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Crème de la Crème of #ASH21: The Late-Breaking Show

December 16, 2021
Naseema Gangat, MBBS

Dr. Naseema Gangat (@n_gangat), Editor of the 2021 ASH News Daily, is an associate professor of medicine in the Division of Hematology at Mayo Clinic in Rochester, Minnesota. She specializes in adult hematology and has a special interest in myeloproliferative neoplasms, myelodysplastic syndromes, and acute leukemia. She received her medical degree at Aga Khan University in Karachi, Pakistan, the city that also happens to be her hometown. She moved to the United States to pursue an internal medicine residency followed by hematology/oncology fellowship training at Mayo Clinic in Rochester. Dr. Gangat first got involved with ASH News Daily in 2018 as an Author. If the Burberry reference wasn’t a hint, Dr. Gangat is a proud “fashion-enthusiast” and regular attendee at London Fashion Week as well as Beverly Hills (Rodeo Drive) runway events — occasions known for being almost as exhilarating as the ASH annual meeting. 

Just as Paris Fashion Week marks the end of fashion month with the elitist showings, the Late-Breaking Abstracts (LBAs) sessionco-chaired by Drs. Anita Rajasekhar and Alison Loren on Tuesday, December 14, closed out the annual meeting, with celebratory final moments inspiring anew with the latest and the very best in hematology. “We chose abstracts that represented excellent science providing fundamental insights in hematology, was clinically relevant to hematologists and their patients, and had the potential to invoke meaningful change in practice,” shared Dr. Rajasekhar. Chimeric antigen receptor T-cells (CAR-Ts) in relapsed lymphoma, fitusiran in hemophilia, and clonal hematopoiesis made yet another showing, and for those seeking newness, the session featured discovery of upstream binding transcription factor tandem duplications (UBTF-TD) in pediatric acute myeloid leukemia (AML). Please read on for a thematic synopsis of the six impactful pieces. 

Futuristic View on Large Cell Lymphoma 

The session kicked off with the POLARIX study, which compared polatuzumab vedotin (CD79b-targeted antibody-drug conjugate) in addition to rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated intermediate- and high-risk large cell lymphoma. Although progression-free survival (PFS) was superior with pola-R-CHP (2-year PFS, 76.7%) versus R-CHOP (70.2%), end-of-treatment positron emission tomography-computed tomography complete response (CR) rate was not significantly different with pola-R-CHP versus R-CHOP (78.0% vs. 74.0%; p=0.16). Importantly overall survival and toxicity, particularly peripheral neuropathy rates, were similar in both treatment arms. Is improvement in PFS truly an incremental gain? And at what “cost?” 

Will CAR-Ts supplant autologous stem cell transplantation as second-line therapy for relapsed or refractory large cell lymphoma? Both the ZUMA-7 and TRANSFORM studies instilled high hopes in favor of CAR-T until the unexpected findings of the BELINDA study were unveiled. The study compared tisagenlecleucel (tisa-cel) to standard of care (platinum-based chemotherapy [PCT]) followed by autologous stem cell transplantation in relapsed large cell lymphoma. Arm A consisted of optional bridging therapy followed by lymphodepletion and a single tisa-cel infusion while arm B was investigator choice of PCT regimen followed by autologous transplant in responders or a second PCT in non-responders. Surprisingly, rates of progressive disease (PD) were higher in arm A (26%) versus arm B (14%); however, CR rate was similar in both arms (28%). These unanticipated observations create much food for thought as we speculate on differences in study design, namely optional bridging chemotherapy in arm A, allowance of a different chemotherapy regimen in arm B after inadequate response to first PCT, and timing of CAR-T infusion together with imbalances in patient characteristics. 

Chronicles of Clonal Hematopoiesis 

We waited with bated breath for a chronicle of clonal hematopoiesis including lifelong clonal dynamics and selective pressure elegantly fashioned by Dr. George Vassiliou and his team. Margarete Fabre highlighted mesmerizing data derived from deep targeted sequencing of 56 clonal hematopoiesis genes performed on serial peripheral blood DNA samples obtained from 385 elderly individuals over a time-frame of 13 years. Noteworthy observations included differential mutational growth rates, with the slowest annual growth rate of approximately 5 percent for DNMT3A and TP53 mutations; meanwhile, TET2, ASXL1, PPM1D, and SF3B1 expanded at roughly twice this rate (i.e., ~10%/yr). Intriguingly, DNMT3A mutations initiated and expanded earlier in life, while TET2 mutations exhibited uniform growth throughout life, eventually overtaking DNMT3A later in life. The most rapidly expanding sinister mutations with growth rates of more than 50 percent per year, SRSF2-P95H and U2AF1emerged later in life and were associated with the highest risk of progression to AML and myelodysplastic syndrome.  

Ray of Sunshine for Hemophilia  

At the Plenary Scientific session, we were introduced to the ATLAS-INH study, which demonstrated remarkable efficacy and safety of fitusiran (siRNA therapeutic targeting antithrombin) as prophylaxis versus on demand treatment with bypassing agents in patients with hemophilia A or B with inhibitors. Similarly, the ATLAS A/B study addressed the efficacy and safety of fitusiran prophylaxis compared with on-demand treatment with factor concentrates in hemophilia A or B without inhibitor. Fitusiran 80 mg subcutaneous monthly prophylaxis demonstrated a significant reduction in annualized bleeding rate which included spontaneous and joint bleeds (zero bleeds with fitusiran)without increased thrombosis, rendering meaningful health-related quality of life (HRQOL) improvements. However, questions brought forth during the discussion included predictors of thrombosis, dose of factor replacement, and study design in reference to use of on-demand vs prophylactic factor concentrates. Dr. Rajasekhar shared her enthusiasm stating, “Fitusiran has the potential to shift treatment paradigms in hemophilia A and B patients without inhibitors to prevent bleeding events. Importantly, fitusiran given once monthly advanced HRQOL to help reduce the treatment burden of this chronic disease.”  

Additionally, for patients with severe hemophilia A and high titre inhibitors, results from the VerITI-8 prospective study were seemingly uplifting; recombinant factor VIII Fc fusion protein for first-time immune tolerance induction demonstrated rapid time to tolerization (median 2.7 months) with durable responses in two-thirds of treated patients. 

Serendipitous Discovery in Pediatric AML 

We were fortunate to catch up with Dr. Jeffrey Klco who revealed the backstory. “We were initially interested in defining the spectrum of mutations that are common in relapsed pediatric AML. Through a large cohort of 136 cases, we identified recurrent (almost 10%) tandem duplications in UBTF (UBTF-TD), a nucleolar protein regulating ribosomal RNA expression. The identification required a lot of diligence by our bioinformatics team as these duplications are commonly missed by many pipelines. We then massively expanded our search to other cohorts and found this event in 4 percent of pediatric AML at diagnosis.” Clinically relevant observations included mutual exclusivity of UBTF-TD from other recurrent fusion oncoproteins, NUP98 and KMT2A rearrangements, and associations with FLT3-ITD,WT1 mutations, normal karyotype, trisomy 8, adolescent age, and inferior outcomes. Accordingly, Dr. Klco concluded, “We never see these events in AML with other classic driver fusions and feel that it represents a new subtype of pediatric AML.” 

Despite ongoing pandemic-induced challenges, the LBA session was an illustration of truly diverse, exciting, original, surprising, and innovative science and for those who missed out, the session is available on-demand via the virtual platform. On that note, #ASH21 draws to a close exuding hope that we must keep on. 

Dr. Gangat indicated no relevant conflicts of interest. 

Masayuki Umeda, MD, presents LBA-4, “Integrated Genomic Analysis...”
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