High-grade Cytokine Release Syndrome Research Articles

Updated Phase 1 Results of Zuma-3: Kte-X19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Background Although ∼1/2 of adult patients (pts) with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes. The initial report of Phase (P) 1 of ZUMA-3, the P1/2 trial of KTE-X19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), demonstrated a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity (Shah et al. ASH 2017. #888). Here, we present updated ZUMA-3 P1 safety and efficacy data. Methods Adult pts (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow (BM) blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy. The primary endpoint for P1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the BM, and duration of remission. Safety analyses included all pts who received KTE-X19; pts with ≥ 2 months of follow-up were evaluated for efficacy. Results As of April 12, 2018, 35 pts have received KTE-X19 (median follow-up of 11 months [range, 2 −25 months]). Median age was 40 years (range, 18 – 69 years), 51% male, 66% ECOG 1, 37% prior blinatumomab, and 60% ≥ 3 prior lines of treatment. Median BM blast burden at Screening was 70% (range, 5 −100). Six, 14, and 15 pts received 2, 1, and 0.5 × 106 cells/kg doses, respectively. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%) pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 cytokine release syndrome (CRS) occurred in 9 pts (26%, median time to onset 5 days [range, 1 −15 days]); events resolved in all pts (excluding 2 with a Grade 5 event), and the median time to resolution was 11 days (range, 7 −42 days). There were 2 KTE-X19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to CRS at the 2 × 106 cells/kg dose. Grade ≥ 3 neurologic events occurred in 16 pts (46%, median time to onset 7 days [range, 4 −24 days]); neurologic events resolved in all pts (excluding 2 patients with unresolved events at death), with a median time to resolution of 17 days (range, 6 −53 days). Among the 32 pts evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60%–91%).CR or CRi was achieved by 23 pts (72%), and 1 pt (3%) had blast-free BM. Conclusion High remission rates were achieved by adult pts with R/R ALL, with ∼3/4 of pts achieving CR or CRi with undetectable MRD after a single dose of KTE-X19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-X19 offers clinical benefit for pts with otherwise limited treatment options.

Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM): Initial Safety and Efficacy from a Phase I Study

Background : BCMA is expressed on MM cells, and CAR T cells targeting BCMA have pre-clinical anti-MM activity. CART-BCMA is an autologous T cell product engineered by lentiviral transduction to express a fully human BCMA-specific CAR with CD3ζ and 4-1BB signaling domains, and then expanded ex vivo using CD3/CD28 beads. Methods: In this ongoing, 3+3 dose-escalation study, relapsed/refractory MM patients (pts) receive CART-BCMA cells as split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2). Three cohorts are planned: 1) 1-5 x 10 8 CART cells alone; 2) cyclophosphamide (CTX) 1.5 g/m 2 + 1-5 x 10 7 CART cells; and 3) CTX 1.5 g/m 2 + 1-5 x 10 8 CART cells. Pts need serum creatinine (Cr) Results: To date, 11 pts have been screened, and 6 treated in cohort 1. Reasons for not receiving treatment were screen fail (n=2), rapid MM progression/renal failure (n=2), and pt/MD choice (n=1). The 6 treated pts were all IMID/PI-refractory with high risk cytogenetics and median 9 lines of therapy (Table). All expressed BCMA on MM cells, and achieved the minimum target dose of 1x10 8 CART-BCMA cells. All but 2 received 100% of planned dose, with 2 (pts 01and 03) receiving 40% (3 rd infusions held for fever). Cytokine release syndrome (CRS) occurred in 5 patients: 2 grade 3 requiring tocilizumab (pts 01 and 03), 1 grade 2, and 2 grade 1. High-grade CRS was associated with elevated levels of IL-6, IFNg, MCP1, MIG, IL2Ra, and IL-10, as seen in our acute lymphoblastic leukemia CTL019 trial (Teachey et al, 2016). There was 1 DLT: grade 4 PRES (posterior reversible encephalopathy syndrome) in pt 03, with severe delirium, recurrent seizures, obtundation, and cerebral edema on MRI. This resolved after anti-epileptics, high-dose methylprednisolone and cyclophosphamide, without long-term neurologic sequelae. Other grade 3/4 toxicities to date include hypophosphatemia (n=3 pts), hypocalcemia (n=2), and anemia, neutropenia, lymphopenia, thrombocytopenia, hypofibrinogenemia, fatigue, pneumonia, UTI, elevated Alk phos and AST, hypokalemia, hypertension, and pleural effusion (n=1 each). CART-BCMA cells were detected in blood and marrow by CAR-specific PCR in all 6 pts, and in 4/6 by flow cytometry, with 2 pts, 01 and 03, having massive CART expansion peaking at 90% and 76% of peripheral CD3+ T cells, respectively. CART-BCMA cells during peak expansion were predominantly CD8+ and highly activated. Pt 01 has ongoing CART-BCMA persistence, with ongoing stringent CR at 7 months and MRD-negative bone marrow by flow cytometry. Pt 03, who had pleural and possible dural MM involvement, had CART-BCMA cells found in pleural fluid and CSF, and achieved VGPR (IF+ only) with resolution of extramedullary disease on PET/CT scan. She progressed at 5 months, associated with significant reduction of CART-BCMA cells and loss of BCMA expression on her MM cells by flow cytometry, suggestive of antigen escape. Two pts (02, 11) had modest CART-BCMA expansion, with 1 minimal response (MR) lasting 2 months, and 1 ongoing MR 1 month post-infusion. Two pts (09, 10) had minimal expansion and no response. Soluble BCMA levels, which were elevated in all pts at baseline, declined in parallel with CART-BCMA expansion and correlated with depth of response, with an accompanying increase in previously suppressed BAFF and APRIL levels in serum. Conclusions: CART-BCMA cells can be manufactured from heavily-pretreated MM pts, and demonstrate promising in vivo expansion and clinical activity, even without lymphodepleting conditioning. Depth of response correlates with degree of CART-BCMA expansion and CRS. Toxicities to date include CRS and in 1 pt, severe reversible neurotoxicity, as described in other CAR T cell studies. Expanded accrual in cohort 1, as well as in cohorts with CTX conditioning, is ongoing, with updated data to be presented at the meeting. Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Garfall: Bioinvent: Research Funding; Novartis: Consultancy, Research Funding; Medimmune: Consultancy. Stadtmauer: Novartis: Consultancy; Takada: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Teva: Consultancy; Janssen: Consultancy. Lacey: Novartis: Research Funding. Lancaster: Janssen: Consultancy; Medimmune, Inc.: Consultancy; Grifols, Inc.: Other: Teaching courses. Vogl: Millennium: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm: Consultancy; Teva: Consultancy; Acetylon: Research Funding; Glaxo Smith Kline: Research Funding; Calithera: Research Funding; Constellation: Research Funding. Ambrose: Novartis: Research Funding. Plesa: Novartis: Patents & Royalties, Research Funding. Kulikovskaya: Novartis: Research Funding. Weiss: Prothena: Other: Travel, accommodations, Research Funding; Novartis: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations. Richardson: Novartis: Employment, Patents & Royalties, Research Funding. Isaacs: Novartis: Employment. Melenhorst: Novartis: Patents & Royalties, Research Funding. Levine: Novartis: Patents & Royalties, Research Funding. June: Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Johnson & Johnson: Research Funding; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria. Milone: Novartis: Patents & Royalties, Research Funding.