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Outcome of Infants Treated on Total Therapy for Infants with Acute Lymphoblastic Leukemia I: Results from a Non-Randomized Multi-Center Study

Authors :
Gruber, Tanja A.
Huang, Minxuan
Jeha, Sima
Deyell, Rebecca J.
Lewis, Victor A.
Chang, Bill H.
Lowe, Eric J.
Frediani, Jamie
Vezina, Catherine
Michon, Bruno
Gossai, Nathan
Breese, Erin H.
Tran, Thai Hoa
Lacayo, Norman J.
Bolen, Christine
Desai, Sunil J.
Pauley, Jennifer L.
Ashcraft, Emily
Cheng, Cheng
Schultz, Kirk R.
Schils, Krysta
Stork, Linda C.
Huynh, Van Thu
Richards, Michael
Messinger, Yoav H.
Bittencourt, Henrique
Horton, Terzah M.
Athale, Uma
Stearns, Duncan
Schiff, Deborah E.
Gaynon, Paul S.
Source :
Blood; November 2023, Vol. 142 Issue: 1, Number 1 Supplement 1 p823-823, 1p
Publication Year :
2023

Abstract

Infants with KMT2A rearranged (KMT2Ar) acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival (EFS) of 33.6-36.9% on recent Children's Oncology Group and Interfant trials. In preclinical studies, we identified bortezomib and vorinostat as novel active agents in primary KMT2Ar infant ALL specimens that have not been included in infant regimens to date. Total therapy for infants with acute lymphoblastic leukemia I (TINI) evaluated this novel combination in a multi-institutional pilot trial for infants with de novoALL. In this study, bortezomib and vorinostat were incorporated into an ALL chemotherapy backbone containing dexamethasone, mitoxantrone, and pegasparaginase during induction and reinduction chemotherapy cycles. A run-in dose escalation evaluated 3 dose levels of vorinostat which was then followed by a dose expansion phase. The primary endpoint of the study was tolerability; secondary endpoints included minimal residual disease (MRD), 3-year EFS and overall survival (OS). Fifty patients enrolled between 2017-2021. Median follow up was 3.4 years (range 1.6-6.8 years). The six patients in the dose escalation phase had no dose-limiting toxicities. Forty-four patients received vorinostat at the third dose level (DL3) of 180 mg/m 2/dose. 68% of patients treated at DL3 had CNS involvement at diagnosis. 68% of DL3 patients carried a KMT2Ar. The most frequent KMT2A partner genes were AFF1 (40%), MLLT1 (20%), and MLLT3 (13%). The most frequent grade 3-4 non-hematologic adverse events during induction include neutropenic fever (45%), hypertension (43%), infection (40%), anorexia (32%), diarrhea (18%) and perineal skin ulceration (16%). There were 3 episodes of sepsis and 1 induction death due to parainfluenza pneumonia. Fewer events and no deaths or proven sepsis occurred during reinduction, with only grade 3 hypertriglyceridemia exceeding 10% of patients affected (18%). 79% of all patients and 69% of KMT2Ar patients became MRD negative by flow cytometry on day 22 of induction following our investigational block. Following induction intensification with cyclophosphamide, cytarabine, and mercaptopurine, 77% and 66% of all patients and KMT2Ar patients respectively were MRD negative at the time of count recovery. Eight of the forty-four patients, all KMT2Ar, underwent stem cell transplant in first remission due to persistent MRD positivity at the end of consolidation.

Details

Language :
English
ISSN :
00064971 and 15280020
Volume :
142
Issue :
1, Number 1 Supplement 1
Database :
Supplemental Index
Journal :
Blood
Publication Type :
Periodical
Accession number :
ejs64699731
Full Text :
https://doi.org/10.1182/blood-2023-177798