Inotuzumab ozogamicin for adult patients with B-ALL in CR with positive MRD: a phase II study

Detecting measurable residual disease (MRD) is a prognostic biomarker of relapse and survival in acute lymphoblastic leukemia (ALL). In the phase III INO-VATE trial, inotuzumab ozogamicin (InO) demonstrated a higher median overall survival (OS) vs standard chemotherapy (7.7 vs 6.7 months), with an MRD negativity rate of 78%.

Here, we summarize the efficacy and safety results from a phase II trial (NCT03441061) of InO in MRD positive adult patients with B-cell ALL in complete remission (CR), published by Jabbour et al.¹ in Blood.

Study design¹

• This study included adult patients aged ≥18 years with B-cell ALL who were in first CR (CR1) or beyond (CR2+) with positive MRD (≥1 × 10⁻⁴).
• Patients received InO at 0.6 mg/m² on Day 1 and 0.3 mg/m² on Day 8 of Cycle 1, followed by 0.3 mg/m² on Days 1 and 8 of Cycles 2−6.
• The primary endpoint was relapse-free survival.
• Secondary endpoints included OS; MRD negativity rate, defined as undetectable MRD by multicolor flow cytometry in Philadelphia chromosome-negative ALL and undetectable MRD by multicolor flow cytometry and polymerase chain reaction in Philadelphia chromosome-positive ALL; and safety.

Efficacy¹

• A total of 26 patients with a median age of 46 years (range, 19–70 years) were treated between November 2018 and June 2022
• Of treated patients, 73% were in CR1 and 27% were in CR2 and beyond
• Overall, 69% of patients achieved MRD-negativity after Cycle 1
• Of responders (n = 18), six patients underwent allogeneic stem cell transplantation, and five patients experienced relapse in the bone marrow (n = 3), in the bone marrow and lymph nodes (n = 1), and in the central nervous system and bone marrow (n = 1)
• There was a total of nine deaths, due to disease progression (n = 4), allogeneic stem cell transplantation complications (n = 2), septic shock (n = 1), sinusoidal obstruction syndrome (n = 1), and unknown (n = 1).

At a median follow-up of 24 months, the median relapse-free survival was 41 months in the total cohort and responders, and the median OS was not reached in the total cohort and responders; 2-year survival rates are reported in Figure 1.

OS, overall survival; RFS, relapse-free survival
*Data from Jabbour, et al.¹

Safety¹

• The most common treatment-related adverse events reported were aspartate aminotransferase/alanine aminotransferase elevations and thrombocytopenia (Table 1).
• Sinusoidal obstruction syndrome was reported in two patients; one case was severe and developed 1 month after Cycle 5 and the other was a moderate case that developed during Cycle 5

Table 1. Treatment-related AEs*

AE, %	Ph− negative ALL (n = 10)	Ph+ ALL (n = 16)
AE, adverse event; ALL, acute lymphoblastic leukemia; ALT/AST, alanine aminotransferase/aspartate aminotransferase; Ph, Philadelphia chromosome; SOS, sinusoidal obstruction syndrome *Adapted from Jabbour, et al.1 †Grade 3 and Grade 4 both 20%. ‡Grade 3 = 19% and Grade 4 = 13%. §Grade 4 = 40%. ‖ Grade 4 = 19%.
ALT/AST level elevation	60	75
Thrombocytopenia	70†	63‡
Neutropenia	50§	25‖
Fatigue	20	13
Abdominal pain/distension	0	19
Constipation	10	13
Hepatic SOS	0	13
Hypertension	10	6
Anemia	10	0

Key learnings
InO was found to be safe and effective in eradicating MRD in adult patients with B-cell ALL who remain in MRD-positive status after achieving CR Further studies are needed to confirm these findings