Daniel Pollyea

University of Colorado | UCD · Section of Hematology, Oncology and Bone Marrow Transplantation

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, particularly when phosphorylated at the...

Background Patients with myelodysplastic syndromes (MDS) with excess blasts (MDS-EB) have poor long-term outcomes. Hypomethylating agents (HMA) are the only approved therapies; more efficacious and rationally designed treatment are needed. Previously we identified a stem cell population in MDS and reported its unique dependency on protein synthesis...

Background: The molecular prognostication risk signature (mPRS) stratifies patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated with hypomethylating agent (HMA)+venetoclax (VEN) therapy (Bataller et. al. Blood Adv. 2023). However, significant variability in overall survival (OS) remains across risk groups. Surface CD7 expression...

Introduction: AML is a highly morbid condition with a 5-year OS rate of 30.5%. However, advancements in treatment options have improved OS (Ho 2023). We previously reported lower SES was associated with worse OS in AML pts (Duarte 2023). This analysis expands on previous research to further describe the OS difference in this population. Methods: Th...

Venetoclax (ven) combined with azacitidine (aza) is a therapeutic standard for newly diagnosed patients with acute myeloid leukemia (AML) who are unfit to receive intensive chemotherapy. Recent studies also suggest that patients eligible for intensive chemotherapy may benefit from ven/aza, reporting comparable rates of complete remission (CR), fewe...

Background: Despite advances in frontline treatment for acute myeloid leukemia (AML), relapsed or refractory (R/R) AML remains a significant therapeutic challenge, with poor outcomes and limited treatment options. One recently approved treatment combination - the BCL-2 inhibitor venetoclax and a hypomethylating agent - has transformed outcomes for...

Signal transducer and activator of transcription 3 (STAT3) is critical to the survival of acute myeloid leukemia (AML) cells. It has previously been shown to regulate mitochondrial functions such as oxidative phosphorylation (OXPHOS) via a MYC-SLC1A5-mediated pathway (Amaya et al. 2022) and regulate the transcription of important mitochondrial gene...

Background: Hypomethylating agents combined with venetoclax (HMA+VEN) represent the standard of care treatment for older or unfit patients (pts) with ND-AML. Event-free (EFS) and overall survival (OS) following HMA+VEN can be stratified using the molecular prognostic risk signature (mPRS), based on mutations within four genes at diagnosis (N/KRAS,...

Background: Venetoclax (ven) with azacitidine (aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. However, this regimen requires 7 consecutive daily subcutaneous or intravenous doses of aza each month, which continues indefinitely. This relative inconvenience, and its negative impact on...

Introduction Chronic myelomonocytic leukemia (CMML) is a rare and lethal hematological malignancy. Hypomethylating agents (HMAs), including azacitidine (AZA), are the only approved treatment for CMML, yet they offer complete remission (CR) rate of only 10%-20%, highlighting the unmet medical need. IO-202 is a humanized IgG1 monoclonal antibody with...

Background: Acute myeloid leukemia (AML) with monocytic differentiation can be associated with resistance to hypomethylating agents plus venetoclax (HMA+VEN). Using a multi-modal analysis in newly diagnosed patients with AML treated with HMA+VEN, we assessed the influence of AML differentiation on clinical outcomes to determine modifying factors of...

Background Venetoclax (ven) with azacitidine (aza) is the standard of care for newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive chemotherapy (IC) due to age or comorbidities. However, fit patients with poor-risk disease biology may not benefit from IC. Furthermore, adverse risk factors for IC are not necessarily adverse ris...

Background Clonal cytopenia of undetermined significance (CCUS) is characterized by cytopenia and a mutation in a gene associated with myeloid neoplasms without overt dysplasia (<10%) in the bone marrow (Valent 2019; Osman 2021; Weeks et al. 2023). This condition is associated with increased risk of development of a myeloid neoplasm (Gallì et al. 2...

Background: Myeloablative conditioning with high dose total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute lymphoblastic leukemia (ALL) is effective, but short-term toxicities may negatively impact long-term survival. As an attempt to reduce toxicity, myeloablative chemotherapy-based r...

The ELN 2024 risk-stratification guidelines for patients with acute myeloid leukemia receiving hypomethylating agents combined with venetoclax were recently published. This analysis demonstrates re-classification and incorporation of new gene mutations in the present model can further improve and individualize prognostication.

European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study...

The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely use...

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed precl...

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of d...

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized...

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic...

Introduction: The BCL-2 inhibitor VEN is approved in combination with hypomethylating agents or low-dose cytarabine for adults with ND AML. The ARC Initiative is a multicenter chart review study of adult pts with AML. This abstract presents real-world clinical outcomes and hospitalizations among ND AML VEN treated pts ineligible for intensive chemo...

Introduction: Dasatinib plus prednisone is a standard induction approach for adults with Philadelphia Chromosome positive (Ph+) ALL known to result in high remission rates with minimal toxicity, however optimal post-remission therapy has not been determined. Given the excellent outcomes observed in recent clinical studies using ponatinib in adult P...

Introduction There has been a rapid evolution in diagnostic and management evaluation for AML, associated with the introduction of new therapies, some of which target specific mutations, over the past decade. The Connect ® Myeloid Registry (NCT01688011) is a multicenter, prospective, observational cohort study that began enrollment in December 2013...

Background: Myeloid sarcoma (MS) is a distinct form of acute myeloid leukemia (AML) found in ~10% of patients, in which mass-forming myeloid blasts proliferate in extramedullary sites. MS may present as an isolated lesion as the primary manifestation of disease, co-occur with AML, or, more commonly, arise in the setting of AML relapse. It is associ...

Introduction Previously, we demonstrated that human leukemia stem cells (LSCs) are preferentially reliant on oxidative phosphorylation (OXPHOS) for survival. Furthermore, inhibition of BCL2 with venetoclax (ven) acts to suppress OXPHOS, leading to the eradication of LSCs. While the activity of ven in targeting LSCs is well-established, nearly all p...

Background: The discovery of IDH1 and IDH2 mutations in AML, and the accompanying functional implications of the resulting neomorphic activity of these mutated enzymes, has resulted in FDA approved targeted therapies. Similarly, the changes brought about in methylation due to IDH mutations in the AML genome have ushered in treatment regimens of ven...

Introduction: Health disparities have been reported in several areas of hematologic and oncologic care. The NCI reports African American males develop cancer 25% more frequently than White males, and they have 43% higher mortality compared to Non-Hispanic Whites in all cancers combined. Hispanic ethnicity is also disproportionately affected in canc...

Introduction: While pediatric-inspired regimens are preferred in younger adults with Ph-negative ALL, the optimal approach for treating adults age >40 with Ph-negative ALL has not yet been defined. In the U.S., hyperCVAD-based regimens are commonly used in this age group; however, hyperCVAD may be less effective than pediatric-inspired regimens in...

Background: Despite the concurrent use of tandem haploidentical-umbilical cord (haplo-cord) and dual-umbilical cord (dual-cord) allogeneic hematopoietic stem cell transplant (HSCT) approaches for over a decade, there have been few comparisons of their outcomes (van Besien et al. Hematologica, 2016). No previous studies have evaluated differences fo...

Background: Venetoclax (Ven) with azacitidine (Aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. It is well known that this treatment also has activity in the relapsed and refractory (R/R) setting. However, this regimen requires 7 consecutive daily subcutaneous or intravenous doses of...

Introduction: AML is a morbid disease with a five-year overall survival (OS) rate of 30.5%. Despite increasing treatment options and improved OS, inequities exist. Some studies cite a 3-year OS difference between Black and White AML patients (pts) at 34% versus 43% (p < 0.001) (Bhatnagar 2021). This study examines data from AML pts in community and...

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising cl...

Measurable residual disease (MRD) is the most important post-treatment predictor of relapse in acute myeloid leukemia (AML). However, molecular MRD is less well validated than flow MRD with respect to prognostic import, particularly after low-intensity therapies like venetoclax/azacitidine (ven/aza). To test the hypothesis that multi-gene molecular...

Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common clas...

The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on...

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia s...

Objectives Dysregulation of BCL‐2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3‐dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven‐chemotherapy or ven‐navitoclax combinations, to assess efficacy and safety. Methods Se...

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blast...

Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among hi...

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: 1)Higher doses of venetoclax are tolerable and more effective, and 2)Azacitidine c...

Introduction: The 2017 World Health Organization classification of myeloid neoplasms and acute myeloid leukemia (AML) recognizes AML with mutated NPM1 as a distinct entity with favorable prognosis. However, as mutations other than NPM1 may further influence disease prognosis, here we assess the prognostic effect of NPM1 co-mutations in patients (pt...

Background: Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and non-clinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influenc...

Purpose: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final...

Intensive chemotherapy (IC) is commonly used to achieve remission in patients with acute myeloid leukemia (AML). Venetoclax plus azacitidine (VEN-AZA) is FDA-approved to treat patients with AML aged ≥ 75 years or who are ineligible for IC. This retrospective analysis used de-identified electronic health records from the US-based Flatiron Health dat...

In the year 2021, there were three new Food and Drug Administration approvals for all leukemia types: asciminib (Scemblix) for chronic myeloid leukemia, brexucabtagene autoleucel (Tecartus) for relapsed/refractory B‐cell acute lymphocytic leukemia, and asparaginase erwinia chrysanthemi (recombinant)‐rywn (Rylaze) for acute lymphocytic leukemia. Thi...

Measurable residual disease (MRD) is the most important post-treatment predictor of relapse in acute myeloid leukemia (AML) [PMID 33030517]. The bulk of clinical MRD studies in AML have been performed via multi-parameter flow cytometry and no molecular MRD platform is established for clinical use in AML. Droplet digital PCR (ddPCR) has been identif...

Patients with relapsed/refractory (R/R) higher‐risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety a...

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums...

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1-5 in 28-day cycles followed by dosing schedule optimization (n =...

Background Acute myeloid leukemia (AML) is associated with a poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with the BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly diagnosed older AML patients compared to AZA alone. However, this regimen is myelosuppressi...

Purpose: Evaluate efficacy and safety of venetoclax+azacitidine in treatment-naïve patients with AML harboring poor-risk cytogenetics and TP53mut or TP53wt. Patients and methods: We analyzed data from a phase-3 study (NCT02993523) comparing venetoclax (400 mg orally days 1-28)+azacitidine (75 mg/m2 days 1-7) or placebo+azacitidine, and a phase-1...

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmoniz...

Background Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly-diagnosed AML who are unfit for IC. If these patients...