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Background: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of invasive fungal infections (IFI). The present study evaluates the cost effectiveness of posaconazole vs. standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands., Methods: A decision-tree model was developed using data from a randomized trial that compared posaconazole and standard azole (fluconazole or itraconazole) prophylaxis in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., N Engl J Med 2007;356:348-359). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI-related death, and death from other causes. Patients surviving the prophylaxis are assumed to have a life expectancy according to the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include cost per life year (LY) gained and cost per quality adjusted life year (QALY) gained., Results: The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to 4412 euros (95% uncertainty interval 3403 euros - 5666 euros), which is -183 euros (-1985 euros to 1564 euros) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.08 (0.02-0.15) QALYs gained in comparison with prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 90% probability that the cost per QALY gained with posaconazole is below 20,000 euros. Additional scenario analyzes with different assumptions confirmed these findings., Conclusion: Given the underlying data and assumptions, the economic evaluation demonstrated that posaconazole prophylaxis is expected to be cost-effective compared with fluconazole/itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.

Enhanced proliferation of MDS progenitors is abrogated by increased apoptosis of their progeny in vivo. We investigated whether bone marrow mononuclear cells (BMMNC) of MDS patients also showed enhanced proliferation and apoptosis in vitro in comparison with acute myeloid leukemia (AML) and normal BM (NBM). NBM showed a decrease in the number of clusters in time due to apoptosis of clusters and due to development of clusters into colonies with low apoptotic level. In MDS patients, about two-fold more clusters have developed at day 4, and in contrast with NBM, the total number of clusters at day 7 remained high in spite of an increasing percentage of apoptotic clusters (from 52 to 76%) in combination with more colony formation. The number of clusters and colonies showed a sharp decrease at day 10 because of persistently high apoptosis at cluster level and increasing apoptosis in colonies. BMMNC of AML patients showed a decreased proliferation with enhanced apoptosis at cluster level in contrast to a relatively low apoptotic levels in the colony-forming cells. This data show that increased proliferation is abrogated by enhanced apoptosis in MDS, whereas AML showed decreased proliferation with a low level of apoptosis in colony-forming cells. These growth profiles of BMMNC are independent of stromal influences and may represent intrinsic features of the MDS progenitors and accessory cell interactions.

Objective: Bone marrows (BM) of myelodysplastic syndrome (MDS) patients show increased proliferation and premature programmed cell death (PCD) in vivo as well as in vitro. We explored the proliferative capacity and apoptotic propensity of CD34+ progenitor cells of MDS patients excluding accessory cell interference., Materials and Methods: CD34+/CD3-/CD19- cells of 5 MDS patients and 5 normal BM were sorted as single cells into single wells and were cultured in liquid medium. Wells were evaluated on days 4, 7, 10, and 14. PCD was determined by staining with annexin V-FITC. Growth rate and cell doubling time (Td) were calculated for each colony-forming cell., Results: Normal BM CD34+ cells formed clusters and colonies and both showed increasing PCD in time, although within colonies the degree of apoptosis was twice as high (about 25%) as compared with clusters at all time points. In MDS increased cluster formation was observed at all evaluation points when compared to normal BM, whereas the number of colonies was markedly reduced (1/7 of normal). These colonies were also smaller, usually smaller than 100 cells. Significantly enhanced levels of PCD of clusters (53-79%) in combination with longer cell doubling times explain this slower formation of smaller colonies. Surprisingly, these colonies showed considerably lower levels of PCD (7-32%) as compared to normal (1-48%, median values)., Conclusions: In the absence of stromal influences and accessory cells, this study in MDS patients showed intrinsically enhanced proliferation and apoptosis of cluster-forming cells, as the opposite was true for colony-forming cells.

Myelodysplastic syndromes (MDS) are highly proliferative bone marrow (BM) disorders where the primary lesion presumably affects a CD34+ early progenitor or stem cell. We investigated the proliferative characteristics of CD34+ cells of 33 untreated MDS patients (19 RA, 5 RARS, 7 RAEB, 2 RAEBt) and five patients with acute myeloid leukemia after MDS (sAML). All patients received a 1-h infusion of the thymidine analogue iodoor bromodeoxyuridine intravenously before a BM aspirate and biopsy was taken. A double-labeling immunohistochemistry technique by monoclonal anti-CD34 (QBend/10) and anti-IUdR/BrdU antibodies was developed and performed. By this technique we recognised CD34+ and CD34- cells actively engaged in DNA synthesis or not. As MDS evolves a significant increase occurred in the percentage of CD34+ cells of all myeloid cells (mean value: RA/RARS 1.67%; RAEB(t) 8.68%; sAML 23.83%) as well as in the percentage of proliferating CD34+ cells of all myeloid cells (RA/RARS 0.19%; RAEB(t) 0.43%; and sAML 3.30%). This was associated with a decreasing trend in the overall myeloid labeling index (LI: RA/RARS 25.8%, RAEB(t) 24.6% and sAML 21.5%). This decrease in overall myeloid LI is due to an exponential increase in the proportion of CD34+ cells of the proliferating compartment during MDS evolution (RA/RARS 0.35%, RAEB(t) 1.44% and sAML 11.98% of all S-phase cells). These CD34+ cells appeared to proliferate more slowly than their more mature CD34 negative counterparts, since we found a progressive increment in the mean total cell cycling time (Tc) of all myeloid cells during MDS progression (RA/RARS 39.8, RAEB(t) 45.2 and sAML 65.8 h). This study showed that during MDS evolution to sAML the CD34+ compartment develops a growth advantage leading to apparent expansion.