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.