Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory philadelphia chromosome-negative acute lymphoblastic leukemia: A phase 2 clinical trial

Elias Jabbour, Farhad Ravandi, Partow Kebriaei, Xuelin Huang, Nicholas J. Short, Deborah Thomas, Koji Sasaki, Michael Rytting, Nitin Jain, Marina Konopleva, Guillermo Garcia-Manero, Richard Champlin, David Marin, Tapan Kadia, Jorge Cortes, Zeev Estrov, Koichi Takahashi, Yogin Patel, Maria R. Khouri, Jovitta JacobRebecca Garris, Susan O'Brien, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

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 1.3mg/m2 for cycle 1 followed by 1.3 to 1.0mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES The primary end pointswere 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.

Original languageEnglish (US)
Pages (from-to)230-234
Number of pages5
JournalJAMA Oncology
Volume4
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

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Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Clinical Trials
Survival Rate
Residual Neoplasm
Stem Cell Transplantation
Recurrence
Drug Therapy
Doxorubicin
Cyclophosphamide
Dexamethasone
Survival
Safety
Hyperbilirubinemia
Inotuzumab Ozogamicin
Poisons
Anthracyclines
Cytarabine
Vincristine
Methotrexate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory philadelphia chromosome-negative acute lymphoblastic leukemia : A phase 2 clinical trial. / Jabbour, Elias; Ravandi, Farhad; Kebriaei, Partow; Huang, Xuelin; Short, Nicholas J.; Thomas, Deborah; Sasaki, Koji; Rytting, Michael; Jain, Nitin; Konopleva, Marina; Garcia-Manero, Guillermo; Champlin, Richard; Marin, David; Kadia, Tapan; Cortes, Jorge; Estrov, Zeev; Takahashi, Koichi; Patel, Yogin; Khouri, Maria R.; Jacob, Jovitta; Garris, Rebecca; O'Brien, Susan; Kantarjian, Hagop.

In: JAMA Oncology, Vol. 4, No. 2, 02.2018, p. 230-234.

Research output: Contribution to journalArticle

Jabbour, E, Ravandi, F, Kebriaei, P, Huang, X, Short, NJ, Thomas, D, Sasaki, K, Rytting, M, Jain, N, Konopleva, M, Garcia-Manero, G, Champlin, R, Marin, D, Kadia, T, Cortes, J, Estrov, Z, Takahashi, K, Patel, Y, Khouri, MR, Jacob, J, Garris, R, O'Brien, S & Kantarjian, H 2018, 'Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory philadelphia chromosome-negative acute lymphoblastic leukemia: A phase 2 clinical trial', JAMA Oncology, vol. 4, no. 2, pp. 230-234. https://doi.org/10.1001/jamaoncol.2017.2380
Jabbour, Elias ; Ravandi, Farhad ; Kebriaei, Partow ; Huang, Xuelin ; Short, Nicholas J. ; Thomas, Deborah ; Sasaki, Koji ; Rytting, Michael ; Jain, Nitin ; Konopleva, Marina ; Garcia-Manero, Guillermo ; Champlin, Richard ; Marin, David ; Kadia, Tapan ; Cortes, Jorge ; Estrov, Zeev ; Takahashi, Koichi ; Patel, Yogin ; Khouri, Maria R. ; Jacob, Jovitta ; Garris, Rebecca ; O'Brien, Susan ; Kantarjian, Hagop. / Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory philadelphia chromosome-negative acute lymphoblastic leukemia : A phase 2 clinical trial. In: JAMA Oncology. 2018 ; Vol. 4, No. 2. pp. 230-234.
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abstract = "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 1.3mg/m2 for cycle 1 followed by 1.3 to 1.0mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES The primary end pointswere 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.",
author = "Elias Jabbour and Farhad Ravandi and Partow Kebriaei and Xuelin Huang and Short, {Nicholas J.} and Deborah Thomas and Koji Sasaki and Michael Rytting and Nitin Jain and Marina Konopleva and Guillermo Garcia-Manero and Richard Champlin and David Marin and Tapan Kadia and Jorge Cortes and Zeev Estrov and Koichi Takahashi and Yogin Patel and Khouri, {Maria R.} and Jovitta Jacob and Rebecca Garris and Susan O'Brien and Hagop Kantarjian",
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TY - JOUR

T1 - Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory philadelphia chromosome-negative acute lymphoblastic leukemia

T2 - A phase 2 clinical trial

AU - Jabbour, Elias

AU - Ravandi, Farhad

AU - Kebriaei, Partow

AU - Huang, Xuelin

AU - Short, Nicholas J.

AU - Thomas, Deborah

AU - Sasaki, Koji

AU - Rytting, Michael

AU - Jain, Nitin

AU - Konopleva, Marina

AU - Garcia-Manero, Guillermo

AU - Champlin, Richard

AU - Marin, David

AU - Kadia, Tapan

AU - Cortes, Jorge

AU - Estrov, Zeev

AU - Takahashi, Koichi

AU - Patel, Yogin

AU - Khouri, Maria R.

AU - Jacob, Jovitta

AU - Garris, Rebecca

AU - O'Brien, Susan

AU - Kantarjian, Hagop

PY - 2018/2

Y1 - 2018/2

N2 - 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 1.3mg/m2 for cycle 1 followed by 1.3 to 1.0mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES The primary end pointswere 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.

AB - 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 1.3mg/m2 for cycle 1 followed by 1.3 to 1.0mg/m2 for subsequent cycles. MAIN OUTCOMES AND MEASURES The primary end pointswere 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.

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