BiTE in ALL and AML Ibrahim Aldoss, MD Assistant Professor, City of Hope Hematology and Hematopoietic Cell Transplantation
Disclosure I am consultant for Helocyte and Speaker Bureau for JAZZ
Immune system as an anticancer therapy Immune surveillance plays a critical role in controlling cancer development Cancer risk increased in congenital & acquired T cell defects Cytotoxic T cell has a remarkable capacity to target cancer Direct correlation between tumor T-cell infiltration and prognosis Xenograft models, T cells were able to eradicate tumors The activity of anti-ctla-4 and PDL-1 inhibitors Reduced relapse after allogeneic HCT Successful T cell therapy is hampered by large number of immune escape mechanisms Stieglmaier J. 2015. Zhang. 2003. Whalin 2007. Galon 2006.
Bi-specific T cell engager (BiTE) BiTE is an antibody construct, linking scfvs of mabs for CD3 and surface molecules on targeted cells The construct is designed to approximate targeted tumor cells in close range to T cells immunological synapse Leads to activation & polyclonal expansion of cytotoxic T cells Activation of T-cells occurs independent of TCR specificity, co-stimulation, or peptide antigen presentation Following synapse formation, T-cells release cytokines, followed by activation of targeted cell caspase and apoptosis Stieglmaier J et al. 2015.
Baeuerle PA et al. 2009.
Blinatumomab Aldoss et al. Leukemia. 2017;31:777-87.
Blinatumomab The target is CD19 Presents on the vast majority of B-cell malignancies, including ALL The FDA approval for r/r Ph- & Ph+ ALL Adults & pediatrics Activity was seen in MRD+ and fully r/r ALL
Blinatumomab in MRD+ALL
MRD+ predicts poor outcomes in ALL CCR Survival Worse outcomes were seen among non-transplanted pts Gokbuget et al. Blood. 2012;120:1868-76
Blinatumomab MRD dosing
MRD studies Study N MRD response Median RFS (m) Median OS HCT Pilot 21 80% 61% at 33 months NA 9 (45) BLAST 116 80% 18.9 36.5 74 (67) Four patients remained in CR without further therapy on long follow-up Allogeneic HCT post blinatumomab did not improve OS in either study Topp M et al. 2012. Topp et al. 2011. Goekbuget et al. Blood. 2018. Jan 22
Gokbuget N et al. Blood. 2018;Jan 22
HCT following blinatumomab for MRD+ ALL HCT did not improve OS 9 (25%) of 36 pts who did not receive HCT remains in CR, with a median f/u of 24 months vs. 49% in HCT cohort Gokbuget N et al. Blood. 2018;Jan 22
Blinatumomab in r/r ALL
Blinatumomab dosing for r/r ALL civ for 28 days every 6 weeks Step-wise escalation in cycle 1 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 Subsequent cycles, blinatumomab is administered at 28 mcg/day on Days 1-28 Pre-med with dexamethasone 20 mg IV 1 hour before starting each cycle Recommended before escalating the dose, or when restarting after an interruption of 4 hours Pre-treatment with dexamethasone & step-wise escalation reduced risk of significant CRS This is did not compromise blinatumomab activity Topp MS et al. Lancet Oncology. 2015. Aldoss I et. Am J Hemat. 2017
Study N Setting CR/CRh (MRD) Topp (phase 2 pilot) Topp (confirmatory) Martinelli (ALCANTARA) Von Stackelberg (pediatric) Kantarjian (phase 3) RFS OS Prior HCT HCT after 36 Ph- 69 (88) 7.6 9.8 15 (42) 13 (50) 189 Ph- 43 (82) 5.9 6.1 64 (34) 32 (40) 45 Ph+ 36 (88) 6.7 7.1 20 (44) 7 (44) 70 Ph+ & Ph- 39 (52) 4.4 7.5 30 (61) 13 (48) 271 Ph- 44 (76) 7.3 7.7 94 (35) (24) Topp MS et al. 2015. Topp MS et al. 2015. Martinelli et al. J Clin Oncol. 2017. von stackelberg et al. J Clin Oncol. 2016. Kantarjian et al. N Engl J Med. 2017
Phase 3 randomized study Kantarjian et al. N Engl J Med. 2017
Kantarjian et al. N Engl J Med. 2017
Topp MS et al. 2015.
Response for Blinatumomab Response was irrespective of prior chemosensitivity or prior reception of allogeneic HCT Similar response in patients who did and did not receive prior allogeneic HCT CR = 45% [N= 64] vs. 42% [n=125] Elderly had comparable outcomes when treated with blinatumomab Stein et al. ASH 2015. Kantarjian et al. ASCO 2015
Response to Blinatumomab Appears Higher Lower pre-treatment marrow blasts Lower pre-treatment PB T regulatory cells Absence of EMD (history or current) Higher platelets count Higher peak of serum IL-10 after initiating therapy Kantarjian et al. ASCO 2015. Duell J et al. ASH 2014. Zhu et. ASCO 2015. Aldoss et al. Am J Hematol. 2017
Relapse/resistance to blinatumomab CD19- ALL relapse Lineage switch in MLL+ Selection of pre-existing CD19- malignant progenitor cells Disruption in CD19 trafficking in the post ER system Retreatment with blinatumomab is feasible among relapsed CD19+ ALL (N=11) Third of patients achieved CR Extra-medullary relapse/resistance Topp et at. 2011. Topp et al. 2014. Topp et al. EHA 2015. Aldoss. Am J Hemt. 2017. Zoghbi et al. Pediatrr Blood Cancer. 2017. Nagel et al. Blood. 2017. Braig et al. Blood 2017.
Pattern of relapse/resistance COH experience N =65 Responders Non-responders Refractory 32 (49) Site of progression BM alone 19 (59) BM + EMD 4 (13) EMD 9 (28) EMD +/- BM 13 (41) CD19 expression at progression Unavailable CD19 expression Negative Dim Moderate/positive 22 (69) 10 4 (18) 5 (23) 13 (59) Aldoss I et al. Am J Hematol. 2017;92:858-65
Aldoss I et al. Am J Hematol. 2017;92:858-65
Blinatumomab responders have lower PB Treg (CD4/CD25/FOXP3) With a cutoff of 8.525%, Treg enumeration can identify 100% of responders and exclude 70% of the non-responders Treg mediate suppression of T cell proliferation and reduced CD8-mediated lysis of ALL cells Duell J et al. Leukemia. 2017.
Overall Survival, % Relapse-Free Survival, % Outcomes of blinatumomab responders undergoing allogeneic HCT 100 80 60 40 20 0 Censored 12-month estimate: 54.0% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Time Since allohsct, months Patients at Risk: 34 33 31 27 26 24 20 19 18 14 12 12 12 11 8 6 6 6 3 3 2 2 1 0 Median RFS, months N = 34 NE 95% CI 5.3 NE RFS events, n Relapse Death Patients censored, n 15 9 6 19 Median follow-up: 13.9 (8.5 17.1) months 100 80 60 40 20 0 Censored 12-month estimate: 62.1% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Time Since allohsct, months Patients at Risk: 34 33 31 30 28 26 24 22 21 17 14 13 13 12 8 6 6 6 4 4 3 3 1 0 Median OS, months Stein AS. ASBMT 2016 N = 34 NE 95% CI 7.1 NE OS events, n Patients censored, n 12 22 Median follow-up: 13.4 (9.4 14.6) months
Lymphocyte kinetics during blinatumomab Unique & predictable B & T cells drop quickly T cells recovered & reached above baseline within days Expansion of CD4 & CD8 effector memory cells No significant change in naïve T cells Topp et al. 2011, Zhu. ASCO 2015, Klinger. 2012
Lymphocyte kinetics during blinatumomab Simultaneously, blinatumomab mediates normal B cell depletion Significant hypogammaglobinemia IgM levels recover early upon completion, but IgG and IgA recovery lag behind NaïveB cells recovered soon afterward but memory/plasma cells do not Serum cytokines increase upon initiating cycle 1 IL-6, IL-10 & TNF No rise is observed in subsequent cycles among responders Topp et al. 2011, Zhu. ASCO 2015, Klinger. 2012. Zugmaier. 2014
Topp et al. 2011
Blinatumomab Toxicities Cytokine Release Syndrome Severe CRS usually occurs in R/R setting, especially with higher disease burden Severe form is uncommon in patients treated for MRD 2% had grade III in R/R ALL With employing pre-dexa & step-wise escalation CNS toxicities Dose-limiting toxicity, and grade III/IV occurred in 22% Appears higher with older age Presented with symptoms of encephalopathy Usually reversible
Future Directions: Blinatumomab in ALL Optimizing drug delivery Incorporating blinatumomab in frontline setting Healthier T cells Ongoing studies (SWOG for older patients [NCT02143414]) An ideal drug to combine with novel agents + checkpoints inhibitors (PDL1 inhibitors) Better understanding the relationship between ALL genetics/host immune profile and response Better understanding unique patterns of resistance CD19 negative relapse Extramedullary ALL Phase 1 of blinatumomab in NHL showed dose-dependent clinical activity (up to 60 ug/m 2 ) Cytoreduction in pts with high T reg/disease burden
Conclusion Blinatumomab is active in MRD+ and r/r ALL Both, Ph+ & Ph- ALL Activity is irrespective of chemo-sensitivity and prior allogeneic HCT reception Potentially curative for MRD+ ALL Longer follow up is needed Serves as a bridging therapy to allogeneic HCT in advanced ALL
CD3/CD33 BiTE in AML CD33 is universally expressed on AML cells AMG330 is CD3/CD33 bi-specific antibody Preclinical studies show high potency & efficacy in destroying CD33+ human AML cells Laszalo GS et al. 2014. Harrington et al. 2015
CD3/CD33 BiTE in AML
Flotetuzumab CD3/CD123 BiTE in AML CD123 is expressed frequently on AML AML LCS (CD34+, CD38-) expresses CD123 at high level while CD34+,CD38- cells from normal bone marrow demonstrates no detectable expression of CD123 Targeting CD123 represents a promising strategy in the preferential of AML cells
Interim results from phase 1- ESMO 2017
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