Ekaterini Stefanoudaki

Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH)

The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.

Preserved levels of uninvolved immunoglobulins are independently associated with favorable outcome in patients with symptomatic multiple myeloma.

Suppression of uninvolved immunoglobulins is common in multiple myeloma (MM) but the prognostic significance of this phenomenon has not been assessed. We evaluated the prognostic significance of the preservation of uninvolved immunoglobulins in 1755 consecutive, unselected, patients with newly diagnosed, symptomatic MM with pre-therapy immunoglobulin levels measured by nephelometry. Suppression of at least one uninvolved immunoglobulin was observed in 87% of patients and was more common in patients with immunoglobulin A myeloma, those aged over 65 years, in patients with advanced-International Staging System (ISS) stage, extensive-bone marrow infiltration, anemia, low platelet counts, high levels of serum M-monoclonal protein or renal dysfunction. Patients with preserved immunoglobulins had a better survival than patients with suppressed immunoglobulins (median survival 55 vs 41.5 months, P<0.001). In multivariate analysis, preservation of uninvolved immunoglobulins was independently associated with better survival (hazard ratio: 0.781, 95% confidence interval: 0.618–0.987, P=0.039); irrespective of the treatment. In a subset of 500 patients, which were strictly followed for disease progression, preservation of uninvolved immunoglobulins was associated with a significantly longer progression-free survival (60 vs 25 months, P<0.001), independently of other common prognostic factors. In conclusion, preservation of uninvolved immunoglobulins in newly diagnosed patients with symptomatic MM was independently associated with long term disease control and improved survival.

No significant improvement in the outcome of patients with Waldenström's macroglobulinemia treated over the last 25 years†‡

The treatment of Waldenströms macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2‐microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent‐based regimens and most patients who started treatment after January 1, 2000 received rituximab‐based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high‐risk disease. Possible differences in the 15‐ or 20‐year survival rate between the two groups may be detected with further follow‐up of these patients. Am. J. Hematol. 2011.

Clinical features, outcome, and prognostic factors for survival and evolution to multiple myeloma of solitary plasmacytomas: a report of the Greek myeloma study group in 97 patients.

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow‐up of 60 months, 5 and 10‐year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5‐ and 10‐year MM‐free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5‐ and 10‐year OS probability, plasmacytoma relapse‐free survival (PRFS), progression‐free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA‐based treatment increased toxicity without offering any survival advantage over R/T. Am. J. Hematol. 89:803–808, 2014.

PET/CT in primary mediastinal large B-cell lymphoma responding to rituximab-CHOP: An analysis of 106 patients regarding prognostic significance and implications for subsequent radiotherapy.

PET/CT in primary mediastinal large B-cell lymphoma responding to rituximab-CHOP: An analysis of 106 patients regarding prognostic significance and implications for subsequent radiotherapy

Circulating angiopoietin‐1 to angiopoietin‐2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

The circulating levels of several angiogenic cytokines [angiopoietin‐1 (Ang‐1), angiopoietin‐2 (Ang‐2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang‐1/Ang‐2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin‐1/angiopoietin‐2 ratio correlated with advanced disease features including international staging system (ISS)‐3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin‐2) we found that angiopoietin‐2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang‐1/Ang‐2 ratio correlated with survival. Patients with circulating Ang‐1/Ang‐2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first‐line therapy with novel agent‐based regimens (65% of our patients). Furthermore, a subset of ISS‐3 patients with serum Ang‐1/Ang‐2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang‐1/Ang‐2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50–2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.

Multiple myeloma in octogenarians: Clinical features and outcome in the novel agent era

Multiple myeloma (MM) affects mainly elderly persons and because the population of octogenarians increases, it is common to treat patients ≥80 years of age. These patients are often not included in clinical trials; thus, there is limited data on their characteristics and treatment outcome.