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A New Angle for #ASH20

November 15, 2020

As an introvert, I am relieved that the virtual platform means avoiding the masses and dodgy coffee. As a human, I mourn the loss of tradition and sense of normalcy. Like most other aspects of 2020, the 62nd ASH Annual Meeting will operate with an “improvise, adapt, and execute” mantra.

However, three hopeful themes have emerged from my preview of the program.

The first is an uplifting story about death: B-cell lymphoma 2 (BCL2) and the clinical development of BH3 mimetics will be the focus of this year’s Ham-Wasserman lecture, presented by Dr. Andrew Roberts from the Walter and Eliza Hall Institute, Australia’s oldest medical research institute and the conceptual birthplace of BCL2 as an archetype of programed cell death inhibitors. In the past 30 years, it has become evident that several hematologic malignancies are governed by a balancing act between antiapoptotic proteins (including BCL2), their “guardians,” and proapoptotic “BH3-only” effectors. Venetoclax (like Prince, “formerly known as” ABT-199) — a BH3 mimetic that selectively inhibits BCL2 — now has full U.S. Food and Drug Administration approval for untreated and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma and untreated acute myeloid leukemia (AML; in combination with low-dose cytarabine or hypomethylating agents) in patients unsuitable to receive intensive induction chemotherapy. However, the road to the clinic was not smooth. Detours included: fatal tumor lysis syndrome, disappointing single-agent activity in AML (until the concept of mitochondrial apoptotic priming through rational drug combinations was enacted), and dependency on alternative antiapoptotic proteins such as BCLXL or MCL1. In the year that both VIALE-C and VIALE-A phase III results were released, there is much to celebrate about (tumor) death.

The second promising theme is the concept of “slaying (former) dragons” in which traditionally difficult clinical scenarios are being addressed head-on. Blast-phase transformation of Philadelphia (Ph) -negative myeloproliferative neoplasms (MPNs) has dismal outcomes relative to de novo AML. The underlying pathogenesis has eluded us. The plenary session to be presented by Christian Marinaccio, MSc, and colleagues promises to make a compelling case for the causal role of serine/threonine kinase 11 (STK11), also known as liver kinase B1 (LKB1), downregulation in blast-phase transformation of Ph-negative MPNs. Moreover, their proposition that this results in downstream upregulation of mTOR signalling and stabilization of hypoxia-inducible factor 1-α, opens the door to “druggable” targets. Another dragon that appears to be losing its fire is the adverse impact of TP53 mutations and associated complex karyotypes in myelodysplastic syndromes and AML. I look forward to the updated early-phase results of drug combinations either targeting (e.g., APR-246) or potentially agnostic to (e.g., magrolimab) TP53-mutated disease. Last but not least, is the acceptance that we are well beyond the “BC” (before cellular) therapy era now, as reflected by the ambitious agenda of the ASH-EHA Joint Symposium “Failure of Targeted Cellular Immunotherapy and Hematopoietic Cell Transplant: Mechanisms and Mitigating Strategies” to be presented by Dr. Crystal L. Mackall from the National Cancer Institute, NIH, and Dr. Luca Vago from San Raffaele Scientific Institute in Milan, Italy.

The third encouraging theme to emerge is the future is now (whether we like it or not, especially for those people still resisting the Apple Watch). The field is moving beyond the clinical application of next-generation bulk sequencing to plasma cell–free DNA (cfDNA), mass spectrometry, and single-cell sequencing, with promises, pitfalls, and standardization, to be covered by two joint scientific committee sessions (“Single Cell Analysis of Hematopoietic Development and Clonal Complexity of Malignant Hematopoiesis” and “Getting the Most from Minimal Residual Disease,” respectively). Multiple oral and poster presentations (“Single-Cell Analysis of the Classical Hodgkin Lymphoma Immune Environment Reveals a Clonally-Expanded CD8+ T Cell Population with a Cytotoxic Phenotype” and “Integrated Cytof, Scrna-Seq and Cite-Seq Analysis of Bone Marrow Immune Microenvironment in the Mmrf Commpass Study,” for two) also advertise the use of single-cell RNA sequencing to capture clinically actionable transcriptome heterogeneity of the bone marrow microenvironment in AML, Hodgkin lymphoma, and multiple myeloma. Indeed, the seed-soil dichotomy is yet another false one.

About the Author

Danielle Hammond, MD, is currently the Chief Leukemia Fellow at the University of Texas MD Anderson Cancer Center, with clinical interests in clonal hematopoiesis, acute leukemias, and inherited and acquired bone marrow failure syndromes. A Canadian, she received her hematology-oncology training at Queen’s University, Kingston, Ontario. For the past few years, she has been a contributing author to the Canadian Hematology Society newsletter, The Microenvironment.

Dr. Hammond grew up in the country amongst a family of veterinarians. “It is remarkable how similar the practice of oncology is in the veterinary world,” she notes. “When my family’s golden retriever was thought to have an aggressive B-cell lymphoma, frontline CHOP chemotherapy was offered. Anti-canine CD20 antibodies are still under development though, as the first-generation ones had disappointing antibody-dependent cellular cytotoxicity. Some would be surprised to learn that the National Cancer Institute has a Comparative Oncology Program and a Pre-medical Cancer Immunotherapy Network for Canine Trials.”

Dr. Hammond’s favorite discoveries in Texas are custom license plates and Topo Chico sparkling water. “My current ‘HEMQUEEN’ license plate was a wonderful gift. The other day I saw a Jeep in my building with a ‘N3PHRON’ plate, and I took the challenge personally — I just couldn’t ‘filter’ it out,” she quipped. “I am genuinely obsessed with lime Topo Chico; I have stashes at the hospital.”

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