MD Anderson Research Highlights: ASH 2022 Special Edition

Key presentations focused on therapeutic advances for hematologic cancers

MD Anderson News Release December 09, 2022

ABSTRACTS 62, 82, 95, 199, 232, 540, 708, 766, 960

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into basic, translational and clinical cancer research from MD Anderson experts. This special edition features presentations by MD Anderson researchers at the 2022 American Society of Hematology (ASH) Annual Meeting on innovative targeted therapies, new combination approaches and novel targets to improve outcomes for patients with leukemias, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma and other hematologic cancers.

In addition to the studies below, forthcoming press releases will feature groundbreaking clinical studies on treatment advances for patients with acute leukemias (Abstracts 61, 213, 709) and a novel menin-targeting therapy for patients with acute leukemias caused by specific genetic alterations (Abstract 63). Complete information on all ASH Annual Meeting content from MD Anderson can be found at MDAnderson.org/ASH.

Novel triplet target therapy demonstrates manageable safety and anti-leukemia activity (Abstract 62)
Despite recent improvements with azacitidine (AZA) and venetoclax (VEN) in patients with acute myeloid leukemia (AML) who are older/unfit or have relapsed/refractory (R/R) disease, long-term survival for these patients remains short. The antigen CD123 is expressed on most AML blast cells and leukemic stem cells, but it is minimally expressed on normal hematopoietic stem cells. In a Phase Ib/II international study led by Naval Daver, M.D., researchers evaluated the combination of AZA, VEN and pivekimab sunirine — a high-affinity CD123 antibody-drug conjugate (ADC) with a novel indolinobenzodiazepine pseudodimer (IGN) payload — in CD123-positive R/R and older/unfit patients. Preliminary data suggests the combination had manageable safety and encouraging anti-leukemia activity across several difficult-to-treat subsets of patients. A frontline expansion in both R/R and newly diagnosed patients is ongoing. Daver will present the results Dec. 10.

Olverembatinib shows promise for ponatinib-resistant patients with CML and Ph+ ALL (Abstract 82)
Olverembatinib is a novel third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) shown to have activity against chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), regardless of genotype. In this Phase Ib study led by Elias Jabbour, M.D., researchers evaluated olverembatinib in patients with all phases of CML and Ph+ ALL whose disease did not respond to previous treatment with the TKI ponatinib and had at least two prior TKI treatments. Olverembatinib demonstrated potent anti-leukemia activity and was well-tolerated in patients with TKI-refractory CML and Ph+ ALL, including CML patients resistant to ponatinib or asciminib (both TKIs) and those with T315I mutations, which are associated with resistance to all available TKIs. This analysis suggests olverembatinib is a potentially viable treatment option for patients with CML and Ph+ ALL, particularly those in need of alternate therapies. Jabbour will present the results Dec. 10.

Long term follow-up positive for ibrutinib and venetoclax as front-line CLL treatment (Abstract 95)
Ibrutinib and venetoclax combination therapy is an effective option for patients with chronic lymphocytic leukemia (CLL). Results from a Phase II trial demonstrated the combination achieved an 88% complete remission rate in 80 previously untreated, high-risk, older patients after 12 treatment cycles. Nitin Jain, M.D., and colleagues have now provided updated data for 120 patients on this study after a median follow-up of four years. The four-year progression-free survival rate was 94.5% and overall survival rate was 96.6%. Continuing the combined therapy in patients with bone marrow-positive minimal residual disease (MRD) during the second and third year of treatment resulted in undetectable MRD for some patients. Jain will present the findings Dec. 10.

Novel c-Myc/GSPT1 degrader causes TP53-independent cell death in AML (Abstract 199)
The c-Myc gene is highly expressed in Burkitt’s leukemia/lymphoma as well as in TP53-mutant and venetoclax-resistant acute myeloid leukemia (AML), making it an important yet unsuccessfully targeted proto-oncogene. Yuki Nishida, M.D., Ph.D.,  Michael Andreeff, M.D., Ph.D., and colleagues developed and improved upon the first active c-Myc degrader, GT19715. In xenograft models, the drug can reduce both c-Myc and GSPT1, an important protein for leukemia stem cell survival. It can also eliminate circulating blast cells and prolong survival in models of Burkitt’s leukemia/lymphoma. GT19715 also induced cell death independent of TP53 mutational status and demonstrated greater efficacy in AML stem/progenitor cells compared to mature AML cells. This study highlights the preclinical therapeutic potential of GT19715 for degrading c-Myc/GSPT1, meriting further clinical development. Nishida will present the results Dec. 10.

Adding zilovertamab to ibrutinib improves responses for CLL and MCL (Abstract 232)
Pre-clinical studies have shown that zilovertamab, a monoclonal antibody against ROR1, has synergy with targeted therapies like ibrutinib. A Phase I/II trial presented by Hun Ju Lee, M.D., is the first study in patients to show clinical synergy. The trial evaluated the combination of zilovertamab and ibrutinib in 33 patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) and 62 patients with treatment-naïve or R/R chronic lymphocytic leukemia (CLL). In R/R MCL, researchers observed an overall response rate of 85%, with a high complete response rate of 40% and median progression-free survival (PFS) of 35.9 months. The combination also achieved robust efficacy in patients with CLL, as the median PFS was not reached in either treatment group. These findings suggest the combination is safe with promising efficacy. The study is ongoing and continues to enroll R/R marginal zone lymphoma patients. Lee will present updated findings Dec. 10.

Long-term outcomes reported in large, prospective study of BPDCN (Abstract 540)
Blastic  plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy associated with poor outcomes. Since the development of CD123-based therapies, significant progress has been made in treating the disease. Naveen Pemmaraju, M.D., led an analysis of characteristics and outcomes from a prospective single-institution study featuring one of the largest groups of BPDCN patients in the world. The data show improved overall survival in younger patients who received a transplant during their first complete response. The study also found a higher incidence of cerebral spinal fluid positivity than previously recognized, and it revealed almost a quarter of patients had a prior or concomitant hematologic malignancy. This information is useful in driving ongoing research for BPDCN. Pemmaraju will present the findings Dec. 11.

DTX1 is inhibited in DLBCL, controls B-cell differentiation in germinal centers (Abstract 708)
The DTX1 gene, which negatively regulates the Notch signaling pathway, is highly expressed in germinal center B (GCB) cells and diffuse large B cell lymphoma (DLBCL). However, its role in B-cell development and lymphomagenesis is not well known. After discovering that 59% of DLBCL tumors have non-coding mutations in regulatory elements near DTX1, researchers led by Atish Kizhakeyil, Ph.D., and Michael Green, Ph.D., generated DTX1 knockout models to characterize its role in GCB cell development. Loss of DTX1 in lymphoma cells increased Notch expression and altered gene expression programs responsible for regulating the polarization of germinal centers and for GCB maturation. The findings also show that DTX1 mutations in DLBCL confer a competitive advantage by increasing light-zone polarization within germinal centers, changing the differentiation trajectories of GCBs and allowing them to disseminate following antigen stimulation. Kizhakeyil will present the findings Dec. 12.

Prior BCMA-targeted therapy associated with inferior outcomes with ide-cel CAR T cell therapy (Abstract 766)
Idecabtagene  vicleucel (ide-cel) is a chimeric antigen receptor (CAR) T cell therapy approved for certain patients with relapsed/refractory multiple myeloma, but earlier trials excluded those who had previously received a BCMA-targeted therapy (BCMA-TT). As part of a retrospective study led by Christopher Ferreri, M.D., researchers evaluated real-world data from 50 patients treated with ide-cel after receiving a BCMA-TT. Prior treatment was associated with lower response rates and a shorter progression-free survival (PFS). However, the overall response rate (ORR) to ide-cel in these patients was relatively high compared to other commercially available therapies for triple-class refractory myeloma. For the small cohort of patients who received a BCMA-targeted CAR T-cell therapy prior to ide-cel, the ORR to ide-cel was 100% and the median PFS had not yet been reached. Further investigation is warranted to analyze other factors associated with poor outcomes, including timing of infusion relative to prior BCMA-TT. Ferreri will present the results Dec. 12.

Combination of pembrolizumab and romidepsin shows high response rates for T-cell lymphomas (Abstract 960)
Peripheral  T-cell lymphomas (PTCL) are a diverse group of rare and aggressive lymphoma types that have not benefited from newer therapies and are associated with poor outcomes. In a Phase I/II study led by Swaminathan Iyer, M.D., and presented by Owhofasa Agbedia, M.D., researchers evaluated the combination of the immune checkpoint inhibitor pembrolizumab and the chemotherapy agent romidepsin in 38 patients with PTCL who had disease progression after at least one prior regimen. The overall response rate was 47.3%, and the combination showed promising progression-free survival and overall survival in patients with relapsed/refractory PTCL. The results support further development of this combination therapy. Agbedia will present the updated survival findings Dec. 12.