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Where It All Comes Together for Chronic Myeloid Malignancies

December 16, 2021
Tania Jain, MBBS

Dr. Tania Jain (@TaniaJain11) is an assistant professor and director of the Adult CAR T Program at Johns Hopkins University. Her academic interest is in cellular therapy, bone marrow transplantation, and myeloproliferative neoplasms including overlap with myelodysplastic syndromes. She is a graduate of Government Medical College, Patiala (Punjab), India, where she received her medical degree, before going on to a residency at Wayne State University/ Detroit Medical Center, and fellowships at Mayo Clinic in Arizona and at Memorial Sloan Kettering Cancer Center for bone marrow transplantation. 

Dr. Jain grew up in Chandigarh, India, and has since been, in her words, “nomadic … our current residence in Baltimore is what we call home now.” She is a longtime enthusiastic attendee of the ASH annual meeting since second year of fellowship (no breaks) as well as speaker at Highlights of ASH® in North America in 2020. Prior to travel restrictions, Dr. Jain enjoys chipping away at some very specific and ambitious travel goals with her husband. “Our travel adventures of late revolved around visiting the four (north, south, east, and west) extreme points of the United States. We have thus far been to Point Barrow in Alaska (northernmost), Point Buoy in Key West, Florida (southernmost for the continental United States), and almost to (less than 10 miles away from) Ka Lae (South Cape) in Hawaii, which is southernmost for the US overall,” she explained. “This got interrupted with COVID, but we are excited to get back to our travel adventures.” Fingers crossed, and happy trails, Dr. Jain! 

The ASH annual meeting is a boundless scientific gala that can easily put you in a state of cognitive dissonance. But the trip back home is the time to allow all you have heard and learned to coalesce, and let it sink in. If chronic myeloid diseases are in your wheelhouse, here I will summarize some sessions I think would probably interest you. So, whether you attended any of these or still need to catch the recordings on the virtual platform, here is a bit of guidance through a few key takeaways. 

Let’s start with what interests me the most: myeloproliferative neoplasms (MPNs). The oral abstract session “Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis,” which happened on Sunday, December 12, highlighted the latest and greatest on an LSD1 inhibitor (bomedemstat) in essential thrombocythemia, as well as PTG-300 (rusfertide) in polycythemia vera. With the recent U.S. Food and Drug Administration (FDA) approval of ropeginterferon for polycythemia vera, the emergence of these novel therapies could be a good problem to have. The Saturday afternoon session titled “Myeloproliferative Syndromes: Clinical and Epidemiological: Non-JAK inhibitor Therapies for Myelofibrosis” highlighted additional novel agents targeting CD123 (tagraxofusp), TGF-β (AVID200), bromodomain and extra-terminal motif (pelabresib), and nuclear export (selinexor). All of them appear to be marching forward with promising early results, and time will tell which of these will eventually demonstrate improved quality of life and better overall survival, while maintaining treatment affordability. 

Multi-omics single-cell analysis was a big theme at #ASH21. In addition to the plenary abstract on TP53-mutated MPNs (see my coverage of the abstract on the ASH News Daily website), the oral abstract session titled “Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational I” featured two single-cell analysis–based abstracts: One of them delineated mechanisms of response in MPNs using interferon, which appears to redirect hematopoietic differentiation based on underlying mutation status and downregulate key pathways implicated in MPN pathogenesis such as TNF-α and TGF-β. The other beautifully highlighted clonal heterogeneity in chronic and blast-phase disease in serial longitudinal samples, again using single-cell mutation analysis with the Tapestri platform.  

Some entities within MPN are scarce as hen’s teeth and have historically met the challenge of academic neglect. But now, with the ever-improving understanding of targets and targeted agents, some of these have gained traction. To that end, Dr. Jason Gotlib presented the results of FIGHT-203, the phase II study of pemigatinib for myeloid/lymphoid neoplasms with fibroblast growth factor receptor (FGFR1) rearrangement (abstract 385). FGFR1 is a receptor tyrosine kinase on chromosome 8p11. Translocation of FGFR1 with one of its 16 translocation partners results in constitutive activation of FGFR1. Pemigatinib, which is a kinase inhibitor currently FDA approved for FGFR1-mutated cholangiocarcinoma, showed 64 to 77 percent complete response rates, and 72 to 76 percent complete cytogenetic response rates, which thus far remain durable. This is all first-of-a-kind in this entity, and we hopefully will hear more about this drug in the future from subsequent trials.  

Let’s transition now into the world of the Philadelphia chromosome–positive MPN- chronic myeloid leukemia (CML), where imatinib made it to the cover of Time magazine in May 2001 and led the way for targeted therapy. While survival has only trended upward from there, with most patients enjoying new-normal life expectancy, we cannot be anywhere near complacent because relapsed or refractory disease and progression to acute myeloid leukemia is real! In an MPN-exclusive clinic, you see it enough to know it’s not trivial. Hence, understanding the biology of insensitivity to tyrosine kinase inhibitors (TKIs), relapse and transformation to acute myeloid leukemia needs ongoing exploration. At the Saturday oral abstract session “Myeloproliferative Syndromes and Chronic myeloid Leukemia: Basic and Translational,” Dr. Helong Zhao presented the role of MS4A3 in differentiation, and downregulation thereof, in favor of the primitive leukemia stem cell state, which is a card-carrying member of the “TKI insensitive” club. Then, from the oral abstract session “Chronic Myeloid Leukemia: Clinical and Epidemiological: Mechanisms of Resistance and Expanded Therapies,” there are many highlights, including asciminib versus bosutinib after two or more prior TKIs (Ascembl study). Recall that asciminib is the newest kid on the CML block, comes with a unique mechanism of binding to the myristoyl site of the bcr-abl1 protein locking it in an inactive conformation, and targets both naïve and mutated bcr-abl1 including the scary T315I mutation. Vodabatinib and olverembatinib are other third-generation TKIs that have shown encouraging early results, albeit not targeting the T315I mutation. 

Last but by no means least, programming in myelodysplastic syndromes (MDS) kicked off via ASH Scientific Workshops and Satellite Symposia on Friday. All taken together, we got coverage of the most current and forward-looking schema of risks, prognostic stratification, and treatment decisions that are becoming more and more personalized. I was also intrigued by the Education Program session “MDS: Beyond a One-Size-Fits-All Approach” (with accompanying live Q&A) held on Sunday, December 12. It’s probably worth emphasizing the “low risk but high risk” ideology from Dr. Amy DeZern, which goes beyond the Revised International Prognostic Scoring System (IPSS-R) in prognostication of individual patients and does a deep dive into how mutation profiling is a key component of this kind of risk stratification. The oral abstract session “Myelodysplastic Syndromes – Clinical and Epidemiological: Treatment of High Risk Myelodysplastic Syndrome,” covered the successes and failures of the various clinical trials conducted recently, including pevonedistat, sabatolimab, eprenetapopt, venetoclax, and others in various combinations and line-ups for MDS treatment. Each of these comes with a lesson, irrespective of the results. For the basic and translational scientists, the oral session “Myelodysplastic Syndromes—Basic and Translational: Clonal Progression and Aberrant Erythropoiesis in Splicing Factor-Mutant MDS” held on Saturday, December 11, provided fundamental insights into the cell-type–specific impact of SF3B1 mutations on hematopoietic differentiation, MDS-RS pathogenesis, and clonal progression. 

Before I forget, I hope you did not forget the related poster sessions, which cover a vast majority of the science that’s presented at the meeting. Until next time! 

Dr. Jain indicated no relevant conflicts of interest. 

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