An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high-risk subset of Ph-like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1, resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph-like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling (CRLF2/EPOR/JAK2 rearrangements or p-CRKL/p-STAT5 high expression) had the worst outcome (3-year overall survival [OS] of 28.8% vs. 80.1% for others, p < 0.001; 2-year event-free survival [EFS] of 6.5% vs. 57.0% for others, p < 0.001). Multivariable analysis demonstrated that this high-risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35-8.81, p < 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99-5.39, p < 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.

Mutations of epigenetic modifier genes predict poor outcome in adult acute lymphoblastic leukemia.

Epigenetic modifier (EM) genes play important roles in the occurrence and progression of acute lymphoblastic leukemia (ALL). However, the prognostic significance of EM mutations in ALL has not yet been thoroughly investigated. This retrospective study included 205 adult patients with ALL engaged in a pediatric-type regimen. Based on targeted next-generation sequencing, they were divided into EM mutation group (EM-mut, n = 75) and EM wild-type group (EM-wt, n = 130). The EM-mut group showed a higher positive rate of minimal residual disease (MRD) on treatment day24 and before consolidation therapy (P = 0.026, 0.020). Multivariate Cox regression analysis showed that EM-mut was an independent adverse factor for overall survival (OS) and event-free survival (EFS) (HR = 2.123, 1.742; P = 0.009, 0.007). Survival analysis revealed that the OS and EFS rates were significantly lower in the EM-mut group than in the EM-wt group (3-year OS rate, 45.8% vs. 65.0%, P = 0.0041; 3-year EFS rate, 36.7% vs. 53.2%, P = 0.011). In conclusion, EM was frequently mutated in adult ALL and was characterized by poor response to induction therapy and inferior clinical outcomes.

PASS-ALL study of paediatric-inspired versus adult chemotherapy regimens on survival of high-risk Philadelphia-negative B-cell acute lymphoblastic leukaemia with allogeneic haematopoietic stem cell transplantation.

This PASS-ALL study was designed to explore the effect of paediatric-inspired versus adult chemotherapy regimens on survival of adolescents and young adults (AYA) with high-risk Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia (HR PH-ve B-cell ALL) eligible for allogeneic haematopoietic stem cell transplantation (allo-HSCT). The PASS-ALL study is a multicentre, observational cohort study, and 143 patients with HR B-cell PH-ve ALL were enrolled from five centres-77 patients allocated in the paediatric-inspired cohort and 66 in the adult cohort with comparable baseline characteristics. Of the 143 patients, 128 cases underwent allo-HSCT. Three-year leukaemia-free survival (LFS) in the paediatric-inspired cohort was 72.2% (95% CI 60.8%-83.6%) compared with 44.6% (95% CI 31.9%-57.3%; p = 0.001). Furthermore, time-to-positive minimal residual disease (TTP-MRD) post-HSCT was marked different, 3-year cumulative incidence of relapse was 25.9% (95% CI 15.8%-37.2%) in paediatric cohort and 45.4% (95% CI 40.0%-57.9%) in adult cohort (p = 0.026). Finally, the 3-year OS rate was 75.3% (95% CI 64.9%-85.7%) for the paediatric-inspired cohort and 64.1% (95% CI 51.8%-76.4%) for the adult cohort (p = 0.074). On a multivariate analysis, paediatric-inspired regimen is a predictive factor for LFS (HR = 2.540, 95% CI 1.327-4.862, p = 0.005). Collectively, our data suggest that paediatric-inspired chemotherapy pre-HSCT results in deeper and durable MRD response reduces relapse post-HSCT and improves survival in HR B-cell PH-ve ALL patients with allo-HSCT.

Prognostic impact of TP53 mutations in adult acute lymphoblastic leukemia treated with a pediatric-type regimen.

The prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remains debatable. Herein, we determined the clinical significance of TP53mut in 283 adult ALL patients treated with a pediatric-type regimen. TP53mut were found in 11.0% (31) of patients, including 19 cases in adolescent and young adult (AYA) patients and 12 cases in non-AYA patients. Patients with TP53mut had poorer overall survival (OS) and event-free survival (EFS) in the non-AYA subgroup (n = 64) (3-year OS, 18.2% vs 50.9%, p = .0033; 3-year EFS, 0 vs 45.3%, p = .00028). however, this had to be taken cautiously due to a limited number of patients. In the AYA subgroup (n = 219), TP53mut did not impact OS or EFS (3-year OS, 60.6%vs71.0%, p = .55; 3-year EFS, 52.5%vs59.6%, p = .57). Collectively, our data reveal that the pediatric-type regimen eliminated the poor prognostic impact of TP53mut in AYA ALL. However, in non-AYA ALL patients, TP53mut remain a potential biomarker associated with poor outcomes.

Allogeneic hematopoietic stem cell transplantation overcome the poor prognosis of patients with IKZF1plus CD20-a very high-risk subtype in B-cell acute lymphoblastic leukemia.

Genetic deletions of IKZF1 (IKZF1del) and IKZF1del plus other mutations (IKZF1plus) have been identified in B-cell acute lymphoblastic leukemia (B-ALL) with a poor prognosis. Herein, we investigated the combination of IKZF1del and CD20 immunotypes in adult patients with B-ALL in the PDT-ALL-2016 cohort. This study cohort consisted of 161 patients with B-ALL with detailed information on IKZF1del and CD20 expression. The independent cohort included 196 patients from the TARGET dataset. IKZF1del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.1 ± 6.7% and overall survival (OS) of 51.5 ± 7.3%, compared to IKZF1 wild-type (IKZF1wt) with an EFS 55.3 ± 5.1% (P = 0.011) and OS 74.4 ± 4.5% (P = 0.013), respectively. CD20-positive (CD20+) was associated with inferior EFS compared to the CD20-negative (CD20-) group (P = 0.020). Furthermore, IKZF1del coupled with CD20+, IKZF1del/CD20+, comprised 12.4% of patients with a 3-year EFS of 25.0 ± 9.7%, compared with IKZF1wt/CD20- (P ≤ 0.001) and IKZF1del/CD20- (P = 0.047) groups. Multivariable analyses demonstrated the independence of IKZF1del/CD20+, with the highest predicted hazard ratio for EFS and OS. Furthermore, the prognostic panel of IKZF1del/CD20+ was confirmed in the TARGET cohort. Notably, neither the IKZF1del, CD20+, or IKZF1del/CD20+ groups were identified to have poor outcomes in the cohort of allogeneic hematopoietic stem cell transplantation (n = 81).Collectively, our data define IKZF1del/CD20+ as a very high-risk subtype in B-ALL, and allo-HSCT could abrogate the poor outcome of both IKZF1del and IKZF1del/CD20+ subsets.

Dynamics of minimal residual disease defines a novel risk-classification and the role of allo-HSCT in adult Ph-negative B-cell acute lymphoblastic leukemia.

The prognosis of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) patients is well established. However, the implementation of dynamic MRD for risk classification and decision-making for allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains vague. In this study, we collected multiparameter flow cytometry (MFC)-MRD data of Ph-negative B-ALL patients (n = 134) from the Precision-Classification-Directed-Target-Total-Therapy-ALL-2016 (PDT-ALL-2016) cohort and stratified it into high-(HR), medium-(MR), and standard-risk (SR) groups. With a median of 3.65 years follow-up (95% CI: 3.037-4.263), 3-year OS rate was 51.8 ± 8.3% in HR, compared with MR 61.5 ± 10.8% (p = 0.472), and SR 73.3 ± 5.9% (p = 0.006). Multivariate analysis shows that integrated dynamic MRD is an independent factor for overall survival. Compared to pediatric-inspired chemotherapy, allo-HSCT significantly improves the survival of the HR cohort (p < 0.001), but not in MR and SR. Finally, our study suggests that integrated dynamic MRD defines a novel risk-classification criteria and highlights the benefits of allo-HSCT in adult patients with Ph-negative ALL.

Direct photochemical cross-coupling between aliphatic acids and BF3K salts.

We describe a novel photoredox hetero-coupling reaction of two C (sp3) radicals from aliphatic acids or BF3K salts. The kinetic differences in radical persistence provide cross-selectivity, using an organic photoredox catalyst and an oxidant with visible light. This method exhibits broad scope, including several examples constructing sterically hindered C(sp3)-C(sp3) bonds.

Collective Synthesis of Phenanthridinone through C-H Activation Involving a Pd-Catalyzed Aryne Multicomponent Reaction.

A palladium-catalyzed multicomponent reaction (MCR) involving aryne, CO, and aniline is established for straightforward assembly of a phenanthridinone scaffold through C-H bond activation. Free combination with multiple kinds of readily available anilines and arynes is facilely achieved for phenanthridinone construction without prefunctionalization. Representative natural products were subsequently synthesized through this MCR strategy highly efficiently. Control experiments and interval NMR tracking revealed the mechanism, particularly the key role of CuF2 in determining the aryne-releasing rate from the precursor in this transformation.

Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry.

The impact of the development of sulfur therapeutics is instrumental to the evolution of the pharmaceutical industry. Sulfur-derived functional groups can be found in a broad range of pharmaceuticals and natural products. For centuries, sulfur continues to maintain its status as the dominating heteroatom integrated into a set of 362 sulfur-containing FDA approved drugs (besides oxygen or nitrogen) through the present. Sulfonamides, thioethers, sulfones and Penicillin are the most common scaffolds in sulfur containing drugs, which are well studied both on synthesis and application during the past decades. In this review, these four moieties in pharmaceuticals and recent advances in the synthesis of the corresponding core scaffolds are presented.

Ligand Controlled Regiodivergent C1 Insertion on Arynes for Construction of Phenanthridinone and Acridone Alkaloids.

A palladium-catalyzed regiodivergent C1 insertion multicomponent reaction involving aryne, CO, and 2-iodoaniline is established to construct the scaffolds of phenanthridinone and acridone alkaloids. Regioselective control is achieved under the guidance of selective ligands. The phenanthridinones are solely obtained under ligand-free condition. In comparison, application of the electron-abundant bidentate ligand dppm afforded the acridones with high efficiency. The release rate of the aryne from the precursor assists the regioselectivity of insertion as well, which was revealed through interval NMR tracking. A plausible mechanism was suggested based on the control experiments. Representative natural products and two types of natural product analogues were synthesized divergently through this tunable method.