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

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.

Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with blinatumomab

“…20 Our and other small series suggest that dasatinib or ponatinib given concomitantly with blinatumomab does not affect its effectiveness. 21 Larger studies are warranted to evaluate efficacy of blinatumomab plus TKI combination. Extramedullary disease in ALL confers poor prognosis with inferior progression-free survival and OS.…”

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

“…The complete hematologic, cytogenetic, and molecular response rates were 50% (3/6), 71% (5/7), and 75% (9/12), respectively [ 64 ]. In another study of 11 patients receiving blinatumomab in combination with TKI therapy, 89% (8/9) of patients with MRD achieved complete molecular response [ 65 ]. An ongoing phase 2 study (NCT02744768) is evaluating the potential for a chemotherapy-free induction-consolidation frontline regimen of dasatinib combined with blinatumomab in obtaining an MRD response in patients with newly diagnosed Ph+ BCP-ALL.…”

Novel monoclonal antibody-based treatment strategies in adults with acute lymphoblastic leukemia

“…46,47,51,52,75 In patients with Ph-positive ALL, retrospective studies have shown the safety and efficacy of combining blinatumomab with TKIs (particularly ponatinib), and several prospective studies of these combinations are ongoing in both the frontline and relapsed/refractory settings. 57,76…”