Melanie Janning

Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma

Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.

A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations.

Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara‐C)/daunorubicin induction (7+3) followed by three cycles of intermediate‐dose Ara‐C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose‐limiting toxicity (DLT), prolonged haemotoxicity and hand‐foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1–7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3–internal tandem duplication and 5/8 with FLT3‐tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse‐free and event‐free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild‐type subclones.

Axl inhibition: a potential road to a novel acute myeloid leukemia therapy?

Novel treatment options in acute myeloid leukemia (AML) are urgently needed; treatment has not changed significantly over the past decades and survival is still dismal, especially in elderly patients. Axl, a member of the Tyro3, Axl, Mer (TAM) receptor family, mediates proliferation and survival of AML cells and is upregulated upon cytostatic treatment. In addition, AML cells induce expression of the Axl ligand growth arrest-specific gene 6 (Gas6) in bone marrow stroma cells, which further amplifies their growth and therapy resistance. Interruption of Axl signaling by pharmacological approaches, including the small molecule Axl inhibitor BGB324, decreased disease burden and prolonged survival of AML mice. The Gas6-Axl pathway has translational relevance because Axl is expressed by approximately 50% of AML patients and Axl-targeting approaches can block growth of primary human AML cells. Thus, Axl represents a potential novel target in AML and BGB324 is now in clinical development.

Chylothorax in a patient with Hodgkin's lymphoma: a case report and review of the literature

BACKGROUND Chylothorax is defined as chyle entering the pleural space. The most common causes of chylothorax are lymphoma followed by bronchogenic carcinoma and trauma. CASE REPORT We report a case of chylothorax in a patient with Hodgkins lymphoma. A 28-year old man was admitted to the hospital with exertional dyspnea and dry cough. A chest X-ray showed the large opacity on the left side suggesting to the presence of pleural effusion. METHODS The effusion was drained, and biochemical tests of the pleural fluid revealed high contents of triglycerides and, hence, confirmed the diagnosis of chylothorax. Cytology of the pleural fluid showed no evidence of Hodgkins cells. Computer tomography scans of the chest and abdomen exhibited the presence of a soft tissue mass located in the left mediastinum. Mediastinal mass biopsy led to diagnosis of Hodgkins lymphoma of the nodular sclerosis subtype. The patient received the standard treatment with two cycles of chemotherapy with prednisolone, doxorubicin, cyclophosphamide, vincristine, bleomycin, procarbazine, and etoposide (BEACOPP), followed by an additional two cycles of therapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). RESULTS After one cycle of chemotherapy, chylothorax initially decreased. Unfortunately, during the following courses of chemotherapy, the pleural effusion reoccurred and repeated pleural taps were necessary. According to the treatment protocol, radiation of the mediastinal bulk was performed after chemotherapy. Now, nearly one year after completion of radiotherapy, the chylothorax has significantly regressed and no further thoracocenteses were necessary. CONCLUSION The case reveals an example of left-sided chylothorax as the first manifestation of Hodgkins lymphoma in a young patient. In this case, radiotherapy was shown to be an effective treatment option for lymphoma-associated chylothorax unresponsive to chemotherapy.

Anti-Angiogenics: Their Value in Lung Cancer Therapy

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. Different targeted therapies and the introduction of immunotherapy have successfully improved outcome for patients with non-small lung cancer (NSCLC). Anti-angiogenic drugs are an essential component in the treatment of NSCLC patients. The vascular endothelial growth factor (VEGF)-A antibody bevacizumab is approved for first-line treatment of advanced-stage patients in combination with platinum-based chemotherapy. Ramucirumab, a VEGF receptor antibody, and nintedanib, an anti-angiogenic multi-tyrosine kinase inhibitor, are approved for second-line treatment in combination with docetaxel. This review provides a summary of pivotal trials with anti-angiogenic drugs in NSCLC in different settings. We give an overview of how to position anti-angiogenic therapy in the current treatment algorithms and highlight future directions. The identification of predictive biomarkers for patient selection could improve the success of anti-angiogenic drugs and represents an important area of research. In addition, novel therapeutic targets including endothelial metabolomic intermediates and cellular components of the tumor microenvironment could lead to the identification of innovative new targets besides the VEGF axis.

Management immunvermittelter Nebenwirkungen

ZusammenfassungDie Therapie mit Immuncheckpointinhibitoren stellt die behandelnden Ärzte vor neue Herausforderungen — auch, was die Nebenwirkungen betrifft. Das frühe Erkennen und Behandeln der Toxizitäten kann helfen, längerfristige Therapiepausen oder -abbrüche zu verhindern.

Serum carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: a biomarker analysis from the GeparQuinto phase III neoadjuvant breast cancer trial

T cell stimulation with different cytokines results in distinct phenotypes and cytotoxic activity of CD19-specific CART cells

Acute Megakaryoblastic Leukemia in a Patient with Xeroderma Pigmentosum: Discussion of Pathophysiological, Prognostic, and Toxicological Aspects

Background: Xeroderma pigmentosum (XP) is an autosomal recessive inherited disease characterized by extreme sensitivity to sunlight. Normal individuals harboring XPD polymorphisms are at increased risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML). Case Report: A 33-year-old male XP patient was diagnosed with acute megakaryoblastic leukemia with a complex karyotype. He received standard induction chemotherapy with cytarabine and daunorubicin. After the first cycle of chemotherapy, persistence of blasts was seen and a re-induction cycle with cytarabine, fludarabine, and idarubicin was administered resulting in complete remission. Due to the high-risk profile of his AML, allogeneic stem cell transplantation (SCT) was performed. Following a conditioning regimen with busulfan and cyclophosphamide, the patient received a matched related SCT from his HLA-identical sister. Despite the existence of his DNA repair gene mutation, chemotherapy was normally tolerated by the patient. Unfortunately, he died due to severe sepsis and relapse of AML 45 days after SCT. Conclusion: The XPD mutation in our patient may have contributed to the emergence of his high-risk AML. Despite the existence of a DNA repair gene mutation, our XP patient could be treated with full doses of AML-type chemotherapy including allogeneic SCT without encountering unusual toxicity.