Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study

Abstract

This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m² per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m² per cycle (0.8 mg/m² on day 1; 0.5 mg/m² on days 8 and 15), with reduction to 1.6 mg/m² per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.

Graphical abstract

Figure 1.

Kaplan-Meier distributions. (A) DOR. (B) PFS. (C) OS. See supplemental Materials for DOR, PFS, and OS definitions. PR, partial response.

Figure 2.

Peripheral blood B-lymphocyte depletion and regeneration. (A) B-lymphocyte concentration in blood was determined vs time for individual patients during InO treatment (red circles; n = 72) and during follow-up (triangles; n = 24). Data were fitted to a linear mixed-effects model (green dashed lines = individual model predictions; solid black line = best fit line for overall mean effect of time on B-lymphocyte depletion and regeneration). (B) B-lymphocyte concentration profiles vs time by InO dose (1.2, 1.6, and 1.8 mg/m² per cycle) for individual patients. (C) InO elimination vs time by percent of BM blasts for individual patients. The 4 panels show serum InO concentration vs time data for InO dosing at cycle 1 day 1 and 15 and cycle 2 days 1 and 15. BM aspirates were collected at screening (circles), cycle 1 day 28 (triangles), and cycle 2 day 28 (squares). Symbol colors are scaled by percent leukemic blasts in BM.

Figure 3.

Relationship between InO PK parameters and MRD status. (A) Box plots of dose normalized (dn) values of median C_max and C_min by cycle (1 to 4) and by achievement of MRD negativity (yes vs no). Boxes correspond to the 25% and 75% percentiles; whiskers extend to the most extreme data point that is no more than 1.5 times the length of the box away from the box. Red points represent potential outliers and correspond to individual values >1.5 times the interquartile range above or below the respective quartile. (B) Relationship between percentage BM blasts at baseline and achieving MRD negativity for individual patients. Green and blue plots correspond to patients achieving and not achieving MRD negativity, respectively. (C) The 5 panels show serum InO concentration vs time by MRD-negativity status for dosing at cycle 1 day 1 and 15, cycle 2 days 1 and 15, and cycle 4 day 1. Symbol sizes represent percent leukemic blasts in BM.