The Relevance of FLT3 in APL

Abstract & Commentary

By Andrew S. Artz, MD, MS, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no relationships to this field of study.

Synopsis: The prognostic relevance of fms-like tyrosine kinase 3 (FLT3) internal tandem duplications and point mutations at D835 in acute promeylocytic leukemia (APL) is controversial. Among APL patients treated with ATRA and anthracycline-based regimens on serial protocols, 22% of 306 patients harbored an internal tandem duplication (ITD) mutation and 9% of 213 evaluable had a D835 mutation. FLT3 ITD mutational status was associated with higher white blood cell count, microgranular variant of APL, and high blast count. In unadjusted analysis, the presence of a FLT3 ITD mutation but not D835 mutation conferred a greater risk of induction death, and inferior relapse-free and overall survival. However, after adjusting for high white blood cell count and other traditional prognostic factors, mutational status was not statistically associated with outcomes. FLT3 mutational status does not retain independent significance for APL outcomes, although it is a rational target for future studies, particularly among the high white blood cell count APL subset.

Source: Barragan E, et al. Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy. Haematologica 2011 [Epub ahead of print].

Acute promeylocytic leukemia (APL) is a prognostically and therapeutically distinct category of acute myeloid leukemia (AML) resulting from a rearrangement of the PML and RAR-alpha genes, usually generating the t(15;17)(q22;q12) classic breakpoints. Variant breakpoints may occur. High white blood cell count (> 10 K/uL) and thrombocytopenia (< 40 K/uL) are adverse prognostic factors. Whether additional markers can better stratify patients or suggest therapeutic targets is of considerable interest.

FLT3 (fms-like tyrosine kinase 3) mutations, particularly internal tandem duplications (ITD), confer an inferior prognosis for patients with normal karyotype AML.1 The adverse impact of FLT3 point mutations arising from the activation loop at D835 may be less significant for outcomes. FLT3 mutations are not uncommon in acute promyelocytic leukemia (APL);2 however, the prognostic value of FLT3 mutational status remains controversial.3

In this study, the authors take advantage of a large cohort of 739 APL patients enrolled in various trials employing oral ATRA and anthracyclines for remission with different combinations of anthracyclines and other drugs for maintenance. FLT3 mutational analysis was available in 306 (41%) for ITD mutations and 213 (29%) for the D835. The authors also evaluated FLT3 ITD mutation length. Among evaluable patients, 22% showed an FLT3 ITD mutation and 9% harbored the D835 mutation. Only one patient had both mutations. FLT3 ITD mutations were clinically associated with leukocytosis, high LDH, microgranular variant as well as peripheral blood and bone marrow blasts greater than 70%, whereas the point mutation was not associated with clinical characteristics.

FLT3 ITD was associated with a greater proportion suffering induction death (16% vs 7%, P = 0.03) and differentiation syndrome (22% vs 13%, P = 0.05). Multivariate analysis revealed high white count, age 60 and older, or creatinine greater than 1.4 mg/dL as risk factors for induction death. The D835 mutation did not affect induction outcomes. FLT3 ITD, but not the point mutation, showed inferior 5-year relapse-free survival (77% for ITD mutation vs 88% without, P = 0.02). However, in multivariable analysis, only high WBC was associated with worse RFS but not FLT3 mutational status or ITD mutation length. Overall survival was shorter for FLT3 ITD mutation patients at 5 years but not D835 mutation-carrying patients. Multivariate analysis only showed that high WBC above 10 K/uL and age older than 60 translated into worse outcomes. Thus, FLT3 mutational status was not independently significant.

Commentary

APL is a relatively uncommon category of AML, but it is essential to diagnose and initiate treatment early to reduce complication rates and potentially improve curability. All oncologists must be aware of APL and be prepared for rapid diagnosis and either immediate treatment or transfer to another facility.

The need to evaluate newly diagnosed AML for molecular abnormalities has increasingly become appreciated. This has not necessarily been standard for APL, which often presents with characteristic morphology and the ability for rapid confirmation either with PCR or FISH studies. In this study, the authors were able to evaluate more than 300 APL patients for FLT3 ITD mutations and more than 200 for D835 point mutations. The incidence of FLT3 ITD mutations and D835 point mutations at 22% and 9% approximates prior studies on the prevalence of FLT3 mutations at diagnosis. Whether the mutation rate differs at relapse requires further study, as FLT3 generally is thought to be a late-acquired event in leukogenesis.4

The authors demonstrated nicely that FLT3 ITD mutations, but not D835 mutations, are associated with numerous clinical features, including leukocytosis, high blast count, coagulopathy, and certain immunophenotypic markers. The most noteworthy findings were that while ITD mutations were associated with greater rates of induction death, inferior relapse-free survival, and worse overall survival, FLT3 ITD mutational status did not retain significance in multivariate analysis whereas high white blood cell count did. The data contrast somewhat with prior studies, suggesting an adverse prognosis of FLT3 ITD and possibly point mutations.2,3,5

To the extent this series is larger and employed multivariate analyses, these data are more likely to be valid. This is an important negative study indicating we should retain leukocytosis and thrombocytopenia rather than FLT3 mutational status into prognostic assessment. Nevertheless the link between FLT3 ITD mutation and high white blood cell count, as has been seen with FLT3 mutational status in non-APL AML, suggest targeted therapy inhibiting the FLT3 tyrosine kinase represents a rational approach, particularly among FLT3 ITD mutated patients with a high white blood cell count, as high white blood cell count results in suboptimal long-term outcomes.

In conclusion, FLT3 ITD and point mutations do not retain independent prognostic significance among APL patients treated with ATRA and anthracyclines. However, the association of FLT3 ITD mutations and high white blood cell count suggest FLT3 inhibitors could be tested in this subset.

References

1. Schlenk RF, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909-1918.

2. Gale RE, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005;106:3768-3776.

3. Chillon MC, et al. Long FLT3 internal tandem duplications and reduced PML-RARalpha expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients. Haematologica 2010:95:745-751.

4. Kottaridis PD, et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: Implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002;100:2393-2398.

5. Beitinjaneh A, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: A systematic review. Leuk Res 2010;34:831-836.