John Theurer Cancer Center Researchers to Present Pioneering Findings at American Society of Hematology Annual Meeting

What You Need To Know

Researchers from the John Theurer Cancer Center, part of the National Cancer Institute (NCI)-designated Lombardi Comprehensive Cancer Center at Georgetown University, are presenting the latest data from their investigations assessing new diagnostic and treatment approaches for hematologic malignancies — including lymphoma, leukemia, and multiple myeloma — at the 65th Annual Meeting of the American Society of Hematology, to be held in San Diego from December 9-12, 2023. 

The JTCC presentations address new approaches to bone marrow transplantation as well as novel treatments for lymphoma, leukemia, and multiple myeloma.

Bone Marrow Transplantation Research

• Trem-Cel Shows Benefit for High-Risk Acute Myeloid Leukemia (AML). (Abstract 483, Hyung C Suh, MD, PhD) Although  cell transplant from a donor is the standard of care for eligible patients with high-risk AML, most of these patients still relapse and then have very poor outcome. Anti-CD33 -directed therapy has not been  possible so far for these patients because it suppresses the host’s own hematopoiesis (by eliminating CD33-positive blood precursors). Trem-cel is a CRISPR/Cas9 gene-edited allograft lacking CD33 that was developed to generate CD33-negative blood cells and would therefore not be attacked by anti-CD33 CAR T cells. This study showed this approach was feasible in the first 6 patients. It could be a huge step in avoiding hematopoietic toxicity during gemtuzumab ozogamicin maintenance therapy after hematopoietic cell transplantation and prevent recurrence.  
• TSC-100 and TSC-101 to Prevent Relapse after Allogeneic Hematopoietic Cell Transplantation. (Abstract 2090, Hyung C Suh, MD, PhD) Allogeneic hematopoietic cell transplantation (HCT) remains the best curative option for hematologic malignancies, yet some 40% of patients still relapse post-HCT, with a high rare of mortality. A potential solution to prevent relapse is to target hematopoietic lineage-specific minor histocompatibility antigens (MiHAs) that are genetically mismatched between HCT patients and donors who are selected based on the compatibility of major HLA antigens. Targeting MiHAs HA-1 or HA-2 with TSC-100/101 following HCT showed early safety and biomarker evidence of effectiveness by completing elimination of all detectable patient hematopoietic cells (normal or malignant), thereby reducing the risk of recurrence.  
• Changes in Post-Transplant NGS MRD Status May Predict Allogeneic Stem Cell Transplant Outcomes of Patients with AML. (Abstract 2238, Abstract 2090, Hyung C Suh, MD, PhD and Michele Donato, MD) Monitoring measurable residual disease (MRD) has become an effective approach to evaluate the response to chemotherapy and to predict relapse in patients with AML. However, the clinical implications of next-generation-sequencing (NGS) MRD change after allogeneic hematopoietic cell transplantation are still under investigation. This study showed that allogeneic stem cell transplant could convert half of MRD-positive AML patients to MRD-negative, which resulted in better survival. Dynamic changes of MRD status pretransplant and 3 months post-transplant may provide better prediction of survival in patients with AML.

Lymphoma Research

• Lisocabtagene Maraleucel (Liso-Cel) Has Value for Persistent CLL/SLL. (Abstract 330, Tatyana Feldman, MD) Patients with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) who experience intolerance to or disease progression after BTK inhibitors and venetoclax treatment have no established standard of care and poor outcome. This study showed that a CAR T-cell therapy called liso-cel demonstrated durable complete response (CR)/CRi, high undetectable minimal residual disease (uMRD) rates, and a manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL
• Prophylactic Anakinra Reduces Neurotoxicity After CAR T-Cell Therapy for Relapsed or Refractory (R/R) Lymphoma. (Abstract 357, Lori A. Leslie, MD) There are no targeted therapies for CAR T cell-associated neurotoxicity syndrome (ICANS). JTCC and Memorial Sloan Kettering Cancer Center investigators showed that early prophylactic use of anakinra, an IL-1 receptor antagonist, significantly reduces the risk of neurotoxicity in patients receiving CAR T-cell therapy for aggressive lymphomas without affecting treatment effectiveness.
• Brexucabtagene Autoleucel (Brexu-Cel) Continues to Show Benefit for R/R Mantle Cell Lymphoma (MCL) in ZUMA-2 and ZUMA-18. (Abstract 106, Andre Goy, MD) Brexu-cel is the only approved CAR T-cell therapy for MCL, based on the pivotal ZUMA-2 study, which showed continued benefit after 4 years of follow-up. ZUMA-18 was a clinical trial of brexu-cel that opened right after FDA approval to allow expanded and rapid access to this treatment. This study showed similar impressive activity among patients with R/R MCL, which included patients who were much more heavily pretreated than those in ZUMA-2. 
• Improved Overall Survival with Axicabtagene Ciloleucel vs Standard of Care for Large B-Cell Lymphoma Among the Elderly. (Abstract 1761, Lori A. Leslie, MD) The ZUMA-7 study compared standard of care high-dose chemotherapy and autologous stem cell transplantation (ASCT) with axi-cel CAR T-cell therapy in R/R diffuse large B-cell lymphoma (DLBCL) and changed the standard of care for the first time in 30 years. Patients with primary refractory disease or relapse within 1 year  now receive CAR T-cell therapy rather than ASCT. In a planned analysis, second-line therapy with axi-cel prolonged survival over standard of care treatments in patients age 65 and older, including those age 70 and older. These findings confirm that age alone should not be a barrier for consideration of CAR T-cell therapy. 
• Mosunetuzumab Shows Value as Initial Therapy for High Tumor-Burden Follicular Lymphoma. (Abstract 604, Lori A. Leslie, MD) Mosunetezumab is a bispecific antibody approved as third-line therapy for R/R follicular lymphoma (FL). In this study, researchers showed that use of subcutaneous mosunetezumab as first-line therapy for patients with high tumor-burden and high-risk FL resulted in an overall response rate (ORR) of 96% and a CR rate of 75%-85%, depending on the risk subgroup and including those with higher-risk disease. Treatment was also well tolerated and will likely become central to the management of patients with FL. 
• Five Year Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axi-Cel. (Abstract 1032, Andre Goy, MD) Investigators from the U.S. Lymphoma CAR-T Consortium report 5-year outcomes for patients with large B-cell lymphoma who received axi-cel as standard of care after its approval. The findings showed that 42% of pts who would have been ineligible for  ZUMA-1 had similar results to those in the ZUMA-1 trial, with 5-year progression-free survival and OS rates of 28.5% and 40.3%, respectively. Toxicity rates were also similar to the ZUMA-1 study. These data show that a significant proportion of patients with large B-cell lymphoma are likely to be cured after axi-cel CAR T-cell therapy

Leukemia Research

• Navitoclax plus Ruxolitinib for Untreated Myelofibrosis. (Abstract 620, James K McCloskey, MD) Transform-1 is the first study to demonstrate the benefit of adding navitoclax to ruxolitinib as first-line treatment for myelofibrosis. The addition of navitoclax doubled the rate of spleen volume response, which has been correlated with better overall survival in myelofibrosis. Responses were durable and side effects (thrombocytopenia and anemia) were common, but manageable with dose modification. 
• TP-3654 Is Active Against R/R Myelofibrosis Patients. (Abstract 626, James McCloskey, MD) The protein PIM1 plays a role in modulating the activity of the PI3K/AKT and JAK/STAT pathways, making it an excellent target for the treatment of myelofibrosis. This clinical trial reported early data on the clinical activity of a PIM1 inhibitor called TP-3654, including reduced spleen volume, improvement in total symptom scores, and reduction in cytokines. This is the first drug developed to target this pathway. It was also associated with limited side effects (worsening cytopenia was not observed) and will likely be combined with JAK inhibitors in the future. 
• Older Adults with Acute Lymphoblastic Leukemia (ALL) Are Not Benefiting from New Leukemia Drugs. (Abstract 1465, Jamie Koprivnikar, MD, and colleagues) Improvements in survival have been observed in children and teens with ALL, thanks to better therapies. This study showed that similar improvement in outcomes has not been achieved in older adults with ALL, despite the availability of blinatumomab, inotuzumab, and other novel targeted agents, as determined by evaluating age-adjusted mortality data in the United States from 1999-2020. The age-adjusted mortality rate for adults with ALL age 55+ has remained stagnant, despite the improvements observed in younger patients. 
• Early Data Show Activity of CYNK-001 for Acute Myeloid Leukemia. (Abstract 2098, James McCloskey, MD) This phase 1 study evaluated the use of donated natural killer (NK) cells (CYNK-001) to treat newly diagnosed or relapsed AML. The researchers demonstrated that CYNK-001 had biological activity, as evidenced by achievement of a morphologic leukemia-free state (MLFS) even in patients with relapsed disease. Moreover, the treatment was well tolerated, with no serious side effects even with the highest dose of the therapy. Future studies will focus on the next generation of NK cell therapies to optimize persistence and effectiveness and limit the requirement for enhanced lymphodepletion.

Multiple Myeloma Research

• Carfilzomib, Iberdomide and Dexamethasone (KID) Show Benefit for Newly Diagnosed Multiple Myeloma. (Abstract 2022, Noa Biran, MD) Iberdomide is a next generation cereblon-E3 ligase modulating agent (CELMoD) that has increased antitumor activity relative to earlier thalidomide analogs. The KID study, initiated by JTCC investigators, demonstrated the safety and effectiveness of carfilzomib, iberdomide, and dexamethasone when used as induction therapy in transplant-eligible patients newly diagnosed with multiple myeloma.
• Effectiveness of Ide-Cel CAR T-Cell Therapy after Transplant. (Abstract 2101, David S. Siegel, MD, PhD) Patients with multiple myeloma have a higher risk of disease progression and death following an inadequate response to frontline autologous stem cell transplantation (ASCT). The phase 2 KarMMa-2 study demonstrated deep durable responses to ide-cel CAR T-cell therapy in patients with multiple myeloma who had an inadequate response to frontline ASCT and that the treatment significantly improved their health-related quality of life.
• Value of Talquetamab and Pomalidomide in R/R Multiple Myeloma. (Abstract 1014, Noa Biran, MD) Talquetamab is a T-cell redirecting bispecific antibody. The MonumenTAL-2 study showed for the first time that combining talquetamab with pomalidomide achieved rapid, deep responses in patients with R/R multiple myeloma who had two or more prior regimens of therapy. Moreover, the side effects of the combination were similar to those associated with each individual drug. 
• Lab Study Demonstrates Role of Cytotoxic CD8 T Cells. (Abstract 2056, Manpreet Bariana, PhD) The Artificial Immune Modulation (AIM) platform mimics natural dendritic cell function. In this lab-based study, researchers used the AIM platform to show that cytotoxic CD8 T lymphocytes influence the effectiveness of T-cell engager therapies.
• Gene Expression Platform Shows Value for Identifying High-Risk Disease. (Abstract 3386, Noa Biran, MD) SKY92 gene expression profiling is a valuable tool for stratifying patients into high-risk and standard-risk groups for progression and survival. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS) confirmed the reliability of SKY92 to identify patients with high-risk multiple myeloma. This study represents the first U.S.-based multicenter prospective evaluation of SKY92 in a real-world clinical setting. 
• Single-Center Study of Carfilzomib-Based Combinations for Patients with Lymphoplasmacytic Lymphoma. (Abstract 1684, Harsh Parmar, MBBS) Bortezomib is used to treat some forms of lymphoma but is associated with peripheral neuropathy (numbness and nerve pain). This single-center retrospective study at JTCC showed that carfilzomib-based combinations produce a high overall response rate and a durable response in patients with symptomatic lymphoplasmacytic lymphoma, and with a lower risk of peripheral neuropathy.