Treatment Of Ph Research Articles

Parathyroid allotransplantation for severe post-surgical hypoparathyroidism: a Brazilian experience.

This study presents the cases of two women who developed severe permanent hypoparathyroidism after neck surgery for papillary thyroid cancer and underwent parathyroid allotransplantation. Despite taking high doses of calcium and calcitriol supplements, the patients experienced persistent hypocalcemic symptoms. Fresh parathyroid tissue was removed and prepared from two patients with hyperparathyroidism secondary to end-stage kidney disease and was implanted in the non-dominant forearm of the recipients. Donors and recipients were ABO-compatible, and immunological screening was performed only in Case 2 (HLA typing, panel reactive antibody, and crossmatch tests). A short-term immunosuppressive regimen was adopted, consisting of 3days of methylprednisolone followed by 7days of prednisone. In Case 1, oral supplementation decreased to half of the initial dose 1month after transplantation and to one-fifth at the end of a 12-month follow-up period. In Case 2, intravenous calcium was discontinued 1-week post-transplantation, with no need for its use during the 12-month follow-up period. Serum parathyroid hormone levels did not increase and remained undetectable in both cases. In contrast, serum calcium levels increased significantly, and both patients experienced relief from hypocalcemic symptoms. Parathyroid allotransplantation can be an effective and safe treatment for PH and should be considered in severe cases. Nevertheless, formal recommendations depend on additional studies and validated protocols.

Clinical features, hemodynamics, and outcomes of pulmonary hypertension in adults with coarctation of aorta

BackgroundPulmonary hypertension (pH) and secondary right ventricle dysfunction is present in 20 % of adults with coarctation of aorta (COA) based on echocardiographic studies. There are limited data about invasive hemodynamic characterization of PH in COA. The purpose of this study was to delineate the clinical features, hemodynamics, and outcomes of PH in COA. MethodRetrospective cohort study of adults with repaired COA that underwent right heart catheterization (RHC). PH was defined as pulmonary artery (PA) mean pressure > 20 mmHg, and PH was classified as isolated precapillary PH and combined pre/postcapillary PH. ResultsOf 99 COA patients that underwent RHC, 57 (58 %) had PH. Of the patients with PH, 14 (25 %) had isolated precapillary PH while 43 (75 %) had postcapillary PH with or without precapillary disease. The correlates of PH were PA compliance (adjusted OR 0.79, 95 % CI 0.71–0.86 per 1 ml/mmHg), left atrial reservoir strain (adjusted OR 0.95, 95 % CI 0921–0.98 per 1 %), and atrial fibrillation (adjusted OR 2.18, 95 % CI 1.20–13.5). Higher PA mean pressure was associated with risk of cardiovascular events (adjusted HR 1.04, 95 % CI 1.02–1.06 per 1 mmHg) and all-cause mortality (adjusted HR 1.05, 95 % CI 1.02–1.08 per 1 mmHg). ConclusionsPH was present in over half of adults with COA referred for RHC, and one-quarter of the patients with PH presented with isolated precapillary PH suggesting an underlying PA vascular dysfunction as a contributing mechanism. Further studies are required to determine optimal therapies and strategies for prevention and treatment of PH in this population. Clinical summaryOf 99 adults with repaired coarctation of aorta (COA) that underwent right heart catheterization, 57 % had pulmonary hypertension (pH). Of the patients with PH, 25 % had isolated precapillary PH while 75 % had combined pre/postcapillary PH. The correlates of PH were pulmonary artery (PA) compliance, left atrial reservoir strain and atrial fibrillation. PH was associated with cardiovascular events and all-cause mortality. These data suggest PA vascular dysfunction in addition to left-sided heart disease as potential etiologies for PH in this population. Further studies are required to determine optimal therapies and strategies for prevention and treatment of PH in this population.

ALL-544 Diagnosis and Treatment of Ph+ Acute Lymphoblastic Leukemia in Armenia: A Comprehensive Analysis From 2012 to 2023

ALL-544 Diagnosis and Treatment of Ph+ Acute Lymphoblastic Leukemia in Armenia: A Comprehensive Analysis From 2012 to 2023

Diagnosis and Treatment of Ph+ Acute Lymphoblastic Leukemia in Armenia: A Comprehensive Analysis From 2012 to 2023

Diagnosis and Treatment of Ph+ Acute Lymphoblastic Leukemia in Armenia: A Comprehensive Analysis From 2012 to 2023

Parthenolide attenuates hypoxia-induced pulmonary hypertension through inhibiting STAT3 signaling

BackgroundPulmonary hypertension (PH) is a chronic lung disease characterized by the progressive pulmonary vascular remodeling with increased pulmonary arterial pressure and right ventricular failure. Pulmonary vascular remodeling involves the proliferation, migration, and resistance to apoptosis of pulmonary artery smooth cells (PASMCs). Parthenolide (PTN) is a bioactive compound derived from a traditional medical plant feverfew (Tanacetum parthenium), and it has been studied for treatment of pulmonary fibrosis, lung cancer, and other related ailments. However, the function of PTN in the treatment of PH has not been studied. PurposeThis study aimed to evaluate the anti-proliferation and pro-apoptosis effects of PTN on PH and investigate its potential mechanisms. MethodsAn in vivo hypoxia-induced pulmonary hypertension (HPH) model was established by maintaining male rats in a hypoxia chamber (10% O2) for 3 weeks, and PTN was intraperitoneally administered at the dose of 10 or 30 mg/kg. We assessed the impact of PTN on mean pulmonary arterial pressure (mPAP), pulmonary vascular remodeling, and right ventricular hypertrophy. In vitro, we evaluated hypoxia-induced cellular proliferation, migration, and apoptosis of rat PASMCs. Proteins related to the STAT3 signaling axis were analyzed by western blotting and immunofluorescence assays. Recovery experiments were performed using the STAT3 activator, colivelin TFA. ResultsPTN significantly alleviated the symptoms of HPH rats by attenuating pulmonary arterial remodeling. It also prevented the proliferation and migration of PASMCs. PTN also induced the apoptosis of PASMCs. PTN could directly interact with STAT3 and markedly inhibited STAT3 phosphorylation and nuclear translocation. In vitro, and in vivo experiments demonstrated that overexpression of STAT3 partially suppressed the effect of PTN. ConclusionOur study indicated that PTN alleviated hypoxia-induced pulmonary hypertension in rats by suppressing STAT3 activity.

Levosimendan mediates the BMP/Smad axis through upregulation of circUSP34-targeted miR-1298 to alleviate pulmonary hypertension

BackgroundPulmonary hypertension (PH) is a long-term disease that impacts approximately 1% of the world’s population. Currently, levosimendan (Lev) is proposed for PH treatment. However, the mechanism of Lev in the treatment of PH is unknown.MethodsWe used hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) to establish a PH cell model. A number of cell biology methods were performed to assay alterations in cell proliferation, migration and apoptosis after Lev treatment. qRT-PCR and WB were performed to test the levels of circUSP34 and miR-1298, and BMP/Smad protein respectively. In addition, the regulatory relationship between circUSP34 or BMPR2 with miR-1298 was verified through the use of double luciferase as well as RIP assay. In addition, we explored the regulatory effect of Lev on the circUSP34/miR-1298/BMP/Smad axis using a rat PH model.ResultsOur results demonstrate that Lev inhibited PASMCs cell proliferation, migration and promoted apoptosis exposed to hypoxia. In hypoxia-treated PASMCs, circUSP34 expression got downregulated while miR-1298 upregulated, whereas the addition with Lev resulted in upregulation of circUSP34 expression and downregulation of miR-1298 expression, indicating that circUSP34 can target and regulate miR-1298. In addition, miR-1298 targets and regulates the expression of BMPR2. In a rat PH model induced by hypoxia combined with SU5416, Lev upregulated circUSP34 targeting miR-1298-mediated BMP/Smad axis to alleviate the PH phenotype.ConclusionWe have shown that Lev can be used as a therapeutic drug for PH patients, which works through the circUSP34/miR-1298/BMP/Smad axis to alleviate PH symptoms.

BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of Ph+ leukemias?

BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve - eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compoundsand suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.

Asciminib antagonizes transplantable BCR::ABL1-positive lymphoid blast crisis in vivo by targeting malignant stem cells

Philadelphia chromosome-positive (Ph+) lymphoid blast crisis (BC), emanating from chronic myeloid leukemia (CML), is a fatal disease with limited treatment options. Asciminib (ABL001) is a novel selective allosteric inhibitor of the ABL kinase with high efficacy against TKI-resistant BCR::ABL1. In this study, we demonstrate significant suppression of an aggressive B-lymphoblastic disease and restoration of normal hematopoiesis in an inducible transgenic mouse model of p210-BCR::ABL1-positive CML-BC. Molecularly, asciminib treatment significantly reduced BCR::ABL1 transcripts to background levels, demonstrating its ability to suppress BCR::ABL1-induced disease. Furthermore, asciminib treatment normalized the long-term repopulating hematopoietic stem cell (LT-HSC) population in the BM, suggesting the selective targeting of malignant LT-HSCs. This was supported by secondary transplantation experiments, resulting in absence of BC in a proportion of mice. Importantly, none of the secondary transplanted mice that received further asciminib treatment developed leukemia. Sanger sequencing of the BCR::ABL1 myristoyl pocket region of both treatment-naïve and treated mice demonstrated a high mutational load. However, there was no indication of asciminib-specific mutations. These promising findings highlight the potential of asciminib as a drug that targets BC stem cells and as an alternative stand-alone or combinatorial therapy for first-line treatment of CML BC or Ph+ acute lymphoblastic leukemia.

RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

RAPSYN-mediated neddylation of BCR-ABL alternatively determines the fate of Philadelphia chromosome-positive leukemia.

Philadelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph+ leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+ leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+ leukemia.

In-depth analysis of responders in the phase 3 PhALLCON trial of ponatinib vs imatinib in newly diagnosed Ph+ ALL.

6533 Background: Ponatinib, a third-generation BCR::ABL TKI, has potent activity against all clinically relevant BCR::ABL1 variants, including T315I. PhALLCON (NCT03589326), a phase 3 trial comparing frontline TKIs in adults with Ph+ ALL, met its primary endpoint with a higher rate of minimum residual disease–negative (MRD-neg) complete remission (CR) at end of induction (EOI) with ponatinib vs imatinib (34.4%/16.7%; P=0.002). Here, we report response rates of MRD-neg at any time and PFS by age and BCR::ABL1 variant subgroups. Methods: Adults with newly diagnosed Ph+ ALL were randomized 2:1 to ponatinib (30 mg QD reduced to 15 mg QD upon MRD-neg CR at or after EOI) or imatinib (600 mg QD) plus 20 cycles of reduced-intensity chemotherapy (induction: 3 cycles; consolidation: 6 cycles; maintenance: 11 cycles), followed by single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. Hematopoietic stem cell transplant (HSCT) was per investigator’s discretion. Post hoc analyses compared MRD-neg ( BCR:: ABL1IS ≤0.01%; MR4) at any time and PFS (any-cause death, failure to achieve CR by EOI, relapse from CR, or failure to achieve/loss of MRD-neg) by age (</≥65 y) and BCR:: ABL1 variant (p190/p210). Data cutoff: Aug 12, 2022. Results: In the population of randomized patients (pts) with p190/p210 confirmed by central lab (n=232; 154/78 ponatinib/imatinib; median follow-up 20.1 mo), 68% vs 50% in the ponatinib vs imatinib arms were MRD-neg at any time, with similar benefit of ponatinib across age and variant subgroups (Table). Median PFS was more than twice as long with ponatinib vs imatinib across subgroups (Table). Pts achieving MRD-neg at any time were less likely to have HSCT with ponatinib vs imatinib (32%/56%). Among 107/42 pts without HSCT, exposure was >2-fold longer in the ponatinib vs imatinib arms (median 12.8/5.1 mo) with comparable rates of arterial occlusive (3%/2%) and venous thromboembolic events (11%/12%), and discontinuations due to TEAEs (13%/14%). Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy for frontline treatment of Ph+ ALL, with higher rates of MRD-neg at any time, substantially longer PFS across age and BCR::ABL1 variant subgroups, and a safety profile comparable to imatinib. Clinical trial information: NCT03589326 . [Table: see text]

A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus Tyrosine Kinase Inhibitor, Blinatumomab, and Chemotherapy in Optimal Responders, and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE)

Introduction: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. Methods: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. Conclusion: This trial will answer several major questions in the treatment of Ph+ALL.

Advances in the Treatment of Ph+ Chronic Myeloid Leukemia: A Comprehensive Study

Advances in the Treatment of Ph+ Chronic Myeloid Leukemia: A Comprehensive Study

The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

Concomitant inhibition of the thioredoxin system and nonhomologous DNA repair potently sensitizes Philadelphia-positive lymphoid leukemia to tyrosine kinase inhibitors.

Breakpoint cluster region-Abelson (BCR::ABL1) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+ B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+ B-ALL. Previous studies have shown that inhibitors of the thioredoxin (TXN) system exert antileukemic activity against B-ALL cells, particularly in combination with other drugs. Here, we present that peroxiredoxin-1 (PRDX1), one of the enzymes of the TXN system, is upregulated in Ph+ lymphoid as compared to Ph+ myeloid cells. PRDX1 knockout negatively affects the viability of Ph+ B-ALL cells and sensitizes them to TKIs. Analysis of global gene expression changes in imatinib-treated, PRDX1-deficient cells revealed that the nonhomologous end-joining (NHEJ) DNA repair is a novel vulnerability of Ph+ B-ALL cells. Accordingly, PRDX1-deficient Ph+ B-ALL cells were susceptible to NHEJ inhibitors. Finally, we demonstrated the potent efficacy of a novel combination of TKIs, TXN inhibitors, and NHEJ inhibitors against Ph+ B-ALL cell lines and primary cells, which can be further investigated as a potential therapeutic approach for the treatment of Ph+ B-ALL.

Pharmacokinetics of Dasatinib in Rats: a Potential Food-Drug Interaction with Naringenin.

The novel tyrosine kinase inhibitor (TKI) dasatinib, a multitarget inhibitor of Bcr-Abl and Src family kinases, has been licensed for the treatment of Ph+ acute lymphoblastic leukemia and chronic myeloid leukemia. Many citrus-based foods include the flavonoid naringenin, which is commonly available. Dasatinib is a Cyp3a4, P-gp, and Bcrp1 substrate, which makes it sensitive to potential food-drug interactions. The concurrent use of naringenin may change the pharmacokinetics of dasatinib, which could result in adverse effects and toxicity. The present investigation examined the impact of naringenin on the pharmacokinetics interactions of DAS and proposes a possible interaction mechanism in Wistar rats. Rats were provided with a single oral dose of dasatinib (25mg/kg) with or without naringenin pretreatment (150mg/kg p.o. daily for 7days, n = 6 in each group). Dasatinib was quantified in plasma by UHPLC MS/MS assay. Noncompartmental analysis was used to compute the pharmacokinetic parameters, and immunoblot was used to assess the protein expression in the hepatic and intestinal tissues. Following 7 days of naringenin pretreatment, the plasma mean concentration of dasatinib was enhanced compared with without pretreatment. In rats that were pretreated with naringenin, the pharmacokinetics of the orally administered dasatinib (25mg/kg) was shown to be significantly different from that of dasatinib given without pretreatment (p < 0.05). There was a significant enhancement in pharmacokinetic parameterselimination half-life (T1/2),time to maximum concentration ( Tmax), maximum concentration )Cmax), area under the concentration-time curve (AUC0-t),area under the moment curve (AUMC0-∞), and mean residence time (MRT) by 28.41%, 50%, 103.54%, 72.64%, 115.08%, and 15.19%, respectively (p < 0.05) and suppression in elimination rate constant (Kel), volume of distribution (Vd), and clearance (CL) by 21.09%, 31.13%, and 46.25%, respectively, in comparison with dasatinib alone group (p < 0.05). The enhancement in dasatinib bioavailability and systemic exposure resulted from the significant inhibition of Cyp3a2, Mdr1/P-gp, and Bcrp1 expression and suppression of the dasatinib hepatic and intestinal metabolism, which enhanced the rate of dasatinib absorption and decreased its elimination. Concurrent use of naringenin-containing supplements, herbs, or foods with dasatinib may cause serious and potentially life-threatening drug interactions. Further studies are necessary to determine the clinical significance of these findings.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Children: A Retrospective Cohort Study at a Pediatric Oncology Center.

Background and objective Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+) is quite rare among pediatric patients. Its management has undergone significant changes in the past few years, leading to some variability in how it is approached. At the Portuguese Oncology Institute of Porto (IPOP),a tertiary oncological center, the standard of carehas been aligned with the guidelines proposed by the European intergroup study of post-induction treatment of ALL Ph+ (EsPhALL). In this study, we aimed to examine the experience and outcomes related tothe treatment of pediatric patients with ALL Ph+ at IPOP. Methods This retrospective cohort study involvedpediatric patients diagnosed with ALL Ph+ at IPOP between January 2008 and December 2022 and analyzed their outcomes. Results A total of 14 patients were included. IKFZ1 was altered in five patients (out of nine in whom it was searched). Five patients were treated according to EsPhALL 2004, which involved starting imatinib later in a discontinuous manner [resulting in both five-year overall survival (OS) and progression-free survival (PFS) of 60%]. The EsPhALL 2010 (preconizing a continuous imatinib regimen instead) was employed in three patients, with a five-year OS and PFS of 66.7%. Allchildren mentioned above received cranial irradiationtherapy (CRT). Finally, six were treated according to the EsPhALL 2015, which stopped including CRT in its backbone. The five-year OS was 100%, whereas every patient progressed with an increase in BCR::ABL1 levels greater than 1-log. Moreover, until 2015, all patients had been recommended to undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). However, since 2015, alloHSCT has been exclusively reserved for relapsed/refractory (R/R) disease or poor responders with positive measurable residual disease (MRD). In total, alloHSCT was performed in nine patients. Conclusions Although initially associated with a poor prognosis, the ALL Ph+ paradigm is drastically shifting. Further studies will hopefully clarify the outcomes in this population and help understand the role of central nervous system (CNS) prophylaxis, alloHSCT, and MRD quantification.

Imatinib “Miracle Medicine” for the Treatment of Ph+ Chronic Myeloid Leukemia (CML)

Imatinib “Miracle Medicine” for the Treatment of Ph+ Chronic Myeloid Leukemia (CML)

Properties of Heat-Assisted pH Shifting and Compounded Chitosan from Insoluble Rice Peptide Precipitate and Its Application in the Curcumin-Loaded Pickering Emulsions.

Curcumin exhibits antioxidant and antitumor properties, but its poor chemical stability limits its application. Insoluble peptide precipitates formed by proteolysis of rice glutelin are usually discarded, resulting in resource waste. The coupled treatment of heat-assisted pH shifting and compounded chitosan (CS) was used to fabricate rice peptide aggregate-chitosan complexes (RPA-CS). The structure, interfacial behavior, emulsion properties, and digestibility of curcumin-loaded RPA-CS Pickering emulsions were investigated. Increasing the CS concentration led to lower interfacial tension but larger particle size, and the three-phase contact angle of the RPA-CS complexes approached 90°. Quartz crystal microbalance with dissipation (QCM-D) indicated that RPA-CS complexes with 6 g·kg-1 of CS (RPA-CS6) had the highest K1 (0.592 × 106 Hz-1) and K4 (0.487 × 106 Hz-1), suggesting that the softest interfacial layers were formed. The solid-liquid balance of RPA-RPA-CS emulsions was lower than 0.5, declaring that they had more elastic behavior than that of RPA emulsions. RPA-RPA-CS4-and RPA-CS6 emulsions had better storage stability, lower FFA release (79.8% and 76.3%, respectively), and higher curcumin bioaccessibility (65.2% and 68.2%, respectively) than RPA emulsions. This study showed that a low-value insoluble rice peptide precipitate could be used as a valuable emulsifier in foods, which may increase the economics and sustainability of the food supply.

A Propensity Score Weighting Analysis Emphasizes the Progress of the Gimema Approach in Adult Ph-Positive Acute Lymphoblastic Leukemia in the TKI Era

Introduction. In 2000, the GIMEMA cooperative study group launched the first frontline protocol with a tyrosine kinase inhibitor (TKI) alone plus steroids and without systemic chemotherapy for elderly (&amp;gt;60 years) Ph+ acute lymphoblastic leukemia (ALL) patients (LAL0201-B; Vignetti et al, Blood 2007). Thereafter, 4 academic clinical trials were conducted for adult patients (&amp;gt;18 years). In all studies, the induction was always based on a TKI alone plus steroids and CNS prophylaxis without systemic chemotherapy. In the GIMEMA LAL0904 trial, patients (18-60 years) received imatinib followed by chemotherapy in the post-induction phase (Chiaretti et al, Haematologica 2016). In the GIMEMA LAL1205 trial (no upper age limit), patients received dasatinib plus steroids, while the post-induction treatment was left to the investigator's choice (Foà et al, Blood 2011). In the GIMEMA LAL1509 total therapy protocol, patients (18-60 years) received dasatinib plus steroids followed by dasatinib alone in patients in complete molecular response (CMR) or chemotherapy and/or allogeneic transplant for those who did not reach a CMR (Chiaretti et al, Haematologica 2021). In the last LAL2116 trial, dasatinib plus glucocorticoids were administered in induction followed by at least two blinatumomab cycles as consolidation (Foà et al, N Engl J Med 2020). The rates of hematologic CR were comparable in the four trials, ranging from 96 to 100%. Methods. In order to perform a reliable comparison, patient-level data from the Ph+ ALL patients enrolled in the LAL0904 (n=51), LAL1205 (n=63), LAL1509 (n=60) and LAL2116 (n=63) protocols were used to conduct a multilevel propensity score weighting analysis. The median follow-up was similar in LAL0904, LAL1509 and LAL2116 - namely, 51.8, 57.4, 52.9 months - while LAL1205 had a shorter follow-up of 24.8 months, due to the trial design. Survival estimates were thus calculated at 24 months, representing the minimum median follow-up within the 4 trials. The weights were calculated with a multinomial logistic regression model. The variables age at diagnosis, gender, WBC, BCR::ABL1 isoform and allogenic transplant rate were included in this propensity score model. Differences in MRD rates were computed after the TKI alone induction using the chisq test. Given that the post-remission strategy was not defined in all protocols, the comparison of post-induction MRD was not appropriate. Survival curves were compared by standard and pairwise log-rank test. Results. Among the balancing weights methods, the matching weights produced the best balance, with standardized mean differences &amp;lt;0.2 for all variables. As shown in Table 1, before weighting the baseline features were uneven; upon weighting, the 4 cohorts were balanced in terms of age, gender, WBC, BCR::ABL1 isoform and transplant rate. After weighting, the MRD negativity rates at the end of induction were as follows: LAL0904 0%, LAL1205 23.9%, LAL1509 18.4%, LAL2116 29% (p=0.0007), mostly sustained by the different effect of dasatinib vs imatinib on the early molecular clearance. Survival outcomes after weighting underlined the superiority of the LAL2116 approach in comparison with the other protocols and the worse outcome for patients treated according to the LAL1205 scheme, presumably due to the lack of a uniform post-induction strategy. Indeed, the OS at 24 months was 89.8% in LAL2116, 71.2% in LAL1509, 52.9% in LAL1205, 66.2% in LAL0904 (p=0.001). Likewise, DFS at 24 months was 84.3% in LAL2116, 53.7% in LAL1509, 32.4in LAL1205, 61.1% in LAL0904 (p=0.001). Conclusions. By using a multilevel propensity score weighting approach, we were able to compare with statistical accuracy the results of 4 GIMEMA protocols for the frontline treatment of adult Ph+ ALL patients. After weighting, two results clearly emerged: on the one hand the markedly superior survival of patients enrolled in the LAL2116 protocol and on the other hand the unfavorable outcome of LAL1205. The marked improvement observed with the LAL2116 trial is ascribable to the consolidation strategy based on blinatumomab, since LAL2116 shared with the earlier LAL1509 and LAL1205 protocols the same induction strategy (dasatinib). It also appears evident that a center-specific post-induction strategy - as in LAL1205 - is not beneficial.