Blinatumomab Administered Concurrently with Oral Tyrosine Kinase Inhibitor Therapy Is a Well-Tolerated Consolidation Strategy and Eradicates Measurable Residual Disease in Adults with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Authors: King Amber C. , Pappacena Jeremy , Tallman Martin S. , Park Jae H. , Geyer Mark Blaine 
Published: October 2019

Abstract
Introduction: Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) to conventional chemotherapy regimens has improved outcomes for adult patients (pts) with (w/) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, the addition of chemotherapy to TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and mortality. As a result, we and others have investigated novel chemotherapy-sparing approaches for pts w/ Ph+ ALL. The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) has demonstrated single-agent activity in pts w/ B-ALL w/ minimal residual disease (MRD) or relapsed/refractory (R/R) ALL, including R/R Ph+ ALL (Martinelli et al., J Clin Oncol, 2017). In an effort to deepen responses, we have used BLIN concomitantly w/ commercially available TKIs as consolidation and re-induction therapy. Reported experience w/ BLIN+TKI is limited. Herein we describe the observed safety and efficacy of BLIN+TKI in pts w/ Ph+ ALL w/ varying disease burden at our institution.
Methods: We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated Ph+ ALL receiving BLIN w/ concomitant, FDA-approved TKIs at Memorial Sloan Kettering Cancer Center (MSKCC) who began BLIN+TKI between March 2017 and April 2018. The primary objectives were to characterize the safety/toxicity profile and rates of MRD negativity by flow cytometry (FACS) and/or quantitative real-time PCR for BCR-ABL1 transcripts following consolidation (n=9) or re-induction (n=2) w/ BLIN+TKI.
Results: Eleven pts (6F, 5M) were identified (Table 1). Median age at start of BLIN+TKI was 61.2 yrs (range, 27.7-76.9). Three pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). No pt had baseline hepatic dysfunction, central nervous system (CNS) or extramedullary (EM) disease prior to BLIN+TKI. All pts had documented CD19 expression on blasts prior to treatment. Ponatinib (PON) was the most commonly used TKI (n=7) followed by dasatinib (DAS, n=3), and nilotinib (NIL, n=1); one pt taking BLIN+PON briefly received BLIN+DAS during cycle 1. All pts were admitted for initiation of BLIN+TKI. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for pts w/ R/R ALL) in 10 pts and at 28 mcg/day IVCI in one pt (per flat dosing schedule described by Gökbuget et al., Blood, 2018).
All 7 pts w/ MRD by FACS (n=5) and/or BCR-ABL1 PCR (n=7) prior to BLIN+TKI exhibited MRD negativity by FACS following 1 cycle of BLIN+TKI; 6 of these 7 pts achieved complete molecular response (CMR) by PCR following 1 cycle (n=5) or 2 cycles (n=1) of BLIN+TKI. All 6 remain in ongoing CMR at 1.8-15.1 months after initial achievement of CMR. Neither of the 2 pts w/ morphologic disease responded to BLIN+TKI and ultimately succumbed to their disease. The 2 pts who began BLIN+TKI in CMR have both maintained continuous CMR. Three pts have proceeded to 1st (n=2) or 2nd (n=1) alloHCT post-BLIN+TKI, without documented, relevant toxicities attributable to prior blinatumomab exposure. Median event-free and overall survival were not reached in this small group of pts, w/ median follow-up of 7.7 months among survivors (range, 3.2-16.0 months).
Three pts developed grade 1 cytokine release syndrome (CRS). Notably, 2 of these pts had morphologic ALL at time of BLIN+TKI; none of these events warranted interruption of therapy or corticosteroids. No pts developed neurologic toxicity. Five pts exhibited transient transaminitis during BLIN+TKI; none reached recommended parameters to discontinue BLIN. Of these 5 pts, 4 were on concurrent PON. One pt required dose attenuation of PON; hepatic enzymes otherwise normalized w/o intervention.
Conclusions: Our small series suggests that BLIN+TKI may be a safe and effective consolidation strategy for pts w/ MRD+ Ph+ ALL to achieve or sustain CMR, creating a platform for alloHCT or other post-remission therapy. Observed rates of CRS were higher and neurologic toxicity appeared lower (none documented) than in other studies of BLIN in pts w/ MRD (Gökbuget et al., Blood, 2018). Higher risk of transaminitis was noted in pts receiving BLIN+PON and warrants further observation, particularly as 28 mcg/day IVCI flat dosing is increasingly used for pts w/ MRD. Earlier incorporation of BLIN+TKI into treatment paradigms for Ph+ ALL may limit toxicity while deepening response and maintaining CMR.

Disclosures
King: Genentech: Other: Advisory Board . Tallman:Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; Cellerant: Research Funding; ADC Therapeutics: Research Funding; AbbVie: Research Funding; AROG: Research Funding; BioSight: Other: Advisory board. Park:Pfizer: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Shire: Consultancy. Geyer:Dava Oncology: Honoraria.