Abstract CT312: Ponatinib is well tolerated and active in patients with relapsed/refractory philadelphia positive leukemias: The Bologna experience

Background: Ponatinib, a third generation BCR-ABL inhibitor, has shown relevant activity against native and mutant forms of BCR-ABL, including the T315I mutant. The aim of this compassionate protocol was to confirm the efficacy and the safety of the compound in patients with advanced Ph+ ALL and CML. Design and Methods: Ponatinib was obtained through a compassionate use named patient program, approved by ARIAD Pharmaceuticals and by the Bologna Ethical Committee. After informed consent was signed, 17 patients (M/F=8/9) have been treated (45 mg orally, once daily) between February 2012 and July 2013, including 14 Ph+ ALL and 3 blast phases of CML (11 p190, 5 p210, 1 p230). The median age of the patients was 64 years (range 23 -77). The median time from diagnosis was 2 years (range 0.2-6). Five patients (29%) had previously received an allogenic stem cell transplantation. All the patients were resistant or intolerant to previous TKIs (11 patients received >=2 TKIs). Median Hb, PLTs and WBC values were 10,1 g/dl (range 8.3-13.9), 100000/mmc (range 14000-325000) and 4400/mmc (range 1700-17000), respectively. In 6 out of 17 patients (35%), additional cytogenetic alterations were revealed. Mutational analysis showed the presence of T315I mutation (8 pts), G250E (1 pt), T315I and Y253H (1 pt), T315I and Y253A (1 pt), V299L (1 pt). Results: The median treatment duration was 153 days (range 42-594+). With a median follow up of 8 months (range 2-21+), a maHR was obtained in 12/17 patients (71%). Among these, 6 were T315I mutated. After one month of treatment, a reduction of BCR ABL fusion transcript to undetectable level was observed in 3/17 patients (18%), which increased to 29% (5/17) after two additional cycles. The progression free survival (PFS) at 12 months was 35% (median 57 days), without differences between patients with T315I mutations and patients harboring other mutations. Furthermore, we observed that, in responder patients, mutations disappeared in all except one case. In contrast, in resistant patients, a specular mutational profile before and after treatment was detected. Currently, 6/17 patients are still on study (35%). Six patients died due to progression disease. In five cases, the response allowed the patients to proceed to a savage allogenic stem cell transplantation. The drug was well tolerated. No SAEs were detected and no thrombotic arterial/venous events occurred. Conclusion: In our experience, the activity of Ponatinib in advanced Ph+ leuk