The significance of MRD detection by PCR on the survival and relapse of AML patients with FLT3 mutation

FMS-related Tyrosine Kinase 3 (FLT3) gene is one of the most frequently mutated genes in Acute Myeloid Leukemia (AML). Patients with FLT3 mutations have a poor prognosis and are at a higher risk of relapse. Allogenic Stem Cell Transplantation (SCT) is currently the preferred therapy, although controversial for FLT3-mutated AML patients due to the lack of prospective studies that address the role of SCT in this subgroup of patients (Levis, 2013). The significance of Minimal Residual Disease (MRD) detected by Polymerase Chain Reaction (PCR) before allogenic SCT on the outcomes of transplant is not known.

Sameh Gaballa from The University of Texas MD Anderson Cancer Center, Houston, Texas, and colleagues published data, which assessed the impact of disease status before transplant on the survival and relapse in 200 adult AML patients (median age = 51 years) with FLT3 mutations who were treated with SCT. In particular, the authors investigated the usefulness of detecting MRD by PCR in predicting the risk of relapse and survival of FLT3-mutated AML patients.

Patients were divided into different subgroups according to disease status; patients in either first or second Complete Remission (CR1/CR2, n = 119), High-Risk CR (CR-HR, n = 31) and patients with morphological evidence of Active Disease (AD, n = 50). Twenty-seven patients in CR1/CR2 (n = 11) and CR-HR (n = 16) had detectable FLT3 mutations. 

The results were recently published ahead of print in the American Journal of Hematology in January 2017.  

The key results of the study:

• In all patients, 2-year Cumulative Incidence (CI) of leukemia relapse was 45%
• CI of relapse in patients with AD = 85%; CR-HR FLT3 MRD positive = 72%; CR-HR FLT3 MRD negative =58%; CR1/CR2 FLT3 MRD positive = 39%; and CR1/CR2 FLT3 MRD negative = 23%
• Age, graft type, graft source, type of FLT3 mutation, and conditioning intensity did not influence the risk of relapse
• Detectable morphological disease and FLT3 MRD by PCR at the time of SCT were associated with increased risk of relapse
• Non-Relapse Mortality (NRM) was significantly higher in patients in CR2 (HR = 3.0, P = 0.02), patients in CR-HR (HR = 3.2, P = 0.02) and in patients with AD (HR = 2.9, P = 0.03), when compared to patients in CR1  
• NRM was higher in patients with Karnofsky Performance Status (KPS) ≤80% compared to patients with KPS >80%; P < 0.001
• Patients with detectable FLT3 by PCR had a higher NRM compared to patients with no detectable FLT3; HR = 2.9, P = 0.004
• At median follow up of 27 months, 2-year Progression Free Survival (PFS) and Overall Survival (OS) were 41% and 43%, respectively
• Compared to patients in CR1, PFS was significantly lower in CR-HR patients (HR = 3.9, P < 0.001) and in patients with AD (HR = 5.9, P < 0.001)
• PFS was higher in patients in CR1/CR2 FLT3 MRD negative (62%) by PCR compared to patients in CR1/CR2 FLT3 MRD positive (41%, P = 0.3), CR-HR FLT3 negative (33%, P = 0.01) and CR-HR FLT3 positive (0%, P< 0.01), and AD (8%, P < 0.01)
• Death occurred in 110 patients, mostly due to leukemia relapse (n = 75, 68%)

The authors highlighted that their study is the largest study to date on AML patients with FLT3 mutations undergoing allogenic SCT, and the first to show a significant impact of MRD detected for the FLT3 mutations on survival and relapse. They also noted that this study had inherent biases and the MRD detected by PCR was not correlated to MRD detected by multi-color flow cytometry and suggest that these findings require confirmation in prospective trials.

In summary, disease status at the time of transplant morphologically and molecularly influences the risk of relapse and survival after transplant in FLT3-mutated AML patients. FLT3 detected by PCR before transplant was associated with an increased risk of relapse and poor survival.

The authors suggested that FLT3 MRD testing before and after transplant by conventional PCR may be a useful tool in predicting disease relapse and could be used as a rationale in identifying patients at high risk of relapse post-transplant. They further concluded that this method may be particularly useful as a guide for pre-emptive therapy interventions after SCT.

Abstract

In patients with AML with FMS-like tyrosine kinase 3 (FLT3) mutations, the significance of minimal residual disease (MRD) detected by PCR before allogeneic stem cell transplantation (SCT) on outcomes after transplant remains unclear. We identified 200 patients with FLT3-AML who underwent SCT at our institution. Disease status at transplant was: first or second complete remission (CR1/CR2, n=119), high-risk CR (third or subsequent CR, marrow hypoplasia, or incomplete count recovery) (CR-HR, n=31), and morphological evidence of active disease (AD, n=50). The median follow-up was 27 months, and the 2-year overall and progression-free survival were 43% and 41%, respectively. Relapse was highest in the AD group (85%) and the CR-HR FLT3 MRD positive group (72%), followed by CR-HR FLT3 MRD negative (58%), CR1/CR2 FLT3 MRD positive (39%), and lowest in the CR1/CR2 FLT3 MRD negative group (23%). On multivariate analysis, independent factors influencing the risk of relapse were detectable morphological disease and FLT3 MRD by PCR pre-transplant. Factors that did not influence the relapse risk included: age, graft type, graft source, type of FLT3 mutation, or conditioning intensity. Morphologic and molecular remission status at the time of transplant were key predictors of disease relapse and survival in patients with FLT3-AML.