Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming.

Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces. Specifically, our strategy permits controlled assembly of small poly(ß-amino ester)/messenger ribonucleic acid (mRNA) nanoparticles into particles with a size that is kinetically tunable between 200 and 1,000 nm with high colloidal stability in physiological media. We found that assembled particles with an average size of 400 nm safely and most efficiently transfect monocytes following intravenous administration and mediate their differentiation into macrophages in the periphery. When a CpG adjuvant is co-loaded into the particles with an antigen mRNA, the monocytes differentiate into inflammatory dendritic cells and prime adaptive anticancer immunity in the tumor-draining lymph node. This platform technology offers a unique ligand-independent, particle-size-mediated strategy for preferential mRNA delivery and enables therapeutic paradigms via monocyte programming.

High-multiplex single-cell imaging analysis reveals tumor immune contexture associated with clinical outcomes after CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has made great progress in treating lymphoma, yet patient outcomes still vary greatly. The lymphoma microenvironment may be an important factor in the efficacy of CAR T therapy. In this study, we designed a highly multiplexed imaging mass cytometry (IMC) panel to simultaneously quantify 31 biomarkers from 13 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) who received CAR19/22 T cell therapy. A total of 20 sections were sampled before CAR T cell infusion or after infusion when relapse occurred. A total of 35 cell clusters were identified, annotated, and subsequently redefined into 10 metaclusters. The CD4+ T cell fraction was positively associated with remission duration. Significantly higher Ki67, CD57, and TIM3 levels and lower CD69 levels in T cells, especially the CD8+/CD4+ Tem and Te cell subsets, were seen in patients with poor outcomes. Cellular neighborhood containing more immune cells was associated with longer remission. Fibroblasts and vascular endothelial cells resided much closer to tumor cells in patients with poor response and short remission after CAR T therapy. Our work comprehensively and systematically dissects the relationship between cell composition, state, and spatial arrangement in the DLBCL microenvironment and the outcomes of CAR T cell therapy, which is beneficial to predict CAR T therapy efficacy.

Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma.

BACKGROUND AIMS: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. METHODS: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. RESULTS: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). CONCLUSIONS: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.

Improving the safety of CAR-T-cell therapy: The risk and prevention of viral infection for patients with relapsed or refractory B-cell lymphoma undergoing CAR-T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy, an innovative immunotherapeutic against relapsed/refractory B-cell lymphoma, faces challenges due to frequent viral infections. Despite this, a comprehensive review addressing risk assessment, surveillance, and treatment management is notably absent. This review elucidates immune response compromises during viral infections in CAR-T recipients, collates susceptibility risk factors, and deliberates on preventive strategies. In the post-pandemic era, marked by the Omicron variant, new and severe threats to CAR-T therapy emerge, necessitating exploration of preventive and treatment measures for COVID-19. Overall, the review provides recommendations for viral infection prophylaxis and management, enhancing CAR-T product safety and recipient survival.

Radical relay cyclization/C-C bond formation of allyloxy-tethered aryl iodides with quinoxalin-2(1H)-ones via polysulfide anion photocatalysis.

A visible-light-induced radical relay cyclization/C-C bond formation of quinoxalin-2(1H)-ones with allyloxy-tethered aryl iodides using polysulfide anions as a photocatalyst is described. This protocol allows efficient access to a variety of complicated molecules bearing both quinoxalin-2(1H)-one and 2,3-dihydrobenzofuran motifs in high yields under mild reaction conditions with a broad range of substrates.

Clinical analysis of 82 cases of acute promyelocytic leukemia with PML-RARα short isoform in children and adults.

Background: Acute promyelocytic leukemia (APL) with PML/RARα fusion gene is a distinct variant of acute myeloid leukemia. According to the different break sites of the PML gene, there are three transcripts: Long (bcr1), Variant (bcr2) and Short (bcr3). Methods: We retrospectively analyzed 82 APL cases with PML-RARα short isoform. Results: A total of 384 patients with APL were seen, of which 85(22.14%) had PML/RARα short isoform (bcr3) and 82 met the inclusion criteria. The median age was 33.5 years (range, 2-72 years). The incidences of hemorrhage in the intermediate- and high-risk group were higher, but only the incidence between medium and low risk differed statistically (P=0.006), and the incidences of fever, fatigue, splenomegaly, and lymph node enlargement and differentiation syndrome (DS) in those groups were not statistically significant (P>0.05). FLT3 gene mutation rate and the mortality rate of the high-risk group were significantly higher than that of other groups (P=0.040 and P=0.004, P=0.041 and P=0.037, respectively). The mortality rate was lowest (4.26%) in the group treated with ATRA combined with arsenic and anthracycline. The 3-year OS and the 3-year DFS of the low and intermediate-risk group were better (P=0.019 and P=0.017, respectively). Conclusions: ATRA combined with arsenic and anthracycline had significant impact on outcomes in APL with PML-RARα short isoform.

Overcoming the challenges encountered in CAR-T therapy: latest updates from the 2023 ASH annual conference.

Chimeric antigen receptor (CAR) -T cell therapy has entered the breakthrough era, characterized by a blend of therapeutic opportunities and challenges. With the integration of genome-editing technology, CAR-T cells will be empowered to become super warriors in eradicating tumor cells and attacking various tumors, including T-cell malignancies and acute myeloid leukemia. Notably, the optimization of CAR-T cells, including efficacy, safety, and manufacturing speed, coupled with other therapeutic strategies such as radiotherapy, hematopoietic stem cell transplantation, small-molecule inhibitors, and bispecific antibodies, could revolutionize the therapeutic landscape of tumors. Consequently, next-generation cellular immunotherapy, including universal CAR-NK cells and synergistic combination approaches, are anticipated to significantly impact cancer treatment in the coming decade. Nevertheless, the failure rates of CAR-T therapy continue to be significant. The challenge lies in determining the optimal combination strategy and identifying reliable and robust biomarkers to effectively select the patients who will derive the greatest benefit from CAR-T therapy. Herein, we highlight recent innovations in CAR-T products, combination strategies and predictive biomarkers of response presented at the 2023 ASH Annual Meeting.

Clinical performance of metagenomic next-generation sequencing for diagnosis of invasive fungal disease after hematopoietic cell transplant.

Background: Timely diagnosis and appropriate antifungal therapy are critical for improving the prognosis of patients with invasive fungal disease (IFD) after hematopoietic stem cell transplantation (HSCT). We evaluated the performance of metagenomic next-generation sequencing (mNGS) and conventional microbiological testing (CMT), as well as the diagnosis, therapeutic management, and outcomes of IFD after HSCT. Methods: We retrospectively studied 189 patients who underwent HSCT and were considered at risk for IFD. In total, 46 patients with IFD were enrolled in this study. The IFD consensus was followed for classifying IFD incidents. Results: Forty-six patients were diagnosed with proven/probable (n = 12), possible (n = 27), and undefined (n = 7) IFD. Aspergillus was the most commonly detected fungal genus. Mucormycosis was found in 15 patients; two had Aspergillus, and one had Candida infections. Compared to CMT, mNGS significantly reduced the time required to identify pathogens (P = 0.0016). mNGS had a much higher sensitivity than CMT (84.78% vs. 36.96%; P < 0.0001). A total of 76.09% of patients received antifungal prophylaxis during fungal infections. All Pneumocystis infections occurred later than 100 days after transplantation. Among patients with Pneumocystis infection, 71.43% occurred following sulfonamide withdrawal, and subsequent treatment with sulfonamide alone or in combination with other drugs was effective. Based on the empirical antifungal treatment, the dosages, modes of administration, frequency of administration, or antifungal of 55.26% of the patients were changed according to the mNGS results. The 4-year overall survival rate of patients diagnosed with IFD after transplantation was 71.55% (95% CI, 55.18%-85.82%). Hypoproteinemia and corticosteroid use are independent risk factors for IFD. Conclusion: mNGS, which has a high sensitivity and a short detection time, aids in the diagnosis and prognosis of pathogenic fungi. As a powerful technology, mNGS can influence treatment decisions in patients with IFD following HSCT.

Nonrandom behavior in the projection of random bipartite networks.

There are two main categories of networks studied in the complexity physics community: Monopartite and bipartite networks. In this paper, we present a general framework that provides insights into the connection between these two classes. When a random bipartite network is projected into a monopartite network, under quite general conditions, the result is a nonrandom monopartite network, the features of which can be studied analytically. Unlike previous studies in the physics literature on complex networks, which rely on sparse-network approximations, we provide a complete analysis, focusing on the degree distribution and the clustering coefficient. Our findings primarily offer a technical contribution, adding to the current body of literature by enhancing the understanding of bipartite networks within the community of physicists. In addition, our model emphasizes the substantial difference between the information that can be extracted from a network measuring its degree distribution, or using higher-order metrics such as the clustering coefficient. We believe that our results are general and have broad real-world implications.

Establishment of an in vitro cell coculture model for investigating the whitening mechanism of Paeonia lactiflora Pall seeds oil.

BACKGROUND: In vitro single-cell experiments may yield inconsistent results compared to clinical trials. To enhance the reliability of cosmetic active ingredient screening, a coculture model of B16F10-HaCaT cells was established in vitro based on the structural characteristics of human skin, thereby improving the credibility of experimental outcomes. Currently, most cosmetic whitening additives primarily target simple efficacy goals such as inhibiting tyrosinase activity or melanin transfer. Therefore, investigating novel and efficient whitening additives has become a prominent research focus. OBJECTIVES: The aim is to establish an in vitro cell coculture model for more reliable experimental results and investigate the mechanism by which Paeonia lactiflora Pall seeds oil inhibits melanin production and transfer. METHODS: The impact of different concentrations of Paeonia lactiflora Pall seeds oil on cocultured cell proliferation rate was assessed using cck8 assay. Tyrosinase inhibition ability in cocultured cells was tested using levodopa as a substrate. Melanin production inhibition ability in coculture cells was evaluated by lysing cells with sodium hydroxide. The effect of Paeonia lactiflora Pall seeds oil on dendrite-related gene expression levels was examined through qPCR analysis. Additionally, Western blotting was employed to study the effect of Paeonia lactiflora Pall seeds oil on dendrite-related protein expression levels. RESULTS: Different concentrations of Paeonia lactiflora Pall seeds oil did not affect the proliferation activity of cocultured cells. A specific concentration of α-MSH increased cell tyrosinase activity, cellular melanin content, as well as Rac1, Cdc42, and PAR-2 gene and protein expression related to dendritic formation. Treatment with a certain concentration of Paeonia lactiflora Pall seeds oil resulted in decreased tyrosinase activity and melanin content in cells along with downregulated expression levels of Rac1, Cdc42, and PAR-2 genes and proteins associated with dendritic formation. CONCLUSIONS: Paeonia lactiflora Pall seeds oil at specific concentrations exhibits the ability to inhibit tyrosinase activity, decrease melanin content, and possesses the potential to impede melanin transfer.

Updates of primary central nervous system lymphoma.

Lymphoma occurring in the central nervous system is considered primary central nervous system lymphoma (PCNSL), usually without systematic lesions. Over the last few decades, a deep understanding of PCNSL has been lacking due to the low incidence rate, and the overall survival and progression-free survival of patients with PCNSL are lower than those with other types of non-Hodgkin lymphoma. Recently, there have been several advancements in research on PCNSL. Advances in diagnosis of the disease are primarily reflected in the promising diagnostic efficiency of novel biomarkers. Pathogenesis mainly involves abnormal activation of nuclear factor kappa-B signaling pathways, copy number variations, and DNA methylation. Novel therapies such as Bruton's tyrosine kinase inhibitors, immunomodulatory drugs, immune checkpoint inhibitors, and phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors are being evaluated as possible treatment options for PCNSL, especially for relapsed/refractory (R/R) cases. Several clinical trials also indicated the promising feasibility and efficacy of chimeric antigen receptor T-cell therapy for selected R/R PCNSL patients. This review focuses on discussing recent updates, including the diagnosis, pathogenesis, and novel therapy of PCNSL.

Finite barrier bound state.

A boundary mode localized on one side of a finite-size lattice can tunnel to the opposite side which results in unwanted couplings. Conventional wisdom tells that the tunneling probability decays exponentially with the size of the system which thus requires many lattice sites before eventually becoming negligibly small. Here we show that the tunneling probability for some boundary modes can apparently vanish at specific wavevectors. Thus, similar to bound states in the continuum, a boundary mode can be completely trapped within very few lattice sites where the bulk bandgap is not even well-defined. More intriguingly, the number of trapped states equals the number of lattice sites along the normal direction of the boundary. We provide two configurations and validate the existence of this peculiar finite barrier-bound state experimentally in a dielectric photonic crystal at microwave frequencies. Our work offers extreme flexibility in tuning the coupling between localized states and channels as well as a new mechanism that facilitates unprecedented manipulation of light.

Infections associated with CAR-T cell therapy in patients with relapsed refractory multiple myeloma: Risks and prevention strategies.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a potent treatment for relapsed or refractory multiple myeloma, demonstrating significant clinical efficacy. Despite these advances, treatment-related toxicities, particularly infections, pose a significant challenge to patient safety. METHODS: This review synthesizes current knowledge on the mechanisms underlying post-CAR-T therapy infections, focusing on the interplay between immune dysfunction, host factors, and treatment-induced toxicity. It provides a comprehensive analysis of the temporal and individual variability in infection characteristics and the confounding clinical presentation of cytokine release syndrome. RESULTS: The review identifies that patients receiving CAR-T cells are at increased risk of concurrent infections due to the heterogeneity in infection characteristics across different time periods, individuals, and patient groups. It highlights the diagnostic and therapeutic complexities introduced by the overlapping symptoms of infection and cytokine release syndrome. CONCLUSION: To enhance the infection control post-CAR-T therapy, this review proposes preventive strategies tailored to the early and long-term management of patients. It underscores the need for a nuanced understanding of infection mechanisms and the importance of personalized prevention plans to improve clinical outcomes in multiple myeloma treatment.

PAA-PU Janus Hydrogels Stabilized by Janus Particles and its Interfacial Performance During Hemostatic Processing.

Hydrogel is a very promising dressing for hemostasis and wound healing due to its good adhesion and long-term moist environment. However, secondary injury caused by tissue adhesion due to homogeneous hydrogel cannot be ignored. The obvious interface existing in Janus hydrogel will weaken its asymmetric function. Here, a hierarchical adhesive polyacrylic acid-polyurushiol water-oil Janus hydrogel (JPs@PAA-PU) without adhesive layer is fabricated by one-pot method in the stabilization of polystyrene@silica-siliver Janus particles (JPs). The morphological structure, mechanical properties, anisotropic chemical composition, and adhesion performance, in vivo, and in vitro hemostatic properties of Janus hydrogel are investigated. Result shows that the obtained Janus hydrogel possesses obvious compartmentalization in microstructure, functional groups, and chemical elements. Janus hydrogel is provided with asymmetric interfacial toughness with top 52.45 ± 2.29 Kpa and bottom 7.04 ± 0.88 Kpa on porcine liver. The adhesion properties of PAA side to tissue, red blood cells and platelets, promoting effect of PU side on coagulation cascade reaction and its physical battier endow Janus hydrogel with shorter hemostatic time and less blood loss than control group. It also exhibits excellent antibacterial effects against Escherichia coli and Staphylococcus aureus (>90%). Janus hydrogel possesses biosafety, providing safety guarantee for clinical applications in the future.

Adverse Reactions in Relapsed/Refractory B-Cell Lymphoma Administered with Chimeric Antigen Receptor T Cell Alone or in Combination with Autologous Stem Cell Transplantation.

(1) Background: The combination of CAR-T with ASCT has been observed to enhance the efficacy of CAR-T cell therapy. However, the impact of this combination on adverse reactions is still uncertain. (2) Methods: Between January 2019 and February 2023, 292 patients diagnosed with r/r B-cell lymphoma received either CAR-T therapy alone or in combination with ASCT at our institution. We evaluated the incidence of CRS and CRES and utilized a logistic regression model to identify factors contributing to severe CRS (grade 3-4) and CRES (grade 3-4). (3) Results: The overall incidence of CRS and CRES was 78.9% and 8.2% in 147 patients receiving CAR-T alone, and 95.9% and 15.2% in 145 patients receiving CAR-T combined with ASCT, respectively. The incidence of overall CRS (p < 0.0001) and mild CRS (grade 1-2) (p = 0.021) was elevated in the ASCT combined with CAR-T group. No significant difference was observed in severe CRS and CRES between the groups. Among the 26 cases of lymphoma involving the central nervous system (CNS), 96.2% (25/26) developed CRS (15.4% grade 3-4), and 34.6% (9/26) manifested CRES (7.7% grade 3-4). Female patients had a lower incidence of severe CRS but a higher incidence of severe CRES. Lymphomas with CNS involvement demonstrated a higher risk of CRES compared to those without central involvement. (4) Conclusions: The combination of ASCT with CAR-T demonstrated a preferable option in r/r B-cell lymphoma without an increased incidence of severe CRS and CRES.

Phantom energy in the nonlinear response of a quantum many-body scar state.

Quantum many-body scars are notable as nonthermal, low-entanglement states that exist at high energies. Here, we use attractively interacting dysprosium gases to create scar states that are stable enough to be driven into a strongly nonlinear regime while retaining their character. We measure how the kinetic and total energies evolve after quenching the confining potential. Although the bare interactions are attractive, the atoms behave as if they repel each other: Their kinetic energy paradoxically decreases as the gas is compressed. The missing "phantom" energy is quantified by benchmarking our experimental results against generalized hydrodynamics calculations. We present evidence that the missing kinetic energy is carried by undetected, very high-momentum atoms.

Amphiphilic Janus cotton gauze with enhanced moisture management and blood coagulation for rapid hemostasis and wound healing.

Cotton gauze is commonly used in initial emergency care. However, its high hydrophilicity and limited clotting capacity can lead to the excessive absorption of blood, resulting in unnecessary blood loss. Herein, an amphiphilic Janus cotton gauze with excellent moisture management and enhanced blood coagulation has been developed via in situ generating bioactive glass (BG) onto the cotton gauze (CG), and then attaching cardanol (CA) onto one side of the BG-loaded CG (CG@BG) via click reaction. The Janus gauze (CA-CG@BG) has asymmetric wetting properties with a hydrophilic side (CA-CG@BGHL) and a hydrophobic side (HBCA-CG@BG). When applied to hemostatic, the porous and active BG on CA-CG@BGHL can rapidly initiate coagulation cascade to form a robust thrombus. CA on HBCA-CG@BG can entangled with each other, creating a hydrophobic barrier that prevents blood from flowing out. The hemostatic performance of CA-CG@BG is superior to that of CG in both rats and pigs. Interestingly, CA-CG@BG possesses unidirectional exudate removal. When applied to wound healing, the exudate can penetrate the hydrophobic HBCA-CG@BG to the hydrophilic CA-CG@BGHL, resulting in faster wound healing than CG. CA-CG@BG exhibits excellent cytocompatibility and hemocompatibility. This unique Janus dressing shows promise as a potential material for clinical applications in the future.

Surface crystallized supramolecular to achieve highly dispersed ultrafine nano-palladium in-situ deposition to promote thermal/electrocatalytic reduction.

To promote the greening and economization of industrial production, the development of advanced catalyst manufacturing technology with high activity and low cost is an indispensable part. In this study, nitrogen-doped hollow carbon spheres (NHCSs) were used as anchors to construct a supramolecular coating formed by the self-assembly of boron clusters and ß-cyclodextrin by surface crystallization strategy, with the help of the weak reducing agent characteristics of boron clusters, highly dispersed ultra-small nano-palladium particles were in-situ embedded on the surface of NHCSs. The deoxygenation hydrogenation of nitroaromatics and the reduction of nitrate to ammonia were used as the representatives of thermal catalytic reduction and electrocatalytic reduction respectively. The excellent properties of the constructed Pd/NHCSs were proved by the probe reaction. In the catalytic hydrogenation of nitroaromatics to aminoaromatics, the reaction kinetic rate and activation energy are at the leading level. At the same time, the constructed Pd/NHCSs can also electrocatalytically reduce nitrate to high value-added ammonia with high activity and selectivity, and the behavior of Pd/NHCSs high selectivity driving nitrate conversion was revealed by density functional theory and in situ attenuated total reflection Fourier transform infrared (ATRFTIR) technique. These results all reflect the feasibility and superiority of in-situ anchoring ultra-small nano-metals as catalysts by surface crystallization to build a supramolecular cladding with reducing properties, which is an effective way to construct high-activity and low-cost advanced catalysts.

Frontline combination of dasatinib and low-intensity chemotherapy in adults with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. RESEARCH DESIGN AND METHODS: Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. RESULTS: Twenty-two patients were enrolled. Median age was 45 years (range, 20-71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5-89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. CONCLUSIONS: Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. CLINICAL TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov as NCT02690922.