A Chemotherapy-free Regimen for Older Adults and Relapsed or Refractory B-ALL

Study Title: A phase II study of inotuzumab ozogamicin followed by blinatumomab for Philadelphia chromosome-negative CD22-positive B-lineage acute lymphoblastic leukemia in newly diagnosed older adults or adults with relapsed or refractory disease

ClinicalTrials.gov Identifier: NCT03739814

Sponsor: Alliance for Clinical Trials in Oncology

Accrual Goal: A total of 64 patients between two cohorts (32 patients in cohort 1 and 32 patients in cohort 2)

Participating Centers: All Alliance sites (lead organization) and National Clinical Trials Network (NCTN) organizations: Southwest Oncology Group (SWOG), Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group. The study is open at both academic centers as well as larger community oncology practices in the United States.

Study Design: A041703 is a phase II open-label multicenter clinical trial designed to examine the efficacy of administering inotuzumab ozogamicin (IO) followed by blinatumomab as initial treatment for older adult patients (age ≥ 60 years) with newly diagnosed Philadelphia chromosome–negative (Ph^-), CD22⁺ B-lineage acute lymphoblastic leukemia (B-ALL; cohort 1) or adults with relapsed or refractory (R/R) CD22⁺, Ph^- B-ALL (cohort 2). The primary end point of this trial is one-year event-free survival (EFS) and will estimate whether the observed one-year EFS rate at least 30 percent, which would be a clinically significant improvement over the historical control rate of 10 percent. Secondary end points include estimating overall survival (OS), relapse-free survival (RFS), and EFS. This trial also will evaluate three exploratory end points: 1) the rate of cytokine release syndrome, 2) the rate and timing of, and the risk factors for, sinusoidal obstruction syndrome/veno-occlusive disease of the liver following inotuzumab exposure, and 3) a nonrandomized comparison of OS, RFS, cumulative incidence of relapse, and nonrelapse mortality.

Rationale: ALL in older adults (commonly defined in the literature as adults ≥ 60 years) is incurable for the majority of patients with the use of intensive chemotherapy and allogeneic stem cell transplantation (SCT). Historically, the five-year OS rate for this older cohort of patients is estimated at six to 20 percent.^1,2  The poor results for older patients with ALL are related to the inherent/innate resistance of leukemia cells to chemotherapy, significant toxicity with time and dose-intensive chemotherapy and SCT, the higher frequency of unfavorable cytogenetic abnormalities, and a higher percentage of patients with comorbid medical conditions and poor performance status.

Since the U.S. Food and Drug Administration (FDA) approval of the bispecific T-cell engager (BiTE) antibody blinatumomab³  and antibody drug conjugate IO⁴  in 2014 and 2017, respectively, for adult patients with R/R B-ALL, these therapies have transformed treatment. Their attractiveness is due to their superior efficacy and their ability to serve as a bridge for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in second complete remission (CR2), as well as their more favorable toxicity profile as compared to traditional multiagent chemotherapy. Now these antibody-based immunotherapies are being incorporated into frontline chemotherapy regimens for B-ALL in pediatric and adult randomized trials that will not only offer improved understanding of the clinical efficacy and potential toxicities of the antibody to the chemotherapy backbone, but may also offer a cure for many patients (NCT03150693, NCT02003222, NCT03914625, NCT03959085). For older patients with B-ALL who are unable to tolerate the intensive chemotherapy backbone used in younger adults, and who are ineligible for allo-HSCT, these antibody therapies are being tested for efficacy in several single-arm trials as a “substitution strategy” to either eliminate or reduce cytotoxic chemotherapy for older adults with Ph^- B-ALL (Table). As always, when new treatment options emerge in the absence of randomized controlled trials, determining the optimal integration of novel therapies into a treatment pathway becomes a new challenge.

The questions posed in the current single-arm trial (A041703) are whether a combination antibody-based therapy, specifically sequencing IO as induction followed by blinatumomab as consolidation therapy, is effective as a novel chemotherapy-free regimen for older patients with Ph^- B-ALL who are not eligible for allo-HSCT, and whether IO followed by blinatumomab is a reasonable sequence of the antibody-based therapies for patients with relapsed disease.

The rationale for using IO as an induction agent comes from the results of two large phase III trials that suggest IO may be better at inducing a remission when disease burden is high. The phase III randomized INO-VATE ALL trial for patients with R/R disease compared inotuzumab to standard-of-care chemotherapy.⁵  The rate of remission following single-agent IO when used as first salvage therapy was 87.7 percent and the rate of undetectable minimal residual disease (MRD) was 78.4 percent. The duration of response, however, was short at 4.6 months. In contrast, the phase III randomized TOWER trial for R/R patients with B-ALL that compared blinatumomab to standard-of-care chemotherapy demonstrated a lower rate of remission of 52.6 percent for patients in first salvage, but with an equivalent undetectable MRD rate of 76 percent.⁶  The efficacy of blinatumomab as a consolidation strategy, however, was recognized in the phase II, single-arm BLAST trial that tested blinatumomab in patients in CR with detectable MRD (≥ 1 × 10^-3).⁷  The rate of undetectable MRD following one cycle of blinatumomab treatment was 85 percent for patients in first CR (CR1) and 72 percent for patients in CR2. The median OS was 36.5 months and the 18-month RFS was 54 percent. Thus, reducing the tumor burden seems to greatly enhance the efficacy of blinatumomab in the frontline setting. Moreover, although most patients in the BLAST trial proceeded to allo-HSCT (45/61 patients in CR1 and 14/25 patients in CR2), 36 patients did not proceed to allo-HSCT and nine of those (25%) remained in CR 24 months following treatment, suggesting durable remission is possible without subsequent allo-HSCT in adult patients. Lastly, for the patients in the R/R cohort, reducing the tumor burden with IO and the sequential addition of blinatumomab as consolidation therapy offers a longer duration of time between IO treatment and allo-HSCT, which serves to decrease the risk of veno-occlusive disease, a potential life-threatening toxicity for patients proceeding to transplant in CR2.

Comment: Clinical trials designed specifically for older adults with Ph^- B-ALL have been limited in the United States. Trial A041703 is designed to test the feasibility and efficacy of a chemotherapy-free frontline regimen for older adults with Ph^- B-ALL and as salvage therapy for adult patients with R/R B-ALL. Further, the trial design, if it demonstrates improved efficacy as compared to standard chemotherapy, may serve as the chemotherapy-free platform onto which additional novel agents could be added for future trials and to guide the design of larger randomized trials, which will be needed to address the antibody-based therapies more rigorously. Of note, cohort 1 has met the accrual goals and the one-year EFS data will be evaluated in June of 2022. Cohort 2 remains open to accrual with 13 of 29 patients enrolled to date.