1.Chemotherapy Options for Poor Responders to Neoadjuvant Chemotherapy for Orbital Granulocytic Sarcoma
Nathan Gossai, Rachel Cafferty, Brenda Weigel. Curr. Treat. Options in Oncol. (2016) 17: 38
Quizartinib (AC220) is another FLT3 inhibitor with additional inhibition of Kit, PDGFRa, PDGFRb, RET, and CSF1R and unique pharmacokinetics of sustained FLT3 inhibition. When used independently, quizartinib demonstrates superior clinical activity than prior FLT3 inhibitors. Data presented in abstract used a composite complete remission (CRc) rate, which included CR, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Patients with FLT3 ITD mutations had a CRc rate of 44 % (4 % CR, 0 CRp, and 40 % CRi), with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. Of those refractory to their last AML therapy, 47 % achieved a CRc with quizartinib. Patients without FLT3 ITD mutations had a CRc rate of 34 % (3 % CR, 3 % CRp, and 29 % CRi), with a median duration of response of 5.1 weeks and median overall survival of 25.6 weeks. Of those refractory to their last AML therapy, 31 % achieved a CRc with quizartinib.
2.Novel Therapeutics in Acute Myeloid Leukemia
Kendra Sweet & Jeffrey E. Lancet. Curr Hematol Malig Rep (2014) 9:109–117
As a single agent, quizartinib appears to be the most clinically active of the FLT3 inhibitors. Most clinical trials with single-agent quizartinib have been conducted in the relapsed/refractory setting. Composite complete response (CRc) rates (CR+CRi+CRp) in adult patients following failure of second-line chemotherapy were 44 % in the FLT3-mutated group and 34 % in the FLT3 WT patients. In elderly patients, CRc rates were 57 % in those with FLT3-ITD mutations and 36 % in FLT3-WT patients. A subset analysis of this study looking at outcomes in patients over 70 years of age found a 53 % CRc rate in those with a FLT3-ITD mutation and 43 % in those without, indicating efficacy in a patient population that has proven to be very difficult to treat in the past. Trials with quizartinib in combination with conventional chemotherapy are ongoing.
3.FLT3 Inhibitors in AML: Are We There Yet?
Akshay Sudhindra & Catherine Choy Smith. Curr Hematol Malig Rep (2014) 9:174–185
Because of high rates of QTc prolongation and myelosuppression in the initial phase II study, a second randomized phase II study explored lower doses of quizartinib (30 or 60 mg) in a similar patient population. Again, an ~50 % rate of CRc was observed at both dose levels and was associated with a decreased rate of QTc prolongation; however, most remissions still occurred in the setting of incomplete neutrophil or platelet recovery. It is also notable that instead of the hypocellular response associated with chemotherapy, in some patients response to quizartinib appears to be associated with a syndrome of terminal myeloid differentiation resulting in marrow hypercellularity associated with a neutrophil surge and inflammatory tissue infiltrates, further suggesting that remissions on FLT3 kinase inhibitor treatment may appear different from those achieved with standard chemotherapy. The lack of traditional CR with full neutrophil and/or platelet count recovery observed in these studies has sparked controversy as to whether the non-conventional endpoint of CRc is associated with true clinical benefit and/or prolongation of overall survival compared to standard chemotherapy. To answer this question, a randomized phase III clinical trial of quizartinib monotherapy versus salvage chemotherapy in FLT3-ITD+ AML patients in first relapse is expected to begin in 2014.
4.FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance
Michael R. Grunwald • Mark J. Levis. Int J Hematol (2013) 97:683–694
FMS-like tyrosine kinase 3 has now been well validated as a therapeutic target in AML. While the FLT3/ITD abnormality does not appear to be an initiating mutation, it appears to be one of the most important cooperating mutations in the development of the disease. In patients with FLT3/ITD AML receiving the TKI quizartinib, characteristic and reproducible point mutations often arise at two particular amino acid residues, conferring resistance to therapy with this drug. This discovery of an adaptive resistance mechanism to FLT3 inhibition is direct evidence that the ITD represents a driver mutation in AML. However, the situation with FLT3/ITD AML is much more complex than a simple case of an oncogeneaddicted malignant cell. Genome-wide sequencing studies of diagnostic and relapsed AML samples suggest that at presentation an AML cell population is made up of several clonal sub-types, sharing a common mutational ancestry, but each with a unique complement of initiating mutations. At relapse, a dominant clone is more likely to emerge. This may directly relate to FLT3 TKIs because selective FLT3 inhibition rarely induces a cytotoxic effect in vitro in diagnostic FLT3/ITD AML samples, while samples collected at relapse (which tend to have a higher mutant allelic burden) are invariably much more responsive. This suggests that at relapse a FLT3-addicted clone dominates the leukemia cell population.
