Palmer, Shanique R.

Abstract Background: We sought to validate the International Prognostic Scoring System (IPSS) for myelodysplastic syndromes (MDS) in a well-characterized group of patients with refractory anemia with ringed sideroblasts (RARS), as well as to assess the validity of novel and easily obtained prognostic factors such as complete blood count (CBC) parameters. For instance, Bowles and colleagues (Br J Haematol2006; 135: 198) recently reported that a low platelet mass (i.e., mean platelet volume (MPV) x platelet count <0.60 mL/L) is a marker for poor survival (median, 5 months) in patients with MDS, and also asserted the MPV and platelet count do not correlate so the MPV provides independent prognostic information. Because platelet parameters have been of particular interest in RARS, especially with respect to the provisional entity RARS with thrombocytosis (RARS-T), we assessed the prognostic relevance of MPV and platelet count/mass in this MDS subtype. Methods: We analyzed all pts diagnosed with RARS by FAB criteria at Mayo Clinic between 1994 and 2002, a period chosen because it was the interval when the MPV was routinely reported along with CBCs at our center. We excluded pts who were evaluated at Mayo Clinic >6 months after initial diagnosis or were being treated for other malignancies (e.g., lymphoma or myeloma). Medical records, blood parameters, bone marrow findings, and cytogenetic results were reviewed. We performed time-to-event analysis using Kaplan-Meier estimates and Cox proportional hazards modelling, with Chi-Square statistics to assess significance (i.e., type I error rate <0.05). Results: A total of 127 pts (79 males; median age 73 years, range 51-90) were identified, with 78 verified events during the follow-up period. The median survival was 3.9 years. The correlation between MPV and platelet count was poor (Pearson correlation coefficient, -0.18). Platelet count was low in 26 pts, within the normal range in 93 pts, and elevated in 8 pts (but >600 ×109/L in only 2). In univariate analysis, lower Hb, lower MCV (but not MPV), higher total white count, lower platelet count, abnormal cytogenetics, and higher IPSS score each predicted poorer survival. In multivariate analysis using a proportional hazards model, only the platelet count (hazard ratio 0.93 for each increase in count by 25, 95% confidence interval (CI) 0.88-0.98, p=0.0055) and IPSS score (hazard ratio 7.7 for each increase in IPSS score by 1, 95% CI 4.1-14.4, p<0.0001) remained independently predictive of survival. Relatively few patients with RARS have either low platelet mass (<0.60 mL/L, 8%) or intermediate platelet mass (0.60-1.20 ml/L, 12%) as defined by Bowles et al. While the platelet mass was indeed predictive of survival (p<0.0001), this was due entirely to the platelet count, and there was no additional information from the MPV. Conclusion: The IPSS is an excellent predictor of survival in pts with RARS, and the quantitative platelet count adds independent information. The MPV has no additional effect on survival in patients with RARS.

Abstract Background: Patients with CLL have a variable clinical course. Current novel prognostic indicators (ZAP-70, CD38, IgVH gene mutation status, FISH) are able to identify early-stage CLL patients at high risk of rapid disease progression. These prognostic factors focus on characteristics of the malignant B cell clone and are not currently changeable factors. Identification of modifiable characteristics of the host unrelated to the leukemic B-cell but that relate to CLL-specific survival may provide opportunities for therapeutic intervention. Since the immune system is likely to modulate disease progression in CLL patients, we evaluated critical features of that system in relation to the size of the circulating clonal B-cell population in a CLL cohort. Methods: 186 consecutive patients with CLL who were evaluated at Mayo Clinic within 2 months of diagnosis between 2000 and 2002 were identified. The primary end-point of the study was to assess if host immunity affected time to treatment (TTT). Baseline flow cytometry analysis was available for 166 patients (88%) and was used to calculate the absolute number of T-cell and natural kill (NK)-cells present at diagnosis. The size of the T-cell/NK-cell compartment relative to the size of the malignant monoclonal B-cell (MBC) compartment was then evaluated by calculating the NK:MBC ratio and T:MBC ratio. Relationships with other prognostic parameters and with TTT were evaluated. Results: Patients exhibited substantial variation in the absolute number of T-cells and NK cells as well as T:MBC and NK:MBC ratios at the time of diagnosis. Higher T:MBC and NK:MBC ratios were observed among patients with early Rai stage and mutated IgVH genes (all P≤0.0002). As continuous variables, both the T:MBC ratio (p value=0.03) and NK:MBC ratio (p value=0.02) were associated with TTT. Since they correlated with TTT as continuous variables, thresholds to classify MBC, T:MBC ratio, and NK:MBC were identified using the method of Contal and O’Quigly. On multivariate Cox modeling including stage, CD38, absolute MBC count, T:MB ratio, and NK:MB ratio, the independent predictors of TTT were disease stage, T:MB ratio, and NK:MB ratio (Table 1). Conclusion: Measurable characteristics of the host immune system appear to relate to the rate of disease progression in patients with newly diagnosed CLL. These characteristics can be modified and continued evaluation of immunomodulatory drugs, vaccination strategies, and cellular therapies to delay/prevent disease progression are warranted. Additional studies exploring how interactions between the host immune system and the leukemic clone influence clinical outcomes are needed.