When I was a little girl, few things got my heart pounding faster and more gleefully than the holiday season. The sweet-spicy buckwheat honey aroma of my Baba’s medivnyk (honey cake) being drawn out of the oven, Nana Mouskouri’s warmly scratched Christmas vinyl whirring “Petit Papa Noël,” the box of Godiva chocolates my Dad would pretend to ”surprise” us with every year, loyally guarding the base of the tree — all of it was, well, simply magical. While the holiday magic remains (with some updates, naturally), new memories marked our professional lives this year due to their potential to revolutionize our field, shaking up our metaphorical hematologic snow globe. So together, let’s peek into the bespoke ASH stash of Late-Breaking Abstracts (LBA)!
Jean M. Connors, MD, and Amy E. DeZern, MD, stalwart co-chairs for this session were quick to share their enthusiasm as they took us for a tour around the LBAs, like presents lining a Fraser fir. Dr. DeZern unabashedly exclaimed, “We are both excited about the LBAs,” as she so cogently summarized the critical headlines of each study.
LBA-1: PERSEUS
This first present is actually four presents wrapped in one. That’s right, we’re talking battle quadruplet versus triplet in multiple myeloma (MM). This phase 3 randomized study presented by Pieter Sonneveld, MD, PhD, evaluated daratumumab (DARA) plus bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with MM eligible for autologous stem cell transplantation (ASCT). The quadruplet was associated with deeper response and superior progression-free survival (PFS), with reassuring safety profile, cementing the combination of DARA-VRd followed by D-R maintenance as a new standard of care.
Dr. DeZern’s takeaway: “Finally seems quadruplets really are superior to triplets!”
LBA-2: SYMPATICO
This next present is a small-but-mighty add-on that will have you declaring, “You complete me.” That is if you consider ibrutinib (Ibr) and venetoclax (Ven) as being in a sort of Cruise-Zellweger situation-ship in the mantle cell lymphoma (MCL) therapy universe. This multinational, randomized, double-blind phase 3 study evaluated complementary agents Ibr, a BTK inhibitor — one of the cornerstones of MCL therapy — and Ven in combination, compared to Ibr and placebo (Pbo) in relapsed/refractory (R/R) MCL. Michael Wang, MD reported superior complete response (CR) rates and time to next treatment (TTNT), as well as higher 24-month PFS rates with Ibr+Ven vs Ibr+Pbo (57% vs 45%). This PFS benefit notably extended across high-risk subgroups including blastoid variants and TP53-mutated cases.
Dr. DeZern’s takeaway: “Addition of Ven is beneficial and non-toxic [working] to improve PFS in refractory patients.”
LBA-3: PATH-HHT
So, this is one of those gifts that performs double duty, let’s call it the (maybe) soon-to-be Swiss Army knife for hereditary hemorrhagic telangiectasia (HHT). I mean, how often does an agent produce clinical benefits while simultaneously improving patient quality of life (QoL)? As a reminder, HHT remains the second most common inherited bleeding disorder worldwide and, as was highlighted at this year’s meeting, one of the most significant bleeding disorders in women. It presents with recurrent, severe, highly morbid manifestations, notably epistaxis — with sundry downstream repercussions (anemia, hospitalizations, impaired QoL, etc.), yet there are still no agency-approved therapies. Let us recall (just to connect the dots) that previous angiogenic profiling demonstrated pomalidomide use was associated with inhibition of the vascular endothelial growth factor pathway in patients with HHT. In fact, Keith R. McCrae, MD, who presented PATH-HHT, a double-blind, randomized placebo-controlled trial of pomalidomide in HHT, reflected on his anecdotal first use of thalidomide (a similar immunomodulatory agent), perhaps sparing a patient with uncontrolled bleeding from a bowel resection. This was an “aha moment,” exclaimed Dr.McCrae, and the rest is, well, history, culminating in PATH-HHT, the first adequately powered randomized trial in HHT. This study showed significant reduction in epistaxis and improved HHT-specific QoL scores in pomalidomide-treated HHT patients. The major adverse event was neutropenia, which was managed by dose reduction (which didn’t decrease efficacy), and there was no thrombosis signal.
Dr. DeZern’s takeaway: “Pomalidomide decreases epistaxis and improves QoL in this rare disease!” We concur that this drug repurposing is a win-win and makes for an unforgettable gift with a gleaming bow on top.
LBA-4: BMT CTN 1507
This present is encased in a teeny-tiny square blue box, and, yup, we’re all thinking the same thing: It’s a diamond! The next LBA is certainly as prized, brilliant, and significant. Sickle cell disease (SCD) remains the most common inherited hemoglobinopathy worldwide. Few curative options exist, including bone marrow transplantation (BMT). The caveat? Scarcity of available donors and prohibitive toxicity of myeloablative conditioning remain major obstacles. The study “Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507,” presented by Adetola A. Kassim, MBBS, MS, sought to circumvent these obstacles, potentially changing the SCD treatment paradigm. This multi-center phase II, prospective trial evaluated event-free survival (EFS) using reduced intensity HLA-haploidentical BMT (haplo-BMT) with post-transplant cyclophosphamide (PTCy) in adults with severe SCD. The result?
Let’s throw the mic to Dr. DeZern: “Haplo-BMT in multi-center study in severe sickle cell disease patients! Cure rates ~90%. 10x less expensive than gene therapy/editing. More widely accessible in the United States and likely elsewhere.” Shining bright.
LBA-5: AUGMENT-101
We couldn’t wait for this one. We were naughty and shook it. It made a faint clinking sound. It was so eye-catching — with its glittery embossed gold luster, cheery red bow, and fresh sprig of holly — that we just ripped it right open, and there it was: a key. This key isn’t going to ping open a sweet new ride, it’s actually better than that. Let’s start with the premise that histone-lysine N-methyltransferase 2A (KMT2A)-rearranged (KMT2Ar) acute leukemia typically portends dismal prognosis. In this LBA, Ibrahim Aldoss, MD, reported topline efficacy and safety results of the pivotal phase 2 AUGMENT-101 study evaluating revumenib monotherapy (i.e., the ‘key’ small-molecule inhibitor of menin-KMT2A interactions, known to drive leukemogenesis) in relapsed/refractory (R/R) KMT2Ar acute leukemia. Overall response rate (ORR) was 63.2% with a high proportion achieving MRD negativity and successful bridging to transplant.
Dr. DeZern’s takeaway: “Results of AUGMENT-101 phase 2 illustrate favorable CR and ORR in highly refractory acute leukemia patients … very fun to see another effective targeted therapy in this disease!”
LBA-6: ERG Is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy
Hmm, this last one is puzzling. It makes no sound when shaken. It appears to be some kind of orb? Some manner of soothsaying transparent ball. This is one of those gifts that, once opened, unveils layers and layers of significance, and maybe also some predictive powers. Bone marrow failure (BMF) syndromes can be chameleons, presenting with a broad spectrum of phenotypic features. Many cases lacking classic symptoms and family history may present cryptically, even in adulthood. As such, BMF syndromes are notoriously challenging to diagnose, risk stratify, and manage. Hamish S. Scott, PhD, and colleagues have made a truly impactful contribution here with their discovery of ERG (required for normal megakaryopoiesis, stem cell function, and definitive hematopoiesis) as a novel predisposition gene for BMF and hematologic malignancies, identifying 15 heterozygous ERG variants in 17 individuals, both pediatric and adult. As a reference point, this syndrome mirrors that of GATA2 deficiency. Delineation of the natural history is a work in progress but direct practical relevance, from diagnosis to surveillance, counselling to therapy is formidable. As Dr. DeZern explained, this is not only a “paradigm for identifying biology of disease but also [understanding] screening and clinical management of patients and their related family members who could be affected.”
So. as we flop around in our PJs, quaffing eggnog and taking inventory of this fine array of offerings our hematology world has been gifted, session co-chair Dr. Connors offered us this simple phrase — to kids (or hematologists) from 1 to 92: “With such a wide range of diseases represented, there [was] something for everyone at this LBA session!” And on that note, off we go now. It’s time to start playing with all these new goodies!
Dr. Szuber declared no relevant conflicts of interest.
