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This contribution focuses on a reconceptualization of the term globalization, drawing on world system theories and the dialectical concept of countermovement. The focus is the Social-Economic Formation (SEF) concept elaborated by the Marxist tradition to understand and analyse the contemporary ascendance of China and its power projection. Based on dialectic methodology, we argue that globalization is a contradictory process of interconnectivity between SEFs in different historical eras with substantive changes in the space–time relationship. Thus, the embryonic Embedded Chinese Globalization is emerging as a historical negation of Neoliberal globalization (NG) [ABSTRACT FROM AUTHOR]

Key Points: Question: Is frontline ponatinib superior to imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)? Findings: In this randomized clinical trial, ponatinib demonstrated a significantly higher minimal residual disease–negative complete remission rate at the end of induction (34.4% vs 16.7% with imatinib) and a comparable safety profile vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. Meaning: These efficacy and safety results support consideration of ponatinib as a frontline tyrosine kinase inhibitor in combination with chemotherapy for adults with newly diagnosed Ph+ ALL. Importance: In newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease–(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase–quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P =.002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326 This randomized trial assesses the effect of ponatinib vs imatinib combined with low-intensity chemotherapy on disease remission in adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL). [ABSTRACT FROM AUTHOR]

Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate that was first evaluated in B-cell lymphomas but was subsequently shown to be highly effective in acute lymphoblastic leukemia (ALL). INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval in the United States in 2017. While the formal approval for INO is as monotherapy in relapsed/refractory ALL, subsequent studies with INO administered in combination with chemotherapy and/or blinatumomab both in the frontline and salvage settings have yielded promising results. In this review, we discuss the clinical development of INO in ALL, highlighting lessons learned from the initial clinical trials of INO, as well as the many ongoing studies that are seeking to expand the role of INO in ALL. [ABSTRACT FROM AUTHOR]

Summary: Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR‐MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX‐351, a liposomal encapsulation of cytarabine and daunorubicin, in a single‐centre, phase 1/2 study for patients with HR‐MDS or CMML after HMA failure. Four doses of CPX‐351 (10, 25, 50 and 75 units/m2) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR‐MDS and 6 (24%) with CMML. Most common grade 3–4 non‐haematological treatment‐emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2. Four‐ and 8‐week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse‐free and overall survivals of 9.2 (95% CI 3.2–15.1 months) and 8.7 months (95% CI 1.8–15.6 months) respectively. These data suggest that lower doses of CPX‐351 are safe. Further studies are needed to evaluate its activity. [ABSTRACT FROM AUTHOR]

The purpose of this article is to shed light on the reasons why Brazilian economist Ignacio Rangel's concept of "Projectment Economy" holds great possibilities for research into China's economic development. The article reworks the concept, offering new means of determination and validation criteria to understand Chinese socialism. Issues addressed include surmounting "Keynesian uncertainty," "creative destruction" planning, monetary sovereignty, and the "tacit adhesion pact." These are taken up as categories offering empirical support for the New Projectment Economy concept. The article concludes that the New Projectment Economy is a higher stage of development of the mode of production dominant in the new socio-economic formation that has emerged in China as a result of the economic reforms begun in 1978. [ABSTRACT FROM AUTHOR]

Deep changes have taken place in China over the past ten years. The debate increasingly revolves around its new dynamics of accumulation, even questioning under which typology to frame the current Chinese model. In this paper, we propose to correlate the Chinese national system of technological innovations, reemerged in the first years of this century, disruptive technologies such as 5G internet, Big Data and Artificial Intelligence, and the emergence of new and superior forms of economic planning in that country, sowing the seeds for what we call "New Projectment Economy". [ABSTRACT FROM AUTHOR]

The article has as its theme the evolution of urban-regional planning in the midst of the Chinese development process in recent decades. It points to the increase in the state's capacity to intervene in the national territory, highlighting the role played by the Communist Party of China. It is based on the concept of economic and social formation, understanding planning as a superstructure that emerges and affects the Chinese social formation. Two aspects are highlighted, the reconfiguration of planning and the consolidation of the new projectment economy. To this end, it deals with the coordinated development of the Beijing-Tianjin-Hebei region and the construction of the High Speed Train network as the most advanced expressions of the Chinese urban-regional planning trend. [ABSTRACT FROM AUTHOR]

PURPOSE: Philadelphia-like (Ph-like) B-cell ALL is a high-risk subtype of B-cell ALL that shares a gene expression profile with Ph-positive ALL, but without a BCR::ABL1 fusion. A subgroup of these patients have fusions or rearrangements involving genes such as ABL1 , ABL2 , PDGFRβ , JAK2 , and EPOR , some of which are potentially sensitive to tyrosine kinase inhibitors (TKIs). Prompt identification of these genetic aberrations are important for prognostication and treatment decisions. PATIENTS AND METHODS: We performed a retrospective review of patients with B-cell ALL treated at MD Anderson Cancer Center to identify recurrent genetic fusions commonly seen in Ph-like ALL and focus on patients treated with TKI. RESULTS: We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had ABL class fusions (eight ABL1 , one ABL2, and five PDGFRβ) and nine had JAK2 class fusions (five JAK2 and four EPOR). Notably, several of these fusions were cryptic by conventional cytogenetics and fluorescent in situ hybridization (FISH) assays and identified only by multiplex fusion assay. Thirteen of these 23 patients received a TKI as part of their treatment; this included ABL1 fusion (n = 8), PDGFRβ fusion (n = 4), and EPOR fusion (n = 1). All four patients with ABL1 fusions who received TKI with induction chemotherapy are alive in first remission. CONCLUSION: Understanding the genomics of B-cell ALL is important for disease prognostication and for precise treatment planning. Besides conventional cytogenetics and directed FISH testing, multiplex fusion assays can help identify recurrent chromosomal translocations that are seen in patients with Ph-like ALL. Early initiation of TKI appears beneficial; larger studies are required to fully understand the benefit of TKI and to design rational combination therapies for these patients. Clinical activity of BCR::ABL TKIs in ABL class rearranged Ph-like ALL: need for early detection and intervention. [ABSTRACT FROM AUTHOR]

Patients with rare diseases such as Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), a hematologic malignancy affecting approximately 1500 new patients per year, experience barriers to care involving both clinical and administrative factors. Optimal patient outcomes depend on timely identification, diagnosis of disease, and treatment initiation. For patients living with Ph+ ALL, the process can be delayed by limited treatment options approved by the US Food and Drug Administration and administrative hurdles that often delay treatment initiation. An overhaul of utilization management processes, such as the requirement for prior authorization (PA) for treatment, are needed to ensure patients have access to appropriate treatments in a timely manner. An AJMC Roundtable in November 2022 brought together a panel of payers and providers to discuss the challenges and shortcomings of current PA processes and to present ideas for potential solutions for improving them. Panelists at the roundtable discussed approaches including the use of guideline-concordant electronic PAs and other digital solutions, expedited approval pathways for use in specific conditions, use of real-world evidence in decision-making, issuance of PA "Gold Cards" to select providers, and a shift to value-based care agreements. Roundtable attendees agreed that, regardless of the strategy for PA-process improvement, there is a need for improved communication between providers and payers to ensure that the decision-making system meets the essential need for timely patient access to optimal care. This article reviews utilization management and guideline-concordant care through the lens of rare diseases and then presents solutions to utilization management challenges to expedite access to therapy. [ABSTRACT FROM AUTHOR]

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65–70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT. [ABSTRACT FROM AUTHOR]

Objective This study was aimed to assess the incidence of and risk factors for autism spectrum disorder (ASD) among preterm infants born <29 weeks' gestational age (GA). Methods A retrospective cohort study of infants born <29 weeks' GA admitted to two tertiary neonatal intensive care units (2009 to 2017) and followed ≥18 months corrected age (CA) at a neonatal follow-up clinic. The primary outcome was ASD, diagnosed using standardized testing or provisional diagnosis at ≥18 months CA. Patient data and 18-month CA developmental outcomes were obtained from the local Canadian Neonatal Follow Up Network database and chart review. Stepwise logistic regression assessed factors associated with ASD. Results Among 300 eligible infants, 26 (8.7%) were diagnosed with confirmed and 21 (7.0%) with provisional ASD for a combined incidence of 15.7% (95% confidence interval [CI] 11.7 to 20.3). The mean follow-up duration was 3.9 ± 1.4 years and the mean age of diagnosis was 3.7 ± 1.5 years. Male sex (adjusted odds ratio [aOR] 4.63, 95% CI 2.12 to 10.10), small for gestational age status (aOR 3.03, 95% CI 1.02 to 9.01), maternal age ≥35 years at delivery (aOR 2.22, 95% CI 1.08 to 4.57) and smoking during pregnancy (aOR 5.67, 95% CI 1.86 to 17.29) were significantly associated with ASD. Among ASD infants with a complete 18-month CA developmental assessment, 46% (19/41) had no neurodevelopmental impairment (Bayley-III<70, deafness, blindness, or cerebral palsy). Conclusions ASD is common among infants born <29 weeks' GA and possibly associated with identified risk factors. Such findings emphasize the importance of ASD evaluation among infants <29 weeks' GA and for continued reporting of developmental outcomes beyond 18-months of corrected age. [ABSTRACT FROM AUTHOR]

We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0–38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3 -mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138. • Azacitidine combined with quizartinib is safe in patients with FLT3 or CBL mutant MDS or MDS/MPN. • Quizartinib is associated with FLT3 mutation clearance. • Azacitidine and quizartinib leads to promising survival in FLT3 mutant MDS and MDS/MPN. [ABSTRACT FROM AUTHOR]

Background: The natural course of untreated chronic myeloid leukemia (CML) is progression to an aggressive blast phase. Even in the current era of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the outcomes of blast phase CML remain poor with no consensus frontline treatment approach. Methods: We retrospectively analyzed the response rates and survival outcomes of 104 consecutive patients with myeloid blast phase CML (CML-MBP) treated from 2000 to 2019 based on 4 different frontline treatment approaches: intensive chemotherapy (IC) + TKI (n = 20), hypomethylating agent (HMA) + TKI (n = 20), TKI alone (n = 56), or IC alone (n = 8). We also evaluated the impact of TKI selection and subsequent allogeneic stem cell transplant (ASCT) on patient outcomes. Results: Response rates were similar between patients treated with IC + TKI and HMA + TKI. Compared to treatment with TKI alone, treatment with IC/HMA + TKI resulted in a higher rate of complete remission (CR) or CR with incomplete count recovery (CRi) (57.5% vs 33.9%, p < 0.05), a higher complete cytogenetic response rate (45% vs 10.7%, p < 0.001), and more patients proceeding to ASCT (32.5% vs 10.7%, p < 0.01). With a median follow-up of 6.7 years, long-term outcomes were similar between the IC + TKI and HMA + TKI groups. Combination therapy with IC/HMA + TKI was superior to therapy with TKI alone, including when analysis was limited to those treated with a 2nd/3rd-generation TKI. When using a 2nd/3rd-generation TKI, IC/HMA + TKI led to lower 5-year cumulative incidence of relapse (CIR; 44% vs 86%, p < 0.05) and superior 5-year event-free survival (EFS; 28% vs 0%, p < 0.05) and overall survival (OS; 34% vs 8%, p = 0.23) compared to TKI alone. Among patients who received IC/HMA + TKI, EFS and OS was superior for patients who received a 2nd/3rd generation TKI compared to those who received imatinib-based therapy. In a landmark analysis, 5-year OS was higher for patients who proceeded to ASCT (58% vs 22%, p = 0.12). Conclusions: Compared to patients treated with TKI alone for CML-MBP, treatment with IC + TKI or HMA + TKI led to improved response rates, CIR, EFS, and OS, particularly for patients who received a 2nd/3rd-generation TKI. Combination therapy with IC + TKI or HMA + TKI, rather than a TKI alone, should be considered the optimal treatment strategy for patients with CML-MBP. [ABSTRACT FROM AUTHOR]

Background: The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL.Methods: We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) compared to conventional hyper-CVAD.Results: Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%.Conclusion: The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL. [ABSTRACT FROM AUTHOR]

AbstractBlinatumomab and inotuzumab ozogamicin (INO) are both active in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and improve outcomes compared with conventional chemotherapy in this setting. Several prospective clinical trials have explored the use of these agents in adults with newly diagnosed B-cell ALL, with promising outcomes observed in younger and older adults and in both Philadelphia chromosome (Ph)-positive and Ph-negative ALL. These novel regimens result in high rates of deep measurable residual disease (MRD) negativity and may improve survival compared with chemotherapy-only approaches, allowing for less reliance on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). This review discusses novel approaches to integrating INO and/or blinatumomab into frontline ALL regimens, including the potential role of chemotherapy-free regimens in some subgroups. The role of MRD monitoring is also discussed, including how this can inform decisions for consolidative allogeneic HSCT or investigational approaches with CD19 CAR T-cells. [ABSTRACT FROM AUTHOR]

The aim of this paper is to demonstrate that the sustained growth of the state sector in the Chinese economy shows that Chinese model is very different from state capitalism, even more from liberal capitalism. In our view, China's market socialist system can be interpreted as classified as a "New Socioeconomic Formation" (NSEF). The most important attribute of the NSEF is complexity, as it is marked by the coexistence of different modes of production. China's market socialism is still in its embryonic stage, and is governed by an ever-evolving combination of different modes and relations of production. In this framework, some basic laws of motion of China's socialist market economy can be identified. [ABSTRACT FROM AUTHOR]

The purpose of this article is to shed light on the reasons why Ignacio Rangel's concept of "Projectment Economy" holds great possibilities for research in the field of Chinese economic development. To this objetive, we seek to re-elaborate the concept and enrich with the new determinations and validation criteria that make it up to the scope of the phenomenon underway in China. Issues such as the possibilities of overcoming "Keynesian uncertainty", planning for "creative destruction", monetary sovereignty and the "tacit adhesion pact" will be addressed and taken as categories that support, as an empirical face, the concept of the New Projectment Economy. We conclude by stating that the New Projectment Economy constitutes a superior stage of development of the dominant mode of production internal to the (new) socioeconomic formation that emerged in China as a result of the economic reforms initiated in 1978. [ABSTRACT FROM AUTHOR]

Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL. [ABSTRACT FROM AUTHOR]

The purpose of this article is to demonstrate that the transformation of "market socialism" into a New Socio-Economic Formation (NSEF) goes beyond a phenomenon located in China. It is about a new economy that the historical process is drawing in and out of the process of financialization, imperialist aggressiveness, the emergence / spreading of new productive and technological paradigms and the new and superior forms of planning being developed and executed in large in China. To this new economy - which develops in the wake of the transition process and change of the dominant mode of production (MP) - we call it the New Theory of Projection, inspired by the Economics of Projection developed by Ignacio Rangel in the late 1950s. of departure is the historical materialism of Marx and Engels plus any existing theoretical collection elaborated over time by the field of economic heterodoxy. This is a demand that history places on economists, since economic science itself changes and changes with the MP, which in turn is constantly changing. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to analyze the catching-up processes of South Korea and post-1978 reforms China, based on a new-developmentalist approach that considers four fundamental factors: 1) a complementarity relationship between the state and the market as a dynamic process that changes over time; 2) necessary complementarity between macroeconomic policy and industrial policy; 3) the key role of public and development banks in attacking the problem of "development financing"; and a particular focus on 4) the centrality of exchange rate and balance of payments administration for the development process in these countries. The paper's fundamental question is to what extent the catchingup process in these countries can be understood as the application of a new-developmentalist strategy, taking each country's particular historical traits into account. [ABSTRACT FROM AUTHOR]

Optimal administration of the hyperCVAD regimen requires awareness of its appropriate administration and supportive care practices. Practical management of anticipated toxicities and treatment of special patient populations with this regimen is reviewed. [ABSTRACT FROM AUTHOR]

Background: Dasatinib, a potent Bcr-Abl tyrosine kinase inhibitor, is approved for the treatment of chronic-phase chronic myeloid leukemia (CML-CP) in the frontline and salvage settings. Notable side effects include pleural effusions and myelosuppression. Dasatinib at 50 mg daily has previously been reported to be active and better tolerated than the approved 100-mg daily dose. The aim of this study was to update the long-term follow-up results of dasatinib at 50 mg daily as frontline therapy for CML-CP.Methods: Eighty-three patients with newly diagnosed CML-CP received dasatinib at 50 mg daily. Eligibility and response criteria were standards used in previous protocols.Results: After a minimum follow-up of 12 months, 81 patients were evaluable. Two patients came off the study in less than 3 months. The rates of BCR-ABL1 transcript levels (International Standard) at ≤10% and ≤1% at 3 months were 96% and 77%, respectively. The cumulative rates for a complete cytogenetic response by 6 and 12 months were 77% and 95%, respectively. The cumulative rates for a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5-log reduction by 12 months were 81%, 55%, and 49%, respectively. Twenty-one patients (25%) had treatment interruptions for a median of 13 days (range, 4-64 days). Five patients (6%) developed pleural effusions; 4 of these patients (80%) required a dose reduction. Two patients (2%) failed to achieve any cytogenetic or molecular response and were taken off the study. At a median follow-up of 24 months, none of the patients had disease transformation to an accelerated or blastic phase. The 2-year event-free and overall survival rates were 100%.Conclusions: These updated results continue to support 50 mg of dasatinib daily as an effective and safe dose for early CML-CP. [ABSTRACT FROM AUTHOR]

BCR-ABL1 tyrosine kinase inhibitors (TKIs) alone and with chemotherapy led to a dramatic increase in survival of chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients [[1]]. The study of dasatinib in the front-line setting for the treatment of CML reported 5% incidence of peripheral neuropathy with 3/62 patients experiencing grade 3-4 peripheral neuropathy [[7]]. In our three reported cases, patients experienced severe neurotoxicity ranging from transverse myelitis to demyelination to optic neuritis. Neurological symptoms appear to occur at any time during treatment (weeks to years) and can last long beyond treatment cessation suggesting cumulative risk for neurotoxicity by TKIs. [Extracted from the article]

Background: Blinatumomab, a bispecific T-cell-engaging (BiTE®) immuno-oncology therapy, demonstrated superior overall survival versus standard-of-care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL) in the phase 3 TOWER study. Herein, the authors reported clinical features and outcomes for those patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with blinatumomab.Methods: In the TOWER study, adults with R/R ALL were randomized 2:1 to receive blinatumomab or SOC. Study treatment consisted of 2 cycles of induction with blinatumomab or SOC followed by consolidation and maintenance therapy. At any time after the first cycle, patients who were eligible for HSCT could proceed to HSCT.Results: Of the 97 patients who underwent HSCT during the study, baseline characteristics generally were comparable and donor types were similar between the patients treated with blinatumomab (65 patients) and those receiving SOC (32 patients). There was no evidence to suggest that the survival benefit of HSCT differed between the patients treated with blinatumomab and those receiving SOC (P = .68). On the basis of descriptive statistics, a survival benefit of HSCT versus no HSCT was not observed in patients who achieved complete remission with full, partial, or incomplete hematologic recovery with blinatumomab (odds ratio, 1.17; 95% CI, 0.54-2.53). The best outcomes were achieved in patients with no prior salvage therapy and with minimal residual disease response to blinatumomab regardless of on-study HSCT status.Conclusions: Survival was found to be driven by response to study treatment and by salvage status regardless of on-study HSCT status. These data should be interpreted with caution because the current study was not designed to prospectively assess survival outcomes associated with HSCT after blinatumomab.Lay Summary: Evidence before this study: Blinatumomab is associated with superior morphologic and molecular response rates and superior overall outcome when compared with standard of care chemotherapy in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Added value of this study: The best outcomes with blinatumomab were observed in patients who achieved minimal residual disease remission in first salvage treatment regardless of subsequent allogeneic stem cell transplantation (HSCT). Implications of all the available evidence: Patients achieving CR/CRh/CRi following blinatumomab can have a durable response with or without HSCT. [ABSTRACT FROM AUTHOR]

Background: The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)‐negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low‐intensity chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low‐intensity chemotherapy (mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone [mini‐HCVD]) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen. Methods: The authors analyzed 135 older patients with newly diagnosed, Ph‐negative ALL who were treated prospectively with standard HCVAD (n = 77) or with the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab (n = 58). A propensity score analysis was conducted using 1:1 matching using the nearest neighbor matching method. Results: Propensity score matching identified 38 patients in each cohort. The antibody plus low‐intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3‐year event‐free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab were 34% and 64%, respectively (P = .003), and the 3‐year overall survival rates were 34% and 63%, respectively (P = .004). By multivariate analysis, age (P = .019; hazard ratio, 1.045) and the combination of inotuzumab plus mini‐HCVD with or without blinatumomab (P = .020; hazard ratio, 0.550) were identified as independent prognostic factors for survival. Conclusions: The combination of inotuzumab ozogamicin plus mini‐HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph‐negative ALL and confers a better outcome compared with standard HCVAD chemotherapy. The combination of inotuzumab ozogamicin plus mini–hyperfractionated cyclophosphamide, vincristine, and dexamethasone with or without blinatumomab is safe and effective in older patients with newly diagnosed, Philadelphia chromosome‐negative acute lymphoblastic leukemia and confers a better outcome compared with standard hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemotherapy. [ABSTRACT FROM AUTHOR]

Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allogeneic or autologous hematopoietic stem cell transplantation (HSCT) most commonly associated with high-intensity chemotherapies. The development of VOD/SOS may be rapid and unpredictable, and the importance of identifying risk factors to facilitate prompt diagnosis and timely treatment has become increasingly recognized. The reporting of new retrospective study data for adults and children and the emergence of novel anticancer therapies that may increase the risk of VOD/SOD also necessitate updates on risk factors, as provided in this review. The latest studies reporting VOD/SOS risk factors support previously published data, although the importance of patient-related factors, such as acute kidney injury, increased international normalized ratio, female sex (in children), and platelet refractoriness, is given greater emphasis in the recent data. Non-transplantation-related chemotherapies associated with increased risk for VOD/SOS include oxaliplatin and 5-fluorouracil chemotherapies. The novel antibody drug conjugates gemtuzumab ozogamicin and inotuzumab ozogamicin are now reported in product labeling to pose risks for VOD/SOS based on clinical trial data; an expert consensus panel has issued recommendations for risk reduction measures with inotuzumab ozogamicin treatment, including VOD/SOS prophylaxis and limitation to ≤2 inotuzumab ozogamicin treatment cycles. A wide range of biomarkers, including genetic, hematologic, hepatic, and inflammatory factors, as well as novel diagnostic techniques such as thromboelastography and measures of liver stiffness, may further enhance future risk calculation for VOD/SOS, although none has been widely adopted. Continual monitoring for and recognition of VOD/SOS risk factors are essential for optimal management of this complication. • Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) can be fatal. • Prompt treatment of VOD/SOS may improve survival. • Recognition of VOD/SOS risk factors helps expedite treatment. • Newly identified VOD/SOS-related risk factors include antibody drug conjugates. • New biomarkers and diagnostic techniques may improve VOD/SOS prediction. [ABSTRACT FROM AUTHOR]

Background: DFP-10917, a deoxycytidine nucleoside analogue, has a unique mechanism of action resulting in leukemic cell death when administered for prolonged periods at low doses. The current phase 1/2 study investigated the safety, maximum tolerated dose, and evidence of antileukemic activity for DFP-10917 administered by 7-day or 14-day continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia (AML).Methods: In the phase 1 dose escalation portion of the study, patients were administered DFP-10917 by 7-day continuous intravenous infusion plus 21-day rest (stage 1) or 14-day continuous intravenous infusion plus 14-day rest (stage 2). The primary objectives of phase 1 were to determine the maximum tolerated dose, the phase 2 dose, and the dose-limiting toxicities (DLTs) of DFP-10917. The primary objectives of phase 2 were to evaluate the overall response rate of DFP-10917 using complete response (CR), CR without platelet recovery (CRp), CR with incomplete blood count recovery (CRi) or partial response.Results: In stage 1 of phase 1 (4-35 mg/m2 /day as a 7-day continuous intravenous infusion), a DLT of grade 3 diarrhea occurred at a dose of 35 mg/m2 /day. In stage 2 of phase 1, a dose of 10 mg/m2 /day as a 14-day continuous intravenous infusion resulted in DLTs of prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m2 /day as a 14-day continuous intravenous infusion was found to be well tolerated and was selected for phase 2. Response rates in patients in phase 2 (N = 29) were 20.7% CR, 3.4% CRp, and 24.1% CRi. The overall response rate was 48.3% (95% confidence interval, 29.4%-67.5%).Conclusions: DFP-10917 as a 14-day continuous intravenous infusion at a dose of 6 mg/m2 /day can be administered safely and appears to be effective in patients with recurrent or refractory AML. A phase 3 investigation comparing DFP-10917 monotherapy versus standard of care in an early recurrent or refractory AML setting is warranted. [ABSTRACT FROM AUTHOR]

We evaluated the impact of molecular monitoring earlier as compared to later in the course of chronic myeloid leukemia (CML) on disease progression and healthcare costs in the real-world setting in the US. Patients with a diagnosis of CML were identified from the MarketScan claims databases (1 January 2006 to 30 June 2016). Multivariable regression analyses were used to control for differences in patient cohorts with earlier versus later monitoring. Of the 2730 CML patients in the study population, 60% (n = 1633) received earlier monitoring and 40% (n = 1097) received later monitoring only. After adjusting for differences in patient characteristics, patients with earlier monitoring had a lower likelihood of CML progression during the follow-up period (odds ratio: 0.72, confidence interval: 0.53–0.96; p =.03) and lower total healthcare costs ($6794 versus $9782 per-patient-per-month, p <.001) than patients with later monitoring. Patients who are monitored earlier in the course of CML may have better outcomes and lower total costs of care. [ABSTRACT FROM AUTHOR]

Background: The outcomes of patients with relapsed or refractory (R-R) acute lymphoblastic leukemia (ALL) are poor. Inotuzumab ozogamicin and blinatumomab have single-agent activity in R-R ALL. Their addition to low-intensity chemotherapy may further improve the outcomes of patients with ALL in their first relapse.Methods: The chemotherapy was lower in intensity than conventional hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone and was called mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone (or mini-HCVD). Inotuzumab was given on day 3 of each of the first 4 cycles at 1.8 to 1.3 mg/m2 for cycle 1, and this was followed by 1.3 to 1.0 mg/m2 for subsequent cycles. From patient 39 onward, the inotuzumab dose was reduced and fractionated into weekly doses (0.6 and 0.3 mg/m2 during cycle 1 and 0.3 and 0.3 mg/m2 during subsequent cycles), and blinatumomab was administered for up to 4 cycles after inotuzumab therapy.Results: Forty-eight patients with Philadelphia chromosome-negative ALL with a median age of 39 years were treated during their first relapse. Overall, 44 patients (92%) responded, with 35 of them (73%) achieving a complete response. The overall minimal residual disease negativity rate among the responders was 93%. Twenty-four patients (50%) underwent allogeneic stem cell transplantation (ASCT). Veno-occlusive disease of any grade occurred in 5 patients (10%). With a median follow-up of 31 months, the median progression-free survival (PFS) and the median overall survival (OS) were 11 and 25 months, respectively. The 2-year PFS and OS rates were 42% and 54%, respectively. Of the 24 patients (50%) who underwent ASCT, 14 patients were alive at the last follow-up (13 [54%] in remission). Of the remaining 20 responding patients who did not undergo subsequent ASCT, 6 (30%) remained in remission at the last follow-up. According to propensity score matching, the combination of mini-HCVD and inotuzumab with or without blinatumomab conferred better outcomes than intensive salvage chemotherapy or inotuzumab alone.Conclusions: The combination of inotuzumab and low-intensity mini-HCVD chemotherapy with or without blinatumomab shows encouraging results in patients with ALL in first salvage. [ABSTRACT FROM AUTHOR]

The main of this article is to demonstrate, from an over view of China's economic reforms, that the emergence of a large private sector and the sophistication and diversification of the industry has required continued reorganization activities between the state and private sector sof the economy. We support in this paper the state began to develop major role in the spheres involving the control of the major industry sector sand big finance, as well as the coordination and socialization of investment - in this case, economic policy (monetary and fiscal), foreign trade and especially, the laun chof innovative and superior form sof economic planning. [ABSTRACT FROM AUTHOR]

Patients diagnosed with chronic myeloid leukemia (CML) and treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs) have long life spans. Selection of an appropriate first-line therapy can be difficult as both the unique characteristics of each TKI and patient need to be taken into account to find the optimal match. Patient characteristics include comorbidities, concomitant medications, lifestyle, risk factors, BCR-ABL1 transcript type (e.g. b2a2 or b3a2) and additional chromosomal abnormalities. Just as patients differ, side effects, drug-drug interactions, administration plans, dosing schedules and treatment-related expenses across TKIs also vary. Alignment of these characteristics with the appropriate TKI is key to successfully initiating CML treatment. Continued success relies on communication between the patient and the healthcare team, adherence and optimization of therapy once it is initiated. In this review, we discuss these factors, in addition to TKI efficacy and safety, the cost of therapy, the future of treating CML and treatment-free remission. [ABSTRACT FROM AUTHOR]

Background: Dasatinib is a potent BCR-ABL1 and Src family tyrosine kinase inhibitor. It is approved at a dose of 100 mg orally daily for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). This dose schedule is associated with myelosuppression and pleural effusions. Anecdotal data suggest that lower doses may be as effective and less toxic. The aim of this study was to assess the efficacy and safety of a lower dose of dasatinib (50 mg daily) in patients with newly diagnosed CML-CP.Methods: Seventy-five patients with newly diagnosed CML-CP received dasatinib 50 mg daily. The eligibility and response criteria were standards used in previous protocols.Results: At a median follow-up of 9 months, 60 patients were evaluable for a response at 3 months. The rates of patients achieving BCR-ABL1 transcript levels ≤ 10% and ≤ 1% at 3 months by the International Standard were 93% and 72%, respectively. The rates of complete cytogenetic response by conventional cytogenetics or fluorescence in situ hybridization at 6 and 12 months were 86% and 88%, respectively. At 12 months, 79%, 71%, and 46% of the patients had achieved a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5-log reduction, respectively. Nine patients had a dose interruption for ≤14 days. Only 1 patient developed a pleural effusion requiring a dose reduction to 20 mg. All patients remained alive and with no transformation so far.Conclusion: Dasatinib 50 mg daily is active and well tolerated in patients with newly diagnosed CML-CP. It should be further explored as a new potential standard-of-care option for chronic myeloid leukemia. Cancer 2018;124:2740-2747. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.Methods: Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/m2 /cycle (0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15 of a 21- to 28-day cycle [≤6 cycles]); 60 patients were aged ≥55 years, and 104 were aged <55 years.Results: For older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged <55 years and those aged ≥55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.Conclusions: InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018;124:1722-32. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML).Methods: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine.Results: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]).Conclusions: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

The main aim of this paper is to demonstrate, through a review of China's economic reforms, that the emergence of a large private sector and the increased sophistication and diversification of industry has required the continual reorganization of activities between the state and private sectors of the economy. We argue in this paper that the state began to play a major role in important industries and in big finance, as well as in the coordination and socialization of investment, such as economic policy (monetary and fiscal), foreign trade and, especially, the launch of new and higher forms of economic planning. Keywords: China; economic reforms; state; private sector; economic planning. [ABSTRACT FROM AUTHOR]

Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodys-plastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDSor MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m² intravenously/subcutaneously daily or decitabine 20 mg/m² intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% (P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine (P = .2). Cytogenetic response rates were 61% and 25% (P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively (P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225). [ABSTRACT FROM AUTHOR]

In patients with chronic lymphocytic leukemia (CLL), persistence of disease after allogeneic stem cell transplantation (alloSCT) can result in poor outcomes. In an effort to improve these outcomes, patients with persistent CLL who were 90 to 100 days beyond alloSCT with no evidence of graft-versus-host-disease (GVHD) were randomized to receive lenalidomide or standard care (withdrawal of immunosuppression followed by donor lymphocyte infusion). Lenalidomide was initiated at 5 mg every other day and increased to 10 mg daily, if tolerated, in each patient. Of 38 patients enrolled, 17 (45%) met the eligibility criteria for randomization. Of these 17 patients, 8 were randomized to undergo lenalidomide therapy. Five (62%) patients had to stop taking the drug because of toxicity. The main reason for drug discontinuation was acute GVHD in 43% of patients. This incidence was 11% in the patients who were randomized to not receive lenalidomide. With a median follow-up of 2.6 years, the median survival was 3.4 years for those receiving lenalidomide. This was not reached in patients randomized to not receive lenalidomide and in patients in complete remission who were not randomized. These results suggested that treatments other than lenalidomide are needed for persistent CLL after alloSCT. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) in the adolescent and young adult (AYA) population is a difficult clinical problem. The AYA population, generally regarded as patients aged 15 to 39 years, currently draws a good deal of attention, particularly in the area of therapy selection. The current trend is to treat this group of patients with leukemia regimens based on pediatric protocols, and results comparing pediatric approaches versus adult approaches to treatment are maturing. Results are pending from a large US trial in which pediatric-based treatment is given to AYA patients with ALL. In tandem with these new clinical trials, researchers have reported disease features in the AYA group that may explain some of the differences in response to treatment observed in the AYA population compared with the pediatric population. In addition, unique social factors in this age group add to the complexity of ALL therapy in the AYA population. AYA patients are developing independence and separating from their parents. They tend to be noncompliant. Young adults suffer from a lack of health care insurance and poor access to clinical trials, and have specific concerns regarding toxicities, in particular fertility. Cancer 2017;123:2398-403. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The outcome of patients with higher-risk myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor. This study evaluated the safety and activity of a combination of low-dose clofarabine and cytarabine for these patients.Methods: Seventy patients with higher-risk MDS who had no response, progressed, or relapsed after at least 4 cycles of HMA therapy were treated.Results: The median age was 72 years. Thirty-nine percent of the patients had high-risk disease according to the International Prognostic Scoring System, and 50% of the patients had poor-risk cytogenetics. Twenty-three percent of the patients had therapy-related MDS. The median number of prior cycles of HMA was 6 (range, 4-45). The overall response rate was 44%. The 6-week mortality rate was 9%. Grade 3 and higher nonhematologic toxicities were rare, but infections occurred in 52% of the patients, and fever of unknown origin occurred in 33%. The median overall survival (OS) was 10 months (95% confidence interval, 1-37 months). Thirteen percent of the patients underwent allogeneic stem cell transplantation. The responding patients had a median OS of 22 months, whereas the nonresponding patients had a median OS of 4 months. A complex karyotype was associated with worse response rates and OS.Conclusions: The combination of low-dose clofarabine and cytarabine is clinically active in these patients with few treatment options. Cancer 2017;123:629-637. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Minimal residual disease (MRD) assessment predicts survival for patients with newly diagnosed acute lymphoblastic leukemia (ALL). Its significance in relapsed/refractory ALL is less clear.Methods: This study identified 78 patients with relapsed/refractory B-cell ALL who achieved a morphologic response with inotuzumab ozogamicin (n = 41), blinatumomab (n = 11), or mini-hyperfractionated cyclophosphamide, vincristine, and doxorubicin plus inotuzumab (n = 26) during either salvage 1 (S1; n = 46) or salvage 2 (S2; n = 32) and had undergone an MRD assessment by multiparameter flow cytometry at the time of remission.Results: MRD negativity was achieved in 41 patients overall (53%). The MRD negativity rate was 57% in S1 and 47% in S2. Among patients in S1, achieving MRD negativity was associated with longer event-free survival (EFS; median, 18 vs 7 months; 2-year EFS rate, 46% vs 17%; P = .06) and overall survival (OS; median, 27 vs 9 months; 2-year OS, 52% vs 36%; P = .15). EFS and OS were similar in S2, regardless of the MRD response. Among MRD-negative patients who underwent allogeneic stem cell transplantation (SCT), EFS and OS were superior for those who underwent SCT in S1 rather than S2 (P = .003 and P = .04, respectively). Patients in S1 who achieved MRD negativity and subsequently underwent SCT had the best outcomes with a 2-year OS rate of 65%.Conclusions: Patients with relapsed/refractory ALL who achieve MRD negativity in S1 can have long-term survival. Patients in S2 generally have poor outcomes, regardless of their MRD status. Cancer 2017;123:294-302. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial.Methods: The authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts.Results: Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib.Conclusions: The clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

The impact of achieving complete molecular response (CMR) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with + ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P = .005) and relapse-free survival (RFS; P = .002) than did MRD status at CR (P = .11 and P = .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P = .009) and RFS (126 vs 18 months, respectively; P = .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P = .01). Patients with + ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT. [ABSTRACT FROM AUTHOR]

Background: Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial.Methods: In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982.Findings: 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment.Interpretation: The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes.Funding: ARIAD Pharmaceuticals Inc. [ABSTRACT FROM AUTHOR]

Significant advances have been made in the last decade toward a better understanding of the disease pathogenesis and the development of novel therapies that target specific subsets of adult acute lymphoblastic leukemia (ALL). Risk-adapted strategies are transforming the disease treatment and prognosis. With current treatment regimens, long-term survival is achieved by approximately 50% of patients with B-cell ALL, 50% to 60% of patients with Philadelphia chromosome-positive ALL, and approximately 80% of patients with Burkitt's leukemia. Genomic profiling in ALL has identified new prognostic markers, new therapeutic targets, and novel ALL subtypes. These may be amenable to future targeted therapies that can further improve outcomes. The early recognition of early precursor T-cell ALL, a distinct pathobiological entity with a poor prognosis, is essential for the development of an effective clinical management strategy. The role of monoclonal antibodies and cytotoxic T-cell therapies continues to be defined. Many of the approaches are currently being evaluated for ALL salvage. Their incorporation into frontline adult ALL therapy, in concomitant or sequential strategies, may increase the cure rates to levels achieved in pediatric ALL and may reduce the need for prolonged intensive and maintenance chemotherapy. Cancer 2015;121:2517-2528. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Elderly patients with acute myeloid leukemia (AML) who are refractory to or relapse following frontline treatment constitute a poor-risk group with a poor long-term outcome. Host-related factors and unfavorable disease-related features contribute to early treatment failures following frontline therapy, thus making attainment of remission and long-term survival with salvage therapy particularly challenging for elderly patients. Currently, no optimal salvage strategy exists for responding patients, and allogeneic hematopoietic stem cell transplant is the only curative option in this setting; however, the vast majority of elderly patients are not candidates for this procedure due to poor functional status secondary to age and age-related comorbidities. Furthermore, the lack of effective salvage programs available for elderly patients with recurrent AML underscores the need for therapies that consistently yield durable remissions or durable control of their disease. The purpose of this review was to highlight the currently available strategies, as well as future strategies under development, for treating older patients with recurrent AML. [ABSTRACT FROM AUTHOR]

With modern intensive combination polychemotherapy, the complete response (CR) rate in adults with acute lymphoblastic leukemia (ALL) is 80-90%, and the cure rate 40-50%. Hence there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy. ALL leukemic cells express several surface antigens amenable to target therapies, including CD20, CD22, and CD19. Monoclonal antibodies target these leukemic surface antigens selectively, and minimize off-target toxicity. When added to frontline chemotherapy, rituximab, an antibody directed against CD20, increases cure rates of adults with Burkitt leukemia from 40% to 80%, and those with pre-B ALL from 35% to 50%. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has resulted in marrow CR rates of 55% and a median survival of 6-7 months when given to patients with refractory-relapsed ALL. Blinatumomab, a biallelic T-cell engaging CD3-CD19 monoclonal antibody, also resulted in overall response rates of 40-50% and a median survival of 6.5 months in a similar refractory-relapsed population. Other promising monoclonal antibodies targeting CD20 (ofatumumab, obinutuzumab), or CD19 or CD20 and bound to different cytotoxins or immunotoxins are under development. Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are a diverse group of myeloid disorders, with patients being at risk for cytopenias or progression to acute myeloid leukemia. Several classification and prognostic scoring systems have been developed. High-intensity treatments are not appropriate for all patients. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of MDS, although many patients do not derive long-term benefit and eventually progress. Deacetylase inhibitors have emerged as novel treatment candidates based on mechanistic rationale and preliminary data. This article reviews existing data on MDS treatment and discusses the rationale and potential for combination with deacetylase inhibitors. [ABSTRACT FROM AUTHOR]