Gene expression risk signatures maintain prognostic power in multiple myeloma despite microarray probe set translation.

INTRODUCTION: Gene expression profiling (GEP) risk models in multiple myeloma are based on 3'-end microarrays. We hypothesized that GEP risk signatures could retain prognostic power despite being translated and applied to whole-transcript microarray data. METHODS: We studied CD138-positive bone marrow plasma cells in a prospective cohort of 59 samples from newly diagnosed patients eligible for high-dose therapy (HDT) and 67 samples from previous HDT patients with progressive disease. We used Affymetrix Human Gene 1.1 ST microarrays for GEP. Nine GEP risk signatures were translated by probe set match and applied to our data in multivariate Cox regression analysis for progression-free survival and overall survival in combination with clinical, cytogenetic and biochemical risk markers, including the International Staging System (ISS). RESULTS: Median follow-up was 66 months (range 42-87). Various translated GEP risk signatures or combinations hereof were significantly correlated with survival: among newly diagnosed patients mainly in combination with cytogenetic high-risk markers and among relapsed patients mainly in combination with ISS stage III. CONCLUSION: Translated GEP risk signatures maintain significant prognostic power in HDT myeloma patients. We suggest probe set matching for GEP risk signature translation as part of the efforts towards a microarray-independent GEP risk standard. (ClicinalTrials.gov identifier: NCT00639054).

Anagrelide treatment in 52 patients with chronic myeloproliferative diseases.

In this retrospective multi-centre study, we report our experience with anagrelide in the treatment of thrombocytosis in patients with chronic myeloproliferative diseases. Our study included 52 patients (age 20-78 years). The initial anagrelide dose was, in general, 0.5 mg once daily and mean maintenance dosage was 1.7 mg/day. The overall response rate was 79% including 75% complete remission and 4% partial remission. Forty-two patients (81%) had adverse effects and in 29% of the study population, the adverse effects necessitated cessation of anagrelide. The most common adverse effect was moderate anaemia (50%). Two patients experienced erectile dysfunction which has been described only once previously in association with anagrelide treatment. One patient progressed to acute leukaemia. However, this patient had been pre-treated with two potentially leukaemogenic drugs and had only been in short-term treatment with anagrelide. Furthermore, a total of 13 events were recorded. More than 25% of these events occurred in patients with platelet counts between 400 and 600 x 10(9)/l and almost 40% of all events occurred in patients with platelet counts above 400 x 10(9)/l. This observation supports the hypothesis that aggressive control of thrombocytosis to a platelet count <400 x 10(9)/l might reduce the number of thrombohaemorrhagic events. Anagrelide is safe and effective in reducing the platelet counts, but a high proportion of the patients discontinue treatment because of the adverse effects of the drug.

Tumor burden as the most important prognostic factor in early stage Hodgkin's disease. Relations to other prognostic factors and implications for choice of treatment.

Two hundred ninety patients with Hodgkin's disease pathologic stage (PS) I or II were treated in the prospective randomized trial of the Danish National Hodgkin Study (see Appendix) with radiotherapy +/- adjuvant combination chemotherapy. The initial tumor burden of each patient was assessed, combining tumor size of each involved region and number of regions involved. Multivariate analyses of prognostic factors including treatment, tumor burden, histologic subtype, pathologic stage, number of involved regions, mediastinal size, systemic symptoms, erythrocyte sedimentation rate (ESR), sex, and age were carried out. With regard to disease-free survival tumor burden was by far the most important prognostic factor for patients treated with adjuvant chemotherapy as well as for patients treated with radiotherapy alone. With regard to survival from Hodgkin's disease only tumor burden and age were independently significant. A combination of tumor burden, histologic subtype, and sex singled out patients with a high relapse rate both after radiotherapy only, and after radiotherapy plus chemotherapy. This combination also singled out patients destined to die from Hodgkin's disease more accurately than other prognostic factors.

Tumour burden in early stage Hodgkin's disease: the single most important prognostic factor for outcome after radiotherapy.

One hundred and forty-two patients with Hodgkin's disease PS I or II were treated with total or subtotal nodal irradiation as part of a prospective randomized trial in the Danish National Hodgkin Study during the period 1971-83. They were followed till death or--at the time of this analysis--from 15 to 146 months after initiation of therapy. The initial tumour burden of each patient was assessed, combining tumour size of each involved region and number of regions involved. Tumour burden thus assessed proved to be the single most important prognostic factor with regard to disease free survival. Other known prognostic factors such as number of involved regions, mediastinal size, pathological stage, systemic symptoms, and ESR were related to tumour burden and lost their prognostic significance in a multivariate analysis. The only other factors of independent significance were histologic subtype and, to a lesser extent, sex. Combining tumour burden and histologic subtype made it possible to single out a group of patients with a very poor disease free survival. These patients also had a poorer survival from Hodgkin's disease and thus clearly candidates for additional initial treatment.

A methodological evaluation of 14 controlled clinical trials in myelomatosis.

A methodological evaluation of the 14 randomized clinical controlled trials so far published on myelomatosis was performed. A quite large heterogeneity was observed among the trials, especially in their presentation of patients included and in the criteria applied for therapeutic response. Additionally, none of the studies accounted for the randomization procedure - and particularly whether the randomizations were performed consecutively. 19 comparisons of the effectiveness of various drugs or drug combinations were performed and in 12 of these an insignificant result was obtained. 2 of these with more than 25% probability have overlooked a beneficial effect of one of the regimens of more than 50% and 6 trials of more than 25%. It is stressed that these situations will arise when sample sizes that are too small are applied in clinical trials. It is concluded that internationally accepted criteria for diagnosis and therapy response are needed. Additionally, a more thorough statistical planning, prior to initiation of a trial, and a more extensive analysis of the results would be helpful.