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

Key Points

Question  Is treatment with inotuzumab ozogamicin plus low-intensity chemotherapy effective in relapsed or refractory acute lymphoblastic leukemia (ALL)?

Findings  In a single-arm, phase 2 clinical trial of 59 adults relapsed or refractory ALL, the overall treatment response rate was 78%, and the 1-year overall survival rate was 46%.

Meaning  Confirmatory studies of the combination of inotuzumab ozogamicin with low-intensity chemotherapy are warranted.

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

In patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) salvage chemotherapy results in complete remission (CR) rates of 30% to 40% in first salvage therapy (salvage 1) and 10% to 20% in salvages 2 and beyond.^1-3 Few patients can be bridged to allogeneic stem cell transplantation (ASCT).⁴ In a randomized phase 3 trial,⁵ inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to calicheamicin, improved outcomes in patients with R/R ALL compared with standard chemotherapy. Herein we report the results of a phase 2 study of low-intensity chemotherapy with inotuzumab ozogamicin.

Patients with R/R Philadelphia chromosome–negative, CD22-positive ALL were eligible. Patients were required to have a performance status of 3 or lower and normal organ function. Patients signed informed consent in accordance with the Declaration of Helsinki. This study was approved by the institutional review board of The University of Texas MD Anderson Cancer Center and registered on clinicaltrials.gov (NCT01371630).

Odd-numbered treatment cycles of mini–hyper-CVD (mini-HCVD) included cyclophosphamide (150 mg/m² every 12 hours, days 1-3), dexamethasone (20 mg/d, days 1-4 and 11-14), and vincristine (2-mg flat dose, days 1 and 8). Even-numbered cycles included methotrexate (250 mg/m², day 1) and cytarabine (0.5 g/m² every 12 hours, days 2 and 3). Cycles were administered every 4 weeks for a total of 8 cycles. Inotuzumab was administered on day 3 of cycles 1 through 4. After the observation of veno-occlusive disease (VOD), the original trial protocol (Supplement 1) was amended in October 2015 to use lower doses of inotuzumab (Supplement 2) (1.3 mg/m² for cycle 1 followed by 1 mg/m² for cycles 2-4). Rituximab was administered during the first 4 cycles in patients with CD20 expression of 20% or higher.⁶ Central nervous system prophylaxis with intrathecal methotrexate and cytarabine was given alternately for a total of 8 doses. Pegfilgrastim, 6 mg subcutaneously, was administered on day 4 of each induction/consolidation cycle. Ursodiol, 300 mg, 3 times daily as VOD prophylaxis was administered after the protocol was amended in October 2015. Maintenance therapy was provided as follows: monthly vincristine at 2 mg and prednisone at 50 mg/d for 5 days every month for 1 year; 6-mercaptopurine, 50 mg twice daily, and oral methotrexate, 10 mg/m² weekly, for 3 years (POMP regimen).

The primary end points of this study were overall survival (OS) and the overall response rate (ORR), which includes CR, CR with incomplete platelet recovery, and CR with incomplete hematologic recovery. Secondary end points included safety measures, relapse-free survival (RFS), the rate of ASCT, and the minimal residual disease (MRD) negativity rate by 6-color flow cytometry.⁷ The current study has 95% power to demonstrate whether mini-HCVD plus inotuzumab can achieve at least a 3.2-month improvement in median OS in patients with R/R ALL from a historical median OS of 4.4 months. For a comparison with a historical cohort of patients treated with inotuzumab monotherapy, inverse probability of treatment weighing using propensity scores calculated from patient characteristics was used to adjust baseline differences between cohorts.⁸ Covariates for the calculation of propensity scores included white blood cell count, age, salvage status, prior ASCT, and the presence of MLL rearrangements, with validation confirmation by graphical comparisons of the distribution of covariates.

From November 2012 to September 2016, 59 patients were treated (Figure 1). Baseline characteristics are summarized in eTable 1 in Supplement 3.

Response rates are listed in eTables 2 and 3 in Supplement 3. Thirty-five patients (59%) achieved CR; the ORR was 78%. The MRD negativity rates at the time of morphologic response and at any time within 3 cycles were 52% and 82%, respectively. The ORR for patients in salvage 1 was 91% (100% in the 13 patients with first CR duration >12 months). Patients received a median of 2 cycles of therapy (range, 1-8 cycles).

With a median follow-up of 24 months, the estimated 1-year OS rate was 46%, and the RFS rate was 40%. The median OS and RFS were 11 months and 8 months, respectively (Figure 2A). Survival by salvage and MRD status is shown in Figure 2B and C. Patients in salvage 1 (n = 33) had a median OS of 17 months, with an estimated 1-year OS rate of 57% (eTable 2 in Supplement 3). The median OS for patients treated in salvage 2 and beyond was 6 months. The 1-year OS rates were 64% for patients with MRD-negative status (n = 36) vs 31% for patients with MRD-positive status (n = 8) (median OS, 25 months vs 9 months, respectively; P = .05).

In a post hoc inverse probability of treatment weighing analysis, we compared the outcomes in this study with previous experience in similar patients treated with inotuzumab monotherapy (n = 84; eTable 4 in Supplement 3). The ORRs for inotuzumab alone and mini-HCVD plus inotuzumab were 63% and 75%, respectively (P = .02). The 1-year OS rates were 27% and 43%, and the median OS times were 5.6 months and 9.3 months, respectively (P = .02) (Figure 2D).

Twenty-six patients (44%) proceeded to ASCT after a median of 3 months (range, 2-8 months). of these, 17 underwent ASCT in salvage 1. The 1-year OS rate of patients who underwent ASCT in salvage 1 was 63% with a median OS of 25 months. We observed VOD observed in 6 (23%) of 26 patients who received subsequent ASCT vs 3 (9%) of 33 patients who did not.

The treatment was well tolerated. Most adverse effects were grade 1 to 2. Toxic effects for mini-HCVD plus inotuzumab and the historical inotuzumab monotherapy cohort are shown in eTable 5 in Supplement 3. Overall, 48 patients (81%) had prolonged thrombocytopenia lasting longer than 6 weeks, either during induction (24 of 52 patients; 46%) or during subsequent courses (30 of 44; 68%). Fifty-six patients (95%) had hepatic adverse events, including grade 3 or higher in 12 patients (20%). In 9 patients (15%), VOD occurred after a median of 3 cycles (range, 1-5 cycles). All 9 patients had received ASCT: 3 had received ASCT prior to inotuzumab therapy; 5 received ASCT after inotuzumab therapy; and 1 had ASCT both before and after inotuzumab therapy. Among patients with prior ASCT who developed VOD, the median time from ASCT to start of mini-HCVD plus inotuzumab was 4.9 months (range, 2.5-11.7 months). Six of the 9 patients with VOD had received a clofarabine-based conditioning, and 4 had received dual clofarabine- and busulfan-based conditioning.

In this phase 2 study, the combination of inotuzumab and mini-HCVD was safe and effective in adults with R/R ALL. The ORR was 78%, and 1-year RFS and OS rates were 40% and 46%, respectively. The results were most encouraging in first salvage (median OS, 17 months compared with 9 months in historical series treated with inotuzumab or blinatumomab).^5,9-11 Almost half of the patients were able to receive subsequent ASCT, mainly in salvage 1 (17 of 27); this may in part explain the improved survival in salvage 1 (1-year OS rate, 57%).

One of the concerns of inotuzumab is the occurrence of VOD, observed at a rate of 15% in this study, similar to what was previously reported.^5,10,11 The incidence of VOD may be further decreased by the use of weekly schedules of lower doses of inotuzumab in combination with low-intensity chemotherapy, mainly in salvage 1 in patients with no prior ASCT, and possibly by delaying subsequent ASCT.¹⁰

This study is limited by its comparison with historical data; a randomized trial is therefore needed to confirm these findings. In addition, the monthly inotuzumab regimen used in the present study may not be optimal—there is evidence that weekly dosing of inotuzumab may result in lower rates of hepatic adverse events and VOD.¹⁰ A weekly regimen of inotuzumab in combination with low-intensity chemotherapy is currently being tested.

In summary, combining low-intensity chemotherapy with inotuzumab in patients with R/R ALL is safe and effective. New strategies, including a weekly schedule of lower doses of inotuzumab and better transplantation strategies to minimize the risks of VOD, may further improve outcomes.

Accepted for Publication: June 9, 2017.

Corresponding Author: Elias Jabbour, MD, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 428, Houston, TX 77030 (ejabbour@mdanderson.org).

Published Online: August 31, 2017. doi:10.1001/jamaoncol.2017.2380

Author Contributions: Dr Jabbour had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Jabbour, Sasaki, Cortes, O’Brien, Kantarjian.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jabbour, Ravandi, Short, Sasaki, Garcia-Manero, Jacob, Garris, Kantarjian.

Critical revision of the manuscript for important intellectual content: Jabbour, Ravandi, Kebriaei, Huang, Short, Thomas, Sasaki, Rytting, Jain, Konopleva, Champlin, Marin, Kadia, Cortes, Estrov, Takahashi, Patel, Khouri, O’Brien.

Statistical analysis: Huang, Short, Sasaki, Garris, Kantarjian.

Obtained funding: Jabbour, Kantarjian.

Administrative, technical, or material support: Jabbour, Ravandi, Thomas, Jain, Champlin, Marin, Estrov, Takahashi, Patel, Khouri.

Supervision: Jabbour, Cortes.

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

Funding/Support: Drs Jabbour and Kantarjian received research grants from Pfizer.

Role of the Funder/Sponsor: Pfizer had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.