Discussion:
The outcome of children with T-ALL
improved markedly; we previously reported the outcome of T-ALL treated
at KHCC per St. Jude total XV
protocol
[14].In September 2014 we adopted a
new protocol of augmented post-induction therapy in all patients with
T-ALL treated at our center regardless of the MRD at end of induction.
The rationale for this approach is early intensification of therapy post
induction to clear any residual MRD and decrease the relapse when the
MRD measurement at day 15 and end of induction may not be successful in
identifying certain groups who are still MRD positive but not detectable
by our current techniques. Patients treated per St. Jude total XV
already exposed dexamethasone,
AIEOP-BFM consolidation /protocol IB that includes cyclophosphamide,
cytarabine and 6- mercaptopurine at week 4 and 5 of remission
Induction[16];and intensive
asparaginase therapy in early
continuation[11]. So, we adopted
different agents for intensification of therapy; fludarabine, high dose
cytarabine, VP16, dexamethasone, peg-asparaginase; combination has been
used and proven to be effective in refractory relapsed ALL
[17,
18].
Our results showed significant improvement of EFS in patients treated
using augmented therapy 87% vs 67% in standard therapy group. Notably,
11 patients in the augmented group had positive MRD
(>=0.01%) and/or M2, M3 marrow at the end of induction.
Eight (73%) of these patients achieved remission with negative MRD
(<0.01%) post FLAG chemotherapy, 7 of them remained in CCR at
date of last follow-up.
Attempts to intensify treatment of patients with T-ALL are well-reported
in the literature; our results are in line with outcomes reported by
other contemporary clinical trials of T-ALL in children and adolescent.
BFM Augmented post-induction chemotherapy results in an excellent
outcome for T-ALL, event-free survival at three years was 92% in the
augmented-therapy group and 71% in the standard-therapy
group[16].
Consolidation phase IB used in
AIEOP-BFM protocols, based on cyclophosphamide, 6-mercaptopurine, and
ara-C at conventional (non-high) doses was shown to be effective in
reducing MRD in Early T-cell precursor ALL; with 3-year event-free
survival of 86%, which is not different from that of the other T-cell
acute lymphoblastic leukemia variants
[19].
Ajay Vora et al reported improved outcome for Children and Young Adults
with T-ALL treated with a regimen that included Pegylated E. Coli
Asparaginase (Peg-ASP) (Oncospar, Medac UK) and Dexamethasone (UKALL
2003 regimen). EFS and OS were significantly better for T-ALL in UKALL
2003 (3 year: EFS 86%, OS 90%) in comparison with a previous regimen-
ALL97/99 (3-year EFS 73%, OS
78%)[20].
Dana Farber Cancer Institute Consortium (DFCI) 85-01 protocols
demonstrated superior outcomes in T-ALL patients treated with intensive
consolidation regimens that included 30 weeks of ASP. Patients with HR
received every 3-wk cycles with vincristine, dexamethasone, 6MP and
doxorubicin. The 4-yr EFS and OS for all T-ALL pts was 83% and 89%,
respectively [21].
In NOPHO 2008, MRD based chemotherapy with intensive three blocks of
chemotherapy for T-ALL with MRD ≥0.1% on day 29, led to favorable
outcomes; The 5-year event-free survival was 74%
[19].
In our cohort, patients who had
rapid early response with M1 marrow at day 15 of remission induction
were at lower risk of relapse when compared with T-ALL with M2/M3 marrow
(p=0.011). Relapse rate in T-ALL patients with positive MRD at end of
induction was 6/15 (40%), while14 patients (17%) of 85 patients with
negative MRD relapsed (p=0.06). While the later MRD timepoint most
effectively identifies high risk patients, the earlier end-of-Induction
time point can be used to identify lower risk patients who can safely
receive less intensive therapy. In the UKALL2003 trial, T-ALL patients
with end-of-Induction MRD <10-4 received standard BFM
consolidation with a standard interim maintenance phase instead of
Capizzi escalating MTX with asparaginase and had a 5yr EFS of 93.1%
[22,
23].
Markedly elevated white blood cell count (Wbc)≥200 in our cohort was not
associated with inferior outcome when compared with patients presented
with WBC <200 (EFS p=0.7), and there was no difference in
outcome at age threshold of 10 years (EFS p=0.4).
In
our study, none of the patients who received CRT in both groups (N=21)
relapsed while 17 of 73 (23%) patients who did not receive CRT
relapsed. Interestingly only 2 of the augmented group patients who did
not receive CRT relapsed. This suggests that systemic augmentation may
compensate for the lack of CRT. This additional benefit should be taken
in consideration, especially when treating young children.
Currently, approaches to the use of CRT for pediatric T-ALL are
variable, with some cooperative groups administering CRT to all T-cell
patients, some omitting CRT in all patients, and some using a
risk-stratified approach.[24]
In Total XV, no patient received prophylactic cranial radiation, but
additional intrathecal therapy during early induction, intensification
with asparaginase, HD-MTX, and dexamethasone seemed to contribute to
improved CNS control; the rate of CNS relapses in T-ALL (7.9%) that was
equivalent to that observed on the predecessor study, in which CRT was
used in selected high-risk patients with T-ALL
[11]
In Total XVI, the cumulative incidence (CI) of CNS relapse in T-ALL was
(Any or Isolated is 4.3%). Only T-ALL retained independent significance
in the multivariable analysis for any CNS relapse (hazard ratio, 5.15
[95% CI, 1.3 to 20.6]; P = 0. 021) and for isolated CNS relapse
(hazard ratio, 6.83 [95% CI, 1.5 to 30.5]; P = .012)
[6]
The European Organization for the Research and Treatment of Cancer
(EORTC) has eliminated CRT in all patients with T-ALL, including those
with CNS disease, in its recent studies and has adopted regimens with an
intensified schedule of high-dose MTX (HD-MTX) and triple intrathecal
chemotherapy (MTX, cytarabine, and hydrocortisone). With this approach,
isolated and overall CNS relapse rates of 5.3% to 8.5% were observed
on study 5895. [8,
15, 25]
Excellent outcomes with 5-year EFS of 81.2% and low rates of isolated
CNS relapse (3.5%) were also reported for T-ALL on the UKALL 2003 trial
with a regimen that did not include either HD-MTX or prophylactic
CRT.[26,
27]
The COG AALL0434 trial treated patients with T-ALL on an augmented BFM
regimen and randomly assigned patients to receive either HD-MTX with
leucovorin rescue or escalating methotrexate without leucovorin
(Capizzi) and Nelarabine and cranial radiation; the cumulative incidence
of central nervous system relapse was lower in patients who received
Capizzi methotrexate and nelarabine.
[28-30]
Our study has multiple limitations that adds to its retrospective
design. First, small number of patients in each cohort and reduced
events limit the power of our statistical analysis. Second, patients
treated per augmented therapy need longer duration of follow up, to
prove that excellent cure rate we have achieved is durable. Third, T-
ALL patients treated after sep/2014 received intensive therapy by adding
two blocks of chemotherapy regardless of MRD response after remission
induction due limitation in our MRD study in T-ALL, 37 patients (77%)
of 48 in augmented therapy group received FLAG consolidation despite
having a negative MRD (<0.01%) at end of induction; the
objective of early intensification therapy is to prevent unsalvageable
relapses which is relatively balanced with treatment burden. The toxic
effects of augmented therapy were considerable but manageable.
Hematological toxicities are balanced against no increase in therapy
related mortality as supportive care improvement over time may also
impacts favorable outcomes; the mean total duration of hospitalization
was slightly longer for patients in the augmented-therapy group than in
the standard-therapy group.
In summary, we showed that early intensification of systemic and
CNS-directed chemotherapy can result in an improvement of outcome in
T-ALL patients as it significantly decreases risk of relapse.
Response-based de-escalation of therapy and Escalation of therapy based
on MRD at later time point is highly needed as this could limit
unnecessary intensification and reduce treatment-related mortality and
morbidity. Additionally; we showed that the rate of relapse in patients
who did not receive CRT was significantly lower in patients who were
treated with our augmented therapy compared to standard therapy. This
was likely related to effective intensive CNS directed therapy; omitting
CRT in setting of augmented therapy is warranted. The use of
prophylactic cranial radiation therapy in the treatment of patients with
T-ALL is declining given the higher rates of neurocognitive sequelae,
endocrinopathies, and secondary malignancies associated with CRT;
several studies have now shown that CRT can be successfully eliminated
from regimens that contain intensive systemic and intrathecal
chemotherapy.