The OBR Blog

By Mary Ellen Schneider

This year’s annual meeting of the American Society of Hematology (ASH) featured new research on chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engager (BiTE) molecules, along with trends toward treating cancer patients with immunotherapies earlier in the course of their disease.

The meeting, which was held virtually for the first time, also highlighted studies evaluating the extent and impact of racial and ethnic health disparities in hematology and oncology.

Health Disparities Highlighted

“As part of caring for patients and our citizens, ASH chose to have a significant light shine upon disparities in health care, or differences in outcomes between different groups of our patients,” Chancellor Donald, MD, an assistant professor of clinical medicine at Tulane University in New Orleans, told OBR.

Bringing attention to disparities in outcomes and access offers the potential for “immediate improvement in outcomes for those persons without a new diagnostic test, or without a new drug,” Dr. Donald said.

The ASH plenary session put the spotlight on poor treatment outcomes for Black patients younger than 60 years with acute myeloid leukemia (AML). In a study that looked both at Surveillance Epidemiology End Results (SEER) data and molecular features by race, researchers found that younger Black patients had a 27% higher likelihood of death than white patients. They also discovered that Black patients had a lower frequency of prognostically favorable NPM1 mutations (Abstract 6).

Another study that focused on health disparities identified a greater risk for cancer-associated thrombosis among Black patients, compared with their white counterparts. These disparities were especially prominent when the researchers looked only at pulmonary embolism (Abstract 203).

What is driving the disparities in cancer-associated thrombosis? The researchers acknowledged possible contributions from underlying biological traits. But they also pointed to the contribution of systemic racism, access to care, and the severity of underlying comorbidities.

“Since current risk prediction models for cancer-associated thrombosis do not include race and ethnicity as parameters, future studies should examine if incorporating these factors can improve predictive value,” said Alisa S. Wolberg, of the University of North Carolina at Chapel Hill and one of the ASH scientific program co-chairs. Dr. Wolberg highlighted the study as part her “Best of ASH” presentation.

Other health disparities research presented at this year’s ASH included a study exploring the impact of living in a socioeconomically disadvantaged neighborhood for Black and Hispanic people with AML. Researchers found that this “structural violence” led to worse survival for minority patients in the study (Abstract 217).

Latest Data in CAR T-Cell Therapy, BiTEs  

The ASH annual meeting also included a variety of studies on CAR T-cell therapy, from clinical trials to real-world data.

“What strikes me now is that in the CD19 CAR T-cell space, you’re getting much more robust real-world data,” Catherine Bollard, MD, director of the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, D.C., and a professor of pediatrics and immunology at George Washington University, told OBR.

Among the noteworthy research, Dr. Bollard pointed to a real-world study that investigated the tumor-specific factors driving inherent or acquired resistance to CAR T cells in large B-cell lymphoma (Abstract 556). The study, led by researchers at Stanford University, identified CD58 status as an important biomarker for durable response to CAR T cells in large B-cell lymphoma.

This type of real-world data will be even more important as CAR T-cell therapy moves earlier in the treatment of disease, Dr. Bollard said.

“As we continue to expand the reach of new targeted therapies, it is imperative that we deeply study our patients to determine the mechanisms that underscore success, and perhaps even more importantly, failure,” said Leslie S. Kean, MD, PhD, of Boston Children’s Hospital and Dana-Farber Cancer Institute and one of the ASH scientific program co-chairs. She highlighted Abstract 556 as part of her “Best of ASH” presentation.

Dr. Kean also highlighted findings from the primary analysis of the phase 2, Zuma-5 trial, which evaluated axicabtagene ciloleucel (axi-cel) in patients with follicular and marginal zone lymphoma (Abstract 700), noting that one of themes of the ASH meeting was an expansion of cellular therapies beyond their initial indications.

“The maturation of the field is evidenced by multiple commercial CARs now being investigated in these more indolent lymphoma patients,” Dr. Kean said.

Dr. Kean also pointed to an early study looking at the combination of the CAR T product lisocabtagene maraleucel (liso-cel) with the BTK inhibitor ibrutinib for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In the phase 1 TRANSCEND CLL 004 study, researchers found promising efficacy and a manageable safety profile with the combination (Abstract 544).

Other immunotherapy studies presented at ASH were focused on the use of these treatments earlier in the course of therapy.

Dr. Kean pointed to a phase 3 trial in children with high-risk first relapse B-cell precursor acute lymphoblastic leukemia (ALL) that assessed the BiTE molecule blinatumomab, compared with high-risk consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Blinatumomab monotherapy achieved significantly better event-free survival, causing the trial’s data monitoring committee to recommend early termination of enrollment due to benefit (Abstract 268).

Another study focused on treatment with a BiTE molecule earlier in the course of therapy was a phase 2 study that examined the use of a hyper-CVAD chemotherapy regimen with sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL (Abstract 464). The researchers found that the combination was effective in front-line treatment, with a high complete response rate and high percentage of patients achieving measurable residual disease negativity.

Potential New Treatments in Multiple Myeloma

Dr. Kean also highlighted two clinical studies of antibody-based and CAR T-cell therapies for the treatment of multiple myeloma.

The phase 1b/2 CARTITUDE-1 study looked at ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-directed CAR T-cell therapy, in the treatment of relapsed/refractory multiple myeloma (Abstract 177). Researchers reported an encouraging progression-free survival profile of at least a year. The safety and efficacy data indicate that larger studies of this agent are warranted, Dr. Kean said.

Along with CAR T-cell advances, Dr. Kean pointed to a new antibody-based therapy with potential in relapsed/refractory multiple myeloma. A phase 1, first-in-human study, evaluated talquetamab, a first-in-class bispecific antibody that binds to the G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) and CD3 (Abstract 290). Researchers reported a manageable safety profile for the antibody treatment.

“This study suggests that there continue to be ‘new kids on the block’ for these otherwise difficult-to-treat patients,” Dr. Kean said.

By Lynne Lederman, PhD

Enhancer Hijacking of BCL11B Defines a Subtype of Lineage Ambiguous Acute Leukemia (LBA3)

Lindsey Montefiori, PhD, MD, St. Jude Children’s Research Hospital, Memphis, TN, presented evidence that BCL11B structural variants (SV) define a new subtype of acute leukemias of ambiguous lineage (ALAL) that includes subsets of T/myeloid mixed phenotype acute leukemia (MPAL), early T cell precursor acute lymphoblastic leukemia (ETP-ALL, acute undifferentiated leukemia (AUL) and acute myeloid leukemia (AML). ALAL are difficult to diagnose, classify, and treat. This study analyzed 2,573 pediatric and adult samples, including 1,411 B-acute lymphocytic leukemia (ALL), 262 AML 126 MPAL, and 774 T-ALL.

Among BCL11B SV, a novel, high-copy, tandem amplification of a 2.5 kb noncoding region 700 kb downstream of BCL11B on chromosome 14, termed BCL11B Enhancer Tandem Amplification (BETA) was identified and occurs in 20% of the BCL11B subtype. BCL11B breakpoints were shown to occur near CD34+ hematopoietic stem/progenitor cell (HSPC) super enhancers.

Histone H3 lysine 27 acetyl (H3K27ac) chromatin conformation capture followed by high-throughput sequencing (HiChIP) confirmed rearranged enhancers are active and loop to BCL11B. BETA therefore represents a new mechanism of de novo super enhancer formation in leukemia.

Dr. Montefiori said they are eager to develop mouse models to investigate BCL11B expression in HSPC. She said that BETA represents a unique mode of generating a transcriptional activator in any context, and that they are pursuing the possibility that it could be used as a biomarker. RNA can be detected from this region in leukemic cells, and in the absence of whole genome sequencing data they have been able to detect samples harboring the tandem amplification, reflecting its strong enhancer activity.

ETNK1 Mutations in Atypical Chronic Myeloid Leukemia Induce a Mutator Phenotype That Can be Reverted with Phosphoethanolamine (LBA5)

Recurrent somatic mutations in ETNK1 kinase, which phosphorylates ethanolamine to phosphoethanolamine (P-Et), a precursor of essential cellular phospholipids. These mutations cluster in the catalytic domain, and occur in 13% of patients with atypical chronic myeloid leukemia (aCML), as well as 3-14% of chronic myelomonocytic leukemia (CMML), and 20% of systemic mastocytosis (SM) with eosinophilia.

Diletta Fontana, PhD, University of Milano-Bicocca, Monza, Italy, discussed experiments to examine the oncogenic role of ETNK1 mutations using a cellular CRISPR/Cas9 and ETNK1 overexpression models as well as aCML patients samples.

Mitochondrial activity was significantly increased in ETNK1 mutant or knockout cells compared to wild-type. P-Et treatment restored this activity to wildtype levels. Likewise, both ETKN1 mutant or knockout cells showed increased levels of mitochondrial reactive oxygen species (ROS) production versus wild-type. Similarly, P-Et treatment restored normal ROS production.

Oxoguanine is a specific marker of ROS-induced DNA oxidative mutagenesis. ChIP-Seq data for ETNK1 mutated cells generated using an antibody raised against oxoguanine, revealed a significant increase in oxoguanine in mutated cells, compared with wild-type (P=0.018).

To see if these lesions were driving the onset of a mutator phenotype, a 6-thioguanine resistance assays in the cell models, was performed, showing that in the mutated cells there was a 5.4-fold increase in colony number compared with the wild-type line (P<.0001) that was completely reversed by P-Et treatment.

ETNK1 mutations were associated with genomic DNA double-strand breaks in the cell models as well as in cells from patients with aCML. Mitochondrial ROS production and genomic DNA damage were decreased after P-Et treatment in both the models and patient cells. Mitochondrial DNA damage was not seen.

P-Et was found to control mitochondria potential through direct inhibition of complex II, also known as of succinate dehydrogenase (SDH), by binding to the SDH catalytic domain and competitively inhibiting succinate at concentrations of at least 50µM.

 

Loss of LKB1/STK11 Facilitates Leukemic Progression of the Myeloproliferative Neoplasms (Abstract 1)

By Lynne Lederman, PhD

Myeloproliferative neoplasms (MPN) arise in the hematopoietic stem cells, and provide a model for the earliest stages of malignancy. Mutations leading to MPN frequently arise in utero or childhood, yet MPN develop at a median age of 60 years, suggesting a potentially long time to targeting those mutations.

MPN can progress to aggressive acute myeloid leukemia (AML), although little is known about how this occurs. Most patients with MPN have mutations in the JAK/STAT pathway, and about 60% have additional mutations, some conferring poor prognosis. Genetic mechanisms of progression were addressed in the presentation by Christian Marinaccio, MSc, Northwestern University, Chicago, IL, retitled STK11/LKB1 is a tumor suppressor in the leukemic progression of MPN.

To identify the genetic determinants of progression, an unbiased CRISPR screen was performed in the Jak2V617F Cas9+ Vav-CRE+ mouse which develops MPN. Colony replating assays led to identification of the loss of serine/threonine kinase 11 (Stk11) also known as liver kinase B1 (LKB1) as the driver of progression. In doubly transduced, Stk11 homozygous mouse bone marrow cells, Stk11 loss led to marked changes in gene expression in MPLW515L cells. One upregulated gene is a target of hypoxia inducible factor (HIF). HIF1α is stabilized and sufficient for proliferation, enhancing a lethal MPN phenotype in MPLW515L mice, with intense osteosclerosis, bone marrow failure, and pockets of undifferentiated, immature cells.

Loss of Stk11 enhances the engraftment of human MPN cells in NSGS mice. In 7 paired chronic versus blast phase (AML) samples from patients with MPN, Stk11/LKB1 expression was downregulated in 6 of 7 in the blast phase, with marked increase of HIF1α expression, among other gene expression differences.

Stk11 loss leads to a spent phase MPN in mouse models, and an increase of engraftment in patient-derived xenograft models, suggesting that cooperating mutations might decrease Stk11, driving leukemic transformation. Pseudohypoxia in MPN blast phase could provide avenues of treatment by targeting hypoxia inducible proteins.

BCL10 Gain-of-Function Mutations Aberrantly Induce Canonical and Non-Canonical NF-Kb Activation and Resistance to Ibrutinib in ABC-DLBCL (Abstract 3)

The activated B-cell (ABC) subtype one of the most aggressive of the diffuse large B cell lymphomas (DLBCL). DLBCL have been further subtyped by mutation profiles. A novel class, Cluster 1 or BN2 comprises mostly ABC DLBCL with high levels of BCL10 gain-of-function mutations. According to presenter Min Xia, PhD, Weill Cornell Medical College, New York, NY, BCL10 drives DLBCL as part of the CBM complex (CARD11-BCL10-MALT1), driving NF-κB activation downstream of B-cell receptor signaling.

BCL10 mutation patterns define 2 broad classes of mutations. Class I consists mostly of CARD missense mutations, and Class II mostly truncating C-terminal mutations. This presentation focused on one in each class, the missense mutation R58Q (CARD domain) and the nonsense truncation mutations E140X. Both of these mutations highly enhanced NF-κB activation, and enhance MALT1 proteolytic activity and IL6 expression.

Dr. Xia’s group looked at the effect of BCL10 Class I and II mutations on CBM complex structure and function. BCL10R58Q stabilizes BCL10 filaments. BCL10E140X rapidly and spontaneously forms polymers at lower concentrations than wild type protein, and is able to interact with MALT1 even though it lacks the MALT1 interaction domain. Both BCL10R58Q and BCL10E140X filaments recruit MALT1.

BCL10 mutations at least partially rescue ABC-DLBCL cells from dependence on CARD11 signaling for the enzymatic activation of MALT1, as a CARD11 knockdown did not impair MALT1 activation, NF-κB signaling, or cell growth in ABC-DLBCL lines expressing both BCL10 mutants. This has clinical implications, because the CBM complex function is normally dependent on BTK activation, which is a target of widely used drugs, including ibrutinib.

The expression of BCL10R58Q and BCL10E140X, but not wild type BCL10, in ABC-DLBCL cell lines prevented ibrutinib from inhibiting MALT1 activity, and rescued ibrutinib impairment of NF-κB activity. Both classes of BCL10 mutations attenuated ibrutinib-induced growth suppression of ABC-DLBCL cells. Therefore, BCL10 mutations are likely to confer resistance to BTK-targeted therapies, suggesting a need for an alterative approach.

ABC-DLBCL cells with BCL10 truncating mutations that are resistant to ibrutinib remain highly sensitive to MALT1 inhibitors, including the MALT1 inhibitor JNJ-67856633, which is in early phase trials in B-cell lymphomas (Abstract 2091).

 

By Lynne Lederman

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102 (Abstract 75)

Although allogeneic hematopoietic stem cell transplant (HCT) improves survival in MDS, it is not offered to many older individuals with high-risk myelodysplastic syndrome (MDS), and is not covered by Medicare. Corey Cutler, MD, MPH, City of Hope, Duarte, CA, presented the first analysis of an open-label, multicenter, biologic assignment trial (BMT CTN 1102, NCT02016781) in individuals age 50-75 years with higher risk de novo MDS who were candidates for reduced-intensity conditioning (RIC) allogeneic HCT. Patients (N=384) were assigned to the No Donor arm, and reassigned to the Donor arm when a suitable donor was identified from eligible family members and a 90-day search of unrelated donor registries.

Overall survival (OS) at 3 years from enrollment, the primary endpoint, in the Donor arm (n=260) was 47.9% versus 26.6% in the No Donor arm (n=124; P=.0001). Leukemia-free survival (LFS) a secondary endpoint, was greater in the Donor arm (35.8%) versus the No Donor arm (20.6%; P=.003). There were no differences in OS or LFS in subgroup analyses, including age >65 or ≤65 years. A sensitivity analysis excluding subjects assigned to the No Donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on OS or LFS.

An as-treated analysis of HCT versus No HCT showed greater improvement in 3-year OS (47.4% vs. 16.0%, P<.0001) and LFS (39.3% vs. 10.9%, P<.0001) for subjects who underwent HCT. Of 25 subjects in the No Donor arm who subsequently underwent alternative donor RIC transplant, 3-year OS and LFS were both 58.5%, underscoring the potential value of alternative donor HCT. There were no clinically significant differences in quality of life (QoL) between Donor and No Donor arms.

Dr. Cutler concluded that HCT should be an integral part of MDS management, with early referral to a transplant center for evaluation and to begin a donor search. Pointing out a bias against referring older patients with MDS for HCT, he said, “We’d love to see these patients earlier in their disease course” because it takes longer to find donors for them. He also hoped that when CMS sees data showing HCT improves OS and LFS with no detriment to QoL, they would reconsider their decision ruling about not paying for this treatment.

Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study (Abstract 77)

Robert Zeiser, PhD, University Medical Center, Freiburg Im Breisgau, Germany, presented the first successful randomized, open-label, phase 3 trial (REACH3 study; NCT03112603) of ruxolitinib, an oral JAK1/2 inhibitor, versus best available therapy (BAT) in steroid refractory/dependent (SR/D) cGVHD.

Patients age ≥12 years post-allogeneic HCT with moderate to severe SR/D cGVHD who had received ≥2 prior lines of systemic therapy in addition to corticosteroids were randomly assigned to ruxolitinib (n=165) or BAT (n=164). Cross-over was allowed on or after week 24.

The primary endpoint was overall response rate (ORR) at week 24; secondary endpoints included failure-free survival (FFS), and modified Lee Symptom Scale (mLSS). Baseline characteristics were balanced in both arms. More patients in the ruxolitinib arm (50.3% vs. 25.6% for BAT) remained on treatment at primary analysis. Lack of efficacy was the most common reason for discontinuation in the BAT arm (42.7%); 37.2% in the BAT arm crossed over to ruxolitinib.

The study met its primary endpoint. ORR with ruxolitinib was 49.5% versus 25.6% for BAT (P<.0001). Best ORR was 76.4% versus 60.4%, respectively. Duration of best ORR was not reached with ruxolitinib versus 6.24 months with BAT. FFS was significantly higher for ruxolitinib (not reached) than BAT (5.7 months; HR 0.370; P<.0001). Patients treated with ruxolitinib had greater improvements in symptoms than those treated with BAT by mLSS response (24% vs 11%; OR 2.62; P=.0011). The safety profile for ruxolitinib was as expected.

The Role of Structural Violence in Acute Myeloid Leukemia Outcomes (Abstract 217)

Irum Khan, MD, University of Illinois, Chicago, presented the first study to integrate clinical molecular data, neighborhood characteristics, and treatment patterns to examine race/ethnic disparities in adult AML survival.

The study included adults with AML (N=822) from 2012-2018 at 6 academic cancer centers in metropolitan Chicago, the third most segregated community in the US. Non-Hispanic whites (NHW; n=497) were less likely to be obese, and were twice as likely to have private insurance as non-Hispanic blacks (NHB; n=126; 51% vs. 25%, respectively). Hispanic patients (n=117) were younger, had a lower co-morbidity score, and were most likely to be uninsured.

Intensive induction was administered to 68% of patients. ICU admission during induction chemotherapy was more frequent for NHB (38%) and Hispanic (41%) than NHW (26%) patients. Allogeneic transplants were less common in NHB (22%) than NHW (47%) or Hispanic (42%) patients.

In a combined mediation analysis, tract socio-economic status (SES) variables accounted for 81% of the black/white disparity in leukemia deaths, with a hazard ratio of 1.58 to 1.11, adjusted for tract SES. Tract SES is a latent variable reflecting differences in environmental exposures, opportunities, and resources. Differences in induction treatment and transplant accounted for 41% of the black/white disparity. Co-morbidities and molecular disease differences did not mediate black/white or non-white disparities.

In a press briefing, Dr. Khan said they would like to understand the role of these proxy measures of structural violence prospectively, and how neighborhood SES and environmental exposure affect AML.

Outcomes of Patients with Hematologic Malignancies and COVID-19 Infection: A Report from the ASH Research Collaborative Data Hub (Abstract 215)

William A. Wood, MD, MPH, University of North Carolina, Chapel Hill, presented an updated analysis of outcomes for 656 patients with hematologic malignancies and COVID-19 infection from the ASH Research Collaborative COVID-19 Registry for Hematology. Malignancies included leukemia (57%), lymphoma (25%), and plasma cell neoplasms (18%).

The overall death rate was 20%; it was 33% in those requiring hospital care, and 65% in those requiring ICU-level care. In the prior year, 65% of patients with moderate or severe disease had been treated with cytotoxic chemotherapy, immunotherapy, targeted therapy, or other therapy. COVID-19 disease severity was higher in those with relapsed disease, who were older, or had a survival estimate of <12 months.

The death rate in those who declined ICU-level care was 73% versus 13% in those who did not. Those with a prognosis of <12 months (20% overall) were more likely to have moderate or severe disease and to have declined ICU-level care.

A key finding is that patients with hematologic malignancies are at increased risk for adverse COVID-19 outcomes and are a medically vulnerable population. The risks are greatest in those who are older, have advanced disease or a limited prognosis, or who forego intensive management of their COVID-19 infection. However, risks are not trivial for others.

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