Unlocking protein-based biomarker potential for graft-versus-host disease following allogenic hematopoietic stem cell transplants.

Despite the numerous advantages of allogeneic hematopoietic stem cell transplants (allo-HSCT), there exists a notable association with risks, particularly during the preconditioning period and predominantly post-intervention, exemplified by the occurrence of graft-versus-host disease (GVHD). Risk stratification prior to symptom manifestation, along with precise diagnosis and prognosis, relies heavily on clinical features. A critical imperative is the development of tools capable of early identification and effective management of patients undergoing allo-HSCT. A promising avenue in this pursuit is the utilization of proteomics-based biomarkers obtained from non-invasive biospecimens. This review comprehensively outlines the application of proteomics and proteomics-based biomarkers in GVHD patients. It delves into both single protein markers and protein panels, offering insights into their relevance in acute and chronic GVHD. Furthermore, the review provides a detailed examination of the site-specific involvement of GVHD. In summary, this article explores the potential of proteomics as a tool for timely and accurate intervention in the context of GVHD following allo-HSCT.

Vitamin D Level and Immune Modulation in Children with Recurrent Wheezing.

INTRODUCTION AND AIM: A direct causal relationship between vitamin D (vit D) deficiency and recurrent wheezing has not been proven. The present study investigated the role of vit D in enhancing the risk of asthma or recurrent wheezing by modifying the intensity of the inflammatory process. MATERIAL AND METHOD: Forty children with wheezing presenting at the emergency service and sixteen healthy control subjects were included in the study. Children with wheezing were either in the first episode (20) or with recurrent wheezing (20). Children with chronic diseases, and other conditions that present with acute wheezing or that might influence the vit D level, were excluded. Blood samples were taken at presentation and 3-6 months later, to evaluate the serum levels of total IgE, vit D, IL-10 and IL-31. Statistical analysis was performed using the SPSS 25 program, with a significance level of p < 0.05. RESULTS AND CONCLUSION: The vit D level was lower in patients with recurrent wheezing compared with those with a single episode and with the control group, and this increased with time. IL-10 was significantly higher in children with wheezing than in the control group, with the highest values in those with an acute episode of wheezing. IL-31 was higher in children with recurrent wheezing than in those with a first episode only at the initial point, while at the final time point it was lower. Low levels of vit D appear to be detected more frequently in recurrent wheezing than in simple wheezing. Immune modulation, as measured by Th2 status reflected by IL-10 and IL-31 levels, appears to depend on the wheezing phenotype and on the general health status.

Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.

MicroRNAs Associated with a Bad Prognosis in Acute Myeloid Leukemia and Their Impact on Macrophage Polarization.

MicroRNAs (miRNAs) are short, non-coding ribonucleic acids (RNAs) associated with gene expression regulation. Since the discovery of the first miRNA in 1993, thousands of miRNAs have been studied and they have been associated not only with physiological processes, but also with various diseases such as cancer and inflammatory conditions. MiRNAs have proven to be not only significant biomarkers but also an interesting therapeutic target in various diseases, including cancer. In acute myeloid leukemia (AML), miRNAs have been regarded as a welcome addition to the limited therapeutic armamentarium, and there is a vast amount of data on miRNAs and their dysregulation. Macrophages are innate immune cells, present in various tissues involved in both tissue repair and phagocytosis. Based on their polarization, macrophages can be classified into two groups: M1 macrophages with pro-inflammatory functions and M2 macrophages with an anti-inflammatory action. In cancer, M2 macrophages are associated with tumor evasion, metastasis, and a poor outcome. Several miRNAs have been associated with a poor prognosis in AML and with either the M1 or M2 macrophage phenotype. In the present paper, we review miRNAs with a reported negative prognostic significance in cancer with a focus on AML and analyze their potential impact on macrophage polarization.

Anthracycline's Effects on Heart Rate Variability in Children with Acute Lymphoblastic Leukemia: Early Toxicity Signs-Pilot Study.

Anthracycline treatments are known to cause cardiotoxic long-term side effects in cancer survivors. Recently, a decrease in heart rate variability (HRV) has been identified in these patients, signaling autonomic dysfunction and altered cardiac fitness. This study aimed at evaluating changes in HRV in children treated with anthracyclines. A total of 35 pediatric patients with acute lymphoblastic leukemia were evaluated by means of a 24 h Holter ECG, at baseline and after reaching half the total cumulative dose of doxorubicin equivalent (120 mg/m2). Parameters of HRV were assessed, as well as any arrhythmic episodes, bradycardia and tachycardia percentages. The results showed a significant decrease in both time-domain and frequency-domain HRV parameters, following anthracycline treatment. The low-frequency (LF) to high-frequency (HF) parameters' ratio also displayed a significant difference (p = 0.035), suggestive of early cardiac autonomic dysfunction. Of note, none of the patients presented symptoms of heart disease or elevated troponins, and only two patients presented echocardiographic signs of diastolic dysfunction. The present study showed that cardiac autonomic nervous system regulation is compromised in children treated with anthracyclines even before reaching the total cumulative dose. Therefore, HRV parameters could be the first indicators of subclinical cardiac toxicity, making Holter ECG monitoring of the oncological patient a necessity.

Design and preclinical testing of an anti-CD41 CAR T cell for the treatment of acute megakaryoblastic leukaemia.

Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio.

A Survival Analysis of Acute Myeloid Leukemia Patients Treated With Intensive Chemotherapy: A Single Center Experience.

INTRODUCTION: Acute myeloid leukaemia (AML) is a haematological disease associated with a dismal prognosis, despite major progress made in recent years in terms of antileukemic agents and supportive care. METHODS: We investigated the results of the intensive treatment of 133 fit AML patients (de novo and secondary) from a referral cancer centre in Romania, treated between January 2015 and December 2021. RESULTS: We included 79 male and 54 female patients with a median age of 53 years (range 18-70). Molecular biology analysis was available for 82.7% of patients, whereas karyotype analysis was only available for 33% of patients. The median overall survival (OS) was 8.7 months, and the disease-free survival rate was 26.3% at a median follow-up of 33.7 months. The complete remission (CR) rate after induction was 48.9% for all patients and 61.9% for patients who were assessable (excluding patients who died before being assessed for response). Twelve patients underwent allogeneic bone marrow transplantation (BMT), with the median OS not reached. Early mortality (EM), defined as death during the first 30 days after admission, was 17.3%, with the main cause of death being septic shock (78.3%). Elderly patients (≥60 years of age) had a lower OS, more primary refractory disease, and higher rates of early mortality. CONCLUSION: Complete remission rates and OS in our cohort were lower than in other reports. Early mortality was unexpectedly high, mainly due to infections, which were the main causes of death in our cohort.

Flow Cytometry of CD5-Positive Hairy Cell Leukemia.

BACKGROUND AND OBJECTIVE: Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder for which diagnosis is typically straightforward, based on bone marrow morphology and flow cytometry (FC) or immunohistochemistry. Nevertheless, variants present atypical expressions of cell surface markers, as is the case of CD5, for which the differential diagnosis can be more difficult. The aim of the current paper was to describe diagnosis of HCL with atypical CD5 expression, with an emphasis on FC. METHODS: The detailed diagnostic methodology for HCL with atypical CD5 expression is presented, including differential diagnosis from other lymphoproliferative diseases with similar pathologic features, by FC analysis of the bone marrow aspirate. RESULTS: Diagnosis of HCL by means of FC started by gating all events based on side scatter (SSC) versus CD45 and B lymphocytes were selected from the lymphocytes gate as CD45/CD19 positive. The gated cells were positive for CD25, CD11c, CD20, and CD103, while CD10 proved to be dim to negative. Moreover, cells positive for CD3, CD4, and CD8, the three pan-T markers, as well as CD19, showed a bright expression of CD5. The atypical CD5 expression is usually correlated with a negative prognosis and thus chemotherapy with cladribine should be initiated. CONCLUSION: HCL is an indolent chronic lymphoproliferative disorder and diagnosis is usually straightforward. However, atypical expression of CD5 renders its differential diagnosis more difficult, but FC is a useful tool that allows an optimal classification of the disease and allows initiation of timely satisfactory therapy.

Real-world study of children and young adults with myeloproliferative neoplasms: identifying risks and unmet needs.

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.

Relationship Between Vitamin D Level and Platelet Parameters in Children With Viral Respiratory Infections.

Apart from their classical roles, both platelets and vitamin D play important roles in inflammation and infectious diseases. This study evaluated the platelet response to viral respiratory tract infection in children aged 4-16 years, 32 with influenza, 27 with non-influenza viral infection tested by nasopharyngeal swab and 21 healthy children of the same age. Blood count, including platelet count (PLT), mean platelet volume (MPV) and other platelet indices, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and vitamin D (vit D) levels were compared. The influenza group showed lower PLT and platelet mass (PLT*MPV), and the non-influenza group showed significantly lower MPV, which was correlated with the vit D levels, but not CRP or ESR, and the value vit D*MPV was significantly lower in this group. These results revealed that platelet activation in viral respiratory tract infections in children, as measured by MPV, is related to the vit D level, with differences between influenza and non-influenza infection. Conclusions: Viral respiratory tract infection in children can diminish the platelet size most likely by suppressing the platelet activation. This response is associated with low levels of vit D. Whether the vit D status is associated with the virus-platelet immune/inflammatory process needs further investigation.

Identification of altered cell signaling pathways using proteomic profiling in stable and progressive chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells' proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography-tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/ß-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy.

SERS-based DNA methylation profiling allows the differential diagnosis of malignant lymphadenopathy.

This study highlights the potential of surface-enhanced Raman scattering (SERS) to differentiate between B-cell lymphoma (BCL), T-cell lymphoma (TCL), lymph node metastasis of melanoma (Met) and control (Ctr) samples based on the specific SERS signal of DNA extracted from lymph node tissue biopsy. Differences in the methylation profiles as well as the specific interaction of malignant and non-malignant DNA with the metal nanostructure are captured in specific variations of the band at 1005 cm-1, attributed to 5-methylcytosine and the band at 730 cm-1, attributed to adenine. Thus, using the area ratio of these two SERS marker bands as input for univariate classification, an area under the curve (AUC) of 0.70 was achieved in differentiating between malignant and non-malignant DNA. In addition, DNA from the BCL and TCL groups exhibited differences in the area of the SERS band at 730 cm-1, yielding an AUC of 0.84 in differentiating between these two lymphadenopathies. Lastly, using multivariate data analysis techniques, an overall accuracy of 94.7% was achieved in the differential diagnosis between the BCL, TCL, Met and Ctr groups. These results pave the way towards the implementation of SERS as a novel tool in the clinical setting for improving the diagnosis of malignant lymphadenopathy.

Potential Biomarkers for the Efficacy of PD-1-PD-L Blockade in Cancer.

A decade ago, immune checkpoint blockade emerged as a major breakthrough in oncology, proposing a novel approach by which immune brakes could be released to enhance antitumor responses. Despite apparently modest improvement of the median duration of response, a spectacular doubling of long-term responses as compared to the available standard of care was seen, for instance, in metastatic melanoma. It soon became obvious that the percentage of patients responding to these novel approaches is relatively small, and the importance of an accurate prediction of responders became more and more clear. Strong predictive markers would allow for the administration of immune checkpoint blocker therapy to the patients most likely to benefit from it, and sparing the potential non-responders of a treatment which is far from innocuous, being associated with significant side-effects and, not least, an important price tag. A number of potential response predictors have already been investigated and partly validated, but they do not cover the major unmet need encountered in the current clinical setting. Here, we review biomarkers for immune checkpoint blockade efficacy, either clinically validated and currently in use, or which have been proposed as candidates and are currently under investigation.

The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10-IL-10R Pathways in Acute Myeloid Leukemia.

Tumor cells promote the suppression of host anti-tumor type 1 T cell responses by various mechanisms, including the upregulation of surface inhibitory molecules such as programmed death ligand (PD-L)-1, and the production of immunosuppressive cytokines such as interleukin-10 (IL-10). There are over 2000 trials investigating PD-L1 and/or its receptor programmed-death 1 (PD-1) blockade in cancer, leading to the approval of PD-1 or PD-L1 inhibitors in several types of solid cancers and in hematological malignancies. The available data suggest that the molecule PD-L1 on antigen-presenting cells suppresses type 1 T cell immune responses such as cytotoxicity, and that the cytokine IL-10, in addition to downregulating immune responses, increases the expression of inhibitory molecule PD-L1. We hypothesize that the manipulation of both the co-inhibitory network (with anti-PD-L1 blocking antibodies) and suppressor network (with anti-IL-10 blocking antibodies) is an attractive immunotherapeutic intervention for acute myeloid leukemia (AML) patients ineligible for standard treatment with chemotherapy and hematopoietic stem cell transplantation, and with less severe adverse reactions. The proposed combination of these two immunotherapies represents a new approach that can be readily translated into the clinic to improve the therapeutic efficacy of AML disease treatment.

Ibrutinib Monotherapy as Bridge-to-Transplant for Relapsed/Refractory Primary Oculo-Cerebral Lymphoma.

INTRODUCTION: Primary central nervous system lymphoma is an uncommon form of extranodal non-Hodgkin's lymphoma, with increasing incidence, a relatively aggressive course and a poor 5-year survival. Because of its localization, the therapeutic compounds used in this disease must be able to pass through the blood-brain barrier. Chemotherapy regimens based on high-dose methotrexate are currently the standard of care for all patients who can tolerate such drugs. Autologous stem cell transplantation is indicated for malignant lymphomas in the relapsed/refractory setting. METHODS: Three patients, with a median age of 60 years, range 53-64, were diagnosed with primary CNS lymphoma, and treated with ibrutinib monotherapy in the Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania, between September 2018 and November 2020 All the patients were relapsed-refractory following high-dose methotrexate chemotherapy. We present our experience using ibrutinib monotherapy-based treatment as a bridge-to-transplant option on a single-center case series and a review of the literature in this field. RESULTS: Two of the patients were given ibrutinib as a second line therapy, both achieving complete remission and being eligible for an autologous stem cell transplantation. The third patient achieved a short remission using six cycles of systemic chemotherapy, but was started on ibrutinib monotherapy, with limited results. CONCLUSION: Our data is limited, and these results should be confirmed by multicentric clinical trials and should be regarded as a single-center case series, with all its limitations. Still, it brings forward a new therapeutic option for this rare subtype of malignant lymphomas, which if left untreated has a dismal prognosis.

The Predictive Role of Modified Early Warning Score in 174 Hematological Patients at the Point of Transfer to the Intensive Care Unit.

INTRODUCTION: The examination of vital signs and their changes during illness can alert physicians to possible impending deterioration and organ dysfunction. The Modified Early Warning Score (MEWS) is used worldwide as a track and trigger system that can help to identify patients at risk of critical illness. Thus, the current study aimed to assess the ability of MEWS to predict the mortality of hematologic patients at the point of transfer from the ward to the intensive care unit (ICU). MATERIALS AND METHODS: The present study was retrospective, longitudinal, and observational, conducted at an oncology hospital in the city of Cluj-Napoca, Romania. We included 174 patients with hematological disorders transferred from the ward to the ICU between the 1st of January 2018 and the 1st of May 2020. We assessed the MEWS at the moment of admission in these patients in the ICU. The accuracy of MEWS in predicting mortality was assessed via the area under the receiver operating characteristic curves (AUC), and sensitivity, specificity, and hazard ratio (HR) were calculated for different MEWS cutoffs. MEWS values considering the status at discharge and frequency of death by MEWS were also analyzed. RESULTS: We calculated MEWS values considering the status at discharge (p < 0.0001), and we assessed the frequency of death by MEWS. We also calculated the hazard ratio (HR) of death depending on the selected MEWS cutoff. The best cutoff point was found to be ≥6, with an accuracy of 0.667, sensitivity of 0.675, specificity of 0.646, and AUC of 0.731. Patients with higher MEWS had a higher probability of mortality. CONCLUSION: The MEWS and cutoff points were determined on a sample of hematologic patients at the moment of admission to the ICU. The final aim is to encourage physicians to use these scores to improve awareness of organ failure to admit patients to the ICU sooner and limit overall morbidity and mortality. The presence of an ICU physician on ward rounds might help in reducing the timeframe of access to a high-dependency unit (HDU) or ICU. An extension of these scores outside hematologic patients or considering hematologic patients outside ICU must be further studied.

Vitamin D Levels in Asymptomatic Children and Adolescents with Atopy during the COVID-19 Era.

This study assessed vitamin D status in asymptomatic children and adolescents in Greece, with and without atopy, and possible changes during the coronavirus disease 2019 (COVID-19) pandemic. Serum levels of 25-hydroxy-vitamin D (25(OH)D) and total immunoglobulin E (IgE), and eosinophil count were measured in 340 asymptomatic children and adolescents (155 males, 185 females), mean age 8.6 ± 4.6 years, recruited over a period of 24 months (February 2019-January 2021). Atopy, defined by high level of IgE for age, was associated with vitamin D deficient status (p = 0.041). Subjects with and without atopy showed similar rates of insufficient and normal levels of 25(OH)D. The median level of 25(OH)D was significantly higher in subjects recruited during the pandemic, when home confinement rules were observed, than before the pandemic, and significantly more children had normal levels of 25(OH)D (p < 0.001), but no differences were noticed for IgE levels or eosinophil count. These results support a link between vitamin D and allergic and infectious inflammations, and specifically the association of vitamin D deficiency with asymptomatic atopy, defined as increased IgE level for age.

Current therapeutic approaches in the management of hemophilia-a consensus view by the Romanian Society of Hematology.

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.

Why Do Children with Acute Lymphoblastic Leukemia Fare Better Than Adults?

It is a new and exciting time for acute lymphoblastic leukemia (ALL). While nearly 50 years ago, only one in nine children with ALL survived with chemotherapy, nowadays nearly 90% of children have a chance of long-term survival. Adults with ALL, as well as the special category of adolescents and young adult (AYA) patients, are catching up with the new developments seen in children, but still their prognosis is much worse. A plethora of factors are regarded as responsible for the differences in treatment response, such as age, ethnicity, disease biology, treatment regimens and toxicities, drug tolerance and resistance, minimal residual disease evaluation, hematopoietic stem cell transplantation timing and socio-economic factors. Taking these factors into account, bringing pediatric-like protocols to adult patient management and incorporating new agents into frontline treatment could be the key to improve the survival rates in adults and AYA.