Health resource consumption and costs attributable to chemotherapy-induced toxicity in German routine hospital care in lymphoproliferative disorder and NSCLC patients.

BACKGROUND: Multidrug chemotherapy (CT) is still associated with relevant side-effects. We assessed, under current practice patterns, frequency and severity of CT-induced toxicity and its economic consequences. PATIENTS AND METHODS: Prospective, multicentre, longitudinal, observational cohort study with lymphoproliferative disorder (LPD) and non-small-cell lung cancer (NSCLC) patients, receiving first- or second-line (immuno-) CT (excluding myeloablative CT). Data were collected from patient interviews and preplanned chart reviews. Costs in 2007 euros are presented from the provider perspective. RESULTS: Two hundred and seventy-three patients (n = 153 LPD; n = 120 NSCLC) undergoing a total of 1004 CT cycles were assessable (age ≥65 years, 40%; female, 36%; Eastern Cooperative Oncology Group performance status ≥2, 11%; tumour stage ≥III, 56%; history of comorbidity, 80%). Fifty percent of cycles were associated with grade 3/4 toxicity and 37% (n = 371) with at least one hospital stay (outpatient/day care n = 154; intensive care n = 19). Mean (median) toxicity-related costs amounted to €1032 (€86) per cycle. Costs rose exponentially with the number of grade 3/4 adverse drug reactions (ADRs) and were highest in cycles affected by more than four ADRs, €10 881 (€5455); in cycles with intensive care, €14 121 (€8833); and in cycles affected by grade 3/4 infections and febrile neutropenia/leukopenia, €7093 (€4531) and €5170 (€2899), respectively. Five percent of CT cycles accounted for 56% of total expenses. CONCLUSIONS: Individualised supportive care strategies are needed. Future research should focus on identifying toxicity clusters and patient characteristics predictive for high costs.

Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients.

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

The role of azacitidine in the management of myelodysplastic syndromes (MDS).

Myelodysplastic syndromes (MDS) are a group of common bone marrow disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a propensity for transformation to acute myeloid leukemia (AML). For many years, the main treatment option for MDS was best supportive care which alleviates symptoms but has no effect on the natural course of the disease. The recent approval of the demethylating agent azacitidine represents a significant advance in the treatment of MDS. The results of two randomized trials with azacitidine have shown an overall response rate between 40% and 60%, an improved quality of life, a reduced risk of transformation to AML and a definite survival advantage compared to best supportive care or low-dose chemotherapy. Current data on azacitidine and its place in the treatment of MDS are reviewed.