Based on preclinical evidence of synergistic interaction between the second-generation selective FLT3 inhibitor quizartinib and azacitidine (AZA) or low-dose cytarabine (LDAC), a phase 1/2 study was initiated to evaluate the clinical activity of both combinations in patients with FLT3-ITD–mutated myeloid leukemias, including acute myeloid leukemia (AML).
In the phase 1 portion of the study, 12 patients (quizartinib + AZA, 6; quizartinib + LDAC, 6) with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), or AML were enrolled, irrespective of FLT3 mutation and salvage status. In the phase 2 portion of the study, 49 patients aged >60 years with untreated MDS/CMML/AML or any age receiving first salvage treatment for AML with FLT3-ITD mutation were enrolled. Other eligibility criteria included performance status ≤2, adequate organ function, and normal electrolytes (potassium, calcium, and magnesium). The treatment regimen consists of AZA 75 mg/m2 subcutaneously (SC) or intravenously for 7 days per cycle, or LDAC 20 mg SC twice daily for 10 days per cycle plus oral quizartinib at 2 planned dose levels (60 mg or 90 mg daily); the treatment cycle is 28 days.
A total of 61 patients were enrolled (phase 1, 12 patients; phase 2, 49 patients); of these, 38 were assigned to the AZA arm and 23 to the LDAC arm. The median age was 67 years (range, 23-83 years) in the AZA arm and 68 years (range, 55-80 years) in the LDAC arm; 16 patients and 10 patients, respectively, showed diploid cytogenetics; and 4 each on the 2 arms had adverse features. Patients had received a median of 1 prior therapy on both arms, with 9 patients reporting prior FLT3 inhibitor treatment. Quizartinib 60 mg daily was identified as the recommended phase 2 dose for both the AZA and LDAC combinations.
Among the evaluable patients, 42 have achieved a response (complete remission [CR] + CRp + CRi + hematologic improvement + PR), with 10 patients achieving a CR, 7 patients achieving a CRp, and 22 patients achieving a CRi, for a composite CR (CRc) rate of 64%. Of the 42 responses, 16 (67%) were in the LDAC arm and 26 (70%) were in the AZA arm. Notably, 6 of the 31 (12%) evaluable responses were minimal residual disease (MRD) negative, with 4 in the AZA arm and 2 in the LDAC arm. Among the 12 patients who were previously untreated, an overall response rate (ORR) of 92% (n = 11) was achieved, with a CRc of 83% (n = 11). Among the 49 previously treated patients, the ORR was 63% and CRc was 59% (n = 39). Four of 5 patients with prior FLT3 inhibitor exposure have achieved a response. Among the 40 relapsed patients with no prior FLT3-inhibitor treatment, the ORR was 65% and CRc was 63% (n = 25). The median time to response was 2.1 months (range, 0.5-6.2 months) in the AZA arm, and 2.1 months (range, 0.9-8.5 months) in the LDAC arm. Five deaths were reported due to sepsis, multiorgan failure, intracerebral hemorrhage, and unknown cause. For the total study population, the median overall survival (OS) was 21 months, and the relapse-free survival was 17.7 months. In the AZA arm, the median OS was 14.8 months, and in the LDAC arm, 7.4 months. The median OS for previously untreated patients was 21.1 months in the AZA arm and not reached in the LDAC arm; and was 12 months and 7.4 months, respectively, for relapsed patients; and 12 months and 7.4 months for relapsed patients with no prior FLT3 treatment.
In terms of safety, grade 3/4 toxicities, regardless of causality, included hypokalemia, hyperkalemia, hypotension, hypophosphatemia, hyponatremia, hypocalcemia, hyperbilirubinemia, elevated ALT, elevated AST, abdominal pain, intracerebral hemorrhage, hypernatremia, hypermagnesemia, diarrhea, dehydration, respiratory failure, hyperglycemia, QTcF prolongation, sinus tachycardia, atrial fibrillation, and pericardial effusion.
These results demonstrated that combination therapy with quizartinib plus AZA or LDAC was a highly active regimen in patients with FLT3-ITD mutation AML.
Swaminathan M, et al. 2017 ASH. Abstract 723.
