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Wednesday, April 18, 2018

Results from a retrospective study of 1,629 patients with non-Hodgkin lymphoma (NHL) showed that survival at 4 years following allogeneic hematopoietic cell transplantation (HCT) for patients age 65 years and older is comparable to patients age 55-64 years. The study demonstrates that age alone should not be a determinant when considering HCT for patients with NHL. The study results were presented in an oral session at the BMT Tandem Meetings (Abstract 78).

This multi-center study—conducted by researchers at the CIBMTR (Center for International Blood and Marrow Transplant Research)—compared the outcomes of 446 patients age 65 years and older with outcomes of 1,183 patients age 55-64 years who underwent allogeneic HCT for NHL from 2008 to 2015. Disease subtypes of NHL included follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and mature T- or NK-cell lymphoma.

No significant differences were found in the 4-year overall survival (46% vs. 51%, p=0.07) and disease relapse/progression (42% vs. 41%, p=0.82) after allogeneic HCT for patients in the 65 and older age group (median age 68), compared to patients in the 55-64 age group (median age 60).

No significant differences were found in the cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) at day 180 in the 55-64 years and ≥65 years cohorts: 37 percent versus 35 percent, respectively (p=0.38). The cumulative incidence of chronic GVHD at 2 years was also comparable in the 55-64 year age group and ≥65 year age group: 48 percent versus 45 percent, respectively (p=0.25).

"Age alone should not be a determining factor in the decision to refer older patients for transplant consultation to determine patient eligibility," said Nirav Shah, MD, lead author and Assistant Professor of Medicine at the Medical College of Wisconsin's Division of Hematology and Oncology. "Advances in conditioning regimens and progress in post-transplant care have allowed more patients more than 65 years old or those with co-morbidities to undergo allogeneic HCT. In 2017 alone, nearly 19 percent of transplant patients were more than 65 years old."

In addition to age, another barrier that patients and their providers face in choosing transplant as a treatment option is the potential lack of insurance coverage. Currently, the Centers for Medicare & Medicaid Services (CMS) has expanded coverage to HCT for myelodysplastic syndromes, sickle cell disease, myelofibrosis, and multiple myeloma under Coverage with Evidence Development. Transplants for these indications need to take place within a CMS-approved clinical study that meets federal guidelines.

Shah noted that use of allogeneic HCT to treat patients with NHL age 65 years or older in the U.S. is limited by Medicare coverage for this indication. Coverage for lymphoma is currently available to those states that reside in the National Government Services jurisdiction. While this effort has been applauded, clearer coverage policy for beneficiaries with lymphoma in all states is needed to reduce this access barrier for patients who are eligible for HCT.

The results will be used for further analysis to develop a strategy for nationwide CMS coverage, according to Susan N. Leppke, Director, Public and Payer Policy at the NMDP/Be The Match. "We are excited about these results and we look forward to using this information to help shape our strategy to reduce access barriers for Medicare beneficiaries with lymphoma," she stated.

This study acknowledges HCT as an important and effective treatment for patients with NHL regardless of age.

Wednesday, April 18, 2018

A new study published in The Journal of Molecular Diagnostics has established that hybrid-capture sequencing is the method of choice for sequencing "actionable" gene mutations across the most common forms of lymphoid cancer, including follicular lymphoma (2018; doi:10.1016/j.jmoldx.2017.11.010).

Due to its applicability in routinely acquired formalin-fixed, paraffin-embedded tissues, this assay can be implemented by clinical laboratories into routine diagnostic workflows. It reliably identifies potentially actionable gene mutations in 91 percent of patients. This assay will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid cancer.

"To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays. Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care," explained Christian Steidl, MD, Senior Scientist at the BC Cancer Agency and Associate Professor in the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. "Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care."

Lymphoid cancers include follicular lymphoma (FL), diffuse large B-cell lymphomas (DLBCL), and chronic lymphocytic leukemia (CLL), which were the focus of the present study. In recent years, several sequencing-based assays have been developed, but their clinical applicability and utility for patients with specific mutations still needs to be shown. Actionable gene mutations are defined by having a reported correlation with treatment outcome, a molecular association with a particular targeted therapy, or increasing pathologic-diagnostic accuracy. Currently, most genetic mutations associated with lymphoid cancers have been identified.

"This study is remarkably comprehensive, which will help any molecular laboratory design implement their own next-generation sequencing lymphoma panel using this work as a template," commented Robert S. Ohgami, MD, PhD, Assistant Professor of Pathology at the Stanford University Medical Center, in an accompanying editorial (J Mol Diagn 2018; doi:10.1016/j.jmoldx.2018.01.002).

Unlike whole-genome sequencing, this assay targets a select set of genes or regions with known associations with lymphoid cancer, allowing for more rapid detection of a variety of mutations. According to this study, capture hybridization is a better method over amplicon-based sequencing, when using formalin-fixed, paraffin-embedded tissue.

Also, this assay is continuously modifiable due to its modular flexible design. The 32-gene next-generation sequencing panel described in the paper was developed with input from a group of six specialists who kept updating it based on the latest available information. "This allows for continuous integration of additional gene features as our knowledge base improves," added Steidl.

The investigators applied the assay to tissues from 219 patients with lymphoid cancers (114 FL, 76 DLBCL, and 29 CLL) who were treated in British Columbia, Canada, between 2013 and 2016. At least one actionable mutation was found in 91 percent of the tumors. The assay revealed cancer subtype-specific mutational profiles that were highly similar to published mutational profiles for all three types of lymphoid cancer. The assay was also found to have 93 percent concordance with whole-genome sequencing.

"Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” noted Steidl. “We believe our study will help establish evidence-based approaches to decision-making in lymphoid cancer care. 

“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories,” he concluded. “Toward the goal of biomarker-driven clinical decision-making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”




Wednesday, April 18, 2018

Updated data from a trial evaluating G100, a novel synthetic TLR4 agonist for intratumoral immunotherapy, supported the potential of the treatment as well as the view that an immunotherapy may provide additional clinical benefit with time. 

The data was recently presented at the 2017 American Society of Hematology Annual Meeting (ASH 2017) from a randomized phase II trial of 26 follicular lymphoma patients. Patients were randomized evenly to one of two treatment arms: G100 with fractionated, low-dose radiation (XRT) or G100+XRT with pembrolizumab combination therapy. 

The data have matured as of the most recent data analysis, with observations as follows:
•Additional responses have been observed in the combination arm (54% ORR, compared to a 15% ORR in the G100+XRT arm). This is an improvement from the ASH 2017 data, which showed an ORR of 39 percent in the combination arm.
•The patient population with high TLR4 expression in the tumor continues to receive greater benefit, with an updated 75 percent ORR on the combination arm (6/8 patients), an increase from the 57 percent ORR reported at ASH 2017.
•These data compare favorably to pembrolizumab monotherapy presented at ASH 2017, which showed an 11 percent ORR in a separate follicular lymphoma study.
•Seventy-seven percent of patients in the combination arm experienced abscopal tumor shrinkage in un-injected tumors, compared to 54 percent of patients in the G100+XRT arm.
•Patients in the combination arm demonstrated a greater increase of CD8 T cells within the tumors, as compared to the G100+XRT arm.
•The safety profile continues to appear favorable when compared to recently approved therapies for patients with relapsed/recurrent disease.

G100 activates innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor's preexisting diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The induction of local and systemic immune responses has been shown in preclinical studies to result in local and abscopal tumor control.


Thursday, March 29, 2018

A study conducted at The Wistar Institute in collaboration with The University of Texas Southwestern Medical Center has demonstrated the efficacy of targeting aberrantly active telomerase to treat therapy-resistant melanoma (Clin Cancer Res 2018; doi:10.1158/1078-0432.CCR-17-2773).

The introduction of targeted therapies and immune checkpoint blockade therapies has revolutionized the therapeutic options for patients with advanced melanoma. However, the long-term therapeutic benefit of these new approaches is still hindered by the onset of therapy resistance, which can develop through different mechanisms.

A hallmark of several cancer types, including melanoma, is the aberrant regulation of telomerase activity due to mutations in the regulatory element of the telomerase gene, which results in increased production of the protein. Telomerase is an enzyme responsible for protecting the integrity of chromosome ends during replication. While it is absent in most normal adult cells that don't actively proliferate, telomerase is reactivated in cancer cells, allowing continuous cell divisions and making them immortal.

"Our work presents pre-clinical evidence that targeting the aberrant telomerase activity may provide a universal strategy to overcome therapy resistance and achieve long-term melanoma control," said lead researcher Meenhard Herlyn, DVM, DSc, Caspar Wistar Professor in Melanoma Research and Director of The Wistar Institute Melanoma Research Center.

Herlyn and his collaborators used a modified telomerase substrate they had previously described, called 6-thio-dG, to impair telomerase activity by inducing telomere dysfunction. They showed that 6-thio-dG induced cell death in melanoma cells carrying mutations in the BRAF gene without affecting the viability of normal skin cells, and it impaired the growth of several BRAF-mutant melanoma cell lines transplanted in mice. The BRAF gene is mutated in approximately half of all cases of melanoma.

The team also studied the ability of 6-thio-dG treatment to stop proliferation and tumor growth of therapy-resistant melanoma cells. They created a large panel of human melanoma cell lines with acquired resistance to targeted therapy and immunotherapy and showed a general sensitivity of these cells to 6-thio-dG both in vitro and in vivo in mouse models.

"Our results add to the mounting evidence supporting the existence of an important relationship between telomeres and telomerase and cancer," said Gao Zhang, PhD, a staff scientist in the Herlyn Lab and first author of the study. "Our data suggest that 6-thio-dG may be used either as monotherapy following first- and second-line therapies to prolong disease control after onset of resistance, or in combination with first-line therapies to overcome intrinsic resistance."

Thursday, February 15, 2018

According to a new study by The Wistar Institute, Philadelphia, EZH2 inhibitors that are currently in clinical development for hematological malignancies and solid tumors may be effectively targeted to epithelial ovarian cancers overexpressing the CARM1 protein. The research was published online in Nature Communications (2018; doi:10.1038/s41467-018-03031-3).

Ovarian cancer is the most lethal gynecological malignancy and only limited therapeutic options are currently available. Because of the high genetic heterogeneity of this type of cancer, scientists are working to expand their knowledge of the molecular alterations underlying tumor onset and progression in order to design individualized therapeutic strategies. Results of this new study demonstrated an elevated expression of the CARM1 protein in a set of ovarian cancer tissues compared with normal tissue. CARM1 is a known oncogene in several cancer types, but prior to this study, there were no reports on its role in ovarian cancer.

"Previous studies suggest that direct targeting of CARM1 activity could result in high toxicity," said lead researcher Rugang Zhang, PhD, Deputy Director of The Wistar Institute Cancer Center, Professor and Co-Program leader of the Gene Expression and Regulation Program. "Therefore, we sought to identify an alternative, clinically applicable therapeutic approach for this specific group of patients. We discovered that inhibitors of EZH2 provide an effective strategy to treat ovarian cancers with elevated CARM1 expression."

Zhang and colleagues analyzed a publicly available atlas of ovarian cancer genetic profiles and observed that CARM1 expression is elevated in approximately 20 percent of cases, and it is associated with poor patient survival. Importantly, high CARM1 expression is mutually exclusive with the presence of mutations in BRCA1/2. They also found that small molecule inhibitors of EZH2, which block the EZH2 enzyme and are in clinical development for hematopoietic malignancies, selectively induce arrest of proliferation and cell death in cells with high CARM1 levels and not in cells with normal CARM1 levels.

Mechanistically, the researchers showed that CARM1 regulates the balance between the antagonistic activities of EZH2 and another protein, BAF155. Both these proteins modify the structure of chromatin in specific positions, exerting opposite effects on expression of a common set of target genes that inhibit tumor progression. Causing BAF155 displacement from these targets, CARM1 favors binding of EZH2, which in turn inhibits expression of these antitumor genes, thus favoring tumor progression. The team demonstrated that EZH2 inhibition is an effective strategy to suppress the growth of tumors expressing CARM1 by reactivating these antitumor genes.

The research also included in vivo studies confirming that the EZH2 inhibitor significantly suppressed tumor growth and improved survival in mouse models of ovarian cancer.

"Our study suggests a therapeutic benefit for repurposing a well-tolerated inhibitor with limited toxicity to treat a specific group of ovarian cancer patients with high levels of CARM1 expression," said Sergey Karakashev, PhD, first author of the study and a postdoctoral researcher in the Zhang Lab. "Given that CARM1 expression is elevated in other types of cancer, our findings may be extended to a broader array of cancer patients."