Prognostic Impact of CNS-2 status in T-ALL: A report from the Children’s Oncology Group.
Authors: Gossai Nathan , Winter Stuart S. , Devidas Meenakshi , Chen Zhiguo , Wood Brent L. , Zweidler-McKay Patrick A. , Rabin Karen R. , Winick Naomi J. , Burke Michael , Carroll William L. , Esiashvili Natia , Heerema Nyla A. , Carroll Andrew J. , Loh Mignon L. , Raetz Elizabeth A. , Hunger Stephen , Dunsmore Kimberly P. , Teachey David T. 
Published: June 2021

10003

Background: In B-acute lymphoblastic leukemia (B-ALL), CNS2 was associated with inferior 5-year (yr) event-free and overall survival (EFS/OS) in recent trials. Here, we report the impact of CNS2 in T-ALL on AALL0434 and AALL1231, recently completed consecutive randomized phase 3 trials for children and young adults with T-ALL and T Lymphoblastic Lymphoma. This report is limited to T-ALL. Both trials used augmented Berlin Frankfurt Münster regimens. AALL0434 compared Capizzi escalating methotrexate+pegaspargase (C-MTX) vs High Dose MTX (HDMTX) +/- six nelarabine (Nel) courses; outcomes improved with CMTX and Nel. CNS1/CNS2 patients, except those defined as low risk (LR) received 12Gy cranial radiation (CRT); CNS3 patients received 18Gy CRT. AALL1231 randomized patients to +/- bortezomib (Bort). AALL1231 changed the AALL0434 backbone, using dexamethasone instead of prednisone throughout. CRT was given only to patients with CNS3 disease (18Gy) and those defined as very high risk (VHR) (12Gy). CNS2 patients could not be classified as LR on AALL0434 or standard risk (SR) on AALL1231. CNS1/CNS2 patients received the same intrathecal therapy frequency on both studies. Methods: CNS status was assigned at diagnosis. CNS2 defined as: presence of < 5/ μL WBCs and cytospin positive for blasts or ≥ 5/μLWBCs with negative Steinherz Bleyer algorithm. Outcomes by CNS status were compared between AALL0434 and AALL1231. Results: From 2007-2014, AALL0434 enrolled 1562 evaluable T-ALL patients, including 1128 (72.8%) CNS1, 306 (19.7%) CNS2 and 116 (7.5%) CNS3. 90.8% received CRT, including 90.4% of CNS1 patients. 5yr EFS rates for CNS1, 2, and 3 were 85.2±1.3%, 83.1±2.6%, and 71.4±5.2% (p = 0.0007); OS rates were 90.4±1.1%, 89.2±2.1%, and 83.1±4.3% (p = 0.0438). There were no differences in 5yr disease free survival (DFS) between CNS1 and CNS2 treated with CMTX (89.7% vs. 92.9%, p = 0.17) or CMTX+Nel (91.8% vs. 89.9%; p = 0.62). AALL1231 accrued 614 evaluable T-ALL patients [CNS1 437 (71.1%), CNS2 134 (21.8%), CNS3 43 (7.0%)] from 2014 to early closure in 2017. Of these, only 12% were scheduled to receive CRT. 3yr EFS rates for CNS1, 2 and 3 were 84.1±2.1%, 84.6±3.8% and 78.6±7.9% (p = 0.50). 3yr OS was: CNS1 87.5±1.9%, CNS2 92.2±2.8%, CNS3 78.5±7.9% (p = 0.017) . 3yr EFS was not statistically distinct without Bort in CNS1, 2 or 3 (85.3±2.9%, 81.4±5.6%, 71.9±13.4%) (p = 0.10) or with Bort (82.9±3.0%, 88.3±4.9%, 83.3±9,4%; p = 0.43). Intermediate risk (IR) CNS1 and CNS2 patients received identical therapy and had similar 3yr EFS (88.8±2.8% vs 88.8±3.5%, p = 0.98). Conclusions: Unlike in B-ALL, EFS/OS was similar for CNS1 and CNS2 on AALL0434 (with CRT) and AALL1231 (without CRT). Further, IR CNS1 and CNS2 on AALL1231 had similar outcomes with identical therapy. Thus, CNS2 status is non-prognostic in T-ALL on these contemporary COG regimens. CNS3 patients have poor outcomes in T-ALL despite CRT and intensive chemotherapy, novel approaches are needed. Clinical trial information: NCT00408005, NCT02112916.