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The Chronicles of #ASH20

December 14, 2020

Dr. Raphael Itzykson presents the abstract
“Decitabine Versus Hydroxyurea for
Advanced Proliferative CMML: Results
of the Emsco Randomized Phase 3 Dacota Trial.”

The ASH annual meeting continues to have a surreal quality to me. Like Lucy, the first child to discover the fantastical land of Narnia accessed through the secret wardrobe in Professor Digory Kirk’s home, I return through my own portal, energized by newfound knowledge about the possibilities. It feels criminal to distill the 2020 annual meeting to the handful of efforts highlighted here, although as Aslan reminds us, “all shall be done, but it may be harder than you think.”

Myeloproliferative neoplasms (MPNs) were the clear belles of the ball this year. Beginning at the translational level, Dr. Christian Marinaccio and colleagues’ Plenary Scientific Session abstract elegantly demonstrated the role that STK11 loss, leading to mTOR upregulation and HIF1a stabilization, plays in the leukemic transformation of chronic Philadelphia-negative MPNs, opening up ripe avenues for investigational therapies. An example of “saving the best for last” was the late-breaking abstract presented by Dr. Jyoti Nangalia, who made the compelling case that somatic JAK2 V617 driver mutations, and even some DNMT3A mutations, are acquired in utero or childhood, decades before any disease manifestation. This suggests that additional inciting events, even if it’s simply the passage of time, are involved in the pathogenesis of MPNs. It also tantalizingly suggests that targeted intervention on higher-risk pre-leukemic states is viable. The most neglected child of the MPNs, myelofibrosis, finally received some therapeutic attention. Demonstrating that perhaps a genie can at least partially be put back in the bottle, phase II data with the use of imetelstat — a competitive inhibitor of telomerase — in patients with higher risk myelofibrosis relapsed/refractory (R/R) to prior JAK inhibitor therapy showed evidence of on-target, disease-modifying effects (including a reduction of marrow fibrosis and clonal cytomolecular changes) with a dose-dependent improvement in overall survival (OS; oral abstracts #346 and #347). Intriguingly, the traditional enfants terrible of myelofibrosis, the “triple negative” cases, demonstrated preferential responses to imetelstat. Details of the upcoming phase III trial can be found online. Chronic myeloid leukemia (CML) is sometimes thought of as the Hodgkin lymphoma of the MPN world given the perception that clinical outcomes are generally so good that pursuing additional investigational therapies has diminishing returns. It was therefore refreshing to see the late-breaking abstract comparing the early experience with asciminib, an inhibitor of the myristoyl pocket rather than the ATP binding site, to bosutinib in refractory cases of chronic-phase CML. Cautions, however, include the exclusion of patients with T315I resistance mutations and a signal of increased arterial occlusive events.

Few allograft-sparing strategies have yet been shown to change the natural history of myelodysplastic syndromes (MDS). Therefore, the practice guiding the BMT CTN 1102 trial (oral abstract #75) is welcome news. Based on biologic randomization (matched vs. unmatched donor, excluding mismatched, haplo, and UCB donor sources), it demonstrated a robust three-year OS (absolute difference, 21.3%) and relapse-free survival (absolute difference, 15.2%) benefit in patients 50 to 75 years of age undergoing reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) compared to continuing with hypomethylating agent therapy or best supportive care. While some questioned the practice of counting patients who died while awaiting a donor search in the “no donor” arm, a sensitivity analysis excluding these patients showed no difference in outcomes. Moving from the pragmatic to the hypothesis generating, is one of the first studies to shed insight on the elusive pathogenesis of paraneoplastic systemic inflammatory autoimmune disease (SAID; oral abstract #539) in myeloid neoplasms. TET2 or IDH1/2 mutations (mutually exclusive given the overlapping functional consequences) were enriched in cases of MDS/chronic myelomonocytic leukemia (CMML) with versus without SIAD. Moreover, these mutations were associated with an imbalanced CD8+ T-cell repertoire, skewed toward terminally differentiated effector memory T cells and demonstrating a deficit of CD96+ coexpression, an immune checkpoint regulator. Given the potentially devastating consequences of SAID in patients with otherwise lower-risk myeloid disease, this warrants further preclinical studies in whether T-cell immune modulation has a role in the treatment of such cases.

I am explicitly devoting a separate section to CMML this year, as this meeting demonstrated that we are doing a disservice to MDS/MPN overlap syndromes by treating them as the motorcycle sidecar in investigations geared toward MDS. The European, multi-institutional Dacota trial (oral abstract #654) is the first phase III randomized control trial (RCT) devoted exclusively to CMML. It compared the frontline use of five-day decitabine (DAC) 20 mg/m2 versus oral hydroxyurea (HU) in 170 patients with advanced, proliferative-subtype CMML. True to form, the French never shy away from controversy: The markedly higher response rates (per International Working Group 2006 criteria modified for CMML) and reduced incidence of leukemic transformation in the DAC arm were offset by increased deaths unattributable leukemic transformation, resulting in no significant differences in event-free survival (12.6 vs. 10.3 months) or OS (18.4 vs. 23.1 months). Details about the supportive care measures and subset analyses will be eagerly anticipated given these discouraging findings.

After the euphoria surrounding the long-awaited advances in treating acute myeloid leukemia (AML) unveiled at the previous three ASH annual meetings, this year was relatively austere. We quickly forget that most of life “is a game of inches.” A reassuringly unified theme from this meeting is the established safety and early efficacy of adding the BCL-2 inhibitor venetoclax to intensive chemotherapy (ICT) backbones in younger/fitter patients with AML, particularly those with adverse-risk disease. Partner regimens included cladribine, idarubicin, and ara-c (CLIA; poster presentation #2854); fludarabine, ara-c, granulocyte colony stimulating factor, and idarubicin (FLAG-IDA; oral abstract #332); daunorubicin/cytarabine (7+3; poster presentation #1038); CPX-351 (oral abstract #28); and even fludarabine + busulfan RIC for HSCT (oral abstract #190). A related provocative question introduced at this meeting is whether intensive chemotherapy is really the preferred partner for venetoclax in younger/fitter patients with European LeukemiaNet adverse risk (i.e., genomically unstable) disease, with the first few results from a pilot study of venetoclax (NB: target dose during induction was 600 mg daily) plus azacitidine reported in this population (poster presentation #2855). The second theme in AML is the expansion of therapies agnostic to the traditionally poor prognosis conferred by TP53 mutations, with updated results from the magrolimab (macrophage checkpoint inhibitor) plus azacitidine combination presented by Dr. David Sallman in patients ineligible for ICT (oral abstract #330). An overall response rate (ORR) of 69 percent (45% complete response [CR]) in TP53 mutated patients translated to an unprecedented median OS of 12.9 months. Consistent with recent efforts to rigorously study the drivers of racial disparities in health outcomes more generally, was the Scientific Plenary session abstract demonstrating worse disease-free survival and OS in Black compared to white patients younger than 60 years treated for AML on CALGB/Alliance ICT protocols. This was despite adjustment for relevant disease and socioeconomic factors as well as similar rates of CR and early death. While many of the causal factors could not be captured in these data, a striking finding was that there were differential outcomes between the two groups even in the subset of patients with “favorable risk” NPM1 mutated/FLT3-ITD low/wildtype disease, calling into question the broad applicability of current prognostic models.

While the management of B-cell acute lymphoblastic leukemia (B-ALL) with targeted and immune-based therapies leapt out of the starting blocks a few years ago, this year was about fine-tuning the application of these tools. The incorporation of blinatumomab and/or inotuzumab into frontline regimens for Philadelphia-negative B-ALL in younger (hyperCVAD [cyclophosphamide, vincristine, doxorubicin, and dexamethasone] backbone, oral abstract #464) and older (reduced intensity hyperCVD backbone, poster presentation #1014) patients was shown to be both feasible and to induce deep, durable responses. A wonderfully practical yet easily overlooked study (oral abstract #584) demonstrated that the use of multiparameter flow cytometry (MFC) performed on the cerebrospinal fluid at baseline in adults with ALL treated with frontline hyperCVAD was more predictive than traditional cytospin for central nervous system (CNS) relapse. Moreover, a traumatic lumbar puncture (>10 red blood cells/microliter) did not increase the risk of CNS relapse if the cerebral spinal fluid sample was negative for disease by MFC. In sharp contrast, effective targeted therapeutic approaches in T-cell ALL (T-ALL) are still lacking. As a starting point, however, the multi-omics characterization of adults with T-ALL treated on GMALL protocols (oral abstract #395) highlighted an age-related distribution of molecular subgroups with TLX1-driven cases demonstrating particularly good outcomes (93% minimal residual disease [MRD] negativity CR after first consolidation, 93% 5-year OS).

In the realm of B-cell non-Hodgkin lymphomas (NHLs), LOXO-305 emerged this meeting as the Bruton tyrosine kinase (BTK) inhibitor “star du jour.” In contrast to ibrutinib and its newer-generation covalent-binding brethren, LOXO-305 is a non-covalent and thus reversible BTK inhibitor. This enables it to have persistent activity even in tumors with high BTK turnover. Moreover, it does not require the C481 site for binding to the ATP domain, thus overcoming C481S resistance mutations. In R/R CLL/small lymphocytic lymphoma, including patients treated with ibrutinib, the ORR with LOXO-305 monotherapy was 62 percent with most responses being partial responses (oral abstract #542). Similarly, in R/R mantle cell lymphoma, including patients previously treated with HSCT or chimeric antigen receptor T-cell (CAR-T) therapy, the ORR was 52 percent (25% CR) with LOXO-305 (oral abstract #117). Follicular lymphoma, long overshadowed by the use of “sexy” cellular therapies in aggressive B-cell NHLs, finally got its due this year with the phase II ELARA trial demonstrating an ORR of 83 percent (CR 65%) and a six-month progression-free survival (PFS) of 73 percent with tisagenlecleucel (poster presentation #1149). Negative findings are informative too, although almost never included in any “best of” series. In contrast to the ECHELON-2 study published earlier this year demonstrating an OS benefit to using BV-CHP (brentuximab vedotin, cyclophosphamide, hydroxydaunorubicin, prednisone) over CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone) in CD30+ peripheral T-cell lymphomas (PTCLs), the addition of the histone deacetylase inhibitor romidepsin to CHOP did not improve outcomes and seemingly worsened toxicity in the final analysis of the phase III presented at the meeting (oral abstract #39).

The therapeutic landscape in multiple myeloma (MM) has become a kaleidoscope to the uninitiated. With respect to frontline regimens that include lenalidomide maintenance, consolidation with an autologous stem cell transplant (ASCT) continues to be supported, even with newer induction regimens. Both the IFM DFCI 2009 study (RVd [lenalidomide, bortezomib, dexamethasone] with upfront ASCT vs. additional RVD and ASCT only at relapse) and FORTE study (KRd [carfilzomib, lenalidomide, dexamethasone] with or without ASCT) favored the ASCT arms with superior MRD negativity and long-term PFS rates (although similar OS) reported this year. While BCMA-directed CAR-T therapies were all the rage in R/R myeloma last year, bispecifics appear to be just as effective and possibly less toxic in the same patient population. In particular, the BCMA-CD3 bispecific TNB-383B yielded a remarkable ORR of 80 percent at the highest dose, and appears to be safe in patients with a low glomerular filtration rate, always a bonus in a nephrotoxic disease (oral abstract #293). Until this ASH annual meeting, I had never heard of FcRH5 as a clinical target in MM (it is universally expressed on plasma cells). The novel bispecific FcRH5-CD3 antibody, BFCR4350A, likewise showed encouraging activity in R/R disease (poster presentation #3213).

There you have it, folks. “And so, for a time it looked as if all the adventures were coming to an end; but that was not to be.” See you next year. (In person?!)

Dr. Hammond indicated no relevant conflicts of interest.

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