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1349 Phase II Study of High Dose Cytarabine Followed By Pembrolizumab in Relapsed/Refractory Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Saturday, December 9, 2017, 5:30 PM-7:30 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Joshua F Zeidner, MD1, Benjamin G. Vincent, MD1, Anastasia Ivanova, PhD1*, Matthew C. Foster, MD1, Catherine C. Coombs, MD1, Katarzyna Jamieson, MD1*, Hendrik Van Deventer, MD1*, Richard Scibilia1*, Laura Blanchard1*, Cassiopeia Frank1*, Sean Gallagher1*, Melissa Matson, AGPCNP-BC1*, Katherine Pepin1*, Lori Vaught1*, Nancy Vogler1*, Ivana Gojo, MD2*, Leo Luznik, MD3* and Jonathan S Serody, MD1

1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
3Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD

Introduction: Outcomes are dismal for patients (pts) with relapsed/refractory (R/R) AML. Innate and adaptive immune aberrations exist in AML pts leading to immune escape. We have previously shown that there is an increased expression of multiple co-inhibitory molecules including programmed death-1 (PD-1) in the peripheral blood of AML pts at diagnosis, and these levels persist in pts with refractory disease (Knaus H, et al. Blood [Abstract] 2015). We hypothesized that administration of pembrolizumab after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML.

Methods: A multicenter phase II study of age-adjusted HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; >=60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 is being conducted in R/R AML pts 18-70 years. The primary endpoint of this study is the rate of complete remission (CR)/CR with incomplete recovery (CRi) after HiDAC followed by pembrolizumab. The study design is a Simon’s like two-stage design (n=37 pts) with relaxed stopping for futility. Relaxed stopping refers to overall response rate (CR/CRi+partial remission [PR]) when stopping rule for futility is applied in the first stage. The null hypothesis that the CR/CRi rate for HiDAC followed by pembrolizumab is 20% will be tested against a one-sided alternative hypothesis yielding a type 1 error rate = 5% and power = 84% when the CR/CRi rate of HiDAC followed by pembrolizumab = 40%. Continuous monitoring for toxicity will be performed to assess for unacceptable toxicity. Overall responders will receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until relapse/progression. Pts can proceed to allogeneic stem cell transplant (SCT) before or after maintenance phase (SCT must be >=30 days from last dose of pembrolizumab). Correlative studies include serial peripheral blood and bone marrow flow cytometry, mRNA-sequencing, and T cell receptor (TCR) clonality studies to determine predictive biomarkers of response.

Results: 13 pts enrolled on this study between August, 2016-July, 2017 (Table 1). There have been 0 unacceptable toxicities to date. Immune-related adverse events have included grade 2 hyperbilirubinemia (n=1), grade 3 hepatic enzymes (n=1), both resolved promptly after systemic corticosteroids, as well as self-resolving grade 3 rash (n=1). Additionally, 1 pt developed grade 3 pulmonary edema without evidence of pneumonitis that resolved spontaneously without steroids. Of the 10 evaluable pts (as of July 1, 2017), overall response rate = 50% (CR/CRi: 4/10= 40%; PR = 1/10=10%), meeting the threshold to proceed to stage 2. Two pts have proceeded to a myeloablative allogeneic SCT in CR (one of whom received 2 cycles of maintenance pembrolizumab) and remain in CR. Post-SCT, both pts developed steroid-responsive acute GVHD of skin, one pt developed a transient increase in hepatic enzymes that was responsive to steroids, and one pt developed moderate chronic GVHD. Four pts have received maintenance pembrolizumab: 2 pts relapsed (median duration of CR = 3.9 months; range: 2-5.7 months), one pt proceeded to SCT after 2 cycles, and one pt initially achieved a PR and remains with stable disease after 11 cycles of maintenance pembrolizumab. No pts have died in remission. 30-day and 60-day mortality = 0% and 10%, respectively. Preliminary findings from the first 6 pts (3 responders vs. 3 non-responders) revealed increased diversity of TCR Vβ repertoire from pre-treatment peripheral blood CD8+ T-cells in responders when compared with non-responders using Shannon entropy analysis (p=0.0058; Figure 1).

Conclusions: Early results of a multicenter phase II study demonstrate the feasibility of adding immune checkpoint blockade with pembrolizumab after HiDAC chemotherapy in R/R AML. An overall response rate of 50% is encouraging in a high-risk R/R AML cohort though ongoing findings are imperative to evaluate the efficacy and future role of pembrolizumab in AML. Interestingly, in a small cohort of patients, broadening of the immune repertoire, perhaps by increasing T cell responses beyond endogenous viral responses, was associated with response to PD-1 blockade. Future directions include a comprehensive immune biomarker discovery approach to determine predictors of response to immune checkpoint blockade in AML.

Disclosures: Zeidner: Tolero Pharmaceuticals: Honoraria; Agios: Honoraria; Merck: Research Funding; Takeda: Research Funding; Tolero Pharmaceuticals: Research Funding; Celgene: Honoraria. Vincent: Merck: Research Funding; Pharmacyclics: Research Funding; Nanostring: Membership on an entity's Board of Directors or advisory committees. Foster: Shire: Honoraria; Incyte: Honoraria; Macrogenics: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Celator: Research Funding. Coombs: Pharmacyclics: Honoraria; H3 Biomedicine: Honoraria. Gojo: Merck: Research Funding; Amgen: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Serody: Merck: Research Funding.

*signifies non-member of ASH