Survivorship in WM: Identification of Factors Associated with Survival of More Than a Decade and with Early WM-Related Death
Authors: Kastritis Efstathios , Kyrtsonis Marie-Christine , Gavriatopoulou Maria , Hatjiharissi Evdoxia , Katodritou Eirini , Repousis Panagiotis , Symeonidis Argiris , Michael Michalis , Pouli Anastasia , Giannakoulas Nikolaos , Christoulas Dimitrios , Megalakaki Aikaterini , Tsirigotis Panagiotis , Giannouli Stavroula , Panayiotidis Panayiotis , Vassou Amalia , Vervessou Elina , Delimpasi Sossana , Kaiafa Georgia D , Tsatalas Konstantinos , Terpos Evangelos , Dimopoulos Meletios A 
Published: October 2019

Abstract
Waldenström's Macroglobulinemia (WM) is a low grade lymphoma with a prolonged course and a median survival exceeding 7 years. However, there are patients who die of WM early during the course of the disease while a significant proportion of WM patients can survive ≥10 years. The characteristics of these two groups of patients may differ and their identification may augment the choice of risk adapted treatment strategies. The aim of our study was to identify and characterize patients with short survival due to WM as well as those with survival exceeding 10 years, and to compare their characteristics in order to evaluate clinical factors associated with poor or with good outcomes, based on data from a large database with long follow up.
The analysis included 492 patients that have been entered in the prospectively maintained database of the Greek Myeloma Study Group, who fulfill the criteria form symptomatic WM requiring therapy. The median follow up of all the patients in the database is 10 years. For the first part of the analysis we included 292 patients who have at least 10 years of follow up (thus, they started therapy at least 10 years ago, before 2006). Among them, we identified 101 (34.5%) patients who survived ≥10 years, and 13% who died due to WM within <3 years after initiation of treatment. When compared to patients who survived less than 10 years, those with survival ≥ 10 years had lower levels of b2microglobulin (p=0.043), higher levels of serum albumin (p=0.004) and were younger (p<0.001); however, cytopenias and IgM levels were not significantly different between the two groups. We then compared the characteristics of those who survived ≥10 years to patients from the same subgroup (i.e those who started therapy before 2006) who died of WM within <3 years: 10-years survivors were younger (64% vs 16% were ≤65 years, p<0.001), had less anemia (hgb<11.5 gr/dl in 69% vs 89%, p=0.006), thrombocytopenia (platelet counts <100x109/L in 8% vs 22%, p=0.017), had less often LDH ≥250 IU/L (12% vs 29%, p=0.014), b2-microglobulin ≥3 mg/L (56% vs 76%, p=0.31), serum albumin <4 gr/dl (68% vs 83%, p=0.001) and splenomegaly (27% vs 51%, p=0.002) compared to those who survived <3 years. Per ISSWM their disposition was 30%, 35% & 35% for low, intermediate and high risk for those that survived ≥10 years and was 33% and 67% for intermediate and high risk for those that survived <3 years (no patient had low risk disease) (p<0.001).
As a validation of the previous results, we evaluated the presence of the above clinical characteristics in patients with survival <3 years who started therapy between 2006 and 2012 (n=177) and thus, had a minimum follow up ≥3 years. The incidence of WM-related death within <3 years was 10%, similar to what was observed in the era before 2006. The characteristics of patients with short survival in the era 2006-2012 were similar to that of patients with short survival in the period before 2006: age >65 in 63%, hgb<11.5 gr/dl in 89%, platelet counts <100x109/L in 11%, LDH ≥250 IU/L n 39%, b2-microglobulin ≥3 mg/L in 82%, serum albumin <4 gr/dl in 89%, splenomegaly in 28% and per ISSWM, 29% were intermediate and 65% high risk. In order to further elucidate the most important characteristics of patients with short WM-related survival we performed further analysis in all patients with a minimum follow up ≥3 years. Based on ROC analysis for early death, serum albumin <4 gr/dL and b2microglobulin >4 mg/L were the two most important predictors of early WM-related death. When age >65 years was also included as a predictor, patients with 0, 1, 2 or 3 of the above factors had 3-year WM-related death rate of 3%, 4%, 16% and 25% (p<0.001). Regarding overall survival, 4 groups with significant 5-year (93%, 89%, 72% and 44%) and 10-year survival (81%, 62%, 38% and 23%) were identified (p<0.001)(figure 1). Also, this staging by b2m, serum albumin and age outperformed IPSSWM.
In conclusion, 34.5% of patients with WM survive ≥10 years, but 10%-13% die of WM within < 3 years from initiation of treatment. These patients with high risk disease are older with higher tumor bulk and increased LDH. However, by applying only the presence of serum albumin < 4 gr/dl, b2 microglobulin ≥4 mg/L and age >65 years we can identify patients at very low risk of early death as well as patients with significant risk of early death and short survival. This simple staging system may also outperform IPSSWM.
Figure 1 Figure 1.

Disclosures
Kastritis: Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Kyrtsonis:Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Katodritou:Genesis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Delimpasi:Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria. Terpos:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.