Prognostic Impact of Splenomegaly on Survival of Chinese with Primary Myelofibrosis

Median survival of persons with primary myelofibrosis (PMF) is about 7 years but ranges from <2 to >10 years. Different scoring systems were developed to predict survival of persons with PMF including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS), and the DIPSS-Plus. These scoring systems were developed predominately in persons of European descent and include few Asians. Recently, we analyzed a large dataset of Chinese with PMF to test validity of these scoring systems and determine if additional clinical or laboratory variables improved the prognostic accuracy of these scoring systems in Chinese with PMF who constitute a substantial proportion of people with PMF worldwide. We found frequencies of splenomegaly and anemia were significantly different between Chinese and persons of European descent with PMF and that splenomegaly, not included in the European-derived scoring systems, was an important independent predictor of survival in Chinese. Based on these data we developed a modified prognostic scoring system for Chinese subjects which included splenomegaly.

The aim of our current study is to validate the prognostic value of this modified DIPSS for Chinese with PMF in a larger cohort of 874 subjects diagnosed August, 1984 to October, 2013 at the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and evaluate the prognostic impact of splenomegaly on survival. All cases were blind re-reviewed by the pathologist and diagnosis based on the 2008 World Health Organization criteria.

495 subjects (57%) had splenomegaly below the left costal margin. Splenomegaly subjects were younger (P=0.006) and had significantly higher hemoglobin concentrations (P<0.001) and levels of WBCs (P<0.001), platelets (P<0.001) and blood blasts (P=0.012). 217 subjects (62%) in the splenomegaly cohort had JAK2^V617Fvs. 115 subjects (50%; P=0.003) in the no splenomegaly cohort. Distributions of RBC-transfusion-dependence (P<0.001) and DIPSS risk-cohorts (P=0.024) were also significantly different. Frequencies of constitutional symptoms and cytogenetic abnormalities were not significantly-different.

Median follow-up is 22 months (range, 1-288 months); 215 subjects (25%) died during follow-up. We calculated DIPSS scores at diagnosis. Risk distribution according to the DIPSS for PMF was low risk in 182 subjects (21%), intermediate-1 risk in 398 subjects (46%), intermediate-2 risk in 281 subjects (32%) and high-risk in 13 subjects (2%). Corresponding median survivals are not reached, 110, 37 and 21 months. Using the DIPSS model survival curves of intermediate-2 and high-risk subjects are not significantly different (P=0.054). In our cohort, only 2% subjects were classified as high-risk in the DIPSS scoring system. The modified DIPSS for Chinese used three independent risk factors for briefer survival: DIPSS scores (low-risk, 0; intermediate-1 risk, 1; intermediate-2 risk, 2; and high-risk, 3), platelet levels <100´10E9/L and no palpable splenomegaly. The revised risk categorization was low-risk (score 0-1), intermediate-risk (score 2-3) and high-risk (score 4-5). Using the modified DIPSS median survivals are 288, 61 and 28 months.

In univariate analyses, variables significantly correlated with survival were male gender (P=0.001), age >65 years (P<0.001), hemoglobin concentration < 100g/L (P<0.001), platelets <100×10E9/L (P<0.001), blood blasts ≥1% (P<0.001), no splenomegaly (P<0.001), RBC-transfusion-dependence (P<0.001) and DIPSS (P<0.001). Median survival in subjects with splenomegaly is 110 months compared with 64 months in subjects without splenomegaly.In multivariate analyses variables significantly correlated with survival were male gender (hazard ratio [HR]=1.63; 95% CI, 1.23-2.15; P=0.001), platelets >100×10E9/L (HR=1.58; 95% CI, 1.19-2.11; P=0.002), no splenomegaly (HR=1.45; 95% CI, 1.10-1.90; P=0.008), RBC-transfusion-dependence (HR =1.51; 95% CI, 1.11-2.06; P=0.009) and DIPSS (HR=1.90; 95% CI, 1.55-2.31; P<0.001).

Our study confirms the predictive value of the modified DIPSS with splenomegaly as a variable in a large cohort of Chinese with PMF. Moreover, we found splenomegaly was strongly associated with several laboratory abnormalities. In contrast to persons of predominately European descent, splenomegaly is an important independent favorable prognostic variable in Chinese with PMF.