MRD Status Did Not Correspond to the Relapse Incidence within One Year of Follow-up By Non-Intensive but Non-Interruptive Approach: The First Interim Results of the Russian Prospective Multicenter RALL-2016 Trial for Ph-Negative Adult ALL
Authors: Gavrilina Olga A. , Parovichnikova Elena N. , Troitskaya Vera V. , Baskhaeva Galina A. , Sokolov Andrey N. , Zarubina Ksenija I. , Gribanova Elena O. , Galtseva Irina V. , Obukhova Tatiana N. , Kaplanov Kamil D , Samoilova Olga , Bondarenko Sergey N. , Borisenkova Elena , Lapin Valery , Zeinalova Pervin , Zinina Elena E. , Zotina Ekaterina N. , Konstantinova Tatiana , Drokov Mikhail Yu. , Kulikov Sergei M. , Savchenko Valery G. 
Published: October 2019

Abstract
Introduction
RALL-2009 study (NCT01193933) has demonstrated that non-intensive but non-interruptive treatment with fewer allo-HSCT is rather effective in adult Ph-negative ALL pts aged 18-55 yy, producing more than 50% OS at 8-years [Parovichnikova, EHA E836, 2017]. In this study we have shown that only age, initial WBC >30*109/l and t(4;11) became the factors of poor prognosis for BCP-ALL and none of the factors - for T-ALL. MRD was not measured in this study. Since Dec 2016 we started a new RALL-2016 (NCT03462095) protocol based on the same principle but modified according to the conclusions drawn from RALL-2009.
Aim.
To evaluate the first interim results of MRD monitoring and 1-year probability of relapse regarding MRD status in Ph-negative ALL treated by RALL-2016 protocol.
Materials and patients.
Taking in consideration the major pitfalls of RALL-2009 (high CR rate, early CNS relapses in T-ALL, selection bias for autologous HSCT in T-cell ALL, absence of MRD testing) a new study was developed. One day high-dose MTX block and one-day high-dose ARA-C block are eliminated and substituted by 2 months of non-intensive and non-interruptive treatment, L-asparaginase is scheduled for 1 year of treatment instead of 2,5 y, 15 intrathecal injections are increased up to 21 during consolidation phase, CR T-ALL patients are brought to randomization after the informed consent: auto-HSCT vs no auto-HSCT, - with further similar maintenance. All primary bone marrow samples are collected and tested for cytogenetic and molecular markers, all included pts are MRD monitored by flow cytometry in a centralized lab at 3-time points (days +70,+133,+190).
Since Dec2016 till July 2018, 86 adult Ph-negative ALL pts from 11 centers (10 regions of Russia) were included in theRALL-2016 protocol: median age 33 y (18-54), m/f 54/32, BCP-ALL was diagnosed in 48 (56%), T-ALL/LBL - in 35 (40,5%), biphenotypic ALL -3 (3,5%).
Results.
CR rate in 76 available for the analysis patients was 80% (n=61), induction death occurred in 12% (n=9) and refractory ALL was registered in 8% (n=6). There were no deaths in CR so far. 2 allo-HSCT were performed (1 MUD and 1 haplo) for BCP-ALL with MRD persistence and T-ALL associated with Nijmegen breakage syndrome, respectively. 26 T-ALL patients after CR achievement were randomized for chemo (n=13) or for auto-HSCT (n=13). Up to now 7 of randomized T-ALL patients were transplanted at a median of 6 mo of CR. OS for the whole cohort constituted 68% at 18 months, relapse probability - 8,7%.
MRD at the 1st time point (+70 day) was measured in 54 pts, at the 2nd time point (+133 day) - in 43 pts and at the 3rd time point (+190 day) - in 36 pts. MRD-positivity was detected in 15 pts (28%) at day+70 (BCP-ALL=11 out of 32 pts, T-ALL=4 out of 22), at day +133 - in 8 pts (19%) (BCP-ALL=7 out of 30 pts, T-ALL=1 out of 13), at day +190 - in 2 pts (5%) (both BCP-ALL). MRD clearance was much better in T-ALL patients, as it was demonstrated by other studies earlier [Bruggemen, Goekbuget]. But we have to mention that regardless our non-intensive approach, the portion of MRD-positive patients was similar at the same time points as in the other studies applying highly intensive protocol.
We did not reveal any differences in early (within 1-year) relapse probability according to MRD status, though we have to assume that the study is small and the period of follow is too short.
Conclusion
Our data demonstrate that non-intensive but non-interruptive approach is as effective as more intensive protocols providing very similar MRD clearance in Ph-negative ALL. MRD is declining better in T-ALL patients comparing to BCP-ALL. And no correspondence was noticed between the MRD-positivity and relapse probability at the 18 mo of follow-up.
Figure. Figure.

Disclosures
Kulikov: Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding.