This article is more than 5 years old. Information may no longer be current.
Ponatinib appears safe, effective for older patients with Philadelphia chromosome-positive ALL
Click Here to Manage Email Alerts
ATLANTA — The combination of ponatinib with steroids induced complete hematological response among more than 90% of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to the results of a phase 2 prospective study presented at the ASH Annual Meeting and Exposition.
“We are starting to believe that for Ph+ patients aged 60 years or older, ponatinib [Iclusig, Takeda Oncology] with steroids is safe and effective and could be a mainstay treatment in these patients,” Giovanni Martinelli, associate professor of hematology at University of Bologna, said during his presentation. “We thought before the study that ponatinib would show an advantage, but not in this way. We didn’t expect it to be so successful.”
Tyrosine kinase inhibitors have significantly improved survival among patients with Ph+ALL. Studies reported that adults with Ph+ALL who received ponatinib in combination with chemotherapy achieved a 3-year EFS rate of 69% and a 3-year OS of 83%. However, TKIs combined with chemotherapy are associated with higher toxicities among elderly or unfit patients.
In the GIMEMA LAL1811 trial, researchers examined the efficacy and safety of ponatinib plus steroids among 42 patients either deemed unfit or aged 60 years or older (median age, 69 years; range, 27 to 85) with untreated Ph+ALL. Unfit patients (n = 9) could not receive intensive chemotherapy and stem cell transplantation.
Researchers assessed patients from March 2014 through December 2016.
Patients received 45 mg oral ponatinib daily for eight consecutive courses of 6 weeks. They also received steroids from 14 days prior to therapy until day 29 during the initial course. Patients received intrathecal therapy (methotrexate, cytarabine and dexamethasone) every 28 days for central nervous system disease prophylaxis.
Researchers obtained patient samples at each of the eight courses. They defined complete molecular response as BCR-ABL/ABL ratio below 0.01 or undetectable, and with a sensitivity of at least 30,000 molecules of ABL.
Complete hematological response served as the primary endpoint.
Median follow-up of the enrolled patients was 11.4 months.
At 6 weeks (1 course), 40 patients (95%) achieved complete hematologic response.
At 12 and 24 weeks (8 courses), 38 patients (90.5%) were in complete hematologic remission. Complete response dropped to 64% (n = 27) at 36 weeks and 42% (n = 18) at 48 weeks.
Two patients stopped treatment after 6 weeks due to disease relapse or excessive toxicity. Two patients dropped out after 12 weeks for medical decisions.
Researchers detected complete molecular response among 11 of 24 patients at 24 weeks (45.8%; 14 patients not evaluable).
Overall, 97.6% (95% CI, 93.1-100) achieved 6-month OS and 87.5% (95% CI, 76.5-99.9) achieved 1-year OS.
During the study, 36 of the 75 reported adverse events appeared related to ponatinib. Twenty-six events were considered serious, 13 of which were considered related to ponatinib. Researchers suspected one death to be related to ponatinib.
“There were no early complications, a high rate of minimal residual disease negativity, a very fast transcript reduction, long-term deep molecular remission and a great advantage in quality of life,” Martinelli said. “That makes single-agent ponatinib a good candidate for trials in a younger population.” – by Chuck Gormley
Reference:
Martinelli G, et al. Abstract 99. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Martinelli reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Nicholas Short, MD
In studies of adults with Ph+ALL treated with intensive chemotherapy, outcomes are improved with successive generations of TKIs, with long-term survival of approximately 30% to 40% for patients who receive imatinib and approaching 80% for those who receive ponatinib.
The reasons for improved outcomes with ponatinib are likely twofold. First, ponatinib-based regimens are associated with deeper response and higher rates of complete molecular response than are regimens that use imatinib or dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka Pharmaceuticals). Second, ponatinib is effective against the T3151 ABL1 kinase domain mutation, present in approximately 25% of patients with Ph+ALL at diagnosis and up to 75% of patients at relapse when treated with earlier-generation TKIs.
Despite advances made in younger, fit patients, elderly patients with Ph+ALL continue to have relatively poor outcomes, driven in part by lack of tolerance to standard-dose chemotherapy. When treated with intensive regimens, older patients with ALL have an induction mortality rate of 10% to 20% and a death in remission rate of 20% to 35%, largely due to myelosuppression-related infections. Novel treatment strategies are, therefore, needed for those patients with Ph+ALL who are unfit for intensive treatment.
The GIMEMA investigators reported the initial results of a phase 2 study of ponatinib and corticosteroids as frontline therapy for adults with Ph+ALL aged 60 years or older, or deemed unfit for intensive chemotherapy. With this chemotherapy-free regimen, nearly all of the 42 treated patients achieved complete hematologic remission. Further, the complete molecular response rate of 45.8% is higher than the rate of 20% to 25% reported in other studies with dasatinib plus corticosteroids, suggesting deeper responses with ponatinib. Although longer follow-up is needed to assess durability of response, the 1-year OS rate of 87.5% is promising and suggests that this chemotherapy-free, ponatinib-based regimen is highly effective in the frontline management of older patients with Ph+ ALL.
Particular concerns with the use of ponatinib are cardiovascular events, hepatic toxicity and pancreatitis. In this study, dose reductions of ponatinib were frequent, with only 15 patients (36%) remaining at the initial 45-mg dose at 24 weeks. Thirteen serious adverse events were reported, and one death was suspected to be related to ponatinib. Refinement of the ponatinib dosing schedule for these older patients may further improve the tolerability of the regimen. For example, in a frontline study of hyper-CVAD — cyclophosphamide, vincristine, doxorubicin and dexamethasone — plus ponatinib for adults with Ph+ALL, a risk-adapted dosing strategy of ponatinib in which the dose was decreased to 15 mg once complete molecular response was achieved appeared to reduce the cardiovascular toxicity without negatively impacting efficacy.
This important study by Martinelli and colleagues reinforces the feasibility of using chemotherapy-free regimens for elderly and unfit adults with Ph+ALL. In particular, the complete molecular response rate of nearly 50% in the GIMEMA study is encouraging and is higher than that seen with the use of other TKIs; however, this appears lower than the complete molecular response rate of approximately 75% achieved with intensive chemotherapy plus ponatinib. Studies are, therefore, ongoing to evaluate the combination of ponatinib with low-intensity chemotherapy or with the CD3-CD19 bispecific T-cell engager blinatumomab (Blincyto, Amgen). The hope of these combination studies is that even deeper responses can be achieved without significantly increased toxicity, which will, in turn, lead to even more durable remissions and higher rates of cure.
Click Here to Manage Email Alerts