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BackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1–2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax. [ABSTRACT FROM AUTHOR]

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) may harbor prognostically relevant gene mutations and thus be categorized into one of the three 2022 European LeukemiaNet (ELN) genetic-risk groups. Nevertheless, there remains heterogeneity with respect to relapse-free survival (RFS) within these genetic-risk groups. Our training set included 306 adults on Alliance for Clinical Trials in Oncology studies with de novo CN-AML aged < 60 years who achieved a complete remission and for whom centrally reviewed cytogenetics, RNA-sequencing, and gene mutation data from diagnostic samples were available (Alliance trial A152010). To overcome deficiencies of the Cox proportional hazards model when long-term survivors are present, we developed a penalized semi-parametric mixture cure model (MCM) to predict RFS where RNA-sequencing data comprised the predictor space. To validate model performance, we employed an independent test set from the German Acute Myeloid Leukemia Cooperative Group (AMLCG) consisting of 40 de novo CN-AML patients aged < 60 years who achieved a complete remission and had RNA-sequencing of their pre-treatment sample. For the training set, there was a significant non-zero cure fraction (p = 0.019) with 28.5% of patients estimated to be cured. Our MCM included 112 genes associated with cure, or long-term RFS, and 87 genes associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were respectively, 0.947 and 0.783 for our training set and 0.837 and 0.718 for our test set. We identified a novel, prognostically relevant molecular signature in CN-AML, which allows identification of patient subgroups independent of 2022 ELN genetic-risk groups. Trial registration Data from companion studies CALGB 8461, 9665 and 20202 (trials registered at www.clinicaltrials.gov as, respectively, NCT00048958, NCT00899223, and NCT00900224) were obtained from Alliance for Clinical Trials in Oncology under data sharing study A152010. Data from the AMLCG 2008 trial was registered at www.clinicaltrials.gov as NCT01382147. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/β-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of β-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML. [ABSTRACT FROM AUTHOR]

Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m2), the maximum tolerated dose was 30 mg/m2. The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML. [ABSTRACT FROM AUTHOR]

Background: We evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic‐ and community‐based health systems within a single Midwestern State. Methods: Retrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011–2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as "standard induction" or "other chemotherapy"/targeted therapy, and hypomethylating agents. Results: Overall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%; p = 0.03), treated in academic versus community hospitals (44% vs. 26%; p = 0.01), and in chemotherapy recipients than non‐therapy recipients (46% vs. 19%; p < 0.001). Most common mutations were ASXL1, NPM1, and FLT3. Patients ≥75 years had highest proportion (46%) of multiple (≥3) mutations. Overall, 31.2% of patients with AML did not receive any therapy for their disease. This subgroup was older than chemotherapy recipients (mean age: 71.4 vs. 55.7 years, p < 0.001), and was highest (66.2%) in patients ≥75 years. Conclusions: Our results highlight the unmet medical need to increase access to genomic testing to afford treatment options, particularly to older AML patients in the real‐world setting, in this new era of targeted therapies. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration has approved several oral, targeted therapies for the treatment of Acute Myeloid Leukemia (AML) in recent years. These agents are approved in patients with relapsed/refractory disease or as frontline therapy in patients who are ineligible for intensive chemotherapy based on age, performance status, or comorbidities. They are also being increasingly utilized frontline in patients of all ages and fitness levels through clinical trials and off label prescribing, but comparative treatment outcomes associated with intensive versus targeted therapy have not been extensively studied. We conducted a single center, retrospective analysis to address the impact of treatment intensity on survival in patients with AML aged 60-75 at diagnosis. This study included 127 patients, 73 of whom received high intensity chemotherapy at any point during treatment (any HiC) and 54 of whom received only low intensity targeted therapy (LITT only). Overall survival (OS) from treatment initiation did not differ significantly between the any HiC and LITT only groups (hazard ratio (HR) for death, 0.67; 95% CI, 0.41 to 1.09; P=0.11). The only three variables that were independently associated with superior OS were lower European Leukemia Net (ELN) risk classification, TP53 unmutated status, and receipt of transplant. Our data suggest that baseline genomic features and receipt of transplant are more important than treatment intensity in predicting survival in this patient population. They also highlight the vital role of transplant in older patients with AML regardless of treatment intensity utilized for remission induction. Larger studies are needed to further address this question, including prospective randomized trials. [ABSTRACT FROM AUTHOR]

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients' T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential. [ABSTRACT FROM AUTHOR]

Advances in genomic technologies and an increased understanding of the molecular pathogenesis of cancer have resulted in development of new effective, mutation-targeted therapies. In turn, these informed the development of Master Trial designs to test these therapies. The Beat Acute Myeloid Leukemia (BAML) Master Trial (Sponsor: The Leukemia & Lymphoma Society) tests several targeted therapies in patients aged ≥ 60 years with AML based on genomic profiling obtained within 7 days of study enrollment. We hypothesized that integrating operational strategies with new electronic technologies (e-technologies) might streamline the conduct and management of this Master Trial. BAML's 5 core operational strategies revolve around the guiding principle of "patients first." The e-technology platforms employed in BAML include: Clinical Oversight Platform: a central collaborative tool; e-Protocol/e-Source Upload/Electronic Data Capture Platform: digitizes the protocol, allows remote data monitoring, and collects/exports data in Study Data Tabulation Model format; and Data Review Platform: ingests data from different sources for clinical response and safety data reviews. The operational approaches, e-technologies and sponsor/contract research organization's (CRO) expertise together allow: the complexity and size of the BAML Master Trial to be better managed; near real-time study data oversight; better collaboration, communication and training; improved data collection, enhanced transmission and accessibility; data integration, review and generation of reports; while maintaining data privacy, and compliance. Initial e-technology challenges were overcome through training, learning, discipline and adjustment. In conclusion, to successfully manage Master Trials, significant time should be spent re-evaluating, improving and developing new operational approaches. Clinical Trial Registration: Clinical Trials.gov Identifier: NCT03013998. https://clinicaltrials.gov/ct2/show/NCT03013998. [ABSTRACT FROM AUTHOR]

A retrospective cohort study was conducted to assess differences in efficacy and tolerability between a busulfan AUC target of 16.4 mg × Hr/L per day (FluBu4K) and a conventional RIC regimen (FluBu2). Adult patients with a diagnosis of AML or MDS who received fludarabine + busulfan conditioning with or without antithymocyte globulin between 2015 and 2018 were included. The primary outcome was relapse free survival. Overall, 74 patients received conditioning with either FluBu4K or FluBu2. At 18 months, relapse-free survival was not significantly different, at 63.9% with FluBu4k compared to 57.5% with FluBu2 (p = 0.49). There was a statistically significant difference in the cumulative incidence of relapse at 18 months in favor of the FluBu4K regimen, at 12.0% vs 32.5% (p = 0.047). The results of this study indicate that for select patients, there may be benefit in choosing targeted FluBu4K over FluBu2. Adverse effects other than mucositis were not significantly different. [ABSTRACT FROM AUTHOR]

CD33 is a transmembrane protein that is found on cells of myeloid lineage. It is also intensely expressed on acute myeloid leukemia (AML) progenitor cells but not on normal stem cells. It internalizes on binding and dimerization, making it a specific and ideal target for AML therapeutics and drug delivery. Several targeted therapies have been tested and many are still currently in development. Gemtuzumab ozogamicin was the first and only CD33‐directed antibody‐drug conjugate to be US Food and Drug Administration approved for AML. Other targeted agents have not achieved such success. Promising new strategies include cellular therapy mechanisms and linker molecules. This is an exciting target that requires a considerable amount of precision to yield clinical benefit. [ABSTRACT FROM AUTHOR]

Recent years have seen tremendous advances in treating acute myeloid leukemia (AML), largely because of progress in understanding the genetic basis of the disease. The US Food and Drug Administration approved 7 agents for AML in the last 2 years: the first new drugs in decades. In this review, the authors discuss these new approvals in the backdrop of an overall strategy for treating AML today. Treating AML in the modern era requires: 1) access to and use of upfront genetic and cytogenetic testing, not only to describe prognosis but also to help identify the best available therapy; 2) effectively working new therapies into a conventional backbone of treatment, including transplantation; and 3) continued commitment to clinical trials designed to capitalize on advances in genetics and immunology to foster the next wave of drug approvals. [ABSTRACT FROM AUTHOR]

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML. [ABSTRACT FROM AUTHOR]

The treatment of acute myelogenous leukemia (AML) relies heavily on cytarabine (Ara-C) containing chemotherapy. (b) Immunoblot analysis of Chk1, Rad51, and GAPDH (loading control) in AML blasts cells after exposure to a 0.25 µM onalespib for 24 or 36 h. (c) OCI-AML3 cells were left untreated (control) or exposed to 0.25 µM onalespib for 24 h before undergoing DNA damage with 2 Gy IR. However, cells exposed to the combination of onalespib and Ara-C strongly induce S-phase arrest which may explain the mechanism by which onalespib sensitizes OCI-AML3 cells to Ara-C. [Extracted from the article]

Initial therapy for acute myeloid leukemia (AML) remained stagnant for approximately four decades despite advances in improved understanding of pathogenesis and prognostication of the disease. Treatment has typically consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the "7 + 3" regimen. Attempts have been made to improve on this regimen with modest improvements in response rates but no change in overalll survival, until the recent introduction of mutation-specific agents. However, the re-vamping of the delivery of both daunorubicin and cytarabine in a liposomal encapsulation, known as CPX-351, did show improvements of overall survival compared to traditional 7 + 3 in newly diagnosed secondary and therapy-related AML in patients aged 60–75. This led to the Food and Drug Administration (FDA) approval of the agent for both of these subtypes of AML in August of 2017. Herein we will review the rationale and preclinical development of CPX-351 and discuss the pivotal studies that led to its FDA approval. [ABSTRACT FROM AUTHOR]

Novelty This is the first report to describe prolonged and sustained remissions in patients with acute myeloid leukemia after limited-duration therapy with hypomethylating agents. Dear Editor, Introduction Hypomethylating agents (HMAs), such as decitabine and azacitidine, have long been considered low-intensity, palliative treatments for patients with acute myeloid leukemia (AML) and are a standard approach for those patients not fit for intensive induction chemotherapy. Five patients had de novo AML, two patients had secondary AML, and one patient had leukemia cutis, with average presenting bone marrow blast percentage of 60% (40-97). Both patients did not obtain early platelet recovery, with one patient's recovery 111 days post-C1D1 with decitabine therapy and the other 29 days post-induction. [Extracted from the article]

Decitabine (DAC) is used for treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Following cellular uptake, DAC is activated to DAC-triphosphate (TP) and incorporated into DNA. Once incorporated into the DNA, DAC-TP binds and inactivates DNA methyltransferases (DNMTs), thereby leading to hypomethylation and re-expression of epigenetically silenced tumor suppressor genes and ultimately antileukemia activity. However, direct evidence of in vivo DAC-TP occurrence in DAC-treated patients has been difficult to demonstrate due to a lack of suitable validated analytical methodology. Thus, we developed and validated a nonradioactive sensitive and specific LC-MS/MS assay for quantification of DAC-TP. The assay is linear from 50 to 1,000 nM and from 1 to 10 µM and has a lower limit of quantitation of 50 nM and a coefficient of variation for both withinand between-day precision <20%. Following DAC treatment, we detected DAC-TP in parental and DAC-resistant AML cells (in vitro) and bone marrow (BM) and spleen of normal and leukemic mice (in vivo). Downregulation of DNMTs and correlation of DAC-TP concentration with proteins involved in mechanisms of DAC resistance were also demonstrated. The clinical applicability of this method was proven by measuring DAC-TP level in BM and blood mononuclear cells from DAC-treated AML patients. Higher levels are seemingly associated with clinical response. Monitoring the DAC-TP intracellular level may serve as a novel pharmacological endpoint for designing more effective DACbased regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies. We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions. [ABSTRACT FROM AUTHOR]

Simple Summary: AML is a common form of blood cancer in adults. This study was undertaken to evaluate if AML patients who have failed the available standard treatment options could tolerate and potentially benefit from a new form of therapy. This new therapy activates patients' own immune system against AML cells. The findings from this research may provide the foundation for a potentially more effective future form of standard therapy that is less likely to fail. APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential. [ABSTRACT FROM AUTHOR]

The article presents a comment on the study that determines the effects of epigenetic priming in patients with acute myeloid leukemia (AML). It states that the researchers have given the AML patients with hypomethylating agent and decatabine, followed by intensive induction chemotherapy to improve clinical outcomes. It commends the elegant correlative design of the study, however, it does not provide sufficient information to support that dectabine can serve as epigenetic priming agent.

PML is a rare infection with JC virus affecting mostly oligodendrocytes and the white matter of the central nervous system. It affects patients with profound cellular immunodeficiency such as uncontrolled HIV or those receiving immunosuppression for neoplastic and autoimmune diseases. Prognosis is poor as there is no effective therapy except for immune recovery which is not feasible in all cases. Herein, we describe using Quadrivalent (CMV,EBV, Adenovirus and BK) VSTs in a recipient of an unrelated donor hematopoietic cell transplant (HCT) with PML. A 64-year-old female with history of acute myeloid leukemia who underwent 10/10 HLA matched unrelated donor peripheral blood HCT complicated by acute mild skin graft vs host disease. She was off all immunosuppression by 7 months post transplant. At 15 months post HCT, she presented with mild confusion, left hemianopia and difficulty performing some routine tasks. Brain MRI showed demyelination involving the right parietal lobe, corpus callosum and bilateral dorsal periventricular areas. Cerebrospinal fluid (CSF) with JC virus DNA load of 389,773 copies/ml. Serum JC virus level was 1112 copies/ml and CD 4 218 (8.7%). Patient was referred to Cincinnati Children's Hospital for third-party VST infusion. A 3/10 HLA matched unit from their existing VST bank was infused 3 days after her PML diagnosis. She received a total of 6 VST infusions, each 28 days apart. Patient was monitored with monthly C SF JC virus and weekly serum JC virus levels. JC virus was cleared from serum and CSF after the fourth and fifth VST infusions, respectively (figure 1). T cell expansion analysis against BK was done by ELISpot (figure 2). Patient received a total of 6 VST infusions. Neuro symptoms stabilized after the second infusion. At 7.5 months from diagnosis (3 months since last VST infusion), she remained neurologically stable with no new deficits, GVHD or other toxicities. VSTs with BK activity is a promising therapy for PML patients in whom immune reconstitution is unlikely to occur in a short time frame. More studies are warranted to evaluate the efficacy and long term outcomes of this method. Physicians should be aware of this novel therapy in selected PML cases given poor disease outcomes and lack of effective alternative therapies. [ABSTRACT FROM AUTHOR]

5-Azacytidine (5-azaC) is an azanucleo-side approved for myelodysplastic syndrome. Approximately 80%-90% of 5-azaC is believed to be incorporated into RNA, which disrupts nucleic acid and protein metabolism leading to apoptosis. A smaller fraction (10%-20%) of 5-azaC inhibits DNA methylation and synthesis through conversion to decitabine triphosphate and subsequent DNA incorporation. However, its precise mechanism of action remains unclear. Ribonucleotide reductase (RR) is a highly regulated enzyme comprising 2 subunits, RRM1 and RRM2. that provides the deoxyribonucle-otides required for DNA synthesis/repair. In the present study, we found for the first time that 5-azaC is a potent inhibitor of RRM2 in leukemia cell lines, in a mouse model, and in BM mononuclear cells from acute myeloid leukemia (AML) patients. 5-azaC-induced RRM2 gene expression inhibition involves its direct RNA incorporation and an attenuated RRM2 mRNA stability. Therefore, 5-azaC causes a major perturbation of deoxyribonucleotide pools. We also demonstrate herein that the initial RR-mediated 5-azaC conversion to decitabine is terminated through its own inhibition. In conclusion, we identify RRM2 as a novel molecular target of 5-azaC in AML. Our findings provide a basis for its more widespread clinical use either alone or in combination. [ABSTRACT FROM AUTHOR]

The development of reduced-intensity conditioning (RIC) regimens has allowed more patients to receive allogeneic hematopoietic stem cell transplant (HSCT) by reducing toxicities associated with myeloablative conditioning (MAC). Key in reducing conditioning regimen intensity is modification of busulfan exposure, expressed as an area under the curve (AUC). Prior studies (including BMT CTN 0901) have demonstrated RIC regimens were associated with less toxicity at the cost of potentially decreased survival relative to weight-based MAC regimens. At OSU, we have utilized an AUC target of 4,000 μmol-min/L per day × 4 days in a subset of patients to balance toxicity with risk of relapse. Here we compare outcomes of AUC 4,000 to weight-based RIC Flu/Bu2. The objectives of this study were to assess differences in safety and efficacy in patients receiving different busulfan dosing strategies. To compare regimens, a retrospective cohort study was conducted of patients undergoing HSCT for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In the AUC 4,000 group, the target busulfan exposure was 16,000 μmol-min/L divided over 4 daily doses. In the RIC group, patents received busulfan 0.8 mg/kg/dose for 8 doses (Flu/Bu2). The primary outcome was relapse free survival (RFS). Secondary outcomes included overall survival (OS); time to count recovery; incidence of acute and chronic graft vs host disease (GVHD); key adverse effects. Seventy-four patients were eligible. There were no differences in disease risk status, rate of AML with myelodysplastic changes, or therapy-related AML/MDS. The percent of patients with HCT-Comorbidity Index score of ≥ 3 was 52.9% for AUC 4,000 and 77.5% for RIC. At 18 months, RFS was not significantly different (p=0.37) (A). Eighteen-month overall survival was also not significantly different (p=0.63) (B). Cumulative incidence of acute and chronic GVHD were not also significantly different (p=0.82, p=0.18, respectively). There was a significant difference in the 18-month cumulative incidence of relapse in favor of AUC 4,000 (hazard ratio 4.08, 95% CI 1.15-14.5) (C). Grade 2-4 mucositis was more common in the AUC 4,000 group (p<0.01), but there were no significant differences in other adverse effects. Though no difference existed in disease risk between groups, regimen choice was driven by physician judgement, perceived fitness, and ability to tolerate toxicity. Thus, the results of this study indicate that with patient selection, there is no significant RFS or OS difference, or risk of acute or chronic GVHD between targeted AUC 4,000 and RIC. However, AUC 4,000 was associated with a significantly lower incidence of relapse. Toxicities other than mucositis were not significantly different between groups. In order to definitively compare these two conditioning regimens, a prospective study is needed. [ABSTRACT FROM AUTHOR]

Haplo-HCT emerged as a reliable option for patients with high risk hematological malignancies with no HLA-matched related or unrelated donors available. Retrospective registry data suggest comparable outcomes to HLA-matched donors; however, relatively little is known regarding predictors of disease relapse following haplo-HCT. We hypothesize that attainment of full-donor CD3 and CD33 chimerism at day 30 (D30) and 100 (D100) is associated with lower incidence of relapse after haplo-HCT. We undertook a retrospective analysis of 78 patients who underwent haplo-HCT at the Ohio State University James Cancer Hospital between January 2013 and December 2017. The associations between patient characteristics including CD3/CD33 donor chimerisms and the cumulative incidence rate (CIR) of relapse were evaluated using proportional sub-distribution hazards model, treating death without relapse as the competing risk. The models were built adopting a landmark analysis approach at D30 and D100. Progression-free survival (PFS) was estimated using the method of Kaplan-Meier. Median age at haplo-HCT was 56 (20-74) years and 68% were males. 50% had acute myeloid leukemia/myelodysplastic syndrome, and 54% had intermediate disease risk index (DRI). Most patients (85%) received reduced-intensity conditioning and 50% received bone marrow (BM) grafts. Complete (100%) CD3 donor chimerism was observed in 63 (84%) patients at D30, and subsequently 59 (95%) patients at D100. Complete CD33 donor chimerism was observed in 67 (89%) patients at D30, and subsequently 56 (88%) patients at D100. In univariable D30 landmark analysis, the CIR of relapse was significantly lower in patients who achieved complete CD3 (and CD33) chimerism compared with patients with less than complete chimerism (Figure 1A; p<0.01 and p<0.01, respectively). Attainment of complete CD3 chimerism at D30 was also associated with PFS (Figure 1B; p<0.01). However, in multivariable analysis, complete CD3 chimerism at D30 was no longer independently associated with the CIR of relapse due to its high correlation with DRI (p=0.01). Receipt of a BM graft was associated with significantly higher CIR of relapse both in univariable and multivariable analyses (HR 2.43, 3.34; p= 0.05, 0.01, respectively). D100 complete CD33 chimerism conferred a significant CIR advantage in both univariable (p<0.01) and multivariable (p<0.01) models, although CD3 chimerism did not retain significance (p=0.35). Complete CD3 and CD33 donor chimerisms at D30 and D100 predict a patient's risk for relapse following haplo-HCT. We observed a strong association between CD3 chimeric status at D30 with DRI, as well suggestive that high risk disease may be associated with impaired immune reconstitution after transplant and perhaps a less robust graft vs disease effect. [ABSTRACT FROM AUTHOR]