Combination Chemotherapy With Tyrosine Kinase Inhibitors Can Overcome Bcr-Abl Mutations In Acute Lymphoblastic Leukemia Or Blast Crisis CML

Point mutations in the kinase domain of bcr-abl confer resistance to tyrosine kinase inhibitors (TKIs) in patients with blast phase chronic myeloid leukemia (CML-BC) and Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL). In particular the presence of T315I mutation is highly resistant to most current available TKIs.

To evaluate whether the combination of chemotherapy with different TKIs can overcome mutations in the kinase domain of bcr-abl in patients with CML-BC or Ph+ ALL compared to TKI alone.

We retrospectively analyzed data from our institution on patients with CML-BC and Ph+ALL that were treated with TKI alone or in combination with chemotherapy. PCR-based DNA sequencing of the bcr-abl fusion transcript was done to analyze the relevant codons of the kinase domain.

A total of 361 patients with CML-BC (93 patients) and Ph+ ALL (252 patients) were evaluated for mutation analysis after treatment with TKIs alone (114 patients) or TKIs combined with chemotherapy (247 patients) between the years 2000-2012. Mutation analysis was available in 182 of the patients, revealing 95 patients (52%) without mutations in bcr-abl domain and 87 patients (48%) with mutations. We have analyzed 34 patients with a second mutation analysis done after treatment with TKIs alone (n=20) or TKIs combined with chemotherapy (n=14). Eighteen patients (53%) received frontline treatment and 16 patients (47%) received salvage therapy, (median 3 prior therapies, range 1-7 prior therapies). The highly resistant ‘gate keeper’ mutation (T315I) was present in 12 (35%) of the patients (6 of 14 patients (43%) treated with TKIs combined with chemotherapy and 6 of 20 patients (30%) treated only with TKIs). Other common mutations included 5 patients with E255K, 5 with F317I and 3 with Y253H. Although higher proportion of patients treated with combined TKIs and chemotherapy received salvage treatment compared to patient that were treated with TKIs alone (7/10, 70% vs 13/24 54%), the median time from treatment to disease progression was not different in the two groups (5.5 months). More patients treated with TKIs combined with chemotherapy achieved complete cytogenetic response (10/14, 71%) than patients that were treated with TKIs alone (6/24, 25%). In 10 patients (29%) the mutation detected before the start of therapy was no longer detectable after therapy. In 3 of these patients T315I mutation was undetectable after treatment with combined dasatinib with hyperCVAD (hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasome), MOAD (methotrexate,vincristine, L-Asparginase, dexamethasone) and dasatinib with subsequent treatment with omacetaxine, respectively. Of the 10 patients in whom mutation was no longer detectable after treatment, 7 were treated with combined TKIs and chemotherapy while only 3 were treated with TKI (dasatinib) alone. Three of these patients had prior allogeneic stem cell transplantation in addition to TKI combined with chemotherapy. Six patients had compound mutations at the end of therapy (vs. three patients before start of therapy). New compound mutations emerged in 3 patients treated with TKIs alone- nilotinib, dasatinib,bosutinib, and 1 patients with combined TKI and chemotherapy. The mutation of T315I was present in 11/34, 33% of patients at the end of therapy. The median survival of patients that had no mutation detected after treatment was not different from patients with persistent mutation (25 months , range 6 to 106 months vs 23 months, range 4 to 118 months, p=NS)

The addition of chemotherapy to TKIs in patients with BC-CML or Ph+ ALL could overcome some of the mutations in bcr-abl kinase domain, including T315I even when using a TKI not expected to be effective against such mutation. In this cohort overcoming bcr-abl kinase domain mutations did not translate into improved survival. Further studies aiming to overcome bcr-abl kinase mutations including patients treated with ponatinib and investigational therapies are warranted.

Cortes:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; BMS: Research Funding; Novartis: Research Funding.