Publications by authors named "John Byrd"

Contemporary studies of Bruton tyrosine kinase inhibitor (BTKi) resistance focus on mutations in the B-cell receptor (BCR) pathway, but alternative mechanisms of resistance remain undefined. Here, we sought to identify novel predictive markers of acquired resistance to acalabrutinib, a second-generation BTKi, in patients with chronic lymphocytic leukemia (CLL). Clinical samples from 41 patients with relapsed/refractory or treatment-naive CLL receiving acalabrutinib as part of a clinical trial (NCT02029443) were divided into two groups: those who continued to respond to treatment (NP, n = 23) and those who developed progressive disease on acalabrutinib therapy (PD, n = 18).

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Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32 -mutant AML patients at different stages of disease.

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Assignment of patients diagnosed with acute myeloid leukemia (AML) to the 2022 European LeukemiaNet (ELN) favorable genetic risk group has important clinical implications, as allogeneic stem cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients receiving chemotherapy alone and transplant-associated mortality. However, not all favorable genetic risk patients experience long-term relapse-free survival (RFS), making recognition of patients who would most likely be cured of high importance. We analyzed 297 patients aged <60 years with AML classified as 2022 ELN favorable genetic risk who achieved a CR and had RNA sequencing (RNA-seq) and gene mutation data from diagnostic samples available (Alliance trial A152010).

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Article Synopsis
  • - The study analyzed data from 229 elderly patients with core binding factor acute myeloid leukemia (CBF-AML) to assess treatment outcomes over two decades, finding a 5-year overall survival (OS) rate of 44.2% and event-free survival (EFS) rate of 32.9%.
  • - In patients over 70 who underwent intensive therapy, those who completed treatment had a median EFS of 11.8 months and a 5-year OS of 40%.
  • - Key factors impacting survival included age, achieving remission after initial treatment, and the number of consolidation therapy cycles, indicating that intensive therapy could be beneficial for selected older patients and should not be overlooked in clinical studies. *
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Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected.

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Acute myeloid leukemia (AML) is the most common and lethal leukemia in adults. AML consists of many genetic subtypes which limits broad applicability of targeted therapy. We discovered that the hematopoietic restricted tetraspanin CD37 is expressed on all primary AML blasts and thus may represent a common therapeutic target for AML regardless of subtype.

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Mutations in protein tyrosine phosphatase non-receptor type 11 ( ) have been considered late acquired mutations in acute myeloid leukemia (AML) development. To interrogate the ontogeny of mutations, we utilized single-cell DNA sequencing and identified that mutations can occur as initiating events in some AML patients when accompanied by strong oncogenic drivers, commonly mutations. The co-driver role of mutations was confirmed in a novel murine model that exhibits an AML phenotype with early expansion of a diverse set of variably differentiated myeloid cells that engrafted into immunodeficient and immunocompetent mice.

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Article Synopsis
  • BTK inhibitors are effective for treating B-cell malignancies but are linked to heart issues like atrial fibrillation (AF), the extent and seriousness of which were previously unknown.
  • A study monitored B-cell cancer patients on BTK inhibitors from 2009-2020, revealing that 72.4% developed arrhythmias, with 16.3% experiencing new cases of AF and 14.3% showing high AF burden.
  • Higher AF burden was correlated with increased risk of major cardiac events and mortality, highlighting the need for careful monitoring and management in patients treated with BTK inhibitors.
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Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax.

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Article Synopsis
  • The 2022 European LeukemiaNet (ELN) classification predicts outcomes for younger acute myeloid leukemia (AML) patients but was tested for those aged 60 and older receiving lower-intensity treatment (LIT), involving 595 patients with varying risk levels.
  • Results showed that while ELN risk is predictive of overall survival, it fails to distinguish between favorable and intermediate risks, prompting further exploration into adverse-risk patients' molecular abnormalities.
  • A new "Beat-AML" risk classification was developed, combining favorable and intermediate risks and integrating mutation scoring, leading to better survival predictions for older AML patients and aiding treatment decisions with clear risk group delineations.
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Introduction: Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses.

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Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients.

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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).

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Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics.

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Before targeted therapies, patients with higher-risk chronic lymphocytic leukemia (CLL), defined as del(17p) and/or TP53 mutation (TP53m), unmutated immunoglobulin heavy chain variable region genes (uIGHV), or complex karyotype (CK), had poorer prognosis with chemoimmunotherapy. Bruton tyrosine kinase inhibitors (BTKis) have demonstrated benefit in higher-risk patient populations with CLL in individual trials. To better understand the impact of the second-generation BTKi acalabrutinib, we pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts.

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Purpose: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established.

Methods: We performed an international multicenter retrospective study of patients with RT who received CAR-T.

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Background: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models.

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A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis.

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Article Synopsis
  • The text discusses the importance of genetic and gene expression diversity in tumors, which allows cancer to adapt and resist treatments.
  • It highlights a lack of tools for connecting the genetic subclones of tumors with their gene expression profiles, leading to the development of a new method called scBayes.
  • scBayes is a Bayesian framework that integrates genomic and transcriptomic data, enabling better comparisons of gene expression across tumor subclones and offering insights into cancer behavior over time and across different sites.
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Standard plain film medical radiographs often form a valuable line of evidence to identify individuals in large-scale fatality events. While commonly available, chest radiographs present a challenge that their analysis is somewhat more involved and complex than radiographic records of other body regions. For example, chest radiographs concern subtler morphological varieties of smaller anatomical features across a larger number of skeletal elements in contrast to frontal sinus comparisons that concern a large, (often) single, highly variable void within one bone.

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Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols.

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Article Synopsis
  • The treatment of chronic lymphocytic leukemia (CLL) has evolved from traditional chemotherapy to modern targeted therapies, particularly Bruton's tyrosine kinase (BTK) inhibitors, which have significantly changed patient outcomes.
  • Despite their effectiveness, the first BTK inhibitor, ibrutinib, is linked to serious cardiovascular side effects, affecting a substantial number of patients with conditions like atrial fibrillation and ventricular arrhythmias.
  • The review discusses the evidence around these toxicities, including risk factors and management strategies, while also highlighting the potential of newer BTK inhibitors and the need for further research into unresolved questions in the field.
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Unlabelled: Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles.

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