diagnosis of MPN together with the trend in modern society toward delaying pregnancy until later life. Areas Covered: The present review aims to provide an overview of the available literature data concerning outcome of pregnancy in MPN. Possible therapeutic modalities are discussed and a management algorithm is suggested. Expert Commentary: Most data are available for women with essential thrombocythemia and we present 793 published pregnancies. Live birth rate is 68.5% with 31.5% miscarriages. Spontaneous abortion is the most frequent complication with 26.5%, followed by stillbirth with 4.8%. Maternal complications are relatively low with 1.8% major thrombotic and 2.4% major bleeding events. In polycythemia vera the situation is clinically more complex and roughly 150 pregnancy reports are available. There is very limited information in primary myelofibrosis with less than 20 reported pregnancies. With active management including control of blood counts, aspirin, low molecular weight heparin and in higher risk cases interferon alpha pregnancy in MPN is manageable with a success rate not far below the normal situation with 80%.

Due to the central role of platelets in hemostasis, the clinical relevance of quantitative changes in platelet counts (< 150 G/l or > 450 G/l) may be significant. Thrombopoesis (= production of platelets) occurs in the bone marrow, and the hormone thrombopoetin takes control on its regulation.In thrombocytosis, primary causes have to be distinguished from the far more common reactive (= secondary) reasons. The most important form of primary thrombocytosis occurs in myeloproliferative neoplasms especially in essential thrombocythemia (ET). Clinically, increased thrombophilia, microcirculatory disturbances as well as an increased hemorrhagic diathesis occur in patients with myeloproliferative neoplasms. According to the WHO diagnosis criteria 2016 standard diagnostic procedure in myeloproliferative neoplasms includes bone marrow biopsy and the detection of one of the acquired and typical MPN mutations in the JAK2, MPL or CALR gene.In contrast, patients with thrombocytopenia more often suffer from bleeding complications, however, in antiphospholipid syndrome or thrombotic microangiopathy (TMA) thrombotic events occur in spite of a low platelet count. Generally it makes sense to differentiate between pathological changes in thrombopoesis and the various causes of increased peripheral platelet turnover. Concerning differential diagnosis a careful anamnesis is very important in order to get hints like drugs associated with thrombocytopenia, signs of infection or autoimmune disorders. As an initial diagnostic approach we recommend examination of the blood smear in order to exclude pseudothrombocytopenia or disorderes like thrombotic microangiopathy, myelodysplasia or other hematological diseases., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naïve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown., Materials and Methods: In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported., Results: In 60 patients (63% female, median age 63 years [range: 30-84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected., Conclusion: Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naïve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations., (©AlphaMed Press.)