Inotuzumab Ozogamicin in Combination with Bosutinib for Patients with Relapsed or Refractory Ph+ ALL or CML in Lymphoid Blast Phase

Background: Outcomes of patients (pts) with relapsed or refractory (R/R) Ph+ acute lymphoblastic leukemia (Ph+ ALL), or those with chronic myelogenous leukemia (CML) in lymphoid blast phase (LBP) remain poor. CD22 is expressed in >90% of pts with ALL. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin is active in R/R ALL (Kantarjian, NEJM 2016). Bosutinib is a tyrosine kinase inhibitor approved for the treatment of chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy.

Methods: We designed an investigator-initiated phase I/II trial of the combination of inotuzumab and bosutinib for pts with R/R Ph+ ALL and CML LBP (NCT02311998). The primary objective of the phase I portion is to determine the safety and maximal tolerated dose (MTD) of the combination. The secondary objectives include assessment of the efficacy of the combination. Pts with R/R Ph+ ALL or CML LBP were eligible. Pts with T315I mutation were excluded. Pts needed to have adequate renal (creatinine ≤2 gm/dl) and hepatic function (total bilirubin ≤2 mg/dl, ALT and AST ≤3 ULN). In the phase I part, three dose levels of bosutinib were evaluated (300mg daily, 400mg daily, and 500mg daily). Bosutinib was initiated on cycle 1 day 1 and continued daily. Each cycle 4 weeks. Inotuzumab was administrated IV weekly during cycle 1 (0.8 mg/m² day 1; 0.5 mg/m² day 8; 0.5 mg/m² day 15). For patients achieving a response, the subsequent cycles of inotuzumab (1 mg/m²) were given once every 4 weeks. A total of 6 cycles of inotuzumab were planned. Once the MTD is established, phase II will commence. We report here results of the phase I part of the trial.

Results: A total of 14pts have been treated. This is the first interim report of this trial. Median age was 62 yrs (range 19-74); diagnosis Ph+ ALL, n=12 and CML LBP, n=2; prior therapies [salvage 1 (S1) n=7, S2 n=5, S3+ n=2]. Six pts had a prior allo-SCT, and 8 pts had an ABL kinase domain mutation (E255K, n=2; V299L, n=2; T315M and E316D, n=1; D276G, n=1; G250E and F317C, n=1; G250E and E279K, n=1). Three pts were treated at dose level 1 (bosutinib 300mg daily); 6 pts at dose level 2 (bosutinib 400mg daily); 5 pts at dose level 3 (bosutinib 500mg daily). Dose level 1 was well tolerated with no DLT. One patient had a DLT at dose level 2 (G3 skin rash), and the cohort was expanded to 6 pts. The first 3 pts at the dose level 3 did not receive at least 80% doses of bosutinib during cycle 1 due to issues other than drug-related toxicities, and this cohort was expanded to 3 additional pts. DLT evaluation is ongoing for the dose level 3. Two pts had reversible G3 ALT elevation. No patient had veno-occlusive disease (VOD). 11/14 (79%) pts had a CR/CRi. 3 pts had no response. 10/11 (91%) responders achieved complete cytogenetic remission; 8/11 (73%) responders were negative by flow-cytometry; 6/11 (55%) responders achieved undetectable BCR-ABL. The median event-free survival (EFS) and overall survival (OS) were 8.1 mos and 8.2 mos, respectively (Figure 1). Five pts underwent a subsequent allo-SCT (4 of these are alive and in remission post-SCT).

Conclusions: The combination of inotuzumab and bosutinib is safe and shows encouraging activity in patients with R/R ALL and CML in LBP.

Figure 1

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Figure 1

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