Contributions
Abstract: EP1102
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Clinical
Background
JAK2V617F mutation is on the genetic basis of myelofibrosis (MF) onset and the role of its mutant allele frequency (VAF) in disease evolution as well as survival remains controversial. Monocyte-derived fibrocytes are involved in MF pathogenesis. A recent study demonstrated that monocytes with higher JAK2V617F allele burden were associated with the onset of MF in patients with myeloproferative neoplasms harbouring JAK2V617F. In addition, it has been previously shown that JAK2V617F with ≥ 50% allele burden was associated with more advanced BM fibrosis.
Aims
To evaluate the association between JAK2V617F allele burden and MF disease presentation and prognosis.
Methods
Retrospective unicentric analysis of patients diagnosed with MF between January 2010 and December 2019. The cutoff value of JAK2V617F VAF was established applying a logistic regression ROC curve. All variables with p<0.05 in the univariate model were included in the multivariate analysis. The Cox regression model and Kaplan-Meier method were used for the analysis of progression free survival (PFS) and overall survival (OS).
Results
Sixty-four (71.1%) out of 90 patients newly diagnosed with MF harboured the JAK2V617F mutation. VAF was evaluated in 54 (60%) patients, with a median mutant allele burden of 33% (range, 1-95%). Median age in this sub-cohort was 66 years old and 64.8% were males. JAK2V617F allele burden did not correlate with levels of hemoglobin (Hb), platelets neither with the presence of constitutional symptoms (p=NS). Based on our sample, there was a statistically significant association between VAF and leucocytes, and as VAF increase, leukocytes increase (rs=0.51; p<0.001). The presence of splenomegaly is associated with higher median VAF (26 versus 47%; p=0.02). About half of the patients (51.9%) were in the overt fibrotic stage (FMF) at diagnosis, which is associated with a trend for higher VAF (26 versus 47%, for prefibrotic (PFMF) and FMF, respectively; p=0.08). Variable dichotomization for allele burden established VAF=40% has the cutoff value to distinguish between PFMF and FMF (sensibility 60.7%; specificity 76.9%; PPV 73.9%; NPV 64.6%), therefore demonstrating VAF>40% as a good predictor of FMF (OR 5.15, p=0.007), even after adjusting to the variables older age, Hb<10g/dL, leucocytes≥11x109/L, elevated lactate dehydrogenase and circulating blasts >1% (OR 9.33, p=0.003). VAF>40% associated with leucocytes >11x109/L (p=0.019) and splenomegaly (p=0.017), at presentation. VAF had no positive predictive value in estimating prognosis according to the International Prognostic Scoring System nor in predicting need of treatment or disease progression to acute leukemia (p=NS).
In our sample, median PFS and OS were identically estimated in 124.6 months. While median PFS and OS were not reached for PFMF patients, FMF patients reached a median PFS and OS of 50.2 (P=0.0196) and 51.7 months (0.0015), respectively. Contrastingly, JAK2V617F VAF>40% had no impact on both PFS (124.6 vs NR months; HR 0.890, p=0.826) and OS (124.6 vs 54.4 months; HR 1.169, p=0.782).
Conclusion
We showed that MF patients with overt fibrosis at diagnosis had worse survival times, compared to PFMF patients. Also, and although the allele burden of JAK2V617F had no impact on PFS and OS of patients with MF, we demonstrated that VAF>40% has an independent positive predictive value for diagnosis of FMF. Thus, our findings identify JAK2V617F allele burden as a valuable tool to discriminate between pre-fibrotic and overt fibrotic stages in MF and suggest higher JAK2V617F VAF as a useful non-invasive marker of fibrosis onset in MF.
Keyword(s): Janus Kinase inhibitor, Myelofibrosis
Abstract: EP1102
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Clinical
Background
JAK2V617F mutation is on the genetic basis of myelofibrosis (MF) onset and the role of its mutant allele frequency (VAF) in disease evolution as well as survival remains controversial. Monocyte-derived fibrocytes are involved in MF pathogenesis. A recent study demonstrated that monocytes with higher JAK2V617F allele burden were associated with the onset of MF in patients with myeloproferative neoplasms harbouring JAK2V617F. In addition, it has been previously shown that JAK2V617F with ≥ 50% allele burden was associated with more advanced BM fibrosis.
Aims
To evaluate the association between JAK2V617F allele burden and MF disease presentation and prognosis.
Methods
Retrospective unicentric analysis of patients diagnosed with MF between January 2010 and December 2019. The cutoff value of JAK2V617F VAF was established applying a logistic regression ROC curve. All variables with p<0.05 in the univariate model were included in the multivariate analysis. The Cox regression model and Kaplan-Meier method were used for the analysis of progression free survival (PFS) and overall survival (OS).
Results
Sixty-four (71.1%) out of 90 patients newly diagnosed with MF harboured the JAK2V617F mutation. VAF was evaluated in 54 (60%) patients, with a median mutant allele burden of 33% (range, 1-95%). Median age in this sub-cohort was 66 years old and 64.8% were males. JAK2V617F allele burden did not correlate with levels of hemoglobin (Hb), platelets neither with the presence of constitutional symptoms (p=NS). Based on our sample, there was a statistically significant association between VAF and leucocytes, and as VAF increase, leukocytes increase (rs=0.51; p<0.001). The presence of splenomegaly is associated with higher median VAF (26 versus 47%; p=0.02). About half of the patients (51.9%) were in the overt fibrotic stage (FMF) at diagnosis, which is associated with a trend for higher VAF (26 versus 47%, for prefibrotic (PFMF) and FMF, respectively; p=0.08). Variable dichotomization for allele burden established VAF=40% has the cutoff value to distinguish between PFMF and FMF (sensibility 60.7%; specificity 76.9%; PPV 73.9%; NPV 64.6%), therefore demonstrating VAF>40% as a good predictor of FMF (OR 5.15, p=0.007), even after adjusting to the variables older age, Hb<10g/dL, leucocytes≥11x109/L, elevated lactate dehydrogenase and circulating blasts >1% (OR 9.33, p=0.003). VAF>40% associated with leucocytes >11x109/L (p=0.019) and splenomegaly (p=0.017), at presentation. VAF had no positive predictive value in estimating prognosis according to the International Prognostic Scoring System nor in predicting need of treatment or disease progression to acute leukemia (p=NS).
In our sample, median PFS and OS were identically estimated in 124.6 months. While median PFS and OS were not reached for PFMF patients, FMF patients reached a median PFS and OS of 50.2 (P=0.0196) and 51.7 months (0.0015), respectively. Contrastingly, JAK2V617F VAF>40% had no impact on both PFS (124.6 vs NR months; HR 0.890, p=0.826) and OS (124.6 vs 54.4 months; HR 1.169, p=0.782).
Conclusion
We showed that MF patients with overt fibrosis at diagnosis had worse survival times, compared to PFMF patients. Also, and although the allele burden of JAK2V617F had no impact on PFS and OS of patients with MF, we demonstrated that VAF>40% has an independent positive predictive value for diagnosis of FMF. Thus, our findings identify JAK2V617F allele burden as a valuable tool to discriminate between pre-fibrotic and overt fibrotic stages in MF and suggest higher JAK2V617F VAF as a useful non-invasive marker of fibrosis onset in MF.
Keyword(s): Janus Kinase inhibitor, Myelofibrosis