Phase II Study of Inotuzumab Ozogamicin for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia: 3-Year Update

Background: The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). In this phase II trial, we evaluate the efficacy and safety of inotuzumab ozogamicin (INO) given at reduced dosing in patients with B-cell ALL in hematologic complete remission with positive MRD status ≥1x10⁻⁴.

Methods: Adult patients in morphologic remission with detectable MRD (due to failure of MRD response or due to MRD relapse) were eligible. Patients in complete remission (CR) with MRD ≥1x10^-4 after ≥3 months from frontline therapy or one month from salvage therapy were enrolled in this phase II trial. In patients with Philadelphia chromosome (Ph)-negative ALL, MRD positivity was defined by at least 1x10^-4 by multiparameter flow cytometry (MFC) and/or any level by next-generation sequencing (NGS) for IG/TR. In patients with Ph-positive ALL, MRD positivity was defined as a ratio of BCR::ABL1 to ABL1 by polymerase chain reaction (PCR) of ≥0.01% or detectable MRD at a level of at least 1x10^-4 by MFC and/or any level by NGS for IG/TR. INO was administered at 0.6 mg/m² on Day 1 and 0.3 mg/m² on Day 8 of Cycle 1, and 0.3 mg/m² on Days 1 and 8 of Cycles 2-6. For patients with Ph-negative ALL, MRD negativity was defined as undetectable MRD by MFC with a sensitivity of ≥ 1x10^-4 For patients with Ph-positive ALL, MRD negativity was defined as undetectable MRD by MFC with a sensitivity of ≥ 1x10^-4 and the absence of quantifiable BCR::ABL1 transcripts by PCR with a sensitivity of ≥1 x10^-5. Furthermore, MRD negativity by NGS was defined as undetectable MRD with a sensitivity of ≥ 1x10^-6 when applicable All patients received ursodiol for hepatic sinusoidal obstruction syndrome (SOS) prophylaxis. Patients with Ph-positive ALL received a concomitant BCR::ABL1 tyrosine kinase inhibitor. MRD negativity was evaluated throughout induction and consolidation therapy using 6-color MFC and/or PCR. The primary efficacy endpoint was relapse-free survival (RFS).

Results: Thirty patients with a median age of 46 years (range, 19-70) were treated; 15 (50%) were males. Twenty-two (73%) were in CR1 and eight (27%) in CR2+; 17 (57%) had Ph-positive ALL. Seventeen patients (57%) had received prior blinatumomab. A median of three cycles (range, 1-6) were administered. Twenty patients (67%) responded and became MRD negative. In patients with Ph-negative ALL and positive MRD by MFC, the MRD negativity rate was 82% (9/11) with a median time to MRD negativity of 26 days (range, 22-44). In those with Ph-positive ALL, 65% (11/17) achieved CMR with a median time to CMR of 28 days (range, 20-51). The 2 patients with Ph-negative ALL and negative MRD by MFC but positive by NGS did not respond.

After a median follow-up of 36 months (range, 1-59), the 3-year OS rate was 56% and the RFS rate 42%. The 3-year OS rates were 60% versus 53%, and the 3-year RFS rates 50% versus 36%, in patients with Ph-negative ALL and Ph-positive ALL, respectively. Patients treated in CR1 had a 3-year OS of 63% compared with 38% in CR2+ (P=0.13).

The 3-year RFS rate was 40% in patients with baseline MRD ≥1x10^-3 and 44% in those with MRD between 1x10^-4 and 1x10^-3 (P=0.97). Seven (35%) responders underwent stem cell transplantation, with no difference in survival compared with those who did not (p=0.75). Most adverse events were of low grade. SOS was seen in three patients: one pt with Ph-negative ALL developed SOS 2 weeks following transplant (recovered after defibrotide therapy), and two pts both with Ph-positive ALL on concurrent ponatinib (of whom one died).

Conclusion: INO resulted in high survival and MRD negativity rates in most patients with B-cell ALL and persistent MRD or MRD recurrence, with a favorable safety profile.