Newswise December 4th, 2020 Hackensack, NJClinical investigators from Hackensack MeridianHealthJohn Theurer Cancer Center (JTCC), amember of the Georgetown Lombardi Comprehensive Cancer Center consortium, are to present updates on treatment advances in multiple myeloma (MM), mantle cell lymphoma (MCL), and other types of B-cell lymphoma (BCL) as well as leukemia at the 62ndAmerican Society of Hematology (ASH) Annual Meeting and Exposition, to be held virtually from December 5-8, 2020.

Once again, and despite COVID, our team has a full presence at ASH 2020, being part of 52 abstracts. This shows our commitment to clinical science and collaboration with other leading institutions, from new studies on CAR-T cells, bispecific T cell engager antibodies, and other new small molecules in leukemia, lymphoma, and myeloma, said Andre Goy, MD, MS, Chairman and Director of John Theurer Cancer Center (JTCC) at Hackensack University Medical Center. It is not just a requirement for our patients but a privilege to contribute to the phenomenal acceleration of cancer medicine.

The 51 abstracts (listed in the table below) cover three of the main themes of ASH this year:

CAR-T cells have emerged over the last few years as a game-changing therapy for patients withhematologicmalignancies. Anti-CD19 CAR-T cells are approved for use in adults with aggressive B-cell non-Hodgkin lymphoma (NHL) or MCL,but also in B-cell acute lymphocytic leukemia (ALL, up to 25years ofage). At ASH,JTCC is part of the team presenting an update from the ZUMA 2 pivotal trial in MCL, in which CAR-T therapy was associated with a durable response (40% of the first28patients still in remission at 32 months follow-up), an unprecedented response in that setting.(Abstract 1120; Dr. AndreGoy).Also, there was a consistent benefitacross all patients with relapsed/refractory MCL, even in those with high-risk features such as blastoid variant or with a high proliferation rate(Abstract 1126; Dr.AndreGoy).

CAR-T cell therapy is also being tested in other blood cancers and will be featured in other presentations at ASH focusing onMM and indolent BCL.

CAR-T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results in the treatment of relapsed/refractory multiple myeloma (RRMM), with very high response rates (>90%), but unfortunately a significant proportion of patientshave relapsed, potentially due to the lack of sustainability of CAR-T cells over time. To address this, bb21217 is an anti-BCMA CAR-T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (called bb2121; see below) but adds the PI3K inhibitor molecule bb007 during theex vivomanufacture/T cells culture to enrich the drug product for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. The rationale is to make CAR-T cells more sustainable and to help prolong treatment responses. The results from a Phase I dose-escalation trial of bb21217(Abstract 130; Dr. DavidSiegel)in which patients with RRMM had received 3 prior regimens, are promising, with no added toxicity. The presence of T cell markers associated with memory-like T cells and the absence of T cell markers associated with differentiation/senescence correlated positively with the T cells peak expansion in the patients and the duration of response, consistent with the investigators hypothesis.

Also, an update on BCMA CAR-T therapy(Abstract 131; Dr.DavidSiegel)confirmed a high response rate of 76% (39% with a complete response [CR]) and a median duration of response of 10.3 months. Similarly, a BCMA CAR-T update from the KarMMA trial (NEJM 2019) showed the same benefit in older patients(65-70 years old), even in those who were heavily pretreated(Abstract 1367; Dr. DavidSiegel)or presenting very high-risk features(Abstract 3234; Dr.DavidSiegel).

Finally, JTCC will be a co-presenter of the ZUMA-5 trial, providing the firstCAR-T therapy data in indolent BCL (146 patients), using an anti-CD19 CAR-T and showing a very high response rate (>90% overall response rate [ORR] and >80% CR).These data are very impressive based on the efficacy -- even in double-refractory patients -- but also because of the favorable toxicity profile(Abstract 700; Dr. Lori Leslie).

Alternative options to generate cell therapies are emerging, including natural killer (NK) cell therapygenerated from a pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf NK cells for broad patient access.Early data on FT538, an investigational, first-of-its-kind, multiplexed engineered NK cell therapy, will be presented in both myeloma and acute myeloid leukemia (AML) at ASH(Abstract 1449; Dr. David Siegel).

The BITE antibodieshelp force the normal immune system to reengage and to fight cancer cells. They are definitely a big topic at ASH, as they continue to show great activity and unlike CAR-T cells, do not necessitate a complex process of cell collection and manufacturing. They may thus offer a form of off-the shelf cell therapy. However, as with CAR-T cell therapy, BITE antibodies can be associated as in CAR-T cells therapy - with cytokine release syndrome (CRS) and/or neurotoxicity both related to the rapid activation and amplification of T cells in patients after infusion. In order to address this, JTCC investigators and colleagues explored the subcutaneous (SC) administration of mosunetuzumab a lead product among BITEs (targeting anti CD3 and CD20) to patients with B-cell relapsed/refractory lymphomas. Results showed an ORR of 60% in heavily pretreated patients with aggressive lymphoma (DLBCL), including in patients who failed prior CAR-T therapy. In addition,researchers observed much less toxicity andhigh bioavailability (>75%), supporting the use of SC dosing for CRS mitigation(Abstract 2096; Dr. AndreGoy).

Usage of both CAR-T cells and BITEs will expand dramatically in the future across many cancers and JTCC has a robust ongoing comprehensive portfolio of CAR-T cells and BITE-based trials, including, off-the shelf CAR-T cells and NK cells, dual/multi-target CAR-T cells, as well as combinations with small molecules to enhance the activity and/or durability of these modifiedT cells.

Another emerging form of immunotherapy involvescheckpoint inhibitors,which also help unleash the immune system and have been approved in many cancers. At ASH a new study using an anti-CD47 checkpoint inhibitor showed very promising results(Abstract 646; Dr. TatyanaFeldman).CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRP) and delivers a"do not eat"signal to suppress macrophage phagocytosis. Overexpression of CD47 can allow tumor cells to escape immune surveillance. TTI-621 (SIRPFc) is a fusion protein consisting of the CD47 binding domain of human SIRP linked to the Fc region of human immunoglobulin G1 (IgG1), designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRP interaction between malignant cells and macrophages.

Finally, the standard of care of patientswith relapsed Hodgkin disease is salvage with high-dose therapy, followed by stem cell transplantation. A subset of these patientsstill relapse and experience a poor outcome. The ability to use immunotherapy as consolidation post-transplantation (brentuximab + nivolumab) was illustrated in a study presented at ASH(Abstract 472; Dr. TatanyaFeldman), in whichonly one of 59 enrolled patientsrelapsed, leading to a remarkable 98% survival rate and no major toxicity issues.

A number of presentations at ASH will focus on novel emerging agents in several diseases with persistent unmet need, including the following examples.

Acute myeloid leukemia (AML):

The FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (Gilt) improves survival compared with standard salvage chemotherapy in relapsed/refractory (R/R)FLT3-mutated (FLT3mut+) AML. However, relapses are common and long-term survival remains poor. Combination therapies of FLT3 inhibitors with agents that induce apoptosis have demonstrated preclinical activity and synergy againstFLT3mut+clones and may delay or prevent drug resistance. This was the subject of a study of Gilt + venetoclax (Ven) in patients with refractory AML, with most having previously failed FLT3 inhibitor therapy (Abstract 333; Dr. JamesMcCloskey),suggesting substantially greater antileukemic activity from Gilt + Ven than with single-agent Gilt in a very difficult-to-treat patient population.

Chronic myeloid leukemia (CML):

CML is a disease literally transformed by kinase inhibitors (TKIs)over the last 20 years.However, patients can develop resistance against these targeted therapies, leading to the development of second-, third-, and fourth-generation kinase inhibitors, offering new options, albeit often with new or different toxicities encountered over time. The OPTIC trial was a randomized Phase 2 trial evaluating different dosing schedules of ponatinib in patients with CP-CML who were resistant/intolerant to 2 TKIs or with a T315I mutation. The results of this large landmark trial will help refine dosing in this population, while minimizing toxicities(Abstract 48; Dr. JamesMcCloskey).

B-cell lymphoma (BCL)

CA-4948 is a novel oral small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 is part of the Myddosome signaling pathway (a group of proteins forming a complex involved in innate immunity) and is essential for downstream signaling of tolllike receptors (TLRs) and the interleukin-1 receptor (IL-1R) family in immune cells including B lymphocytes. Dysregulated signaling in these pathways is frequently observed in certain types of BCL, particularly in ABC-subtype of DLBCL and Waldenstrm macroglobulinemia (WM). In this early trial CA-4948 demonstrated a good safety profile, desirable pharmacokinetic properties, and preliminary clinical activity. This offers a new venue to target B-cell signaling in BCLs and provides a rationale for combination therapy with BTK and/or BCL2 inhibitors, expanding the portfolio of emerging non-chemotherapy options for these patients(Abstract 703;Dr. LoriLeslie).

Epstein-Barr virus (EBV) can play a role in several subtypes of lymphoma including Hodgkin, B and T cell lymphomas. EBV-positive (EBV+) lymphomas are generally associated with poor clinical outcomes, particularly for patientswho have relapsed or are refractory (R/R) to standard therapies. Targeting EBV by using the antiviral valganciclovir and the histone deacetylase (HDAC) inhibitorNstat showed promising results, with an ORR up to 80% (50% CR) in T/NK cell lymphoma (a very difficult-to-treat subtype) and 60% in aggressive BCL, providing a potential new approach, as there are currently no approved therapies for these EBV+lymphomas(Abstract 1154; Dr. TatyanaFeldman).

Multiple myeloma (MM):

Proteasome inhibitors were the firstnew class of drugs approved in myeloma; they typically disrupt the system responsible for protein recycling inside the cells and have become the backbone of MM therapy. Attempts to refine these drugs have led to new compounds including IBER, an oral, potent novel cereblon E3 ligase modulator (CELMoD) agent, which has shown marked synergistic tumoricidal and immune-stimulatory effects in combination with bortezomib or daratumumab in preclinical models.CC-220-MM-001 is a phase 1/2 study evaluating dose escalations of IBER with different treatment combinations in independent cohorts in patients with RRMM, expanding the combination of biological agents and providing new options in this population(Abstract 724; Dr. DavidSiegel).

Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells.STOMP is a multicenter, open-label, phase 1b/2 study ofcombination therapy with SEL, pomalidomide, and dexamethasone in patients with RRMM who previously failed lenalidomide and proteasome inhibitor therapy, two of the key therapies in myeloma. This combination almost doubled the response rate (58% vs 31%) and led to a durable response in these heavily pretreated patients(Abstract 726; Dr. NoaBiran).

Stem cell transplantation:

Despite prophylaxis, graft versus host disease (GVHD) remains a significant cause of morbidity and non-relapse mortality after allogeneic hematopoietic cell transplantation (HCT). ITA is a potent, selective Janus kinase (JAK) 1 inhibitor that has been combined safely with steroids in patients with acute GVHD. Results from a proof-of-concept study evaluating ITA + a calcineurin inhibitor (CNI) for GVHD prophylaxis, co-presented by the JTCC Bone Marrow Transplantation team, were promising, showing reduced incidence of severe GVHD, a crucial complication post-transplantation(Abstract 356; Dr. ScottRowley).

Clinical trials help move the field and establish new standards with more and more options for multiple cancer types, raising the complexity of treatment decisions. Real-world evidence (RWE) can help confirm a clinical benefit observed in a given trial and refine potential toxicities but also can help inform the best sequence of care among the many available options -- one of the biggest current challenges in oncology. Several abstracts at ASH report on this specific issue.

JTCC was part of the largest series to date comparing the first-line use of chemoimmunotherapy (CIT) to targeted therapy (e.g., ibrutinib [IBR]) in more than 500 high-risk patients with chronic lymphocytic leukemia (CLL) (Abstract 372, Dr. LoriLeslie). Results showed that patients treated with single-agentIBRtherapy had significantly longer responses and longer time to next therapy than those treated with CIT, despite similar demographics and clinical characteristics. This RWE study also demonstrated that IBR therapy provided sustained clinical benefit regardless of risk status and supports the use of IBR in the first-line setting.

JTCCs Euro-oncology group was part of a RWE study in patients with primary central nervous system lymphoma (PCNSL). Thetreatment of older patients with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). Investigators from this large series showed that outcomes in these older patients are suboptimal, and the use -- when possible -- of high-dose methotrexate truly makes a difference (as in younger patients)(Abstract 476, Dr. SamuelSinger),helping guide oncologists in this rare disease.

Burkitt lymphoma is a rare lymphoma which carries the most aggressive features and requires very intensive therapy. Authors from several institutions including JTCC reported on a new prognostic model and its impact of modern therapy(Abstract 706; Dr. TatanyaFeldman)as well as the outcome in HIV-infected patients where this lymphoma subtype is more common(Abstract 705; Dr. TatanyaFeldman).

Finally, JTCC was part of two studies reported at ASH on the impact of COVID-19 on cancer patients. The first, a global observation of more than 400 patients with CLL who were hospitalized with COVID, which showed that advanced age was the highest risk factor for mortality(Abstract 1590, Dr.LoriLeslie andDr.Michael Koropsac), while CLL treatment did not seem to have a consistent impact across cohorts. Another study looked at 89 evaluable BCL patients with COVID, with the goal of determining the impact of immunosuppression due to the lymphoma itself and/or therapies received.Survival was poor in lymphoma patients with hypertension, diabetes, or age 70 years. Interestingly, the rate of seropositivity (i.e., developing antibodies to COVID) in patients treated with monoclonal CD20 antibody therapy was significantly lower (12.5% vs 55%). Patients exposed to anti-CD20 therapy also required significantly more days to clear viral shedding (median 56 days vs 14 days). Such patientsmight be candidates for plasma therapy to help control virus expansion and induce its clearance(Abstract 2553; Dr. AndrewIp and Dr. TatanyaFeldman).

The full set of ASH data presentations by JTCC researchers is as follows:

Abstract #

Type

Title of Abstract

Authors

Presenting (PST)

48

Oral

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

James K. McCloskey, MD

Saturday, December 5, 2020: 8:15 AM

130

Oral

Updated Results from the Phase I CRB-402 Study of Anti-Bcma CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma: Correlation of Expansion and Duration of Response with T Cell Phenotypes

David S. Siegel, MD

Saturday, December 5, 2020: 9:45 AM

131

Oral

Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy, in Patients with Relapsed and Refractory Multiple Myeloma: Updated Results from Phase 1 CRB-401 Study

David S. Siegel, MD

Saturday, December 5, 2020: 10:00 AM

333

Oral

Efficacy and Safety of Venetoclax in Combination with Gilteritinib for Relapsed/RefractoryFLT3-Mutated Acute Myeloid Leukemia in the Expansion Cohort of a Phase 1b Study

James K. McCloskey, MD

Sunday, December 6, 2020: 10:15 AM

356

Oral

A Single-Arm, Open-Label Phase 1 Study of Itacitinib (ITA) with Calcineurin Inhibitor (CNI)Based Interventions for Prophylaxis of Graft-Versus-Host Disease (GVHD; GRAVITAS-119)

Scott D. Rowley, MD

Sunday, December 6, 2020: 10:15 AM

372

Oral

Clinical Outcomes Among Real-World Patients with Chronic Lymphocytic Leukemia (CLL) Initiating First-Line Ibrutinib or Chemoimmunotherapy (CIT) Stratified By Risk Status: Results from a US Retrospective Chart Review Study

Lori A. Leslie, MD

Sunday, December 6, 2020: 10:00 AM

472

Oral

Consolidation with Nivolumab and Brentuximab Vedotin after Autologous Hematopoietic Cell Transplantation in Patients with High-Risk Hodgkin Lymphoma

Tatyana A. Feldman, MD

Sunday, December 6, 2020: 2:30 PM

476

Oral

Real World (RW) Outcomes and Prognostication of Older Patients with Primary Central Nervous System Lymphoma (PCNSL) in the Contemporary Era

Samuel Singer, MD,

Samuel Goldlust, MD

Sunday, December 6, 2020: 2:00 PM

646

Oral

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Tatyana A. Feldman, MD

Monday, December 7, 2020: 12:00 PM

677

Oral

Resolution of Serious Vaso-Occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Stacey Rifkin-Zenenberg, DO

Monday, December 7, 2020: 1:30 PM

700

Oral

Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

Lori A. Leslie, MD

Monday, December 7, 2020: 1:30 PM

703

Oral

Safety, Pharmacokinetics and Activity of CA-4948, an IRAK4 Inhibitor, for Treatment of Patients with Relapsed or Refractory Hematologic Malignancies: Results from the Phase 1 Study

Lori A. Leslie, MD

Monday, December 7, 2020: 2:15 PM

705

Oral

Continued here:
John Theurer Cancer Center (JTCC) Researchers to Present 52 Abstracts across Hematological Malignancies at the 2020 American Society of Hematology...