IMPORTANCE: The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL. OBJECTIVE: To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL. DESIGN, SETTING, AND PARTICIPANTS: A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston. INTERVENTIONS: The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES: The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. RESULTS: Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03). CONCLUSIONS AND RELEVANCE: The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01371630.
IMPORTANCE: The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL. OBJECTIVE: To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL. DESIGN, SETTING, AND PARTICIPANTS: A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston. INTERVENTIONS: The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES: The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. RESULTS: Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03). CONCLUSIONS AND RELEVANCE: The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01371630.
Authors: Hagop Kantarjian; Anthony Stein; Nicola Gökbuget; Adele K Fielding; Andre C Schuh; Josep-Maria Ribera; Andrew Wei; Hervé Dombret; Robin Foà; Renato Bassan; Önder Arslan; Miguel A Sanz; Julie Bergeron; Fatih Demirkan; Ewa Lech-Maranda; Alessandro Rambaldi; Xavier Thomas; Heinz-August Horst; Monika Brüggemann; Wolfram Klapper; Brent L Wood; Alex Fleishman; Dirk Nagorsen; Christopher Holland; Zachary Zimmerman; Max S Topp Journal: N Engl J Med Date: 2017-03-02 Impact factor: 91.245
Authors: Hagop Kantarjian; Deborah Thomas; Jeffrey Jorgensen; Elias Jabbour; Partow Kebriaei; Michael Rytting; Sergernne York; Farhad Ravandi; Monica Kwari; Stefan Faderl; Mary Beth Rios; Jorge Cortes; Luis Fayad; Robert Tarnai; Sa A Wang; Richard Champlin; Anjali Advani; Susan O'Brien Journal: Lancet Oncol Date: 2012-02-21 Impact factor: 41.316
Authors: Farhad Ravandi; Jeffrey L Jorgensen; Susan M O'Brien; Elias Jabbour; Deborah A Thomas; Gautam Borthakur; Rebecca Garris; Xuelin Huang; Guillermo Garcia-Manero; Jan A Burger; Alessandra Ferrajoli; William Wierda; Tapan Kadia; Nitin Jain; Sa A Wang; Sergei Konoplev; Partow Kebriaei; Richard E Champlin; Deborah McCue; Zeev Estrov; Jorge E Cortes; Hagop M Kantarjian Journal: Br J Haematol Date: 2015-10-22 Impact factor: 6.998
Authors: Hagop M Kantarjian; Daniel J DeAngelo; Matthias Stelljes; Giovanni Martinelli; Michaela Liedtke; Wendy Stock; Nicola Gökbuget; Susan O'Brien; Kongming Wang; Tao Wang; M Luisa Paccagnella; Barbara Sleight; Erik Vandendries; Anjali S Advani Journal: N Engl J Med Date: 2016-06-12 Impact factor: 91.245
Authors: E Tavernier; J-M Boiron; F Huguet; K Bradstock; N Vey; T Kovacsovics; A Delannoy; N Fegueux; P Fenaux; A Stamatoullas; O Tournilhac; A Buzyn; O Reman; C Charrin; C Boucheix; J Gabert; V Lhéritier; J-P Vernant; H Dombret; X Thomas Journal: Leukemia Date: 2007-07-05 Impact factor: 11.528