Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. All inhibitors demonstrated a concentration-dependent antiproliferative effect, although there was considerable heterogeneity among patients. For fostamatinib and TAK-659, the antiproliferative effects were significantly higher in FLT3 mutated patients compared to nonmutated patients. Fostamatinib, entospletinib, TAK-659, and RO9021 induced significant apoptosis in primary AML cells, although the proapoptotic effects of the SYK inhibitors were less pronounced than the antiproliferative effects. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment.

Pure Red Cell Aplasia with Del(20q) Sensitive for Immunosuppressive Treatment.

Pure red cell aplasia (PRCA) is a rare syndrome that only affects the erythroid lineage. It is defined by a normocytic, normochromic anemia with a marked reticulocytopenia and severe reduction or absence of erythroid precursors in the bone marrow. Treatment of primary, idiopathic PRCA is immunosuppressive therapy. Although it is rare, isolated cytogenetic abnormalities can be seen in PRCA, and abnormal karyotype is associated with poor response to immunosuppressive therapy and poor prognosis. We describe a 77-year-old male with primary, idiopathic PRCA and a deletion of chromosome 20q, del(20q), in the bone marrow cells. He was successfully treated with immunosuppressive therapy and became transfusion-independent. The same cytogenetic abnormality has also been described in a few other reports; taken together, these observations suggest that del(20q) may represent a recurrent cytogenetic abnormality in PRCA. Our case report clearly illustrates that even patients with primary PRCA and an abnormal karyotype can respond to immunosuppression and become transfusion-independent.

Dasatinib as an investigational drug for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis; clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy. Areas covered: Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined. Expert opinion: Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1+ patients or is attributed to inhibition of the fusion protein alone, or a combined effect on several kinases, and whether dasatinib-containing combination treatment should be preferred in these patients instead of other emerging strategies, e.g. monoclonal antibodies.

Philadelphia chromosome positive AML arising from JAK2-positive myelofibrosis.

BACKGROUND: A feature of myeloproliferative neoplasia is transforming to more aggressive and malignant myeloid neoplasia, including acute myeloid leukemia. Different pathogenesis mechanisms participate in transformation, including transformation of existing potential preleukemic clones, since JAK2-mutant myeloproliferative neoplasms often transform to JAK2 wild-type acute myeloid leukemia. CASE PRESENTATION: Here, we present an 80 year old man with a JAK2-V617F mutant primary myelofibrosis. After 10 months the disease transform into a Philadelphia chromosome positive acute myeloid leukemia, detecting the cytogenetic aberration; t(9;22)(q34;q22) encoding the rare BCR-ABL1 fusion gene; e6a2. The patient had treatment response to tyrosine kinases, illustrating the potential benefits of such approach in treating these patients subset. CONCLUSION: The case illustrates the potential of leukemic transformation to Philadelphia chromosome positive myeloid malignancies from potential existing preleukemic clones, and the awareness of such an evolution among patients with myeloproliferative neoplasms. Tyrosine kinases have potential effect also in patients presenting without chronic myeloid leukemia and with rare BCR-ABL1 fusion transcripts, and should probably be a part of the treatment approach.

Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia.

INTRODUCTION: Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase. It is important for downstream signaling from several cell surface receptors, including Fc receptors, complement receptors and integrins. SYK can have either oncogenic or tumor suppressor activity in human malignancies. Recent studies suggest that SYK inhibition may have an antileukemic effect in human acute myeloid leukemia (AML). AREAS COVERED: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of SYK inhibition; (ii) published articles describing the importance of SYK in human malignancies, especially AML. EXPERT OPINION: SYK is important for the downstream signaling from several cell surface receptors. There is also a crosstalk between SYK and signaling initiated through ligation of Toll like receptors, and SYK is thereby linked with the NFκB mediated transcriptional regulation. SYK activation will also influence PI3K-Akt-mTOR signaling. Several of these signaling events are important for survival and proliferation of primary human AML cells. In the present review we describe and discuss the role of SYK in human AML, and these data suggest that SYK inhibition is a possible therapeutic strategy in human AML.