NEWPORT BEACH, CALIF. – A five-drug regimen was deemed safe in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and it appeared to be effective regardless of patients’ FLT3 status.
Researchers tested this regimen – sorafenib plus granulocyte colony–stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone (GCLAM) – in a phase 1 trial.
Kelsey-Leigh Garcia, a clinical research coordinator at Seattle Cancer Care Alliance, and her colleagues presented the results at the Acute Leukemia Forum of Hemedicus.
“The background for doing this study was our institutional results of GCLAM [ ] that showed a higher minimal residual disease–negative complete response rate than 7+3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] and an international study by Röllig that showed the addition of sorafenib to 7+3 increased event-free survival versus [7+3 and] placebo [ ],” Ms. Garcia said.
“GCLAM is the standard backbone at our institution, and we wanted to ask the question, ‘If we add sorafenib, can this improve upon the results of GCLAM?’ ” said, a hematologist-oncologist at the University of Washington, Seattle and principal investigator of the phase 1 trial.
The trial () included 47 patients, 39 with AML and 8 with MDS. Patients were aged 60 years or younger and had a median age of 48. They had a median treatment-related mortality score of 1.76 (range, 0.19-12.26). A total of 11 patients (23%) had FLT3-ITD, and 4 (9%) had FLT3-TKD.
Treatment and toxicity
For induction, patients received G-CSF at 5 mcg/kg on days 0-5, cladribine at 5 mg/m2 on days 1-5, and cytarabine at 2 g/m2 on days 1-5. Mitoxantrone was given at 10 mg/m2, 12 mg/m2, 15 mg/m2, or 18 mg/m2 on days 1-3. Sorafenib was given at 200 mg twice daily, 400 mg in the morning and 200 mg in the afternoon, or 400 mg b.i.d. on days 10-19.
For consolidation, patients could receive up to four cycles of G-CSF, cladribine, and cytarabine plus sorafenib on days 8-27. Patients who did not proceed to transplant could receive 12 months of sorafenib as maintenance therapy.
There were four dose-limiting toxicities.
- Grade 4 intracranial hemorrhage with mitoxantrone at 12 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 prolonged count recovery with mitoxantrone at 15 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 4 sepsis, Sweet syndrome, and Bell’s palsy with mitoxantrone at 18 mg/m2 and sorafenib at 200 mg b.i.d.
- Grade 3 cardiomyopathy and acute pericarditis with mitoxantrone at 18 mg/m2 and sorafenib at 400 mg b.i.d.
However, these toxicities did not define the maximum-tolerated dose. Therefore, the recommended phase 2 dose of mitoxantrone is 18 mg/m2, and the recommended phase 2 dose of sorafenib is 400 mg b.i.d.
There were no grade 5 treatment-related adverse events. Grade 3 events included febrile neutropenia (90%), maculopapular rash (20%), infections (10%), hand-foot syndrome (2%), and diarrhea (1%). Grade 4 events included sepsis, intracranial hemorrhage, and oral mucositis (all 1%).