ORLANDO – For adults with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL), the combination of hyper-CVAD chemotherapy and ponatinib is associated with high complete molecular response and 5-year overall survival rates, investigators reported.
Long-term follow-up of 86 adults with Ph+ALL treated in the front line with chemotherapy plus ponatinib (Iclusig), a third-generation tyrosine kinase inhibitor (TKI), showed a complete remission (CR) rate of 100%, complete molecular remission (CMR) rate of 86%, and a 5-year overall survival (OS) rate of 74%, reported, from the University of Texas MD Anderson Cancer Center in Houston.
“Although we observed two treatment-related cardiovascular deaths with the original trial design, with almost 50 patients treated since instituting a risk-adapted dosing schedule with lower doses of ponatinib, no additional ponatinib-related deaths have been observed,” he said at the annual meeting of the American Society of Hematology.
The standard of care for adults with Ph+ALL is chemotherapy plus a TKI. With a first- or second-generation TKI plus chemotherapy, reported 5-year OS rates range from 35% to 50%.
“However, relapses are still common, and these are usually driven by the development of new resistance mutations in the ABL gene, particularly the T315I gatekeeper mutation which has been reported in up to 75% of patients at the time of relapse,” he said.
Ponatinib is a pan-BCR-ABL TKI with activity against ALL with T315I mutations, and the combination of this agent with hyper-CVAD chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has been associated with higher response rates than those seen with earlier-generation TKIs, as well as higher levels of minimal residual disease (MRD) negativity, he noted.
Dr. Short and colleagues hypothesized that, compared with the standard of care, hyper-CVAD plus ponatinib would be associated with higher MRD levels, low relapse rates by suppression of T315I subclones, decreased reliance on stem cell transplantation in first remission, and improved long-term survival.
To test this, they treated 86 adults with newly diagnosed Ph+ALL, including those who had undergone one or two previous courses of chemotherapy with a TKI other than ponatinib. The patients had Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no clinically significant cardiovascular disease.
The patients underwent eight cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. The first 37 patients were treated with, ponatinib 45 mg daily for the first 14 days of cycle 1, then continuously for subsequent cycles. Patients with CD20 expression of 20% or greater also received rituximab during the first four cycles. CNS prophylaxis was also administered with 12 doses of intrathecal chemotherapy with alternating methotrexate and cytarabine.
Patients who had a CR received maintenance with ponatinib and vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely.
Out of concern for vascular toxicity with long-term use of high-dose ponatinib, including the two deaths mentioned before, the protocol was amended after the first 37 patients were treated. The amended protocol reduced ponatinib to 30 mg starting at cycle 2, with further reduction to 15 mg once a CMR (absence of BCR-ABL on polymerase chain reaction) was achieved.
At a median follow-up of 44 months, the event-free survival rates – the primary endpoint – were 71% at 3 years and 68% at 5 years. The 3-year OS rate was 78%, and the 5-year OS rate was 74%.
All patients had complete remission and complete cytogenetic remission as assessed by conventional karyotyping. Additionally, 73 of 85 evaluable patients (86%) achieved a CMR at some point during therapy.
“We had previously reported that achievement of a complete molecular response by 3 months is associated with superior outcomes. Approximately three quarters of patients achieved this milestone,” Dr. Short said.
Grade 3 or greater adverse events of particular concern included transaminase elevations in 29% of patients, elevated bilirubin and pancreatitis in 15% each, and hypertension in 14%.
Four patients had grade 3 or greater venous thromboembolic or arterial events, including the two previously noted deaths from myocardial infarction, both of which occurred prior to the protocol amendment.
At the most recent follow-up, 11 patients had experienced relapse (no CNS-only relapses), and of this group, 5 died and 6 were still alive. Nineteen patients underwent hematopoietic stem cell transplant, and of this group, 13 were still alive and 6 died.
Causes of death in the nine patients who died while in CR included the two myocardial infarction deaths on study, three deaths from sepsis during consolidation, one from lung cancer, one from a head injury after a fall, one from myocardial infarction in a 79-year-old patient 4 years after stopping ponatinib (off study), and one from preexisting congestive heart failure in a 74-year-old patient.
In all, 47 patients were either in ongoing therapy or observation at last follow-up, including three patients who were transitioned to MRD-directed therapy including blinatumomab (Blincyto).
“As a next step, we are now evaluating lower-intensity regimens with ponatinib and blinatumomab in both the frontline and relapsed/refractory settings, with the goals of decreased chemotherapy-related toxicity, increased MRD-negativity rates, further decreased reliance on transplant, and improved long-term outcomes,” Dr. Short said.
The study was sponsored by MD Anderson with support from the National Cancer Institute. Dr. Short reported consulting for AstraZenca, honoraria from Amgen, and consulting and receiving research funding from Takeda Oncology.
SOURCE: Short NJ et al. ASH 2019,