Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias.

Since 2001, chronic myelomonocytic leukemia (CMML) is classified by the WHO as myeloproliferative/myelodysplastic neoplasm. Herein we tried to better describe CMML patients with regard to hematological characteristics and prognosis using data of the Duesseldorf registry. We created 6 CMML subgroups, by dividing dysplastic and proliferative CMML at the cut-off of white blood cell count of 13,000/µL and splitting these two groups into 3 subgroups: CMML 0 with <5% blasts (n=101), CMML I with 5-9% blasts (n=204) and CMML II with 10-19% blasts (n=81). For comparison we included patients with RCMD, RAEB I and II. The newly created CMML 0 group had better prognosis than CMML I and II, median survival times were 31 months (ms), 19ms and 13ms, respectively (p<0.001). Median survival times between the corresponding dysplastic and proliferative subgroups 0 and 1 differed significantly: CMML 0 dysplastic 48ms and CMML 0 proliferative 17ms (p=0.03), CMML I dysplastic 29ms and CMML I proliferative 15ms (p=0.008), CMML II dysplastic 17ms and CMML II proliferative 10ms (p=0.09). Outcome of CMML patients worsens with increasing medullary blasts and when presenting as proliferative type. Therefore it is justified to separate CMML with <5% medullary blasts.

The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells.

In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adeno-associated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62-82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3-14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vector-mediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.