Prognostic Impact of JAK2V617F Mutation In MDS: a Matched Case Control Study

The JAK2V617F mutation is found in a small proportion of MDS, especially in RARS-T and occasionally in other MDS subtypes, but the overall impact of JAK2V617F on MDS characteristics and outcome remains unclear.

Diagnostic and follow up data on MDS patients (pts) with known JAK2V617F mutation status were collected from 19 centers of the Groupe Francophone des Myélodysplasies (GFM) and the French Intergroup of MPN (FIM). MDS post MPN and CMML were excluded. Patient characteristics and outcome according to JAK2V617F status were analyzed by univariate analysis. Survival analysis with Cox model matched on age, IPSS score and sex according to JAK2 status was also made. Analysis was performed using STATA 10.0 software.

161 cases were collected, including 65 JAK2V617F mutated (JAK2 pos) and 96 unmutated (JAK2 neg) cases. Median age was 75 years and M/F ratio 1.2 in JAK2 pos vs 71 years (p=NS) and 1 (p=NS) in JAK2 neg pts, respectively (resp). WHO 2008 distribution was RA (8%), RARS (12%), RARS-T (41%), CRDM (15%), RAEB-1 (11%), RAEB-2 (5%), 5q- (3%), unclassified (5%) in JAK2 pos pts and RA (25%), RARS (9%), RARS-T (1%), CRDM (14%), RAEB-1 (28%), RAEB-2 (19%), 5q- (1%), unclassified (3%) in JAK2 neg pts, resp (p<0.001). Hb (median 103 vs 98 g/L, p=NS) and MCV (98 vs 98 fL, p=NS) were similar in JAK2 pos and JAK2 neg pts resp but WBC (median 7.3 vs 4.4 G/L, p<0.001), ANC (4.85 vs 2.1 G/L, p<0.001) and platelets counts (541 vs 160 G/L p<0.001) were higher in JAK2 pos than in JAK2 neg pts. Conversely, marrow blasts % was significantly lower in JAK2 pos than in JAK2 neg pts (median 2% vs 4%, p<0.001). Karyotype was abnormal in 40% JAK2 pos pts (10% +8, 17% del5q, 7% −7/del7q, 3% del20q) and in 35% JAK2 neg pts (3% +8, 5% del5q, 2% −7/del 7q, 3% del20q) (p=NS). Unfavorable karyotypes (complex and −7/del7q) were seen in 9% JAK2 pos and 13% JAK2 neg pts (p=NS). IPSS was low or int-1 in 93% JAK2 pos and in 82% JAK2 neg pts (p=0.056). Median follow up was 44 months [8-350] in JAK2 pos and 62 months [25-182] in JAK2 neg pts. Progression to AML occurred in 6% JAK2 pos and in 20% JAK2 neg pts (p<0.001). 5-year OS was 88% in JAK2 pos and 57.8% in JAK2 neg pts (p<0.001). When the analysis was performed after exclusion of RARS-T (n=133) median age was 74 years and M/F 1.1 in JAK2 pos vs 70 years (p=NS) and 0.7 (p=NS) in JAK2 neg pts resp. Hb (median 103 vs 98 g/L, p=NS) and MCV (102.5 vs 98 fL, p=NS) remained similar in JAK2 pos and JAK2 neg pts, resp. WBC (median 6.4 vs 4.4 G/L, p<0.001), ANC (3.88 versus 2.1 G/L, p=0.001) and platelet counts (268 versus 156 G/L p<0.001) were still higher in JAK2 pos than in JAK2 neg pts. Marrow blasts % was still significantly lower in JAK2 pos than in JAK2 neg pts (median 2% vs 4%, p=0.016). IPSS was low and int-1 in 88% JAK2 pos and in 82% JAK2 neg pts (p=NS). Progression to AML occurred in 9.7% JAK2 pos and in 20% JAK2 neg pts (p=NS). 5 year OS was 92.2% in JAK2 pos and 57.6% in JAK2 neg pts (p=0.0052). When survival analysis was matched on age, IPSS and sex, JAK2 mutation was associated with better OS both in the whole population (p=0.011) and after excluding RARS-T (p=0.028). Finally, in JAK2 pos RARS-T pts (n=27) no AML progression was seen, and 5-year OS was 84.9%.

We found JAK2V617F mutation in MDS to be associated with higher WBC, ANC and platelet counts, lower % marrow blasts, less progression to AML and better survival than JAK2V617F neg MDS. This positive prognostic impact persisted after exclusion of RARS-T. However, our results will require confirmation in a prospective study.

Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.