David M. Ross

Description:Objective: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential. Methods: Using both primary donor AML cells and cell lines, we developed an in vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistance. Results: We identified that anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signaling as a contributing factor; the adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing the adhesion of the most primitive CD34high AML cells in primary autologous co-cultures. Conclusions: Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanized monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.

Description:Objective: Myelofibrosis (MF) is a complex and clinically heterogeneous myeloproliferative neoplasm, presenting significant challenges for patient care and clinical decision making. Although global guidelines exist for MF management and continue to evolve with the advent of novel therapies, they do not consider regional variations in drug accessibility nor the availability of diagnostic tools and resources. The notable gap in regional guidance for managing patients with MF in the Asia-Pacific (APAC) region has led to regional disparities in patient care practices. To bridge this gap, a steering committee (SC) of 14 expert hematologists from the APAC region collaborated to develop evidence- and consensus-based consensus statements (CSs) for MF management in the APAC region. Methods: On the basis of evidence from a systematic literature review and their own clinical experience, the SC drafted 13 clinical practice recommendations across four consensus themes: (1) defining the thresholds for anemia and when to initiate or modify treatment; (2) defining when to initiate or modify treatment for thrombocytopenia; (3) defining Janus kinase inhibitor failure and what would warrant switching treatment; and (4) defining the most appropriate risk stratification model for MF in the APAC region. The SC and an extended faculty (EF) of 47 hematologists and two patients voted on the CSs in a modified Delphi process using a 9-point scale (1 = strongly disagree, 9 = strongly agree), with consensus achieved when 75% agreed within the range of 7-9. Results: Following amendments to align with EF feedback, consensus was achieved for all 13 CSs. Conclusions: These CSs offer pragmatic guidance tailored to the MF landscape in the APAC region, which aims to enhance the quality of patient care and outcomes. The CSs in this study are formally endorsed by the Asian Myeloid Working Group.

Description:Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ~70% of patients discontinue ruxolitinib after ~5 years, a third of whom report suboptimal splenic response. ADORE was a Phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib+siremadlin (N=23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1-5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib+siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at Week 24 were observed, notably in several patients with SVR. An increase in GDF-15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.

Description:Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X-ray crystallography and cryo-electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL-3 receptor ternary complex forms higher-order assemblies, like those found earlier for the GM-CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL-3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine-receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism-based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.