Despite risk-stratification in adult ALL by WBC count, age, and neurologic involvement, there remains marked heterogeneity in outcome among standard- and high-risk patients. Although minimal residual disease kinetics using T-cell receptor rearrangements are likely to contribute significantly toward stratification protocols in the future,22,23
minimal residual disease in adult T-ALL is less robust at predicting prognosis and identifying early relapse than it is in adult B-ALL, or pediatric B- or T-ALL.24–26
Subsequently, simple mutation screening strategies that predict outcome could prove invaluable in clinical decision making in adult T-ALL, particularly in evaluation of patients for allogeneic hematopoietic stem-cell transplantation.
Here we show a high incidence of activating mutations in the NOTCH1
(60%) and FBXW7
genes (18%) in adult T-ALL, similar to that seen in pediatric T-ALL cohorts,7,16
and this indicates that the presence of these mutations, in themselves, is unlikely to explain the disparity in outcome seen between these age groups. There was a significant positive association between having a NOTCH1
mutation in the HD domain only and an FBXW7
mutation and a strong negative association between having a NOTCH1
PEST mutation and FBXW7
mutation. This observation is consistent with the hypothesis that NOTCH1
HD and FBXW7
mutations act in concert, similar to dual HD and PEST mutations.11,14
Although FBXW7 also targets c-Myc for degradation,11,27
the association described here favors the concept that FBXW7
mutations are acquired by T-ALL cells primarily as a means of increasing NOTCH1
signal strength. If FBXW7
mutations were acquired by tumor cells predominantly to upregulate c-Myc, they would likely be found in conjunction with PEST mutations in some cases.
Although our data did not show a significantly improved outcome in those patients with mutations in the Notch pathway, the trend is in accord with data previously presented in pediatric patients treated on the ALL-BFM protocol16
and, more recently, in adults on the French LALA-94 and GRAALL-2003 trials,18
and in contrast to the association with poor prognosis reported in adults by Zhu et al.17
Other molecular markers have been reported to have some impact on prognostic outcome in adult T-ALL. For example, TLX1
mRNA upregulation has been shown to be associated with an improved prognosis.28
It was not possible to evaluate this in our cohort because of lack of RNA samples from all patients. However, patients with TLX1
upregulation constitute a minority of patients and are strongly associated with NOTCH1
mutations (20 of 21 patients with TLX1
upregulation were NOTCH1
MUT in the French study).18 NOTCH1/FBXW7
has also been shown to be prognostically important independently of TLX1
Together, these data suggest it is valid to evaluate patient outcome according to NOTCH1/FBXW7
status alone. Furthermore, when the three most robust prognostic factors on the overall UKALLXII/ECOG trial were taken into account (age, WBCs, and treatment arm), the differences in EFS and OS were unaffected, and the NOTCH1/FBXW7
MUT and WT groups were equally balanced in regard to the percentages of standard- and high-risk patients.
Although we found no significant difference in outcome in NOTCH1
MUT patients when analyzed individually, the combined NOTCH1/FBXW7
MUT group showed a trend toward improved outcome (P
= .1), highlighting the importance of the addition of FBXW7
status to that of NOTCH1.
Thus unlike the situation of FLT3
mutations in acute myeloid leukemia, where activating the same receptor by either point mutation or internal tandem duplication is associated with a diametric prognostic outcome,29
the suggestion in T-ALL may be that it is Notch pathway activation itself that is important in determining treatment response.
To date, this is the largest adult cohort of T-ALL patients treated on a single trial addressing outcome by NOTCH1/FBXW7
mutation status. Although the data show a nonsignificant difference between the MUT and WT groups, it is compatible with the MUT group having a better prognosis, as shown by Asnafi et al,18
and much larger studies of adult patients will be required to demonstrate this unequivocally. The current study has 80% power to detect a 30% increase in EFS. The data on this adult cohort do show that, even if there is a better outcome in those with a Notch pathway mutation, the magnitude of the improvement in EFS is likely to be too low to consider de-intensification of therapy in this group of patients.