ORLANDO, Florida—Two tyrosine kinase inhibitors (TKIs)—one a new drug from Korea, the other designed to target hard-to-treat T315I mutations—show promise as potential treatments for chronic myeloid leukemia (CML) to replace imatinib or allogeneic stem cell transplant (SCT) in selected patients, according to two new studies presented here at the American Society of Hematology Annual Meeting.
In an interview, OT's Clinical Advisory Editor for Hematology/Oncology, Hagop Kantarjian, MD, Chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, explained that radotinib is a TKI in South Korea that shows better outcomes when compared with imatinib in patients with chronic-phase CML.
“In the future, radotinib could become established as the sixth TKI that could be effective for CML patients,” he said.
Currently, five TKIs are available for CML—imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. Radotinib is a novel, selective oral, second-generation BCR-ABL TKI already approved in Korea for CML.
In the Phase III study reported at the ASH meeting by Jae-Yong Kwak, MD, PhD, of Chonbuk National University Medical School & Hospital in Jeonju, South Korea (Abstract 476 ), radotinib demonstrated efficacy and tolerability in patients with chronic-phase CML who had previously not responded to TKI therapy.
Kwak noted that recent data suggest that the efficacy and safety profiles of TKIs in Asian patients may differ from those of non-Asian populations.
The study evaluated the efficacy and safety of two doses of radotinib versus imatinib in Asian patients with newly diagnosed CML. The researchers randomized 241 patients, median age of 45, to radotinib at 300 mg twice daily (79 patients) or 400 mg twice daily (81 patients), or imatinib at 400 mg once daily (81 patients).
The primary endpoint was the rate of major molecular response (MMR) by 12 months. Molecular response was assessed by real-time polymerase chain reaction at baseline and every three months. Patient characteristics, including baseline age, gender, race, and Sokal risk score, were well-balanced across all arms, Kwak said. With a minimum follow-up of 12 months, a large proportion of patients in all three groups received the study drug (72% to 86%).
By 12 months, the rates of MMR were significantly higher in patients receiving the radotinib 300 mg dose (52%) and the radotinib 400 mg dose (46%) compared with imatinib (30 percent). At 12 months, MMR for radotinib 300 mg was significantly higher than for imatinib,” Kwak said.
Among responding patients, the median time to MMR was shorter on radotinib (5.6 to 5.7 months) than imatinib (8.2 months). The deep molecular response rates by 12 months were also higher for both radotinib 300 mg doses (15.2%) and 400 mg doses (13.6%) as compared with imatinib (8.6%).
In addition, the complete cytogenetic response rates by 12 months were also higher for radotinib 300 mg twice daily (91.1%) as compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis CML in any of the groups by 12 months. “Both doses of radotinib were significantly better versus imatinib at reducing BCR-ABL transcripts at three months,” Kwak said.
Discontinuation due to adverse events or laboratory abnormalities occurred in seven patients (9%), 16 patients (20%), and 5 patients (6%) for the radotinib 300 mg, radotinib 400 mg, and imatinib groups, respectively.
Grade 3/4 thrombocytopenia occurred in 17 percent of patients receiving the radotinib 300 mg dose, 14 percent of those receiving the radotinib 400 mg dose, and 20 percent of patients receiving imatinib. Grade 3/4 neutropenia occurred in 19, 24, and 30 percent, respectively.
The most common non-laboratory adverse events of any grade were skin rash (35% and 33%), nausea/vomiting (23% and 24%), headache (19% and 31%), and pruritus (19% and 30%) in radotinib 300 mg doses and radotinib 400 mg doses, respectively.
Adverse events in the imatinib group were edema (occurring in 35% of patients), myalgia (28%), nausea/vomiting (27%), and skin rash (22%). Overall, grade 3/4 non-laboratory adverse events were uncommon in all groups, Kwak said.
Three patients in the radotinib arms died and one patient died in the imatinib arm.
In conclusion, Kwak said: “In this Phase III trial of two doses of radotinib versus imatinib in patients with newly diagnosed chronic- phase CML, radotinib was associated with significantly higher molecular response rates. Treatment failure and suboptimal responses were lower in the radotinib arms.”
The safety profiles were different, with a relatively low incidence of grade 3/4 adverse events, although there were higher grade 3/4 laboratory abnormalities with radotinib. Most adverse events were manageable with optimal dose reduction, he said.
Kwak suggested that consideration should be given to “radotinib as a new frontline therapy option in patients with newly diagnosed chronic-phase CML.”
Ponatinib in CML and ALL with T3151 Mutation
Another presentation Kantarjian identified as significant at this year's ASH Annual Meeting was the impact of ponatinib versus allogeneic SCT on outcomes in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with the T315I mutation (Abstract 480).
Franck E. Nicolini, MD, PhD, of the Centre Hospitalier Lyon Sud in Pierre-Bénite in France, who presented the data, said that historically, the BCR-ABL T315I mutation has been associated with significantly shorter overall survival (OS) in TKI-resistant chronic phase CML. Allogeneic SCT is able to rescue some patients, and is considered standard treatment for patients with advanced-phase CML (i.e., accelerated phase or blast crisis), de novo Ph+ ALL, or patients in chronic phase who are resistant or intolerant to at least two TKIs.
Ponatinib is FDA-approved for the treatment of CML or Ph+ ALL in patients with the BCR-ABL T315I mutation or for whom no other TKI therapy is indicated.
“In patients harboring the T315I mutation, ponatinib currently represents a suitable alternative treatment option to allogeneic SCT,” Nicolini said, noting that no studies of overall survival have compared ponatinib with allogeneic SCT in these patients.
In the study reported at the ASH meeting, he and his colleagues conducted a retrospective observational study of 671 adult patients with T315I-positive CML (any phase) or previously untreated Ph+ ALL, excluding allogeneic SCT patients in second chronic phase.
Data from a Phase II trial of 449 patients taking ponatinib and 222 patients in the European Bone Marrow Transplant registry were pooled to conduct an indirect comparison of ponatinib with allogeneic SCT, he noted.
A total of 184 patients (128 ponatinib, 56 allogeneic SCT) were included in the analysis. Ninety patients were in chronic-phase CML, 26 were in accelerated-phase CML, 41 were in blast-phase CML, and 27 had Ph+ ALL.
On average, patients in the ponatinib group were older (median age of 53) than those in the allogeneic SCT group (median age of 45) on the date of intervention.
In chronic-phase CML, the ponatinib group had a significantly longer time from diagnosis to index date, but a shorter time from T315I detection to intervention than the transplant group. In accelerated- and blast-phases CML, the ponatinib group had a significantly shorter time from T315I detection to intervention.
In terms of survival, for chronic-phase CML, ponatinib achieved significantly longer adjusted overall survival (not yet reached) versus allogeneic SCT (103.3 months).
The median OS was not significantly different between the two treatment groups in patients with accelerated-phase CML. For blast-phase CML, allogeneic SCT achieved significantly longer adjusted OS (10.5 months) than did ponatinib (7 months).
Nicolini said although it was not a statistically different difference, OS for Ph+ ALL was longer for allogeneic SCT (32.4 months) versus ponatinib (6.7 months).
In conclusion, Nicolini noted that although allogeneic SCT remains a potential curative therapy for patients with blast-phase CML, ponatinib did produce significantly longer overall survival in patients with T315I-positive chronic phase CML compared with use of allogeneic SCT and could represent a promising therapeutic alternative in this setting.