Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. Patients and Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II. Results: Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed. Conclusions: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.
Background Denintuzumab mafodotin (SGN-CD19A) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. CD19 is a B cell-specific marker that is expressed in nearly all patients (pts) with B-lineage acute leukemia or lymphoma. Methods A phase 1 dose-escalation study is ongoing to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-ALL, B-cell lymphoma (B-LBL), or Burkitt leukemia/lymphoma (NCT 01786096). Eligible pts are ≥1 year of age and are R/R to ≥1 prior systemic regimen; patients with Philadelphia chromosome-positive (Ph+) disease must have failed a 2nd-generation TKI. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation. The study evaluated 2 dosing schedules: first weekly (Days 1 and 8 of 21-day cycles) and then once every 3 weeks (q3wk). This report presents data from the adult subset of pts in the study (≥18 years). Results To date, 71 adult pts with R/R B-ALL (n=59), B-LBL (n=6) or Burkitt leukemia/lymphoma (n=6) have been treated; median age is 45 years (range 18−77). Pts received a median of 2 prior therapies (range 1−8); 20 pts (28%) had prior allogeneic stem cell transplant. On the weekly schedule (0.3−3 mg/kg), 40 pts received a median of 2 cycles (range 1−27); 2 pts remain on treatment. On the q3wk schedule (4−6 mg/kg), 31 pts received a median of 3 cycles (range 1−6); 4 pts remain on treatment. An MTD was identified at 5 mg/kg q3wk and was not reached with weekly dosing. Best clinical responses to date for pts with B-ALL are summarized below: Table 1.Response category per Cheson 2003Efficacy-evaluable adult pts with B-ALLweekly dosing, N=32 n (%)q3wk dosing, N=23 n (%)Complete remission (CR)6 (19)3 (13)CR with incomplete platelet recovery (CRp)−3 (13)CR with incomplete blood recovery (CRi)−2 (9)Partial remission (PR)1 (3)−Resistant disease with clinical benefit15 (47)12 (52)Resistant disease without clinical benefit2 (6)-Progression8 (25)3 (13)CRc (CR+CRi+CRp), % (95% CI)19% (95% CI 7, 36)35% (95% CI 16, 57) In the q3wk schedule, the CRc rate was similar at 4, 5, and 6 mg/kg. The median duration of response across schedules is currently 27 weeks (95% CI 7, −). Of 12 pts with CRc and available minimal residual disease (MRD) assessment, 7 were MRD negative. 3 patients with MRD-negative CRs have been in remission for >1 year, 2 of whom have been on continuous treatment for 19 and 22 months. In the subset of pts with Ph+ B-ALL, 4 of 8 pts achieved CR and 1 pt a PR. In 6 pts with Burkitt leukemia/lymphoma, 1 achieved a CR. In 6 pts with B-LBL, objective responses were 1 CR and 2 PR. The adverse event (AE) profiles were similar across both dosing schedules; the most frequently reported AEs were pyrexia (54%), nausea (52%), fatigue (51%), headache (44%), chills (38%), vomiting (37%), blurred vision (35%), and anemia (34%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 40 pts (56%); symptoms were less severe than the associated corneal exam findings. Keratopathy was managed with topical steroids and dose modifications, and improved/resolved within a median of ~3 wks (range 1-17) in pts with sufficient follow-up. ADC exposures increased with dose, and in leukemia patients, target-mediated disposition was observed that diminished with higher doses in the q3wk schedule. Post treatment, flow cytometry data demonstrate that unbound CD19 on peripheral blasts inversely correlates with ADC concentration in circulation, and is present in the majority of evaluable patients at the end of the q3wk cycle. Conclusions Denintuzumab mafodotin is generally well tolerated and demonstrates activity in heavily pretreated adult pts with B-ALL and B-lineage highly aggressive lymphomas, including durable MRD-negative responses. The results of this trial indicate that the q3wk schedule, with a CRc rate of 35% in B-ALL, warrants further clinical investigation. Based on the encouraging responses observed to date in Ph+ B-ALL (CRs in 4 of 8 pts), an expansion cohort of these pts is currently enrolling on the q3wk schedule. Disclosures Fathi: Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use.. Borate:Seattle Genetics: Research Funding; Genoptix: Consultancy; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. DeAngelo:Agios: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. O'Brien:Seattle Genetics, Inc.: Research Funding. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. Shah:NCCN: Consultancy; SWOG: Consultancy; Seattle Genetics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Plexus Communications: Honoraria; Spectrum: Speakers Bureau. Hale:Seattle Genetics, Inc.: Research Funding; Hyundai: Research Funding; V Foundation: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Pauly:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Eli Lilly: Consultancy. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Huang:Seattle Genetics, Inc.: Employment, Equity Ownership. Pan:Seattle Genetics, Inc.: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau.
Idelalisib and duvelisib are FDA approved oral inhibitors of PI3K delta and PI3K delta/gamma, respectively. Previously, we reported a decrease in regulatory T cells (Tregs) associated with autoimmune hepatotoxicity in untreated CLL patients receiving idelalisib-ofatumumab. We hypothesized that a Th17 inflammatory phenotype may be involved. To directly assess Th17s, we performed IL-17A and IL-17F intracellular staining in CD4 and CD8 T cells from this cohort (no / low toxicity group (grade 0-2 AEs) n=4; high toxicity group (grade 3+ by CTCAE) n=6), and found that the percentage of CD8 cells positive for IL-17F was significantly higher at cycle 2 in patients with high tox compared to patients with low tox (p = 0.0095). Interestingly, pre-treatment, patients who developed high tox had higher IL-17F expression in CD8s compared to CD4s compared to patients with low or no tox. The ratio of IL-17F staining in CD8 to CD4 T cells was significantly higher in patients who developed high tox compared to patients with low tox at the pre-treatment timepoint (p = 0.0381). Furthermore, IL-17A and IL-17F in CD8 T cells were also higher at baseline among mutated IGHV patients (p = 0.1048 and p = 0.0095 respectively), who were also at much greater risk of autoimmune toxicity. These data implicate the Th17 pathway in the autoimmune toxicity of idelalisib. Additionally, single cell mass cytometry (CyTOF) on relapsed/refractory patients treated with idelalisib (n=10) and duvelisib (n=2) showed that the percentage of Tregs decreases with treatment (p = 0.0405 for idelalisib), consistent with our data from the previously untreated idelalisib cohort. To understand this decrease in Tregs, we tested whether PI3K inhibition skews the differentiation of T cell subsets. Naïve CD4 T cells from healthy individuals were isolated and differentiated toward a Treg or Th17 phenotype in the presence of 10 µM idelalisib, duvelisib, or DMSO. Treg differentiation was determined by measuring intracellular FOXP3 by flow cytometry and Th17 differentiation was evaluated by RORγT intracellular staining. Idelalisib treatment significantly decreased Treg differentiation from a median of 53.8% with DMSO to 43.4% (n=4; p = 0.0002), and increased Th17 differentiation from 24.7% with DMSO to 37.2% (n=5; p = 0.0005). Similarly, with duvelisib, Treg differentiation decreased significantly from a median of 53.8% with DMSO to 47.1% (n=4; p = 0.0005), and Th17 differentiation increased from 24.7% with DMSO to 36.9% (n=5; p = 0.02). These results indicate that both idelalisib and duvelisib can skew T cell differentiation toward a more inflammatory phenotype in vitro. Additionally, the effects of idelalisib and duvelisib on proliferation of CD3 cells from healthy PBMCs were evaluated with 3 days in-vitro treatment using the cell division tracker dye CellTrace Violet. The proliferation index was calculated using the ModFit algorithm to quantify the increase in cell number. The proliferation index of CD3 cells in the presence of 1 µM idelalisib and 1 µM duvelisib decreased by a median of 19.3% (n=4; p = 0.0031) and 28.6% (n=4; p = 0.0028) respectively, compared to DMSO; duvelisib led to greater inhibition of T cell proliferation in vitro than idelalisib (n=4; p = 0.0241) which may impact on risk of irAEs. To further identify predictors of toxicity with PI3Ki therapy and to characterize differences between idelalisib and duvelisib, we are analyzing CyTOF data on a cohort of 13 patients treated on a DFCI upfront trial with 7 days duvelisib lead-in, then FCR. With one week of duvelisib monotherapy we found an increase in ICOS expression on CD8 T cells in the low tox group (n=5; p = 0.0495) but not in the high tox group (n=8; p = 0.2245). Furthermore, cluster analysis of the CyTOF data by RPhenograph and FlowSOM demonstrated significant changes associated with high tox in 3 cell population clusters showing markers indicative of Tregs. In conclusion, frontline idelalisib treatment appears to increase a Th17 phenotype while decreasing Tregs, which we showed in vitro to be likely related to the drug altering naïve CD4 T cell differentiation. We hypothesize that an imbalance of Tregs and Th17 T cells is contributing to irAEs in some idelalisib treated patients. Preliminary data with duvelisib suggest alternative mechanisms which we are still analyzing, along with performing cytokine analysis and immunohistochemistry on patient biopsies to further validate these findings. Disclosures Pan: Gilead Sciences: Employment, Equity Ownership. Brown:Teva: Honoraria; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; TG Therapeutics: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Octapharma: Consultancy; Morphosys: Other: Data safety monitoring board; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Invectys: Other: Data safety monitoring board; Janssen: Honoraria.
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