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

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 1.3 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.

Conflict of interest statement

Conflict of Interest Disclosures: Pfizer provided free drug from the Pfizer Investigator Sponsored Trial program. No other disclosures are reported.

Figures

Figure 1.. Patient Flowchart

Mini-HCVD indicates the following treatment regimen: cyclophosphamide and dexamethasone at 50% dose reduction from more conventional treatment, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses. Inotuzumab was given on day 3 of each 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.

Figure 2.. Survival Charts

In all charts, the dotted lines represent the measurement times detailed in the survival tables. A, Overall survival (OS) for the whole cohort and relapse-free survival (RFS) for the 46 responders. B, OS by salvage status. C, OS by minimal residual disease (MRD) status. D, OS by therapy: inotuzumab (INO) monotherapy vs INO plus mini-HCVD using an inverse probability of treatment weighing analysis. For a full expansion of mini-HCVD, see the caption of Figure 1.