Carsten Mueller-Tidow

The synthetic furanonaphthoquinone induces growth arrest, apoptosis and differentiation in a variety of leukaemias and multiple myeloma cells.

2‐Methyl‐naphtho[2,3‐b]furan‐4,9‐dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin‐C and adriamycin, the cytotoxicity of FNQ3 is often 10‐ to 14‐fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose‐dependent fashion (50% inhibitory concentration ≈1·25 μg/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL‐60 myeloid cells in the presence of either 1α, 25(OH)2 dihydroxyvitamin D3 [1α,25(OH)2D3] or all‐trans‐retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies.

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene.

Dear Editor, A 45-year-old woman with a longstanding history of severe hereditary thrombocytopenia was diagnosed with acute myeloid leukemia (AML) of the M1 subtype. Genetic analysis of peripheral blood samples revealed a base pair change leading to a Pro236LeufsX48 mutation in the AML1 gene which is known to confer a propensity to develop AML. The identical mutation was found in her three sons suffering from thrombocytopenia, as well, suggesting an inherited germline mutation in this family. Thus, in the rare case of AML diagnosed in a patient with familial thrombocytopenia, a germline mutation in the AML1 gene should be considered. Analysis of families with inherited predisposition to develop malignancies has supported the multistep pathogenesis of human malignancy [1, 2]. A spectrum of genes when mutant in the germ line increase the likelihood of developing cancer during an individual’s lifetime. These genes have been identified by linkage analysis and positional cloning strategies. A loss of function of the residual allele is often the result of a second mutation. This has contributed to the concept of tumor suppressor genes in which homozygous loss of function is essential for the development of a malignant phenotype. Most mutant genes causally implicated in the pathogenesis of AML have been identified by cloning acquired chromosomal translocation breakpoints in hematopoietic progenitor cells [3]. Mutations in the AML1 gene have been shown in patients with familial platelet disorders, e.g., familial thrombocytopenia. These patients are described to have a propensity to develop AML [4]. The patient, a 45-year-old teacher with macrothrombocytopenia known since her youth, was diagnosed with AML (French–American–British classification M1 with dysplastic features including ring sideroblasts). She was referred to a hospital for diagnostic workup of gastric hemorrhage due to severe thrombocytopenia. On admission, she had also been suffering from non-specific symptoms. Cytogenetic analysis of the bone marrow revealed a female karyotype with complex chromosomal alterations in chromosomes 3, 4, 5, 6, and 8. Fms-like receptor tyrosine kinase 3 (FLT3) and nucleophosmin (NPM) mutations were excluded by molecular studies. The patient was treated with three courses of chemotherapy containing cytarabine, mitoxantrone, and daunorubicin (first course—high dose cytarabine plus daunorubicin, second course—high dose cytarabine plus mitoxantrone, and third course—high dose cytarabine) and achieved a complete remission (CR). Subsequently, she underwent allogeneic transplantation from an unrelated donor in 1.CR. Since an association between hereditary thrombocytopenia and development of leukemia has been described recently [3–6], blood samples from the patient and her three sons were examined for known mutations in the AML1 gene (Fig. 1). A Pro236LeufsX48 mutation was found, which corresponds to a heterozygous deletion of one base pair (707delC). This mutation induces a preterm stop codon which inhibits the formation of a complete AML1 Ann Hematol (2009) 88:1037–1038 DOI 10.1007/s00277-009-0722-x

High-dose chemotherapy with autologous peripheral blood stem cell transplantation in patients with poor- and intermediate-prognosis metastatic germ cell tumors: A retrospective monocenter analysis of 44 cases.

e15043 Background: Metastatic germ cell tumors (GCT) are curable. The International Germ Cell Cancer Collaborative Group (IGCCCG) reports a poor prognosis subgroup with a 5-year survival rate of 48%. High-dose chemotherapy with autologous peripheral blood stem cell transplantation (HD-PBSCT) in these patients showed promising results in phase II trials, but failed to show significant advantage in randomized trials. We report on our series of patients with poor and intermediate prognosis GCT treated with individually tailored multiple-course HD-PBSCT and secondary surgery of remaining tissue. METHODS We performed a retrospective analysis of our complete single center series of 44 patients (40 poor prognosis; 4 intermediate prognosis) treated with HD-PBSCT. All patients received 1 up to 6 cycles of standard-dose cisplatin-etoposide-ifosfamide (PEI) chemotherapy followed by granulocyte colony-stimulating factor and stem cell mobilisation. Subsequent high-dose chemotherapy regimen HD-PEI was adapted from a phase I/II trial of the German Testicular Cancer Study Group (GTCSG). In 14 patients we added paclitaxel according to another phase I/II study by the GTCSG. Up to 4 cycles of HD-chemotherapy were administered according to individual patients response and tolerability. Patients with residual disease in computed tomography (CT) or positron-emission tomography (PET)-CT underwent secondary surgery. RESULTS In this retrospective analysis the CR rate after up to 4 cycles of HD-PBSCT and resection was 73%. Three patients showing a marker-negative PR did not undergo surgery, because they were PET negative and/or fine needle aspiration did not show viable tumor. The 3-year survival rate was 80%, with a median follow up of 43 months (range: 3-130 months). Disease-related death rate was 16%. Treatment-related death after HD-PBSCT did not occur. One patient died postoperatively. CONCLUSIONS In our single center experience multiple courses of individually tailored HD-PBSCT is a safe and effective treatment option in poor and intermediate prognosis metastatic germ cell cancer.