First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL; indeed, pts with at least major molecular response (MMR; BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48; TFR rate at wk 96 and 144; BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Interim results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau; Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

Epigenetic Priming with Pre-Transplant Oral Panobinostat Followed By Post-Transplant Consolidation

Despite the rich armamentarium of novel agents that are available to treat multiple myeloma (MM), high dose melphalan (HDM) and stem cell transplant (SCT) remain an essential therapy that achieves long-term durable remissions. However, most patients relapse following HDM-SCT due to the persistence of minimal residual disease (MRD). Therefore, there remains an unmet clinical need to overcome chemoresistant MRD and potentially achieve a cure for MM patients. Here, we describe a phase Ib trial designed to epigenetically priming with pre-transplant oral panobinostat to increase MRD sensitivity to HDM-SCT. The contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides a strong rationale for the use of epigenetic modulators, such as the histone deacetylase (HDAC) inhibitor panobinstat as anti-myeloma therapy. Access to DNA is primarily governed by chromatin structure such that its configuration is under control of histone acetylators and deacetylators. Inhibition of histone deacetylases weakens the histone-DNA bonds and decondenses chromatin, i.e., epigenetic priming, which potentially enhances sensitivity to melphalan. Pre-clinical studies have demonstrated a strong synergistic effect between panobionostat (LBH589) and melphalan in in vitro as well as in vivo studies utilizing patient-derived xenograph models, i.e., SCID-hu model of human MM, LAG-1(Sanchez et al. Leukemia research. March 2011). Furthermore, HDAC inhibitors suppress multi-drug resistance protein-1 (MRP1) and it can count as another mechanism of synergy for this class of drugs and alkylating agents in hematologic disorders (Tsubaki M. et al. Leukemia research. Oct 2012). Taken together, these studies support HDAC inhibitors in combination with melphalan to augment anti-myeloma efficacy of HDM-SCT. Here, we propose the combination through a pre-SCT epigenetic priming phase with high dose panobinostat and a post-SCT lower dose panobinostat consolidation phase (Study Schema). Trial design: We propose a Simon 3+3 design to test panobinostat at three dose levels of 20, 30 and 40 mg every other day for four doses prior to high dose melphalan as study schema illustrates. There will not be any intra-patient dose escalation. The study will be extended to another 15 patients at the maximum tolerated dose for the pre-SCT phase. All patients regardless of the pre-SCT panobinostat dose level will received fixed dose of Panobinostat. Primary and Secondary objectives and endpoints are listed in Table 1. Rationale for high dose panobinostat in epigenomic phase: Previous reports of HDACi combined with standard-dose chemotherapy (e.g., Ifosfomide, Carboplatin, and Etoposide for lymphoma or 7+3 for acute myeloid leukemia) had shown prolonged myelosuppression as the main adverse effect, but no significant increase in the non-hematological toxicities. Therefore, we predict the use of peripheral blood progenitor cells in the offered study has potential to circumvent the increased myelotoxicity associated with pre-SCT high dose panobinostat, and it may render the opportunity to test higher doses such as 40 mg every other day before SCT as epigenetic priming strategy. Rational for low dose panobinostat dosing for the consolidation phase: The Panobinostat consolidation design will follow the positive landmark trial by the Australian group (Mithraprabhu S. et al. British J. Hemat. Apr 2021). In their study panobinostat was given at 20 mg three times weekly on alternate weeks for 6 months started 8-12 weeks post-transplant was administered. Forty eight percent of patients improved their depth of response after a median range of 4.3 months of panobinostat. In responders, T lymphocyte histone acetylation increased after both three cycles and six cycles of panobinostat when compare to baseline, with no differences in no-responders. Figure 1 Figure 1. Disclosures Malek: Janssen: Other: Advisory board ; Bluespark Inc.: Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Sanofi: Other: Advisory Board; Medpacto Inc.: Research Funding; Takeda: Honoraria. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. Stricker: Secura Bio: Current Employment. OffLabel Disclosure: Panobinostat has been used as single agent therapy before and after transplant in this trial.

Optimal Timing for Intermittent Administration of Parathyroid Hormone (1-34) for Distraction Osteogenesis in Rabbits

BackgroundTo date, the usefulness of parathyroid hormone (PTH (1-34)) in distraction osteogenesis has been reported in several studies. We aimed to determine the optimal timing of PTH (1-34) administration in a rabbit distraction osteogenesis model.MethodsThe lower hind leg of a Japanese white rabbit was externally fixed, and tibial osteotomy was performed. One week after the osteotomy, bone lengthening was carried out at 0.375 mm/12 h for two weeks. After five weeks, the lower leg bone was collected. Bone mineral density (BMD), peripheral quantitative computed tomography (pQCT), micro-computed tomography (micro-CT), and mechanical tests were performed on the distracted callus. The rabbits were divided into three groups according to the timing of PTH administration: four weeks during the distraction and consolidation phases (group D+C), two weeks of the distraction phase (group D), and the first two weeks of the consolidation phase (group C). A control group (group N) was administered saline for four weeks during the distraction and consolidation phases. Furthermore, to obtain histological findings, lower leg bones were collected from each rabbit at two, three, and four weeks after osteotomy, and tissue sections of the distracted callus were examined histologically.ResultsThe BMD was highest in group C and was significantly higher than group D. In pQCT, the total cross-sectional area was significantly higher in groups D+C, D, and C than group N, and the cortical bone area was highest in group C and was significantly higher than group D. In micro-CT, group C had the highest bone mass and number of trabeculae. Regarding the mechanical test, group C had the highest callus failure strength, and this value was significantly higher compared to group N. There was no significant difference between groups D and N. The histological findings revealed that the distracted callus mainly consisted of endochondral ossification in the distraction phase. In the consolidation phase, the chondrocytes were almost absent, and intramembranous ossification was the main type of ossification.ConclusionWe found that the optimal timing of PTH (1-34) administration is during the consolidation phase, which is mainly characterized by intramembranous ossification.

Enhancing the Efficiency of Distraction Osteogenesis through Rate-Varying Distraction: A Computational Study

Distraction osteogenesis (DO) is a mechanobiological process of producing new bone and overlying soft tissues through the gradual and controlled distraction of surgically separated bone segments. The process of bone regeneration during DO is largely affected by distraction parameters. In the present study, a distraction strategy with varying distraction rates (i.e., “rate-varying distraction”) is proposed, with the aim of shortening the distraction time and improving the efficiency of DO. We hypothesized that faster and better healing can be achieved with rate-varying distractions, as compared with constant-rate distractions. A computational model incorporating the viscoelastic behaviors of the callus tissues and the mechano-regulatory tissue differentiation laws was developed and validated to predict the bone regeneration process during DO. The effect of rate-varying distraction on the healing outcomes (bony bridging time and bone formation) was examined. Compared to the constant low-rate distraction, a low-to-high rate-varying distraction provided a favorable mechanical environment for angiogenesis and bone tissue differentiation, throughout the distraction and consolidation phase, leading to an improved healing outcome with a shortened healing time. These results suggest that a rate-varying clinical strategy could reduce the overall treatment time of DO and decrease the risk of complications related to the external fixator.

Multisensory Input Modulates P200 and L2 Sentence Comprehension: A One-Week Consolidation Phase

Multisensory input is an aid to language comprehension; however, it remains to be seen to what extent various combinations of senses may affect the P200 component and attention-related cognitive processing associated with L2 sentence comprehension along with the N400 as a later component. To this aim, we provided some multisensory input (enriched with data from three (i.e., exvolvement) and five senses (i.e., involvement)) for a list of unfamiliar words to 18 subjects. Subsequently, the words were embedded in an acceptability judgment task with 360 pragmatically correct and incorrect sentences. The task, along with the ERP recording, was conducted after a 1-week consolidation period to track any possible behavioral and electrophysiological distinctions in the retrieval of information with various sense combinations. According to the behavioral results, we found that the combination of five senses leads to more accurate and quicker responses. Based on the electrophysiological results, the combination of five senses induced a larger P200 amplitude compared to the three-sense combination. The implication is that as the sensory weight of the input increases, vocabulary retrieval is facilitated and more attention is directed to the overall comprehension of L2 sentences which leads to more accurate and quicker responses. This finding was not, however, reflected in the neural activity of the N400 component.

Dasatinib-based Two-step Induction for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

The standard treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, approximately 40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities and relapse before HSCT, and older age. We evaluated dasatinib-based two-step induction with the primary endpoint of 3-year event-free survival (EFS) in this study. The first induction (IND1) was dasatinib plus prednisolone to achieve CR and the second (IND2) was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD)-negativity. Patients who achieved CR and had an appropriate donor were recommended to undergo HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate. Prophylactic dasatinib after HSCT was assigned to patients with positive pre-transplant MRD. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD-negativity after IND2. Non-relapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight (74.4%) patients underwent HSCT in CR1 and 44 (75.9%) were negative with pre-transplant MRD. At a median follow-up of 4.0 years, the 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based two-step induction was demonstrated to improve the 3-year EFS. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

El mercado del vídeo en streaming: un análisis de la estrategia de Disney+

The international launch of Disney+ in November 2019 marked the entry of Disney with its own brand into the market for direct sales of subscription video-on-demand (SVOD) consumer services. This market, although with Netflix as a prominent leader, is still in a consolidation phase that could lead to the disappearance of many operators since although traditional pay TV operators, such as cable operators in the US, are developing their own platforms due to subscriber loss in their core business, all face new threats such as increased operating costs, the need to increase investment in own production and others derived from new consumption habits such as consumer fatigue. This article analyzes, through the applied case study methodology, Disney’s strategy to position Disney+ successfully in a short period of time and confirms findings from previous studies on the nature and evolution of the sector and trends like its high degree of concentration. which points to the complex reality of the SVOD market, the value that global brands would continue to have at this stage and finally allows us to analyze the real possibilities of creating a new streaming video market with lower entry barriers. Resumen El lanzamiento internacional de Disney+ en noviembre del 2019 significó la entrada de Disney con una marca propia en el mercado de la venta directa de servicios al consumidor de vídeo bajo demanda por suscripción (SVOD). Este mercado, aunque con Netflix como líder destacado, se encuentra en una fase de consolidación que podría llevar a la desaparición de muchos operadores, ya que aunque las cadenas de TV de pago, como los cableoperadores en EUA, están creando sus propias plataformas por la pérdida de abonados en su negocio principal, todos se enfrentan a nuevas amenazas como el aumento de los costes de operación, la necesidad de incrementar la inversión en producción propia y otras derivadas de los nuevos hábitos de consumo como la fatiga del consumidor. Este articulo analiza, mediante la metodología del caso de estudio aplicado, la estrategia de Disney para posicionar Disney+ con éxito en un corto periodo de tiempo y confirma hallazgos de estudios previos sobre la naturaleza y evolución del sector y tendencias como su alto grado de concentración, lo que apunta hacia la compleja realidad del mercado SVOD, el valor que siguen teniendo las marcas globales en esta etapa y finalmente permite analizar las posibilidades reales de crear un nuevo mercado del vídeo en streaming con menores barreras de entrada.

Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives

The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients.

Hemophagocytosis or emperipolesis by lymphoblast after rapid transformation of chronic myeloid leukemia

A Male, 11-Years-Old, Admitted In March 2019 With Chronic myelogenous leukemia (CML) in treatment with Imatinib. Three months after diagnosis in outpatient visit was observed increase of splenomegaly and appearing of inguinal and cervical adenomegalies. Bone marrow apiration revealed 70% of blasts, some of them with hemophagocytosis (Figure 1). The immunophenotyping showed blasts positive for CD10, CD19, CD20, CD22, CD79a, CD45, HLA-DR, indicating transformation to B precursors ALL. Bone marrow karyotype was 46,XY,t(9;22), FISH (BCR-ABLES probe) confirmed rearrangement with p210. The patient was treated with higher dose of Imatinib (600 mg/m²), but evolved with bone marrow aplasia and infectious process, being then reajusted to 400 mg/m² with clinical and hematologic improvement. After 30 days had disease aggravation and resistance to Imatinib. The patient initiated EsPh-ALL 2009 protocol, but in D33 with no remission of disease continued with protocol. In September, during consolidation phase evolved with Central Nervous System infiltration and disease persistence, dying for disease in progress. This patient had no clinical findings of Hemophagocytic Lymphohistiocytosis (HLH) and bone marrow cytology showed the several hematopoietic cells inside blast cells.

Numerical Analysis of an Upstream Tailings Dam Subjected to Pond Filling Rates

One of the challenges in upstream tailings dam projects is to ensure the allowable rate of deposition of tailings in the pond (i.e., pond filling rate) while maintaining the stability of the dam. This is due to the fact that an upstream tailings dam is constructed by placing dikes on top of previously deposited soft tailings, which could lead to a decrease in dam stability because of the build-up of excess pore water pressure. The main purpose of this work is to investigate the effects of pond filling rates on excess pore water pressure and the stability of an upstream tailings dam by a numerical study. A finite element software was used to simulate the time-dependent pond filling process and staged dam construction under various pond filling rates. As a result, excess pore water pressure increased in each raising phase and decreased in the subsequent consolidation phase. However, some of the excess pore water pressure remained after every consolidation phase (i.e., the build-up of excess pore water pressure), which could lead to a potentially critical situation in the stability of the dam. In addition, the remaining excess pore water pressure varied depending on the pond filling rates, being larger for high filling rates and smaller for low filling rates. It is believed that the approach used in this study could be a guide for dam owners to keep a sufficiently high pond filling rate but still ensure the desirable stability of an upstream tailings dam.