A Phase II Study of Weekly Inotuzumab Ozogamicin (InO) in Adult Patients with CD22-Positive Acute Lymphoblastic Leukemia (ALL) in Second or Later Salvage

Background: InO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on the majority of cells derived from patients (pts) with B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Kantarjian, et al. Cancer. 2013;119(15):2728-36).

Aims: This ongoing study was preceded by phase 1 dose-escalation and expansion cohorts to select the recommended phase 2 dose (RP2D), determined as 1.8 mg/m²/cycle (0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15) as an initial starting dose followed by a dose reduction to 1.6 mg/m²/cycle upon achievement of complete response (CR) or CR without absolute neutrophil count (ANC) or platelet recovery (CRi). One dose-limiting toxicity (elevated lipase) was reported at this starting dose; however, dose delays and reductions were subsequently required in 5 patients for AEs (mostly owing to increased aspartate aminotransferase [AST]). Here we report the results of the phase 2 portion of the study which further evaluates the safety and efficacy of this regimen in patients with CD22+ relapsed/refractory ALL in the second and later salvage settings.

Methods: Pts aged ≥18 y with CD22+ ALL in second or later salvage and no known central nervous system disease were enrolled. InO was administered in 28-d cycles up to 6 cycles. Adverse event (AE) severity was assessed per Common Terminology Criteria for Adverse Events (CTCAE) v3. CR was defined as <5% bone marrow blasts without peripheral blasts, ANC ≥1,000/µL, platelets >100,000/µL and no extramedullary disease. Blood samples were collected for pharmacokinetic analyses.

Results: We report data for 35 pts: median age was 34 y (range, 20–79y); 77% were men; 6 (17%) pts were in salvage 5 or greater; 15 (43%) pts had prior allogeneic stem cell transplant (SCT). CD22 was expressed on a median of 99% blasts (range, 78%–100%); median peripheral blast count was 317.6/µL (range, 0–41,099/µL) and 28 (80%) pts presented with ≥50% bone marrow blasts. Aberrant baseline cytogenetics were reported in 27 (77%) pts including 9 (26%) with Ph+, 9 (26%) with complex cytogenetics (5 aberrations) and 9 (26%) with other aberrations. Three pts had normal cytogenetics at baseline and 5 had insufficient yield/unknown. Median follow-up in surviving pts was 4.4 (range, 0.7–11) months. Thirty-four pts discontinued InO: 17 owing to progressive disease (PD)/relapse or resistant disease; 7 proceeded to SCT (1 relapsed before SCT); 5 owing to AEs (grade [gr] 4 respiratory failure, gr 2 ascites in the setting of global deterioration, gr 2 increased alkaline phosphatase, gr 2 elevated AST and gr 2 increased transaminases); 2 died due to PD; 1 completed 6 cycles of InO and proceeded to maintenance therapy; 1 refused further treatment and 1 proceeded to DLI. InO-related gr ≥3 AEs (≥10% of pts) were thrombocytopenia (31%), neutropenia (26%) and febrile neutropenia (20%). Other gr ≥3 hepatic AEs included increased ALT/ increased transaminases (6%). Venoocclusive disease/sinusoidal obstruction syndrome occurred in 3 pts during the follow-up period: 2 (salvage 2 and 5) post-SCT and 1 (salvage 4) after the start of subsequent therapy. Prestudy SCT was not reported for these 3 pts. Nineteen deaths were reported: leukemia (n=14), hepatic failure/SOS (n=1), pneumonia (n=1), septic shock and graft versus host disease (n=1), subdural hematoma (n=1), and leukemia/liver failure (n=1).

The remission rate (CR+CRi) was 65.7% (95% CI, 47.8, 80.9); 18/23 (78%) patients with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 25 d (range, 15–86 d) and 25.5 d (range, 21–80 d), respectively. Six (67%) Ph+ pts and all 13 pts (100%) without peripheral blood blasts at baseline achieved CR/CRi. The median overall survival for the study population was 7.4 months (95% CI, 4.3–9.9).

Summary/Conclusion: InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this multiply relapsed/refractory population. Further exploration in CD22+ ALL is ongoing.