Hematology End-of-Year Report 2021

Presentation Summary

Deep dive into maturing data for the “kitchen sink approach” in frontline therapy for transplant eligible multiple myeloma (TEMM)

• Kitchen sink with Dara is likely required to maximize response depth
• Achievement of MRD negativity (ideally MRD negative CR) is the goal for all patients
  • For High Risk MM likely need to continue therapy long-term in some way
  • For Standard Risk finite therapy could be considered only in those that achieve (sustained) MRD negative CR but decision point still needs to be addressed in phase III trials
• To make such a decision clinically and economically relevant you need to commit to a regimen where the MAJORITY of patients will achieve the endpoint
  • Dara/Isa – RVD = ~60% MRD neg
  • Dara – KRD = ~80% MRD neg

Immune micro-environment

• Select ASH abstracts 329, 731

Canadian Myeloma Research Group (CMRG) activity

• Evolving options in the post-Lenalidomide and post-daratumumab space for RRMM
  • Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone

ASH Abstracts of Interest

82. Daratumumab (DARA) with Bortezomib, Thalidomide, and Dexamethasone (VTd) in Transplant-Eligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM): Analysis of Minimal Residual Disease (MRD) Negativity in Cassiopeia Part 1 and Part 2

79. Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients (Pts) with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 24 Months of Maintenance

463. Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone As Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma Patients: The Phase III GMMG-HD7 Trial

329. Normalization of the Immune Microenvironment during Lenalidomide Maintenance Is Associated with Sustained MRD Negativity in Patients with Multiple Myeloma

731. Mapping the Multiple Myeloma T Cell Landscape By Immunotherapeutic Perturbation Reveals Mechanism and Determinants of Response to Bispecific T Cell Engagers

1653. Part 1 Results of a Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

[add Red Maple Leaf] Canadian Myeloma Research Group (CMRG) activity

Presentation Summary

Refining diagnostic testing and risk stratification

Primary central nervous system lymphoma (PCNSL)

• Often requires invasive procedures for diagnosis
• Ultrasensitive detection of ctDNA may have important applications in the diagnosis of PCNSL, avoiding the need for more invasive procedures

Improving outcomes in front-line therapy

Front line – DLBCL

• pola-R-CHP – POLARIX Study

Front line – HL

• Single Agent Pembrolizumab (PEM) Followed By AVD Chemotherapy

Novel strategies for salvage therapy in r/r NHL

• Mosunetuzumab – Fully humanized IgG1, bispecific for CD20 and CD3

ASH Abstracts of Interest

6. Profiling of Circulating Tumor DNA for Noninvasive Disease Detection, Risk Stratification, MRD Monitoring in Patients with CNS Lymphoma

LBA-1. The POLARIX Study: Polatuzumab Vedotin with Rituximab, Cuclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

231. Frontline Treatment with Single Agent Pembrolizumab (PEM) Followed By AVD Chemotherapy for Classic Hodgkin Lymphoma: Updated Results and Correlative Analysis

127. Mosunetuzumab Monotherapy is an Effective and Well-Tolerated Treatment Option for Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Who Have Received > 2 Prior Lines of Therapy: Pivotal Results from a Phase I/II Study

Presentation Summary

Key Questions / Data at ASH 2021

High Dose Therapy (HDT) autoHSCT prior to CAR-T

• CAR-T works well in the second line setting for patients with primary refractory disease for whom standard ritux-chemo based therapy is ineffective
  • Data presented at ASH will be practice changing

Defining “Fit” for CAR-T

• ECOG status is extremely important
• Important to consider CAR-T has unique toxicities
• Cell therapy (transplant) historically was restricted by age in order to limit toxicity
  • More evidence is showing that fitness rather than age is the main factor

Driving beyond B cell malignances

• CAR T data becoming available in new indications (MM, Primary CNS Lymphoma, T-Cell Lymphoma)

ASH Abstracts of Interest

HDT autoHSCT prior to CAR-T

2. Primary Analysis of ZUMA-7: A Phase 3 Randomized Trial of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma

91. Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study

LBA-6. Tisagenlecleucel Vs Standard of Care As Second-Line Therapy of Primary Refractory or Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma: Analysis of the Phase III Belinda Study

Defining “Fit” for CAR-T

530. Real-World Outcomes of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Large B-Cell Lymphoma (LBCL): Impact of Age and Specific Organ Dysfunction

570. Physical Therapy Assessment of Baseline Function and Endurance Predicts Short Term Outcomes in Commercial CAR T Patient with Lymphoma

New Indications

550. Ciltacabtagene Autoleucel for Triple-Class Exposed Multiple Myeloma: Adjusted Comparisons of CARTITUDE-1 Patient Outcomes Versus Therapies from Real-World Clinical Practice from the LocoMMotion Prospective Study

258. Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

654. Early Signals of Anti-Tumor Efficacy and Safety with Autologous CD5.CAR T Cells in Patients with Refractory/Relapsed T-Cell Lymphoma

Presentation Summary

COVID 19

• Use of thromboprophylaxis in patients with COVID-19 patients continues to evolve, but may consider extended prophylaxis in selected cases
• COVID vaccination does not appear to be associated with increased risk of DVT post vaccination

Factor Xi inhibition

• Updates from NEJM on Abelacimab and Mivexian

Anticoagulants – Refining optimal duration

• Duration of anticoagulation remains a controversial area within thrombosis but risk stratification based on individual patients characteristics may better refine optimal duration
• Funding for anticoagulants – particularly newer anticoagulants – varies depending on the province
  • For Ontario – funding continues to be limited to 6 months for VTE indication (DOACs) and LU code (LMWH) with no funding for thromboprophylaxis outside of orthopedic surgery

ASH Abstracts of Interest

COVID and Thrombosis

291. Deep Vein Thrombosis after COVID-19 Vaccinations

1065. Extended Thromboprophylaxis in Patients with COVID-19

3214. Inherited Thrombophilias Are Associated with an Increased Risk of COVID-19 Associated Venous Thromboembolism: A Prospective Population-Based Cohort Study

Anticoagulants – Oral sessions

775. Identification of Patients with Unprovoked Venous Thromboembolism and a Low Risk of Recurrence Estimated By Vienna Prediction Model: A Prospective Cohort Management Study

776. Risk of Recurrence after Stopping Anticoagulants in Women with Combined Oral Contraceptive-Associated Venous Thromboembolism: A Systematic Review and Meta-Analysis

Presentation Summary

• There is no more a one size fits all approach- treatment is tailored to result in the best individual outcomes.
• The algorithm for newly diagnosed AML has evolved a lot in recent year with more options now available (see figure below).
• Moving forward – how to use the options and combinations available to us to maximize outcomes while also minimizing toxicity.

ASH Sessions of Interest

AML : So Many Options, So Little Time by Dr. Felicitas Thol, Dr.Christian Thiede, and Dr. Margaret Kasner on Dec 11,2021

MDS: Beyond a One-Size-Fits-All Approach by Dr. Maria Teresa Voso, Dr. Elizabeth Griffith and Dr. Amy DeZern on Dec 12,2021

ASH Abstracts of Interest

871. Long-Term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 Trial

798. Hypomethylating Agent (HMA) Therapy and Venetoclax (VEN) with FLT3 Inhibitor “Triplet” Therapy Is Highly Active in Older/Unfit Patients with FLT3 Mutated AML

691. Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

693. Intensified Cytarabine Dose during Consolidation Therapy in AML Patients Under 65 Years Is Not Associated with Survival Benefit

Presentation Summary

Inpatient anticoagulation management of patients with COVID-19

• Hospitalized Patients with COVID-19 often have laboratory test values suggestive of coagulopathy
• Heparin is effective for the moderately ill with COVID-19
  • HEP-COVID and RAPID multiplatform Randomized Control Studies (mpRCT) of moderately ill patients, provide strong evidence for benefit of therapeutic heparin in moderately ill ward patients with COVID-19 irrespective of D-dimer levels, but not in severely ill ICU patients
• Rivaroxaban is unlikely to have the anti-inflammatory and anti-viral properties attributed to heparin

What we know about VITT (Vaccine-induced Immune Thrombotic Thrombocytopenia)

• Very rare, severe immunological reaction to adenoviral vector-based COVID-19 vaccines
• [Low] Incidence varies according to region
  • AZ vaccine – 1/30,000 – 1/130,000 1st doses
  • J&J vaccine – 1/500,000 1st doses

Additional Presenter Perspective:

• Ask about COVID-19 vaccination and timing as part of routine history taking
• Therapy – anticoagulation and immune modulation

ASH Abstracts of Interest

582. The Deglycosylated Form of 1E12, a Monoclonal Anti-PF4 lgG, Strongly Inhibits Antibody-Triggered Ceullar Activation in Vaccine-Induced Thrombotic Thrombocytopenia, and is a Potential New Treatment for VITT

292. Vaccine-Induced Thrombocytopenia and Thrombosis (VITT) Antibodies Recognize Neutrophil-Activating Peptide 2 (NAP2) As Well As Platelet Factor 4 (PF4): Mechanistic and Clinical Implications

1066. The Immediate Effect of COVID-19 Vaccination on Anticoagulation Control in Patients Using Vitamin K Antagonist

Presentation Summary

Key Trials from this Year

• ELEVATE –R/R (acalabrutinib v ibrutinib in r/r CLL)
• ALPINE (zanubrutinib vs ibrutinib in r/r CLL)
• GLOW (ibrutinib+ ven fixed duration therapy for 1st line CLL v CLB-O)

Key News out of ASH 2021

• new frontline studies to watch (GAIA, FLAIR)
• more hope for the future (BRUIN, MK-1026)

Canadian impact of ASH presentations

• Venetoclax + obinutuzumab (VO or GVe) soon to be funded across Canada (already funded in QC)
  • Current funding only includes FCR ineligible patients
• Lack of OS benefit of IR over FCR in the FLAIR study (much larger study than ECOG 1912) could change the perspective that BTKi is the gold standard for unmutated young, fit patients
• Could some brave provinces extrapolate CLL14 and CLL13 data to allow broader access to VO in Canada? (Make this SOC for all but del(17p)?)
• Where will we place Ibrutinib+Venetoclax when it is eventually approved?
• Given ELEVATE-R/R data, can we replace Ibrutinib with Acalabrutinib

ASH Abstracts of Interest

Frontline

71. GAIA (CLL13) – 1st line fit (FCR/BR, RVe, GVe, GIVe) Eichhorst
Eichhorst et al.

642. FLAIR – 1st line fit (FCR vs IR) Hillmen
Hillmen et al.

639. Long term f/u on Alliance – 1st line older BR vs I +/- R Woyach
Woyach et al.

396. SEQUOIA – 1st line older – BR vs zanubrutinib Tam
Tam et al.

More hope for the future

• 391. BRUIN study update (pirtobrutinib) for r/r CLL Mato A391
  Mato et al.
• 392. Another reversible BTKi (like pirtobrutinib) = MK-1026 Woyach A392
  Woyach et al.
• 68-70. Phase 2 studies of IV (CAPTIVATE update + Nordic study) + more MRD data from GLOW
  Ghia A68, Niemann A69, Munir A70

Presentation Summary

Translational science – Immunotherapy and gene therapy and where they overlap

CAR Cell therapy

CAR-T cell therapy is now established as standard of care for a small subset of hematological malignancies

Near future – New cell subtypes are being integrated into CAR platforms to create “off-the-shelf” products

CRISPR/Cas9 gene editing

CRISPR technology is also being used to remove checkpoint inhibitors in T-cells to improve efficacy

Near future – genetically modify cell therapies to render them unresponsive to inhibitory factors emanating from the tumour microenvironment

Immunotherapy – Checkpoint Inhibitors

New checkpoints inhibitors are being developed that target axes other than PD-1/PD-L1

(Near) Future – TIM-3 and TIGIT are being investigated as a target for many early phase drugs. Similarly, new biomarkers are being identified and targeted with antibodies and BiTEs

Microbiome and Immune System

The gut microbiota can have both immune stimulating and immune inhibitory effects which has important implications for immunotherapy

Research is being pursued to gain a deeper understanding of the mechanisms of microbiota-mediated immunomodulation

ASH Abstracts of Interest

823. Safety and Efficacy of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy in Relapsed/Refractory B-Cell Lymphoma

801. Single Cell Characterization of the Immune and Leukemic Cells Following Anti-TIM3 and Hypomethylating Agent Combination Therapy in Patients with AML or MDS

328. The Combination of Anti-Tigit and Lenalidomide Promotes Synergistic Myeloma-Specific Immunity after ASCT

253. The Intestinal Microbiota Correlates with Response and Toxicity after CAR T Cell Therapy in Patients with B-Cell Malignancies

87. Microbial-Derived Metabolites Induce Epithelial Recovery Via the Sting Pathway in Mice and Men and Protect from Graft-Versus-Host Disease