Ten years ago, at the 55th ASH Annual Meeting and Exposition in New Orleans, the headline was, “Excitement Over CAR-Engineered T-cells in Leukemia and Lymphoma” since, for the first time, patients with relapsed refractory lymphoma and B-cell acute lymphoblastic leukemia (ALL) were treated with CD19 chimeric antigen receptors (CARs). The “Best of ASH 2013” also proclaimed imetelstat as the newest disease modifying agent for myelofibrosis which reversed marrow fibrosis in a small study, calreticulin (CALR) was first identified as a driver mutation in myeloproliferative neoplasm (MPN) patients and obinutuzumab was new to the chronic lymphocytic leukemia (CLL) therapeutic armamentarium. That reflection is truly a testament to the scientific progress made each year, which ultimately culminates in scientific leaps over time. Now, there are five FDA approved CAR-T products, imetelstat has moved to a Phase III IMerge trial for myelodysplastic syndromes (MDS) (reported at this year’s ASH), and the CLL treatment landscape has shifted considerably. On December 12, Kojo Elenitoba-Johnson, MD, eloquently reviewed 10 abstracts which spanned from groundbreaking scientific discoveries that mechanistically elucidated new genes and pathways, to practice-changing clinical abstracts. If you weren’t there, here’s what you missed.
Bad drivers, signaling issues: “Dependence of IL-7R-Mediated Signaling on Sphingosine Kinase Activity in Acute Lymphoblastic Leukemia, but Not Healthy Lymphoid Cells, Is an Exploitable Therapeutic Vulnerability” (Abstract 38): For acute lymphoblastic leukemia, interleukin-7 receptor A (IL-7R) is a critical oncogene, and sphingosine kinases (SK) have been shown to promote leukemic cell survival. The investigators unraveled the web of interactions and oncogenic signaling between IL7R and SK which confirmed SK’s role as a positive modulator of IL7-IL7R signaling in ALL thereby identifying a potential new therapeutic target for IL7R dependent ALL. “N/KRAS-Mutant AML LSCs Originate from Committed Myelomonocytic Progenitors and Drive Clinical Resistance to Venetoclax" (Abstract 403): RAS mutations occur late in acute myeloid leukemia (AML). Here the investigators mapped the oncogenic and hematopoietic hierarchical mutational landscape of AML and demonstrated that the late temporal acquisition of RAS mutation transforms only progenitors committed to myelomonocytic lineage derived from ancestral AML clones. Through re-analysis of a trial of newly diagnosed AML patients treated with decitabine and venetoclax, the investigators established that it is not the monocytic stage of AML that portends poor prognosis but that the RAS mutant leukemic stem cells which harbor altered BCL2 gene expression at the crux of venetoclax.
Promising new drugs: “Stem-Cell Enriched Cellular Hierarchy of TP53 Mutant Acute Myeloid Leukemia Is Vulnerable to Targeted Protein Degradation of c-MYC” (Abstract 583): We could have a new therapeutic for TP53 mutant AML on the horizon! In defining the cellular hierarchy of TP53 mutant AML which demonstrated an excess expression of c-MYC, the investigators have identified a first-in-class cereblon modulator (CELMoD), which can degrade MYC and improve survival in TP53 mutant AML based on PDX models. “RSK1 Is an Exploitable Dependency in Myeloid Malignancies” (Abstract 46): These investigators collated the largest comprehensive atlas of myeloproliferative neoplasms and secondary acute myeloid leukemias through RNA sequencing and mass cytometry which ultimately implicated aberrant PI3K/AKT/mTOR signaling as a central pathway in myeloid malignancies with ribosomal S6 kinases (RSK) as the central modulator of the hyperactive signaling pathways. They discovered that PMD026, an oral RSK inhibitor originally studied in breast cancer, could instead be redeployed to target and treat RSK1 dependent myeloid neoplasms.
Splicing and dicing: While specific splicing mutations are typically a hallmark of myelodysplastic syndromes, abnormal splicing resulting in unique products such as MBD1-L (long isoform of Methyl-CpG-Binding Domain 1) have been observed. Yet, is there any significance of these aberrant splicing products on hematopoiesis? The presenters of “Aberrant Splicing of MBD1 Reshapes the Epigenome to Drive Convergent Myeloerythroid Defects in MDS” (Abstract 317) tackled this question and demonstrated in cell lines how various isoforms of mutation independent splicing impacted erythroid differentiation. The full-length isoform of MSD1-L impaired hematopoiesis while reversal of MBD1-L splicing restored hematopoiesis. In determining the contribution of mutation independent splicing to dyserythropoiesis and MDS phenotype, the researchers have identified potential new targets to modulate splicing.
Blame the microbiome: The plot thickens when it comes to graft-versus-host disease (GVHD). In addition to MHC-incompatibility between donor and recipient, microbiome specific donor T-cells responding to recipient microbiota could be another mechanism for gastrointestinal GVHD. Functional studies in allogeneic stem cell transplant murine models elegantly supported this hypothesis. The investigators of “Microbiota-Specific T Cells Contribute to Graft-Versus-Host Disease After Allogeneic Stem Cell Transplantation” (Abstract 345) demonstrated microbiome-specific alloreactive T-cell expansion. The microbiome could be the next target to modulate GVHD!
Predisposed to clonal hematopoiesis? Does germline variation impact clonal hematopoiesis? It definitely seems that way. In a study of just under 450 000 individuals from the U.K. biobank with a validation cohort from Memorial Sloan Kettering and Cancer Genome Atlas, the investigators of “Genetic Determinants of Clonal Hematopoiesis and Progression to Hematologic Malignancies in 479,117 Individuals” (Abstract 811) not only identified polygenic variants in 15 genes (eight of which were novel) that increased risk of clonal hematopoiesis but identified another 102 germline genes that predisposed to clonal hematopoiesis in specific genes/genetic regions on SNPS. This important study showed that germline polygenic variants result in a specific clonal hematopoiesis profile, and should inform patient screening and risk stratification.
MRD-directed care: Minimal residual disease (MRD)-targeted approaches to guide and personalize treatment decisions continued to be a focus at this year’s ASH. The “Phase III FLAIR Study” (Abstract 631), in which venetoclax and ibrutinib were administered to newly diagnosed CLL patients, not only showed impressive progression-free survival (PFS) superiority over the fludarabine-cyclophosphamide-rituximab (FCR) control arm, but optimized outcomes by individualizing treatment duration with venetoclax and ibrutinib based on MRD response.
Pass on the transplant? It appears that patients with intermediate risk NPM1-mutated AML, regardless of FLT3 status, may not need an allogeneic transplant in the first remission (CR1allo) if they are MRD negative given the low risk of relapse and negligible benefit of transplant in this population. Abstract 425 masterfully outlined how MRD testing can stratify transplant decision-making in such patients, based on a cohort of 737 patients on U.K. NCR1 AML17 and AML19 trials.
New standard of care? Could Nivolumab-AVD (Nivo-AVD) potentially be the new standard of care in older patients with advanced Hodgkin lymphoma? In a subset analysis of patients older than 60 years with advanced Hodgkin lymphoma, Nivo-AVD proved to be far better tolerated with substantial improvements in PFS and event-free survival (Abstract 181).
The annual ASH meeting continues to be the premier platform for the dissemination of the most novel discoveries leading to practice-changing treatment approaches. Certainly, these “Best of ASH” selections showcase our exponential scientific journey and forecast the remarkable future for care of patients with hematologic malignancies.
Dr. Cook indicated no relevant conflicts of interest.
