Results of Second Generation Tyrosine Kinase Inhibitor Frontline Therapy in Chronic Myeloid Leukemia with Variant Philadelphia Chromosome

Variant Philadelphia (Ph) chromosomes are observed in 5–10% of patients (pts) with CML, involving one or more additional chromosomes besides 9 and 22. Deletions of derivative chromosome 9 (del der (9)) occur in 10–15% of pts, and frequently these abnormalities coexist. Prior to the advent of TKIs pts with variant Ph or del der (9) had a worse outcome. With imatinib the adverse prognosis conferred by these abnormalities has been minimized. To our knowledge there are no published reports regarding the outcomes of pts with variant Ph or del der(9) while on treatment with a 2^nd generation TKI as initial therapy for CML. We analyzed the significance of these abnormalities among patients with CML in chronic phase (CP) enrolled in 2 parallel trials of dasatinib or nilotinib as initial therapy.

A total of 205 pts with CML in CP treated between 2005 and 2012 at our institution with frontline dasatinib or nilotinib based protocols were included in this analysis. Among them 193 (94%) had classic Ph chromosome, and 12 (6%) had a variant Ph chromosome. Nineteen of the 205 pts (9%) had del der (9). Their characteristics and outcomes were compared.

Only one additional chromosome was present in the Ph rearrangement in each of the variant Ph-positive cases. The additional chromosomes found were 17 in three patients and chromosomes 1, 3, 4, 5, 9, 11, 14, 19, 21 in one patient each. Del der (9) was found in 2 of 12 pts with variant Ph and in 17 with classic Ph. Five (50%) of the pts with variant Ph were treated with dasatinib and 5 (50%) with nilotinib. Of those with classical Ph 93 (48%) were treated with dasatinib and 100 (52%) with nilotinib. The median age was 48 yrs (range 17 to 86) for those with classic Ph, and 53 yrs (24 to 79) for those with variant Ph. The Sokal risk group for those with classic Ph was high in 16 (8%), intermediate in 53 (28%), and low in 124 (64%). For the patients with variant Ph risk classification was 10%, 50% and 40%.

No significant differences were observed in response to therapy between pts with variant Ph and those with classic Ph (CCyR 100% vs. 93%; MMR 100% vs. 85%, respectively), or between those with del der (9) and those without it (CCyR 100% vs. 93%; MMR 100% vs. 84%). The 3-year probability of overall survival (OS) was 99% for pts with classic Ph and 89% for those with variant Ph. Corresponding values for 3-year event-free survival (EFS) were 96% and 89%, and transformation-free survival (TFS) 99% and 100% respectively. 3-year OS, EFS and TFS were also similar between pts with del derv (9) and those without it (Table 1). Among the 2 pts with concomitant variant Ph and del der (9), one achieved CCyR at 3 months and has maintained it with 12 months of follow up. The second one achieved CCyR but became pregnant during the course of treatment; the TKI was temporarily discontinued and she lost cytogenetic response, but regained response after 3 months of reinitiating TKI therapy and delivering a healthy baby.

The presence of variant Ph chromosome or del der (9) does not affect the clinical characteristics or outcome of pts with CML CP treated with second generation TKI as initial therapy.

Kantarjian:Pfizer: Research Funding; Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Jabbour:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.