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This letter, published in the Blood Cancer Journal, discusses the use of venetoclax in combination with hypomethylating agents (HMA) for the treatment of TP53-mutated acute myeloid leukemia (AML). TP53 mutations are associated with poor prognosis and resistance to traditional therapies. The study analyzed a database of 381 patients with TP53-mutated AML and found that the combination of venetoclax and HMA resulted in higher complete remission rates and a longer duration of response compared to HMA alone. However, there was no significant difference in overall survival between the two treatment groups. The study highlights the need for more effective treatment strategies for TP53-mutated AML. [Extracted from the article]

Background: Although the clinical outcomes of patients with TP53‐mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative‐intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53‐mutated AML. Methods: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53‐mutated AML (275 non‐Hispanic White [NHW] and 65 non‐Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. Results: The median patient age was comparable between NHW and NHB patients (p =.76). A higher proportion of NHB patients had therapy‐related AML (31% vs. 20%; p =.08) and had co‐mutations (74% vs. 61%; p =.06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p =.02). Conversely, a higher proportion of NHB patients received low‐intensity chemotherapy (9% vs. 5.5%; p =.02) or best supportive care (22% vs. 7%; p <.001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p =.39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p =.02). The proportion of patients who were event‐free (18.5% vs. 8.5%; p =.49) or who remained alive (24.9% vs. 8.3%; p =.13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. Conclusions: The current study highlights disparities between NHW and NHB patients with TP53‐mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations. Non‐Hispanic Black patients with TP53‐mutated acute myeloid leukemia (AML) were more likely to have concurrent mutations and therapy‐related AML than non‐Hispanic White patients. Non‐Hispanic Black patients who had TP53‐mutated AML received disease‐directed therapies less often compared with non‐Hispanic White patients. [ABSTRACT FROM AUTHOR]

FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3-ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors. [ABSTRACT FROM AUTHOR]

This phase 1 b study evaluated the safety, efficacy, and pharmacokinetics of atezolizumab in combination with guadecitabine in patients with relapsed/refractory (R/R) or first-line acute myeloid leukemia (AML). Patients received atezolizumab 840 mg (days [D] 8 and 22) and guadecitabine 60 mg/m2 (D1 and D5) over 28-day cycles. Sixteen patients (median age 73.0 years) enrolled (R/R cohort, n = 11; first-line cohort, n = 5). All patients reported at least 1 AE; 15 patients (93.8%) reported grade ≥ 3 AEs, and 15 patients (93.8%) reported SAEs. Fourteen of the 16 patients (87.5%) died during the trial period due to disease progression (8/14) or AEs (6/14), hence the study was terminated early. One patient (from the R/R AML cohort) achieved a response (CR with incomplete platelet recovery) with a DOR of 27.8 months at study termination. Atezolizumab plus guadecitabine had limited clinical activity in AML and an overall unfavorable benefit-risk profile at the investigated dose levels. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.02.006 Byline: Aaron D. Goldberg (1), C. David Allis (1), Emily Bernstein (1) Abstract: Epigenetics has recently evolved from a collection of diverse phenomena to a defined and far-reaching field of study. In this Essay, we examine the epistemology of epigenetics, provide a brief overview of underlying molecular mechanisms, and suggest future challenges for the field. Author Affiliation: (1) Laboratory of Chromatin Biology, The Rockefeller University, New York, NY 10021, USA

Patients with hematological malignancies are at risk for poor outcomes when diagnosed with coronavirus disease 2019 (COVID-19). It remains unclear whether cytopenias and specific leukemia subtypes play a role in the clinical course of COVID-19 infection. Here, we report outcomes and their clinical/laboratory predictors for 65 patients with acute and chronic leukemias diagnosed with COVID-19 between 8 March 2020 and 19 May 2020 at Memorial Sloan Kettering Cancer Center in New York City. Most patients had CLL (38%) or AML (26%). A total of 14 (22%) patients required high flow nasal cannula or were intubated for mechanical ventilation and 11 patients (17%) died. A diagnosis of AML (OR 4.7, p=.028), active treatment within the last 3 months (OR 5.22, p=.047), neutropenia within seven days prior and up to 28 days after SARS-CoV-2 diagnosis (11.75, p=.001) and ≥3 comorbidities (OR 6.55, p=.019) were associated with increased odds of death. [ABSTRACT FROM AUTHOR]

Immunotherapy in the form of allogeneic stem cell transplantation (SCT) plays an instrumental role in the treatment of acute myeloid leukemia (AML), with non-transplant modalities of immunotherapy including checkpoint blockade now being actively explored. Here, we provide an overview of the graft versus leukemia (GVL) effect in AML as a window into understanding the prospects of AML immunotherapy. We explore the roles of various cell types in orchestrating anti-leukemic immunity, as well as those contributing to the unique immune suppressive state of myeloid diseases. We discuss specific approaches to engage the immune system, while noting the challenges of the AML antigen landscape and the barriers to immune modulation. We review the potential for immunomodulatory agents in combination with cellular therapies, donor lymphocyte infusion, and following SCT. Finally, to address the challenge of minimal residual disease (MRD) following chemotherapy, we propose combination epigenetic and immunotherapy for the eradication of MRD. [ABSTRACT FROM AUTHOR]

Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase 2 studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space. Novel combination approaches exploring PD-1 inhibitors with epigenetic modifiers in leukemia are underway. [ABSTRACT FROM AUTHOR]

Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients. The adverse impact of measurable residual disease (MRD) on outcomes after AML directed therapy is well recognized [[1]]. [Extracted from the article]

The article discusses the case of a female patient whose ovarian carcinoma metastasized to the heart. The patient, who has a history of Wolff-Parkinson-White syndrome, presented with new atrial fibrillation with rapid ventricular response. Echocardiography is the initial imaging test for detecting tumor metastasis to the heart. The patient exhibited worsening hemodynamic instability, was transferred to the intensive care unit and eventually died.

Histone proteins often come in different variants serving specialized functions in addition to their fundamental role in packaging DNA. The metazoan histone H3.3 has been most closely associated with active transcription. Its role in histone replacement at active genes and promoters is conserved to the single histone H3 in yeast. However, recent genetic studies in flies have challenged its importance as a mark of active chromatin, and revealed unexpected insights into essential functions of H3.3 in the germline. With strikingly little amino acid sequence difference to the canonical H3, H3.3 therefore accomplishes a surprising variety of cellular and developmental processes. [Copyright &y& Elsevier]

In this issue of Blood, Rauch et al provide evidence for a novel mechanism to explain a fundamental yet enigmatic observation that has plagued hematologists for decades: the decline in nonleukemic hematopoiesis in the bone marrow of patients with acute myeloid leukemia (AML). The authors found that high expression of the thrombopoietin (TPO) receptor MPL on AML blasts predicts neutropenia and thrombocytopenia, and that AML blasts expressing high levels of MPL deplete TPO in cell culture and in mouse models. Rather than crowding out normal bone marrow hematopoietic stem cells (HSCs), might MPL-expressing AML blasts impair hematopoiesis by stealing the cytokine TPO?. [ABSTRACT FROM AUTHOR]

AbstractHypomethylating agents (HMA) and venetoclax (VEN) are commonly used in patients with IDH-mutated (IDHm) acute myeloid leukemia (AML) ineligible for induction chemotherapy. While prior studies demonstrated high response and survival rates with HMA/VEN in IDHm AML, the impact of treatment modifications in real-world settings is unclear. We retrospectively reviewed 89 IDHm AML patients treated with HMA/VEN from January 2018 to June 2023. CR/CRi rates were 76% in newly diagnosed (ND) and 55% in relapsed/refractory (R/R) patients, and median overall survival was 29.2 months (ND) and 17.1 months (R/R), respectively. Treatment modifications were common. Early VEN reductions were associated with lower response rates but not worse survival. Prolonged cycles were not associated with worse response rates or survival. Significant neutropenia and ED visits or unplanned hospitalizations were considerable before and after CR/CRi, though febrile neutropenia decreased afterward. HMA/VEN is efficacious, with treatment modifications not affecting survival, though long-term toxicities are notable. [ABSTRACT FROM AUTHOR]

Purpose of Review: Immune checkpoint therapy has dramatically changed the therapeutic landscape of solid malignancies. Here, we review the scientific rationale and current data evaluating immune checkpoint inhibitors in acute myeloid leukemia (AML). Recent Findings: Immune checkpoint inhibitor monotherapy has shown limited clinical activity in AML. Initial results from early-phase clinical trials suggest that rational combinations of immune checkpoint inhibition with hypomethylating agents (HMAs) are safe and potentially more promising. There are currently no data directly comparing immune checkpoint inhibition to standard therapies. Emerging immune targets more specific for leukemia cells including LILRB4 may improve future therapeutic efficacy. Summary: The success of immune checkpoint inhibition in AML has been modest to date. However, an improved understanding of the biology and the use of rational combinations has potential to improve rates of durable responses. Multiple clinical trials in AML are currently evaluating the use of immune checkpoints alone and in combination. [ABSTRACT FROM AUTHOR]

Acute idiopathic hyperammonemia in an adult patient is a life-threatening condition often resulting in a rapid progression to irreversible cerebral edema and death. While ammonia-scavenging therapies lower blood ammonia levels, in comparison, clearance of waste nitrogen from the brain may be delayed. Therefore, we used magnetic resonance spectroscopy (MRS) to monitor cerebral glutamine levels, the major reservoir of ammonia, in a gastric bypass patient with hyperammonemic coma undergoing therapy with N -carbamoyl glutamate and the ammonia-scavenging agents, sodium phenylacetate and sodium benzoate. Improvement in mental status mirrored brain glutamine levels, as coma persisted for 48 h after plasma ammonia normalized. We hypothesize that the slower clearance for brain glutamine levels accounts for the delay in improvement following initiation of treatment in cases of chronic hyperammonemia. We propose MRS to monitor brain glutamine as a noninvasive approach to be utilized for diagnostic and therapeutic monitoring purposes in adult patients presenting with idiopathic hyperammonemia. [ABSTRACT FROM AUTHOR]

Summary: Polycomb repressive complex 2 (PRC2) regulates gene expression during lineage specification through trimethylation of lysine 27 on histone H3 (H3K27me3). In Drosophila, polycomb binding sites are dynamic chromatin regions enriched with the histone variant H3.3. Here, we show that, in mouse embryonic stem cells (ESCs), H3.3 is required for proper establishment of H3K27me3 at the promoters of developmentally regulated genes. Upon H3.3 depletion, these promoters show reduced nucleosome turnover measured by deposition of de novo synthesized histones and reduced PRC2 occupancy. Further, we show H3.3-dependent interaction of PRC2 with the histone chaperone, Hira, and that Hira localization to chromatin requires H3.3. Our data demonstrate the importance of H3.3 in maintaining a chromatin landscape in ESCs that is important for proper gene regulation during differentiation. Moreover, our findings support the emerging notion that H3.3 has multiple functions in distinct genomic locations that are not always correlated with an “active” chromatin state. [ABSTRACT FROM AUTHOR]

Background Relapse continues to be the major cause of death in AML/MDS patients following allogeneic hematopoietic cell transplantation (HCT). Advanced age has emerged as a strong predictor of relapse due to both generally increased disease risk and reduced ability to deliver myeloablative conditioning due to comorbidities and functional impairment. The impact of measurable residual disease (MRD) prior to HCT has not been assessed in the context of older patients receiving CD34+ selected allografts. Methods We retrospectively examined 297 AML/MDS patients aged 60 years and older who underwent first allo-HCT at our institution from 2001 to 2016. We included only patients who received either a conventional or CD34+ selected graft. We collected MRD data using flow cytometry, cytogenetics (karyotype and/or FISH), and molecular mutation analysis from patients who had achieved a hematologic complete remission pre-HCT. Factors associated with the cumulative incidence of relapse (RI) and progression-free survival (PFS) were analyzed using cause-specific hazard models. Results The median age was 65.8 years (range 60-78.4), and 42% were women. One hundred and eighty-four patients had AML (62%). Fifty-nine percent of patients had HCT-CI >2; 51% had pre-HCT KPS >80; and 37% had high/very high disease risk index (DRI). Seventy-five percent of patients received a myeloablative regimen and 61% received a CD34+ selected graft. Sixteen percent of patients had a mismatched donor. With a median follow-up of 5.1 year for survivors, the 2- and 5-year overall survival was 50% (95% CI: 44-55) and 39% (95% CI: 33-45) respectively. The 2- and 5-year of PFS was 46% (95% CI: 40-51) and 37% (95% CI: 31-43) respectively. By June 30, 2018, 93 patients had relapsed, or their disease progressed, with 3-year cumulative RI of 31% (95% CI: 26-36). Two hundred and four patients had available MRD data and 71, 35%, were MRD positive pre-HCT. In multivariate analysis of RI (Table below), high/very high DRI score (HR 2.2, 95% CI: 1.3-3.8, p=0.004) and MRD positivity (HR 1.9, 95% CI: 1.1-3.2, p=0.027) were associated with an increased risk, with CD34+ selection approaching statistical significance for a reduced risk (HR 0.6, 95% CI: 0.3-1, p=0.064). In multivariate analysis of PFS, only high/very high DRI score (HR 1.8, 95% CI: 1.2-2.7, p=0.003) was associated with an increased risk. Conclusions In this study, we characterized relapse following allogeneic HCT in an older cohort of AML/MDS patients. While limited by the retrospective nature with likely underestimation of MRD status due to different assays and time periods, and by the lack of data on post-transplant maintenance, we confirmed the association of pre-HCT MRD with relapse risk. CD34+ selection has no impact on the risk of relapse. [ABSTRACT FROM AUTHOR]