An early session on the first day of the annual meeting and exposition of the American Society of Hematology, being held December 5-8, 2015, in Orlando, Florida, saw presentations on the promise of newly approved hematology/oncology agents, in addition to the challenges that clinicians face in treating patients with these drugs.
An early session on the first day of the annual meeting and exposition of the American Society of Hematology, being held December 5-8, 2015, in Orlando, Florida, saw presentations on the promise of newly approved hematology/oncology agents in addition to the challenges that clinicians face in treating patients with these drugs. Physicians with clinical experience using these agents discussed the appropriate population, dosing, side effects, and adverse events presented by the real-world use of the molecules.
Chaired by Mikkael A. Sekers, MD, MS, from the Cleveland Clinic, participants included Kenneth A. Bauer, MD, from the Beth Israel Deaconess Medical Center, Anjali S. Advani, MD, from the Leukemia Program at Cleveland Clinic, and Sagar Lonial, MD, Winship Cancer Institute, Emory University School of Medicine.
The first presentation by Bauer introduced idarucizumab (Praxbind), a humanized monoclonal antibody indicated for patients with dabigatran (Pradaxa), for reversal of the anticoagulant effects of dabigatran. Developed by Boehringer Ingelheim Pharmaceuticals, idarucizumab is used in emergency surgery or urgent procedures and to protect against life-threatening bleeding. Preclinical studies have shown that idarucizumab protects patients from bleeding when treated with the direct oral anticoagulant (DOAC) dabigatran.
“Idarucizumab, a fully humanized antibody fragment, or Fab, has high affinity specifically for dabigatran and has shown no non-specific binding to other agents,” said Bauer, echoing results presented at the meeting of the American Heart Association last month.
Presenting updates from the REVERSE-AD or Reversal Effects of Idarucizumab on Active Dabigatran study, which led to the drug’s approval, Bauer said that the management of dabigatran-related major bleeding using reversal agents can prove challenging.
REVERSE-AD included 90 patients treated with idarucizumab, who were divided into 2 cohorts. Group A included 51 patients who had uncontrolled bleeding with dabigatran, while those in group B were 39 patients who needed emergency surgery or procedure following dabigatran treatment. The patients were administered 5 g intravenous idarucizumab, back-to back in 2 separate infusions over 0 to 15 minutes. Within minutes of administration, idarucizumab normalized either elevated dilute thrombin time (dTT) or elevated ecarin clotting time (ECT), the study reported.
“The primary endpoints of maximum percent reversal of anticoagulant effect of dabigatran, based on central-lab assessment of dTT or ECT within 4 hours of idarucizumab,” explained Bauer. “Secondary endpoints were cessation of bleeding in group A and hemostasis during procedure in group B.”
While dTT normalized in 98% of group A and 93% of group B patients, ECT normalized in 89% of group A and 88% of group B patients, Bauer showed.
“Safety issues are a concern with idarucizumab,” said Bauer, including some thrombotic events observed within 3 days and 4 events later on. While there were no cases of hypersensitivity, the trial saw 18 deaths, 9 in each group. “But deaths were primarily related with comorbidities that these very sick patients suffered from,” Bauer added
An ideal treatment strategy for the management of dabigatran complications, according to Bauer, includes:
He then listed some challenges associated with using reversal agents with DOACs, including:
“For intracerebral bleeding, early presentation to a healthcare facility, prompt diagnosis, and prompt administration of an effective reversal agent is critical to improve outcomes,” Bauer concluded.
Introducing the case of an adult acute lymphoblastic leukemia (ALL) patient in her clinic, Advani explained that while overall survival (OS) for pediatric ALL patients is very encouraging, “Novel approaches are needed for treating adult ALL patients. The 3-year OS for 759 adults enrolled in a Cancer and Leukemia Group study is low—it’s an unmet need,” said Advani. She explained that while 80% of ALLs are B-cell subtype, most are pre-B ALL, and that CD19 has been a particularly attractive target for new therapies that are being developed.
“Blinatumomab is unique in that it’s an anti-CD19 antibody, but it is a bispecific T-cell engager antibody. Of the 2 arms of this antibody, 1 engages the B-lymphoblast and the other the anti-CD19 antibody,” Advani said. So the molecule can act as a bridge, she explained. Blinatomumab (Blincyto) was approved late last year for the treatment of ALL.
A major challenge, in Advani’s opinion, is the need for continuous drug infusion with blinatumomab, a complication with treatment that arises due to the short half-life of the drug. Short-term intravenous infusion schedules with blinatumomab were disappointing, Advani said.
Some early results with the drug found an 80% rate of complete response in patients on blinatumomab, Advani showed. A follow-up study published in Lancet Oncology showed promising results in adult patients with relapsed or refractory B-precursor ALL. The trial, Advani said, recruited 189 patients who were Philadelphia chromosome (Ph) negative, heavily-pretreated, and almost 70% had a bone marrow blast count that was ≥50%.
“While response rate was lower in this multi-center trial, it’s important to note that these were more heavily pretreated patients,” Advani said, explaining the results. While a complete response was observed in 43% of patients, minimal residual disease response was high, observed in 82% of trial participants.
The most significant side-effects blinatumomab include fever, headache, and febrile neutropenia.
Advani then pointed out several management issues with blinatumomab.
Advani said that she is part of a phase 2 study that is currently recruiting elderly ALL patients who are either Ph+ or Ph-, for treatment with blinatumomab in combination with prednisone, vincristine, methotrexate, 6-mercaptopurine, also known as POMP. “We have hopes of improving patient outcomes with this combination,” she said.
“Blinatumomab is a new class of bispecific T-cell engaging antibodies with significant activity in B-ALL that can hopefully improve outcomes,” Advani concluded.
The last molecule, introduced by Lonial, was panobinostat, a histone deacetylase inhibitor (HDAC) approved earlier this year for the treatment of patients with multiple myeloma (MM).
“It is very important to know how to use drugs once they have been approved,” said Lonial, underscoring the importance of real-world experience with drugs.
Some other drugs currently being developed in the HDAC inhibitor class include, vorinostat, givinostat, ricolinostat, and romidepsin, Lonial said.
A unique feature of myeloma cells, according to Lonial, is that they continue with their normal function, unlike most other cancerous cells whose normal cellular functions are compromised. “Myeloma cells continue to produce antibodies, which can then be used as a biomarker to measure response,” Lonial explained.
Lonial showed that while preclinical data with panobinostat, generated by various groups, has confirmed the drug’s activity, preliminary data from animal models has shown antiosteoclast activity of panobinostat.
The study published in Blood in 2013 by Richardson et al, presenting results from the PANORAMA 2 trial, showed that panobinostat could resensitize refractory patients to a combination of bortezomib and dexamethasone, Lonial explained.
“Best responders, based on subgroup analysis, were patients with high-risk disease and those who had been heavily exposed to prior therapies, including bortezomib and IMiD,” Lonial said.
The major toxicities observed with panobinostat include diarrhoea and fatigue (asthenia). While grade 3 or 4 diarrhea has been consistently observed across studies, the combination of panobinostat with bortezomib is what may be causing these grade 3 or 4 toxicities, Lonial clarified. “So there is a need for better partners with panobinostat, and our options include carfilzomib and ixazomib,” which he said are currently being evaluated in the clinic.