Chromosomal and FISH Study of 286 Patients with Primary Myelofibrosis (PMF) Reveals Cryptic Abnormalities and Identifies Lesions Associated with Favorable Prognosis and Disease Progression,

Abstract 3526

The pre-treatment karyotype is frequently a potent prognostic determinant of survival in patients (pts) with hematological malignancies. The prognostic significance of chromosomal aberrations, detected at time of diagnosis in pts with essential thrombocythemia (8–10%), polycythemia Vera (PV) (29%) and PMF (approximately 50%), is not well appreciated. We performed a retrospective analysis of 286 pts with PMF who had cytogenetic analyses at our single center between 1984 and July 2011. We first hypothesized that interphase FISH (I-FISH) studies might increase detection of chromosomal rearrangements. Initially, between 2000 and 2008 we performed I-FISH for the detection of the 5 most frequently rearranged loci in Ph negative myeloproliferative neoplasms and extended to 10 loci (1q21, EGR1 at 5q31, D7S511 at 7q31, P15/P16 at 9p21, ATM at 11q22.3, RB1 at 13q14, D20S108 at 20q11 and for numerical detection of chromosomes 7, 8, and 9) as of 2008. The addition of molecular cytogenetics revealed 146 pts (51%) with a normal karyotype and 140 (49%) with abnormal chromosomal lesions, including 12 pts with previously unrecognized lesions. To investigate the relationship between specific chromosomal lesions and JAK2V617F, testing when available after 2007, was performed in 170 of 286 (59%) pts. The V617F mutation was present in 66%. Wild type JAK2 (35%) PMF pts showed del(20q) (4 pts), del(13q) (3 pts), +8 (3 pts, one had cryptic +8), inv(12)(p11q15) (4pts), + der(19)t(1;19) (2pts), complex karyotype (2pts) as well as cryptic lesions (1pt)in a setting of a normal karyotype. The median follow up time of 31pts with normal baseline cytogenetics was 18 months (range 5 to 216 months) and 33% of these patients acquired an abnormal karyotype within the median time of 38mos (range 13–122 months). Four pts acquired a complex karyotype within the mean time of 13 mos (range 11–16 mos) while 2 pts acquired del(20q) within an average of 105 mos (126 and 84 mos). No patient developed a monosomal karyotype. Among 140 pts with an abnormal baseline karyotype, follow up studies were available for 29 pts. The median follow up time was 11 mos (range 5–93 mos) and clonal evolution was observed in 9 pts (31%). The most frequent recurrent abnormalities included del (20)(q11q13) in 30%, del(13q) in 18%, + 8 in 17%, +9/+9p in 16%, trisomy 1q/dup1q in 16%, and i(17q)/del(17p) in 9%. Complex karyotype involving 3 or more chromosomes was identified in 19% while monosomal karyotype, including loss of chromosomes 5, 6,7,17 and18 was observed in 11%. All 6 pts with +der(9)t(1;9)(q21;q12), had PV related PMF and 3 of these pts underwent allogeneic SCT, implying that this abnormality is associated with disease progression. A unique rearrangement, t(1;9) (p36;p24), resulted in identification of a novel JAK2 fusion partner. Survival of these pts based on their cytogenetic risk categories will be presented. Our observations demonstrated that a novel der(19)t(1;19) was detected only in JAK2V617F negative pts, while other abnormalities such as del(20q) and del(13q) are present in both mutation positive and wild type pts. These results confirm previous observations made by us and others that chromosomal abnormalities may occur either before or after JAK2V617F (Wang et al 2009). Even though 33% of pts will progress from a normal to an abnormal karyotype, monosomal karyotype does not appear to be a cytogenetic risk factor in these pts. The observation that the del(20q) abnormality developed over a 7–10 year period in pts with PMF, leads us to conclude that this specific cytogenetic abnormality should be considered a favorable prognostic risk factor.