Role of MRD in Ph+ Pediatric Acute Lymphoblastic Leukemia Patients Treated with and without Tirosine Kinase Inhibitor in the Esphall Study
Authors: Cazzaniga Giovanni , Schrappe Martin , de Lorenzo Paola , Castor Anders , Lucchini Giovanna , Gandemer Virginie , Pieters Rob , Stary Jan , Escherich Gabriele , Hancock Jeremy , Arico' Maurizio , Röttgers Silja , Saha Vaskar , Biondi Andrea , Valsecchi Maria Grazia 
Published: October 2019

Abstract
Abstract 1467

Background.
Prognosis of Philadelphia chromosome positive (Ph+) ALL has generally improved after the introduction of Tyrosine Kinase Inhibitor (TKI) on top of chemotherapy and allogeneic stem cells transplantation (SCT). Several studies in children and adults with ALL have shown that MRD status is a strong and independent prognostic factor. In the EsPhALL study, MRD was prospectively measured at relevant time-points (TP), and this allowed us to investigate the prognostic significance in this rare subgroup.

Methods.
A total of 178 patients aged 1 to 18 years diagnosed with ALL and documented presence of t(9;22)(q34;q11) were enrolled in the EsPhALL study and classified as Good Risk (GR) or Poor Risk (PR) according to early response to induction treatment. GR patients were randomized to receive (GR-IM) or not (GR-noIM) post-induction imatinib, while PR patients received post-induction imatinib along with chemotherapy. The chemotherapy regimen was modeled upon a BFM high risk backbone with all patients receiving four post-induction blocks after which they became eligible to SCT. MRD was analyzed by real-time quantitative PCR analysis of rearranged immunoglobulin genes and T-cell receptor genes at various TP during therapy on a subset of 112 study patients.

Results.
At baseline (TP1), in 35 GR and 47 PR patients treated with imatinib, positive MRD at any level (n=76) was associated to a lower outcome compared to negative MRD (n=6), although not significantly (4-year EFS (SE) was 60% vs. 100%, p=0.11). In GR patients, MRD at TP2 (i.e. after the first exposure to Imatinib in Protocol IB) was low (<5×10−4) in 26/30 (87%) patients receiving imatinib, compared to 8/13 (62%) patients not receiving imatinib (p=0.10). MRD at TP2 tends to have a prognostic impact with a 4-year EFS (SE) of 73% (12%), 58% (13%) and 42% (17%) in patients with negative (n=19), <5×10−4 (n=15) and ≥5×10−4 (n=15) MRD levels, respectively (p=0.40). In patients with negative MRD at TP2, 5 did not receive imatinib and 2 relapsed, while 14 received imatinib and 1 relapsed (p=0.15). In patients with positive MRD at any level, 8 did not receive imatinib and 2 relapsed, while 16 received imatinib and 7 relapsed (p=0.66). Among 33 PR patients, MRD was low at TP1 in 2 patients (6%), while it became low in additional 5 patients after TP2 (21%). Of these 7 patients, 2 relapsed, while 7 relapsed among the 26 patients with high MRD (≥5×10−4) at both time-points.

Conclusions.
The exposure to Imatinib resulted in a reduced tumor load, providing a better quality of molecular remission, which turned to have clinical impact in the outcome. The evaluation of MRD after early exposure to Imatinib has a prognostic impact: low or negative MRD levels at TP2 identify a subgroup of GR patients with a better outcome. To lesser extent the same trend was observed in PR. Altogether, these findings support the current use of MRD at TP2 in clinical trials (amended EsPhALL and BMS CA-180372) to identify those patients eligible for receiving treatment with chemotherapy and TKI only, and accordingly spared SCT.

Disclosures:
No relevant conflicts of interest to declare.