A Single-Arm, Open-Label Phase 2 Pilot Study of Vyxeos (CPX-351) in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Shah Bijal D. , Rozario Nicole , Turba Elyce P. , Bello Celeste , Chavez Julio C. , Sokol Lubomir , Brayer Jason , Lancet Jeffrey E. 
Published: November 2021

Abstract
Introduction:
Vyxeos® is a liposomal formulation employing a 1:5 molar ratio of daunorubicin:cytarabine. Clinical trials in high risk acute myeloid leukemias demonstrated a significant benefit in CR rates and median OS, culminating in FDA approval August 2017. Emerging pediatric data suggest this benefit may extend to acute lymphoblastic leukemia (ALL). The following pilot trial was performed to better understand the activity and toxicity profile in adults with relapsed and refractory ALL.
Methods:
Adults with ALL or mixed phenotype leukemia were eligible if &gt;5% lymphoblasts and/or extramedullary disease &gt;1x1cm. Induction consisted of Vyxeos 100 units/m2 on days 1, 3 and 5. Those with clinical benefit could receive up to 3 cycles of consolidation delivered at 65 units/m2 on days 1 & 3 after recovery of neutrophils (&gt;500 cells/uL) and platelets (&gt;50,000 cells/uL).
Response:
11 patients (pts) have been treated to date, with median age of 39y (22-74y), 9 male, and 3 Caucasian. Six pts had B-ALL, including 1 B-myeloid. Four of 5 T-ALL pts had early T-cell precursor (ETP) phenotype. NGS was available in 9 pts, and included TP53 mutation (n=4), and PH-like changes (n=2). Median prior lines of therapy was 3, with 7 pts showing primary refractory disease. Prior blinatumomab, inotuzumab, CAR-T cell therapy, and allogeneic transplant were noted in 5, 2, 1, and 3 pts.
Pancytopenia was uniform during induction, with febrile neutropenia noted in 9 pts. One pt passed from pneumonia after moving to comfort measures in lieu of intubation 20 days after Vyxeos, and is non-evaluable for response. A second pt developed grade 3 sepsis. The remainder of infections were grade 1-2. One pt had grade 3 gastrointestinal bleed, and 3 pts had grade 1 spontaneous subdural bleeding. One pt developed recurrent pericarditis in setting of anterior mediastinal mass. One case of veno-occlusive disease was observed in a pt with prior allogeneic transplant and inotuzumab. Median time to ANC recovery was 33.5 days among 10 evaluable pts. Two pts with refractory disease failed to recover platelets; among the remaining pts, median time to platelet recovery was 30.5 days. Adverse events were uncommon during consolidation, and include foot cellulitis and myopericarditis, each in 1 pt.
Among 10 evaluable pts, 3 achieved CR/CRi, including 2 ETP T-ALL and one B-ALL. Two pts with TP53 mutation demonstrated &gt;50% blast reduction with hematologic recovery, allowing for prolonged time to subsequent therapy. Four pts received 1-3 cycles consolidation. One pt was bridged to donor leukocyte infusion. Responses were noted in only 2 pts after progression following Vyxeos, highlighting refractory status of those enrolled. Median PFS was 57 days (95%CI: 10, 105), time to next therapy 76 days (95%CI: 47, 105), and OS 223 days (95%CI: 144, 302).
Conclusions
Vyxeos in high-risk refractory adult ALL was overall well tolerated and active, with median OS of approximately 7.5 months in this pilot trial. Confirmation of benefit in a larger study is warranted, incorporating a second induction course and/or the addition of novel agents to further improve on remission rate and duration of response.

Disclosures
Shah: Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; BeiGene: Consultancy, Honoraria; Acrotech/Spectrum: Honoraria; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Chavez: Astra Zeneca: Research Funding; Novartis: Consultancy; Merck: Research Funding; Morphosys: Speakers Bureau; Adaptive Biotech: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Beigene: Speakers Bureau; Kite/Gilead: Consultancy; karyopharm: Consultancy; Epizyme: Speakers Bureau; Abbvie: Consultancy. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Lancet: Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy.

OffLabel Disclosure:
Vyxeos is being evaluated in the described trial for the treatment of relapsed or refractory acute lymphoblastic leukemia in adults.