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Ponatinib in combination with steroids is effective in elderly patients with Philadelphia-positive acute lymphoblastic leukaemia and showed a low incidence of cardiovascular adverse events

Primary results of the phase II GIMEMA LAL1811 study indicate high efficacy of the combination of the next generation BCR-ABL tyrosine kinase inhibitor (TKI) ponatinib with steroids in the treatment of elderly, or unfit patients with Philadelphia-positive acute lymphoblastic leukaemia (Ph+ ALL). The treatment led to a high rate of minimal residual disease (MRD) eradication and induced very fast BCR-ABL transcript reductions. Of particular importance in the less fit population in this study, the treatment was well tolerated, with manageable toxicity and a low incidence of cardiovascular adverse events.

The incorporation of TKIs in treatment schedules of Ph+ ALL has remarkably improved the survival of these patients. In fact, in adult Ph+ ALL patients, ponatinib in combination with chemotherapy showed a 3-year event-free survival (EFS) rate of 69% with a 3-year overall survival (OS) rate of 83%. Compared to combinations of dasatinib and chemotherapy, ponatinib-chemotherapy also induced a higher rate of response. Ponatinib is a more potent BCR-ABL1 inhibitor and selectively suppresses the resistant T315I clones. Unfortunately, TKIs combined with chemotherapy are often too toxic for unfit or elderly ALL patients, warranting the development of effective and better tolerable treatment combinations for these patients. In this light, the GIMEMA LAL1811 trial assessed the efficacy and safety of steroids plus ponatinib in the treatment of elderly or unfit patients with Ph+ ALL.

In the study at hand, 42 patients were treated with oral ponatinib (45 mg/day) for 8 consecutive courses of 6 weeks. Steroids were administered from day -14 to day 29 during course 1. In order to be eligible for the study, patients had to be 60 years or older, or had to be unfit for intensive chemotherapy and stem cell transplantation. A performance score (PS) of 0-2 and a normal organ function were also prerequisites for study participation. Patient samples were obtained at diagnosis and at every therapy course to perform a BCR-ABL mutational analysis and to calculate the BCR-ABL/ABL ratio by quantitative real time PCR. For this study, a complete molecular response (CMR) was defined as a BCR-ABL/ABL ratio below 0.01.

The median age of the 42 patients in the study was 67 years and 87% had a PS of 0-1. Twenty-six patients had the p190 fusion transcript, 4 had the p210 transcript and in 12 patients the p190/p210 transcript was reported. Prior to starting ponatinib, steroid pre-treatment was given to 39 patients resulting in a reduction in circulating blasts of 75% or more in 14 patients. The primary endpoint of the study, defined as having a complete haematological response (CHR) at 24 weeks in 75% of the patients, was prematurely reached. In fact, a CHR was obtained in 40 patients (95.2%) after course 1 (6 weeks). After 8 courses, corresponding to 24 weeks, 38 of 42 patients (90.5%) were in CHR. At week 48, the CHR rate on ponatinib was still 42% (18/42). Considering a CMR test sensitivity of at least 10,000 ABL molecules and testing peripheral blood whenever a bone marrow was not obtained, 19 of 33 patients (58%) were in a deep CMR at 24 weeks. After 12 months, the OS rate was 89.2% (95%CI: 79.7% - 99.8%). The 12-month estimate for an on-going CMR was 81.7% (95%CI: 67% - 99.7%), while the EFS rate at 12 months reached 60.3% (95%CI: 46.1%-78.9%).

Of note, at week 24, only 15 of the initial 42 patients still received 45 mg of ponatinib daily and 4 patients permanently withdrew their study drug. During the study, 75 adverse events were reported, of which 36 were considered to be related to ponatinib. In total, 26 serious adverse events were seen (13 ponatinib related). Specifically looking at cardiac toxicity, 5 cardiac disorders were reported. This included one grade 5 event (acute coronary syndrome) and 3 grade 3 events. Six patients experienced vascular disorders, reaching grade 3/4 severity in 5 patients.

Finally, a BCR-ABL mutational analysis was performed in 22 patients at diagnosis, and in 15 patients at week 24. This analysis revealed a T315L mutation in one patient who relapsed during ponatinib therapy. Apart from that, no other emerging mutations were identified.

In summary, ponatinib and steroids showed a high efficacy in newly diagnosed unfit/elderly Ph+ ALL patients, with manageable toxicity and limited cardiovascular risk.


Martinelli G, Piciocchi A, Papayannidis C, et al. First Report of the Gimema LAL1811 Phase II Prospective Study of the Combination of Steroids with Ponatinib As Frontline Therapy of Elderly or Unfit Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic leukemia. Presented at ASH 2017; Abstract #99.


Speaker Giovanni Martinelli


Giovanni Martinelli, MD, PhD, Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy


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