Background: FMS-like tyrosine kinase-3 (FLT3) mutation is present in approximately one-third of AML patients. Internal tandem duplication mutations of FLT3 (FLT3-ITD) mutation in AML have been associated with poorer prognosis compared to FLT3 wild type (WT). Treatment patterns and outcomes among FLT3 mutated AML patients have not been well understood.

Aims: To compare real-world treatment patterns and clinical outcomes in 18-59 year-old patients with FLT3 mutated vs. FLT3 WT AML.

Methods: An online medical records review of 209 patients 18-59 years with a confirmed diagnosis of AML in 2010, 2011, or 2012 was conducted by US hematologists/oncologists. Physicians (n=112) with experience treating AML were chosen from a nationally-representative panel to conduct a review of patients’ medical charts. Charts of patients treated in a variety of practice settings (e.g., solo and group practices, teaching and community hospitals, hospital clinics) were abstracted using a secure online portal. Patient characteristics at diagnosis, treatment patterns (induction and consolidation chemotherapy and stem cell transplantation [SCT]) and clinical outcomes (complete remission [CR] and relapse) were compared between FLT3 mutated and WT patients using chi-square tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.

Results: Medical records for 104 FLT3 mutated and 105 WT AML patients were reviewed. FLT3 mutation was associated with having poorer risk status at initial AML diagnosis based on National Comprehensive Cancer Network (NCCN) guidelines (p<0.0001). There was also a trend towards poorer Eastern Cooperative Oncology Group (ECOG) and Karnofsky performance scores among FLT3 mutated patients at diagnosis (Table 1). FLT3 mutated patients were numerically less likely to receive induction therapy compared to WT patients (92% vs. 98%, p=0.0586). Among patients who received induction therapy, FLT3 mutated patients were significantly less likely than WT patients to receive the standard 7+3 regimen vs. other treatment regimens, including cytarabine combinations without daunorubicin and idarubicin and non-cytarabine combinations (52% vs. 72%, p=0.0295). FLT3 mutated and WT patients who received induction therapy were similarly likely to receive consolidation therapy (77% vs. 80%, respectively, p=0.2488), but having FLT3 mutation was associated with receiving fewer cycles of consolidation therapy (p=0.0158). Similar proportions of FLT3 mutated and WT patients achieved CR (80% vs. 79%, p=0.8890). Forty-one percent of FLT3 mutated and 30% of WT patients received SCT (p=0.0740), the majority of whom received standard-intensity allogeneic SCT (88% of FLT3 mutated patients and 61% of WT patients). Compared to WT patients, FLT3 mutated patients were numerically more likely to relapse after achieving CR from induction therapy (12% vs. 7%, p=0.3639) and after SCT (14% vs. 6%, p=0.8674).

Conclusions: FLT3 mutated patients were significantly more likely to have poorer risk status at diagnosis and were significantly more likely to receive fewer cycles of consolidation compared to WT patients. FLT3 mutated patients were as likely to achieve CR as WT patients, but results suggest a higher proportion of FLT3 mutated patients relapsed following induction and SCT. These results confirm that FLT3 mutation is associated with a poorer prognosis and suggest the need for improved treatment options for FLT3 mutated patients.

Table 1.

Patient disease characteristics at initial diagnosis

Characteristic, n %FLT3 mutated patients (n=104)FLT3 WT patients (n=105)P-value
Patient disease risk (based on NCCN guidelines)      <0.0001* 
Better-risk 19 20%  40 41%  
Intermediate-risk 37 38%  46 47%  
Poor-risk 41 42%  12 12%  
Karnofsky Performance Score1      0.7309 
100% 8 9%  11 12%  
90% 22 24%  29 31%  
80% 25 27%  23 24%  
70% 7 8%  7 7%  
60% 4 4%  3 3%  
50% 5 5%  5 5%  
40% 3 3%  5 5%  
30% 8 9%  4 4%  
20% 8 9%  7 7%  
10% 3 3%  0 0%  
Eastern Cooperative Oncology Group performance status2      0.1594 
0 28 27%  30 29%  
1 52 50%  57 55%  
2 13 13%  15 14%  
3 7 7%  1 1%  
4 4 4%  1 1%  
*p < 0.05       
[1] Lower score indicates poorer performance; range from 100% = Normal, no complaints, no evidence of disease to 10% = Moribund, fatal processes progressing rapidly. 
[2] Higher score indicates poorer performance; range from 0 = Fully active, able to carry on all pre-disease performance without restriction to 4 = Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 
Characteristic, n %FLT3 mutated patients (n=104)FLT3 WT patients (n=105)P-value
Patient disease risk (based on NCCN guidelines)      <0.0001* 
Better-risk 19 20%  40 41%  
Intermediate-risk 37 38%  46 47%  
Poor-risk 41 42%  12 12%  
Karnofsky Performance Score1      0.7309 
100% 8 9%  11 12%  
90% 22 24%  29 31%  
80% 25 27%  23 24%  
70% 7 8%  7 7%  
60% 4 4%  3 3%  
50% 5 5%  5 5%  
40% 3 3%  5 5%  
30% 8 9%  4 4%  
20% 8 9%  7 7%  
10% 3 3%  0 0%  
Eastern Cooperative Oncology Group performance status2      0.1594 
0 28 27%  30 29%  
1 52 50%  57 55%  
2 13 13%  15 14%  
3 7 7%  1 1%  
4 4 4%  1 1%  
*p < 0.05       
[1] Lower score indicates poorer performance; range from 100% = Normal, no complaints, no evidence of disease to 10% = Moribund, fatal processes progressing rapidly. 
[2] Higher score indicates poorer performance; range from 0 = Fully active, able to carry on all pre-disease performance without restriction to 4 = Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 
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Disclosures

Xie:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Goldmann:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Roy:Novartis Pharmaceuticals Corporation: Employment. Yang:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Wu:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Paley:Novartis Pharma: Employment.

Topics:
flt3 gene, leukemia, myelocytic, acute, medical records, ms-like tyrosine kinase 3, mutation, treatment outcome, neoadjuvant therapy, consolidation therapy, cytarabine, chemotherapy regimen

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2014 by The American Society of Hematology
2014
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