Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study.

Abstract

BACKGROUND:

Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to a toxin, calicheamicin, has shown single-agent activity in relapsed or refractory acute lymphoblastic leukaemia. We aimed to assess the activity and safety of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with acute lymphoblastic leukaemia.

METHODS:

We did a single-arm, phase 2 study at the MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, acute lymphoblastic leukaemia, and an Eastern Cooperative Oncology Group performance status of 3 or lower. The induction chemotherapy regimen used was mini-hyper-CVD (a lower intensity version of the conventional hyper-CVAD). Odd-numbered cycles (1,3, 5, and 7) comprised intravenous cyclophosphamide (150 mg/m2 every 12 h on days 1-3) and oral or intravenous dexamethasone (20 mg per day on days 1-4 and days 11-14); no anthracycline was administered. Intravenous vincristine (2 mg flat dose) was given on days 1 and 8. Even-numbered cycles comprised intravenous methotrexate (250 mg/m2 on day 1) and intravenous cytarabine (0·5 g/m2 given every 12 h on days 2 and 3). Intravenous inotuzumab ozogamicin was given on day 3 of the first four cycles at the dose of 1·3-1·8 mg/m2 at cycle 1, followed by 1·0 -1·3 mg/m2 in subsequent cycles. Maintenance therapy with dose-reduced POMP (purinethol [6-mercaptopurine], oncovin [vincristine sulfate], methotrexate, and prednisone) was given for 3 years. The primary endpoint of this study was progression-free survival at 2 years. Analyses were by intention to treat. The study is ongoing, recruiting patients for an approved expansion phase with a modified treatment plan by protocol amendment. The trial is registered with ClinicalTrials.gov, number NCT01371630.

FINDINGS:

Between Nov 12, 2011, and April 22, 2017, 52 patients with a median age of 68 years (IQR 64-72) were enrolled. With a median follow-up of 29 months (IQR 13-48), 2-year progression-free survival was 59% (95% CI 43-72). The most frequent grade 3-4 adverse events were prolonged thrombocytopenia (42 [81%] patients), infections during induction (27 [52%]) and consolidation chemotherapy (36 [69%]), hyperglycaemia (28 [54%]), hypokalaemia (16 [31%]), increased aminotransferases (ten [19%]), hyperbilirubinaemia (nine [17%]), and haemorrhage (seven [15%]). Veno-occlusive disease occurred in four (8%) patients. Six (12%) patients died from adverse events that were deemed treatment related (five [10%] from sepsis and one [2%] from veno-occlusive disease).

INTERPRETATION:

Inotuzumab ozogamicin plus mini-hyper-CVD chemotherapy is a safe and active first-line therapy option in older patients with newly diagnosed acute lymphoblastic leukaemia and could represent a new therapy for this population. Randomised, phase 3 trials to evaluate the efficacy of this combination compared with the current standard of care in this setting, combination chemotherapy without inotuzumab ozogamicin, are warranted.

FUNDING:

MD Anderson Cancer Center.

• Authors: Hagop Kantarjian, Farhad Ravandi, Nicholas J Short, Xuelin Huang, Nitin Jain, Koji Sasaki, Naval Daver, Naveen Pemmaraju, Joseph D Khoury, Jeffrey Jorgensen, Yesid Alvarado, Marina Konopleva, Guillermo Garcia-Manero, Tapan Kadia, Musa Yilmaz, Gautam Bortakhur, Jan Burger, Steven Kornblau, William Wierda, Courtney DiNardo, Alessandra Ferrajoli, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Elias Jabbour
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 19 Issue 2 Pg. 240-248 (02 2018) ISSN: 1474-5488 [Electronic] England
• PMID: 29352703 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Vincristine
• Dexamethasone
• Doxorubicin
• Cyclophosphamide
• Inotuzumab Ozogamicin

Topics

• Academic Medical Centers
• Aged
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cancer Care Facilities
• Cyclophosphamide (therapeutic use)
• Dexamethasone (therapeutic use)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Doxorubicin (therapeutic use)
• Drug Administration Schedule
• Female
• Geriatric Assessment
• Humans
• Induction Chemotherapy
• Inotuzumab Ozogamicin
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Patient Safety (statistics & numerical data)
• Patient Selection
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, mortality, pathology)
• Prognosis
• Proportional Hazards Models
• Retrospective Studies
• Single-Blind Method
• Survival Analysis
• Texas
• Treatment Outcome
• Vincristine (therapeutic use)