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Blood
Finding the PerPh+ect Balance in Ph+ ALL
Luskin MR
In this issue of Blood, Chalandon et al report that attenuation of postremission chemotherapy in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with nilotinib leads to increased relapse. Ph+ ALL is a formerly dreaded subtype of ALL in adults as resistance to conventional chemotherapy resulted in miserable survival rates, especially in the absence of allogeneic hematopoietic stem cell transplant (alloHSCT). In 2001, “the activity of a specific inhibitor of the BCR-ABL tyrosine kinase” was reported and revolutionized the treatment and outcomes of Ph+ ALL. The specific tyrosine kinase inhibitor (TKI) (imatinib) was swiftly incorporated into conventional chemotherapy ALL regimens increasing responses, rates of transplantation, and overall survival.
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Blood
Fixed-Duration Pirtobrutinib Plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial
Brown JR
Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial (NCT03740529). Prior covalent BTKi therapy was allowed, but not prior venetoclax. Patients were assigned to receive PV (n=15) or PVR (n=10) for 25 cycles. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4), and 17 (68%) patients had received prior covalent BTKi. At the data-cutoff date (May 5, 2023), median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% CI:68.1-99.8%) for PV and 100% (95% CI:69.2-100.0%) for PVR, with 10 complete responses (PV:7; PVR:3). After 12 cycles of treatment, 85.7% (95% CI:57.2-98.2%) of PV and 90.0% (95% CI:55.5-99.7%) of PVR patients achieved undetectable minimal residual disease assessed in peripheral blood by clonoSEQ® assay at a sensitivity of <1x10-4. Progression-free survival at 18 months was 92.9% (95% CI: 59.1-99.0) for PV patients and 80.0% (95% CI: 40.9-94.6) for PVR patients. No DLTs were observed in either treatment combination during the 5-week assessment period. The most common grade ?3 adverse events for all patients included neutropenia (52%) and anemia (16%). Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.
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Gastroenterology
Novel Approach for Pancreas Transcriptomics Reveals the Cellular Landscape in Homeostasis and Acute Pancreatitis
Aney KJ, Jeong WJ, Chen E, Wang A, Koak P, Dougan SK, Nissim S
BACKGROUND & AIMS: Acinar cells produce digestive enzymes that impede transcriptomic characterization of the exocrine pancreas. Thus, single-cell RNA-sequencing studies of the pancreas underrepresent acinar cells relative to histological expectations, and a robust approach to capture pancreatic cell responses in disease states is needed. We sought to innovate a method that overcomes these challenges to accelerate study of the pancreas in health and disease.
METHODS: We leverage FixNCut, a single-cell RNA-sequencing approach in which tissue is reversibly fixed with dithiobis(succinimidyl propionate) before dissociation and single-cell preparation. We apply FixNCut to an established mouse model of acute pancreatitis, validate findings using GeoMx whole transcriptome atlas profiling, and integrate our data with prior studies to compare our method in both mouse and human pancreas datasets.
RESULTS: FixNCut achieves unprecedented definition of challenging pancreatic cells, including acinar and immune populations in homeostasis and acute pancreatitis, and identifies changes in all major cell types during injury and recovery. We define the acinar transcriptome during homeostasis and acinar-to-ductal metaplasia and establish a unique gene set to measure deviation from normal acinar identity. We characterize pancreatic immune cells, and analysis of T-cell subsets reveals a polarization of the homeostatic pancreas toward type-2 immunity. We report immune responses during acute pancreatitis and recovery, including early neutrophil infiltration, expansion of dendritic cell subsets, and a substantial shift in the transcriptome of macrophages due to both resident macrophage activation and monocyte infiltration.
CONCLUSIONS: FixNCut preserves pancreatic transcriptomes to uncover novel cell states during homeostasis and following pancreatitis, establishing a broadly applicable approach and reference atlas for study of pancreas biology and disease.
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JAMA
PhALLCON Soars to New Heights-Faster, Stronger, but Better?
Bystrom RP, DeAngelo DJ, Garcia JS
In this issue of JAMA, Jabbour and colleagues report results from the interim analysis of the PhALLCON randomized trial with ponatinib vs imatinib, combined with reduced-intensity chemotherapy. They found ponatinib to have superior efficacy and a comparable safety profile for frontline treatment of adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). On the heels of these results, the US Food and Drug Administration granted ponatinib accelerated approval for this indication on March 19, 2024.
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JAMA Oncology
Assessing the Environmental and Downstream Human Health Impacts of Decentralizing Cancer Care
Hantel A, Cernik C, Walsh TP, Uno H, Larios D, Slutzman JE, Abel GA
IMPORTANCE: Greenhouse gas (GHG) emissions from health care are substantial and disproportionately harm persons with cancer. Emissions from a central component of oncology care, outpatient clinician visits, are not well described, nor are the reductions in emissions and human harms that could be obtained through decentralizing this aspect of cancer care (ie, telemedicine and local clinician care when possible).
OBJECTIVE: To assess potential reductions in GHG emissions and downstream health harms associated with telemedicine and fully decentralized cancer care.
DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study and counterfactual analyses using life cycle assessment methods analyzed persons receiving cancer care at Dana-Farber Cancer Institute between May 2015 and December 2020 as well as persons diagnosed with cancer over the same period from the Cancer in North America (CiNA) public dataset. Data were analyzed from October 2023 to April 2024.
MAIN OUTCOMES AND MEASURES: The adjusted per-visit day difference in GHG emissions in kilograms of carbon dioxide (CO2) equivalents between 2 periods: an in-person care model period (May 2015 to February 2020; preperiod) and a telemedicine period (March to December 2020; postperiod), and the annual decrease in disability-adjusted life-years in a counterfactual model where care during the preperiod was maximally decentralized nationwide.
RESULTS: Of 123?890 included patients, 73?988 (59.7%) were female, and the median (IQR) age at first diagnosis was 59 (48-68) years. Patients were seen over 1.6 million visit days. In mixed-effects log-linear regression, the mean absolute reduction in per-visit day CO2 equivalent emissions between the preperiod and postperiod was 36.4 kg (95% CI, 36.2-36.6), a reduction of 81.3% (95% CI, 80.8-81.7) compared with the baseline model. In a counterfactual decentralized care model of the preperiod, there was a relative emissions reduction of 33.1% (95% CI, 32.9-33.3). When demographically matched to 10.3 million persons in the CiNA dataset, decentralized care would have reduced national emissions by 75.3 million kg of CO2 equivalents annually; this corresponded to an estimated annual reduction of 15.0 to 47.7 disability-adjusted life-years.
CONCLUSIONS AND RELEVANCE: This cohort study found that using decentralization through telemedicine and local care may substantially reduce cancer care's GHG emissions; this corresponds to small reductions in human mortality.
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Journal of Clinical Oncology
PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer
Mayer EL, Ren Y, Wagle N, Sinclair N, Faggen M, Block CC, Ko N, Partridge AH, Chen WY, DeMeo M, Attaya V, Okpoebo A, Alberti J, Burstein HJ, Regan MM, Tolaney SM
PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting.
METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P.
RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations.
CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.
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Journal of the National Cancer Institute
Association of N-Terminal Pro-Brain Natriuretic Peptide with Survival Among US Cancer Survivors
Cao C, Nohria A, Mayer EL, Partridge AH, Ligibel JA
BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a cardiac biomarker associated with the risk of heart failure and death in the general population, but it has not been explored in cancer survivors.
METHODS: Using a US nationally representative sample of adults 20?years of age and older from the National Health and Nutrition Examination Survey from 1999 to 2004, this study compared NT-proBNP levels between adults without cancer (n?=?12?574) and adult cancer survivors (n?=?787). It examined the association of NT-proBNP with all-cause and cause-specific mortality among cancer survivors.
RESULTS: Cancer survivors had higher NT-proBNP levels than adults without cancer (median [interquartile range]?=?125.4 pg/mL [52.4-286.0] vs 43.2 pg/mL [20.3-95.0]). In particular, survivors of breast, prostate, and colorectal cancers had higher NT-proBNP levels than adults without cancer (multivariable-adjusted P?
Nature
Targetable Leukaemia Dependency on Noncanonical PI3K? Signalling
Luo Q, Raulston EG, Prado MA, Wu X, Whalen KS, Yan K, Booth CAG, Xu R, van Galen P, Doench JG, Shimony S, Long HW, Neuberg DS, Paulo JA, Lane AA
Phosphoinositide-3-kinase-? (PI3K?) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3K? are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3K? complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3K?5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3K? that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3K? inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3K? inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3K?-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.
Nature Chemical Biology
Antibody Discovery Identifies Regulatory Mechanisms of Protein Arginine Deiminase 4
Zhou X, Kong S, Remesh SG, Leung KK
Unlocking the potential of protein arginine deiminase 4 (PAD4) as a drug target for rheumatoid arthritis requires a deeper understanding of its regulation. In this study, we use unbiased antibody selections to identify functional antibodies capable of either activating or inhibiting PAD4 activity. Through cryogenic-electron microscopy, we characterized the structures of these antibodies in complex with PAD4 and revealed insights into their mechanisms of action. Rather than steric occlusion of the substrate-binding catalytic pocket, the antibodies modulate PAD4 activity through interactions with allosteric binding sites adjacent to the catalytic pocket. These binding events lead to either alteration of the active site conformation or the enzyme oligomeric state, resulting in modulation of PAD4 activity. Our study uses antibody engineering to reveal new mechanisms for enzyme regulation and highlights the potential of using PAD4 agonist and antagonist antibodies for studying PAD4-dependency in disease models and future therapeutic development.
Nature Communications
Germline Variation Contributes to False Negatives in CRISPR-Based Experiments with Varying Burden Across Ancestries
Misek SA, Fultineer A, Kalfon J, Noorbakhsh J, Boyle I, Roy P, Dempster J, Petronio L, Huang K, Saadat A, Green T, Brown A, Doench JG, Root DE, McFarland JM, Beroukhim R, Boehm JS
Reducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale. Here, we analyze data from 611 genome-scale CRISPR/Cas9 viability experiments in human cell line models to identify ancestry-associated genetic dependencies essential for cell survival. Surprisingly, we find that most putative associations between ancestry and dependency arise from artifacts related to germline variants. Our analysis suggests that for 1.2-2.5% of guides, germline variants in sgRNA targeting sequences reduce cutting by the CRISPR/Cas9 nuclease, disproportionately affecting cell models derived from individuals of recent African descent. We propose three approaches to mitigate this experimental bias, enabling the scientific community to address these disparities.
New England Journal of Medicine
Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy
Sadigh S, Armand P, Anderson KC
Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy for treatment of myeloma. Targeted messenger RNA sequencing revealed the presence of CAR gene product in tumor cells. Whole-genome sequencing of samples of tumor and peripheral blood identified a single lentiviral insertion site within the second intron of the SSU72 gene. In addition, numerous genetic alterations that may have contributed to malignant transformation were identified in the tumor sample. (Funded by MedStar Georgetown University Hospital).
AJNR American Journal of Neuroradiology
Time-Saving 3D MR Imaging Protocols with Millimeter and Submillimeter Isotropic Spatial Resolution for Face and Neck Imaging as Implemented at a Single-Site Major Referral Center
Guenette JP, Qin L
American Journal of Hematology
Persistent Sweet Syndrome Post-Hematopoietic Stem Cell Transplantation Heralding Molecular Relapse of Myelofibrosis
Xiang DH, Pakyari M, Koreth J, Shi CR
American Society of Clinical Oncology Educational Book
Hematopoietic Stem-Cell Transplantation: Exploring the Latest Advances and Gaps in Disparities, Psychosocial and Symptom Management Interventions, and Chronic Graft-Versus-Host Disease Care
Guo M, Amonoo HL
Biomedicine and Pharmacotherapy
Nocebo Expectations Rather than Placebo Expectations Affect Topical Pain Relief: A Randomized Clinical Trial
Yang M
Biomedical Physics and Engineering Express
Lung Sparing in MR-Guided Non-Adaptive SBRT Treatment of Peripheral Lung Tumors
Lee HY, Lee G, Ferguson D, Hsu SH, Hu YH, Sudhyadhom A, Williams CL, Fitzgerald KJ, Kann BH, Kozono D, Leeman JE, Mak RH, Han Z
Blood Advances
An Indirect Comparison of Acalabrutinib with and without Obinutuzumab vs Zanubrutinib in Treatment-Naive CLL
Davids MS
Blood Advances
Organ Involvement in Adults with BPDCN is Associated with Sun Exposure History, TET2 and RAS Mutations, and Survival
Shimony S, Keating J, Fay CJ, Luskin MR, Neuberg DS, LeBoeuf NR, Lane AA
Blood Reviews
Endothelial Injury and Dysfunction with Emerging Immunotherapies in Multiple Myeloma, the Impact of COVID-19, and Endothelial Protection with a Focus on the Evolving Role of Defibrotide
Mo CC, Calabretta E, Corrado F, Baron RM, Connors JM, Wei LJ, Richardson PG
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